Science.gov

Sample records for multiple myeloma non-hodgkin

  1. Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-04-19

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; Waldenström Macroglobulinemia

  2. Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-06-17

    B-Cell Prolymphocytic Leukemia; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  3. Bortezomib and Filgrastim in Promoting Stem Cell Mobilization in Patients With Non-Hodgkin Lymphoma or Multiple Myeloma Undergoing Stem Cell Transplant

    ClinicalTrials.gov

    2016-04-19

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular

  4. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    ClinicalTrials.gov

    2015-10-30

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

  5. Study to Assess Safety, Pharmacokinetics, and Efficacy of Oral CC-223 for Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma or Multiple Myeloma

    ClinicalTrials.gov

    2016-08-09

    Multiple Myeloma; Diffuse Large B-Cell Lymphoma; Glioblastoma Multiforme; Hepatocellular Carcinoma; Non-Small Cell Lung Cancer; Neuroendocrine Tumors of Non-Pancreatic Origin; Hormone Receptor-Positive Breast Cancer

  6. Sorafenib in Treating Patients With Metastatic or Unresectable Solid Tumors, Multiple Myeloma, or Non-Hodgkin's Lymphoma With or Without Impaired Liver or Kidney Function

    ClinicalTrials.gov

    2013-01-04

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

  7. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2010-08-05

    Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  8. European data on stem cell mobilization with plerixafor in non-Hodgkin's lymphoma, Hodgkin's lymphoma and multiple myeloma patients. A subgroup analysis of the European Consortium of stem cell mobilization.

    PubMed

    Hübel, K; Fresen, M M; Apperley, J F; Basak, G W; Douglas, K W; Gabriel, I H; Geraldes, C; Jaksic, O; Koristek, Z; Kröger, N; Lanza, F; Lemoli, R M; Mikala, G; Selleslag, D; Worel, N; Mohty, M; Duarte, R F

    2012-08-01

    The effectiveness of the novel hematopoietic stem cell mobilizing agent plerixafor was evaluated in nationwide compassionate use programs in 13 European countries. A total of 580 poor mobilizers with non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) and multiple myeloma (MM) were enrolled. All patients received plerixafor plus granulocyte CSF with or without chemotherapy. Overall, the collection yield was significantly higher in MM patients (>2.0 × 10(6) CD34+ cells/kg: 81.6%; >5.0 × 10(6) CD34+ cells/kg: 32.0%) than in NHL patients (>2.0 × 10(6) CD34+ cells/kg: 64.8%; >5.0 × 10(6) CD34+ cells/kg: 12.6%; P<0.0001) and also significantly higher in HL patients (>2.0 × 10(6) CD34+ cells/kg: 81.5%; >5.0 × 10(6) CD34+ cells/kg: 22.2%) than in NHL patients (P=0.013). In a subgroup analysis, there were no significant differences in mobilization success comparing patients with diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. Our data emphasize the role of plerixafor in poor mobilizers, but further strategies to improve the apheresis yield especially in patients with NHL are required. PMID:22080971

  9. Multiple myeloma

    MedlinePlus

    Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... Multiple myeloma most commonly causes: Low red blood cell count ( anemia ), which can lead to fatigue and ...

  10. Occupational use of insecticides, fungicides ~and fumigants and risk of non-Hodgkin lymphoma and nultiplc myeloma in the Agricultural Health Study

    EPA Science Inventory

    Farming and exposure to pesticides have been linked to non-Hodgkin lymphoma (NHL), and multiple myeloma (MM) in previous studies. We evaluated use of insecticides, fungicides and fumigants and risk of NHL, including MM and other NHL sub-types in the Agricultural Health Study, a ...

  11. Multiple myeloma

    MedlinePlus

    Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... myeloma most commonly causes a low red blood cell count ( anemia ), which can lead to fatigue and ...

  12. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

    PubMed

    Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

    2016-06-01

    The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. PMID:26800393

  13. Diffuse large B-cell non-Hodgkin's lymphoma and osteosclerotic myeloma with features of POEMS syndrome

    PubMed Central

    Ngamdu, Kyari Sumayin; Torabi, Alireza; Badri, Nabeel; Teleb, Mohammed

    2016-01-01

    Multiple myeloma is a clonal hematopoietic neoplasm characterized by the proliferation of malignant plasma cells and associated end-organ damage, most notably lytic lesions in the bones. Osteosclerotic myeloma is an unusual variant of the disease in which the skeletal involvement is characterized by sclerotic lesions instead of classical lytic lesions. The disease can be associated with paraneoplastic symptoms, which have been given the acronym POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes). In addition to clonal plasma cell dyscrasias, some cases of POEMS syndrome are associated with Castleman's disease, and in 11% to 30% of the cases both Castleman's disease and clonal plasma cell proliferation are present. POEMS syndrome has rarely been described in patients with non-Hodgkin's lymphoma. PMID:27365880

  14. Diffuse large B-cell non-Hodgkin's lymphoma and osteosclerotic myeloma with features of POEMS syndrome.

    PubMed

    Ngamdu, Kyari Sumayin; Torabi, Alireza; Badri, Nabeel; Teleb, Mohammed; Gaur, Sumit

    2016-07-01

    Multiple myeloma is a clonal hematopoietic neoplasm characterized by the proliferation of malignant plasma cells and associated end-organ damage, most notably lytic lesions in the bones. Osteosclerotic myeloma is an unusual variant of the disease in which the skeletal involvement is characterized by sclerotic lesions instead of classical lytic lesions. The disease can be associated with paraneoplastic symptoms, which have been given the acronym POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes). In addition to clonal plasma cell dyscrasias, some cases of POEMS syndrome are associated with Castleman's disease, and in 11% to 30% of the cases both Castleman's disease and clonal plasma cell proliferation are present. POEMS syndrome has rarely been described in patients with non-Hodgkin's lymphoma. PMID:27365880

  15. Newly discovered quick, non-invasive screening method of bone marrow malignancies including various leukemias, Hodgkin's lymphoma, non-Hodgkin's lymphoma, & multiple myeloma by abnormality of small rectangular area within bone marrow organ representation areas of the face.

    PubMed

    Omura, Yoshiaki; O'Young, Brian; Jones, Marilyn; Nihrane, Abdalla; Duvvi, Harsha; Paluch, Kamila; Shimotsuura, Yasuhiro; Ohki, Motomu

    2012-01-01

    Diagnoses of bone marrow associated malignancies such as Acute & Chronic Lymphocytic Leukemia, Acute & Chronic Myelogenous (Myeloid) Leukemia, Hodgkin's Lymphoma & Non-Hodgkin's Lymphoma, and Multiple Myeloma are often missed without a blood test. However, in 2008, Omura Y reported several newly discovered organ representation areas that exist between the lower end of the eyebrows and upper end of the upper eyelid. This space was divided into 5 organ representation areas. The first space (more than 1/4 of entire space) near the side of the face (temple) is the bone marrow representation area (BMRA). Therefore, we examined the bone marrow representation areas non-invasively using the Bi-Digital O-Ring Test (BDORT). When the small rectangular shaped part of the BMRA is strong negative (-) with more than -2, often there is a malignancy associated with bone marrow. In this area, we found 1) Integrin alpha5beta1 & Oncogen C-fos Ab2 increased very significantly between 125-300 ng BDORT units; 2) very high Chrysotile Asbestos (0.11-0.14 mg); 3) markedly reduced Acetylcholine of less than 1 ng; 4) significantly reduced telomere of less than 1 yg (= 10(-24) g); and 5) Increased 8-OH-dG (often more than 5 ng). Once the abnormal small rectangular area is localized by BDORT, by detecting the specific microscope slide which produces EMF (electromagnetic field) resonance, one can diagnose these malignancies non-invasively in about 10 minutes. When a subject has any one of the above 7 types of bone marrow associated malignancies, the 5 aforementioned abnormal parameters can be detected. When Acetylcholine is markedly reduced to 0.25 ng or less, 8-OH-dG is 10 ng or higher, and Sirtuin 1 (one of the 7 mammalian longevity genes products) in both the Hippocampus and the body is 0.025 pg or less, most of the patients have a very poor prognosis. However, we found that increasing normal cell telomere & longevity gene product Sirtuin 1 can often improve both pathology & prognosis. All

  16. Multiple myeloma.

    PubMed

    Raab, Marc S; Podar, Klaus; Breitkreutz, Iris; Richardson, Paul G; Anderson, Kenneth C

    2009-07-25

    Multiple myeloma is characterised by clonal proliferation of malignant plasma cells, and mounting evidence indicates that the bone marrow microenvironment of tumour cells has a pivotal role in myeloma pathogenesis. This knowledge has already expanded treatment options for patients with multiple myeloma. Prototypic drugs thalidomide, bortezomib, and lenalidomide have each been approved for the treatment of this disease by targeting both multiple myeloma cells and the bone marrow microenvironment. Although benefit was first shown in relapsed and refractory disease, improved overall response, duration of response, and progression-free and overall survival can be achieved when these drugs are part of first-line regimens. This treatment framework promises to improve outcome not only for patients with multiple myeloma, but also with other haematological malignancies and solid tumours. PMID:19541364

  17. Multiple myeloma

    PubMed Central

    2010-01-01

    Abstract Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management. PMID:20159661

  18. Multiple myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2008-01-01

    Multiple myeloma is a clonal plasma cell malignancy that accounts for slightly more than 10% of all hematologic cancers. In this paper, we present a historically focused review of the disease, from the description of the first case in 1844 to the present. The evolution of drug therapy and stem-cell transplantation for the treatment of myeloma, as well as the development of new agents, is discussed. We also provide an update on current concepts of diagnosis and therapy, with an emphasis on how treatments have emerged from a historical perspective after certain important discoveries and the results of experimental studies. PMID:18332230

  19. Multiple myeloma.

    PubMed

    Röllig, Christoph; Knop, Stefan; Bornhäuser, Martin

    2015-05-30

    Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future. PMID:25540889

  20. Multiple Myeloma

    MedlinePlus

    ... myeloma is a cancer that begins in plasma cells, a type of white blood cell. These cells are part of your immune system, which helps ... germs and other harmful substances. In time, myeloma cells collect in the bone marrow and in the ...

  1. Design of the EXercise Intervention after Stem cell Transplantation (EXIST) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of an individualized high intensity physical exercise program on fitness and fatigue in patients with multiple myeloma or (non-) Hodgkin's lymphoma treated with high dose chemotherapy and autologous stem cell transplantation

    PubMed Central

    2010-01-01

    Background The use of high-dose chemotherapy combined with autologous stem cell transplantation has improved the outcome of hematologic malignancies. Nevertheless, this treatment can cause persistent fatigue and a reduced global quality of life, role and physical function. Physical exercise interventions may be beneficial for physical fitness, fatigue and quality of life. However, the trials conducted so far to test the effects of physical exercise interventions in this group of patients were of poor to moderate methodological quality and economic evaluations are lacking. Hence there is need for a rigorous, appropriately controlled assessment of the effectiveness of exercise programs in these patients. The aims of the present study are (1) to determine the effectiveness of an individualized high intensity strength and interval training program with respect to physiological and psychological health status in patients with multiple myeloma or (non-)Hodgkin's lymphoma who have recently undergone high dose chemotherapy followed by autologous stem cell transplantation; and (2) to evaluate the cost-effectiveness of this program. Methods A multicenter, prospective, single blind randomized controlled trial will be performed. We aim to recruit 120 patients within an inclusion period of 2 years at 7 hospitals in the Netherlands. The patients will be randomly assigned to one of two groups: (1) intervention plus usual care; or (2) usual care. The intervention consists of an 18-week individualized supervised high-intensity exercise program and counselling. The primary outcomes (cardiorespiratory fitness, muscle strength and fatigue) and secondary outcomes are assessed at baseline, at completion of the intervention and at 12 months follow-up. Discussion The strengths of this study include the solid trial design with clearly defined research groups and standardized outcome measures, the inclusion of an economic evaluation and the inclusion of both resistance and endurance

  2. What Is Multiple Myeloma?

    MedlinePlus

    ... other tissues. If someone has only a single plasma cell tumor, the disease is called an isolated (or solitary ) plasmacytoma . If someone has more than one plasmacytoma, they have multiple myeloma . Multiple myeloma is ...

  3. Multiple Myeloma Symptoms

    MedlinePlus

    ... it is multiple myeloma . Stay on top of discoveries, trials, research and more. Click here to sign up for the MMRF Newsletter First name Last name E-mail address CLOSE News & Press Multiple Myeloma Knowledge Center Privacy Policy Donor Privacy Policy Terms of ...

  4. Multiple Myeloma Overview

    MedlinePlus

    ... is slightly more common in men than in women. It can often run in families. Multiple myeloma is also more common in blacks than in whites. Some studies suggest that workers in agriculture or petroleum-based industries may be ...

  5. Pomalidomide for Multiple Myeloma

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

  6. Non-Hodgkin's Lymphoma of Multiple Skeletal Muscles Involvement Seen on FDG PET/CT Scans

    PubMed Central

    Dai, Yue; Sowjanya, Medapati; You, Jia; Xu, Kai

    2015-01-01

    Abstract As normal healthy skeletal muscle does not contain lymphoid tissue, extra nodal lymphoma involving multiple muscles is rare, as well. This study reports a case of non-Hodgkin's lymphoma (NHL) of multiple skeletal muscles involvement and a review of differential diagnosis of it. A 37-year-old female presented to our hospital after being diagnosed with NHL for 7 months. She had received six courses of cyclophosphamide hydroxydaunorubicin oncovin prednisolone etoposide (CHOPE) chemotherapy. Then she felt pain and noticed swelling on her left calf. The fluorodeoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) image showed abnormal focal FDG uptake in hypo-pharynx, which was the primary NHL and also in multiple groups of muscles in whole body. As the patient has history NHL, lymphoma of multiple muscle involvement was suspected. Finally, an ultrasound-guided tissue biopsy was performed on the left calf and histological examination yielded lymphomatous cells infiltration in the left gastrocnemius. Through this report, we emphasize that a multidisciplinary team approach with clinician, radiologist, and pathologist is essential for proper diagnosis, staging, and management of such rare lesions. PMID:25950693

  7. Can Multiple Myeloma Be Found Early?

    MedlinePlus

    ... Topic Signs and symptoms of multiple myeloma Can multiple myeloma be found early? It’s difficult to diagnose multiple myeloma early. Often, multiple myeloma causes no symptoms until it reaches an ...

  8. [Treatment of multiple myeloma].

    PubMed

    Terriou, L; Leleu, X; Yakoub-Agha, I

    2006-01-01

    Treatment of patients with multiple myeloma has shown considerable progress these last two decades. While autologous stem cell transplantation seems to be agreed as the "gold standard" of front-line treatment in the young patients, the result of IFM99-06 prospective study would probably lead to a change regarding treatment of elderly as patients who received the thalidomide-melphalan-prednison association had better overall survival than those who received either the standard melphalan-prednison association or an intensive treatment. The best innovative therapeutic concept is illustrated by the new molecules that target both the myeloma cells and the bone marrow microenvironment. Thus, thalidomide and derivatives (Revlimid and the Actimid) and Velcade have transformed considerably the history of multiple myeloma. They have not to be considered as competitors but rather complementary whose impact will probably come of their combination and their association with the intensive treatments. The issues of maintenance therapy and allogeneic stem cell transplantation in the treatment of patients with myeloma remain to be addressed. PMID:16455512

  9. Non-Hodgkin Lymphoma risk and insecticide, fungicide and fumigant use in the Agricultural Health Study

    EPA Science Inventory

    Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL an...

  10. IRON IN MULTIPLE MYELOMA

    PubMed Central

    VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel; Lichtenstein, Alan

    2013-01-01

    Multiple myeloma is a non-curable B cell malignancy in which iron metabolism plays an important role. Patients with this disorder almost universally suffer from a clinically significant anemia, which is often symptomatic, and which is due to impaired iron utilization. Recent studies indicate that the proximal cause of dysregulated iron metabolism and anemia in these patients is cytokine-induced upregulation of hepcidin expression. Malignant myeloma cells are dependent on an increased influx of iron and therapeutic efforts are being made to target this requirement. The studies detailing the characteristics and biochemical abnormalities in iron metabolism causing anemia and the initial attempts to target iron therapeutically are described in this review. PMID:23879589

  11. Artifactual hypercalcemia in multiple myeloma

    SciTech Connect

    Annesley, T.M.; Burritt, M.F.; Kyle, R.A.

    1982-09-01

    A calcium-binding IgG K monoclonal protein in a patient with multiple myeloma and asymptomatic hypercalcemia was recognized, isolated, and characterized. In addition to binding by the whole IgG molecules, calcium was bound by purified Fab fragments and recombined heavy and light chains. In a competitive binding study, the isolated myeloma protein did not bind magnesium. Recognition of calcium-binding myeloma proteins is important in order to avoid therapy for hypercalcemia.

  12. Smoldering multiple myeloma

    PubMed Central

    Landgren, Ola; Mateos, María-Victoria

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. PMID:25838344

  13. Smoldering Multiple Myeloma

    PubMed Central

    Gao, Minjie; Yang, Guang; Kong, Yuanyuan; Wu, Xiaosong; Shi, Jumei

    2015-01-01

    Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage of multiple myeloma (MM) characterized by clonal bone marrow plasma cells (BMPC) ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC) ratio, peripheral blood plasma cells (PBPC), pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI), cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population. PMID:26000300

  14. Multiple myeloma. Houses and spouses

    SciTech Connect

    Kyle, R.A.; Greipp, P.R.

    1983-02-15

    Two families in which successive spouses who lived in the same house developed multiple myeloma are reported. In the first instance, a man whose first wife died of multiple myeloma remarried, and his second wife also developed myeloma. In the second family, a woman's first husband died of multiple myeloma and her second husband did too. Radiation studies of the houses and yards showed no increased radioactivity. No evidence was found for excessive exposure to chemicals or other environmental agents, for contact with other patients having similar malignancies, or for exposure to viruses or other transmissible factors. The significance of the occurrence of multiple myeloma in subsequent spouses is unknown. It is hoped that this report will stimulate research for other instances and lead to careful epidemiologic, radiologic, and virologic studies.

  15. Kidney Disease and Multiple Myeloma

    PubMed Central

    Rennke, Helmut G.; Laubach, Jacob P.; Richardson, Paul G.

    2013-01-01

    Summary Kidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve. PMID:23868898

  16. Multiple Myeloma: Patient Handbook

    MedlinePlus

    ... way in which these agents cross-link the DNA of myeloma cells and block cell division. Amyloidosis: ... a cancer treatment regimen. Chromosome: A strand of DNA and proteins in the nucleus of a cell. ...

  17. Obesity and multiple myeloma.

    PubMed

    Friedman, G D; Herrinton, L J

    1994-09-01

    An exploratory study was conducted of common clinical conditions as predictors of subsequent cancer in 143,574 outpatients of a health maintenance organization (in California, USA). An association was noted between obesity, diagnosed in 14,388 patients, and the subsequent development of multiple myeloma (MM) in up to 21 years (33 cases observed, 21.3 expected based on the experience of the entire cohort; standardized morbidity ratio = 1.55, 95 percent confidence interval [CI] = 1.06-2.17). This association was evaluated further in a second cohort of 163,561 multiphasic-checkup examinees followed up for as many as 24 years. Body mass index (BMI) at entry examination was associated positively with the incidence of MM in White men (e.g., relative risk [RR] = 1.07, CI = 1.01-1.15 per unit increase in BMI; and RR = 1.68, CI = 0.75-3.78, comparing the highest with lowest quartile). This association was absent in White women, partially confirmed in Black men and women (BMI quartiles two, three, and four showed higher risk than quartile one), and not explained by the presence of diabetes mellitus. The association was reduced or absent with BMI based on reported greatest adult-weight, and in White women was inverse with BMI based on reported lowest adult-weight. Among subjects with more than one checkup, increased risk was associated directly with weight loss among White men and associated inversely with weight gain among Black women. These findings suggest that body build or nutritional status may be involved in the development of MM by mechanisms that are presently unknown.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7999970

  18. Multiple Myeloma Cancer Stem Cells

    PubMed Central

    Huff, Carol Ann; Matsui, William

    2008-01-01

    Multiple myeloma is characterized by the clonal expansion of neoplastic plasma cells within the bone marrow, elevated serum immunoglobulin, and osteolytic bone disease. The disease is highly responsive to a wide variety of anticancer treatments including conventional cytotoxic chemotherapy, corticosteroids, radiation therapy, and a growing number of agents with novel mechanisms of action. However, few if any patients are cured with these modalities and relapse remains a critical issue. A better understanding of clonogenic multiple myleoma cells is essential to ultimately improving long-term outcomes, but the nature of the cells responsible for myeloma regrowth and disease relapse is unclear. We review evidence that functional heterogeneity exists in multiple myeloma and discuss potential strategies and clinical implications of the stem-cell model of cancer in this disease. PMID:18539970

  19. Multiple myeloma: evaluation by CT

    SciTech Connect

    Schreiman, J.S.; McLeod, R.A.; Kyle, R.A.; Beabout, J.W.

    1985-02-01

    Although patients who have multiple myeloma usually have straightforward clinical symptoms and corroborative radiographs, in some instances, these patients will present atypically, with symptoms suggesting active disease but radiographs that are normal or nonspecific. The authors reviewed the records of 32 patients who had documented multiple myeloma and had undergone CT examinations, assessing the value of those examinations. Although CT is not indicated in all patients who have multiple myeloma, it is especially useful in patients who have bone pain and normal or nonspecific radiographs. CT provided confirmatory information in all cases in which lesions were seen on radiographs. CT also frequently demonstrated a greater extent of disease than could be appreciated on the radiographs.

  20. Multiple Myeloma: Diagnosis and Treatment.

    PubMed

    Rajkumar, S Vincent; Kumar, Shaji

    2016-01-01

    The diagnosis and treatment of multiple myeloma has changed dramatically in the past decade. The disease definition has been updated to include highly specific biomarkers in addition to established markers of end-organ damage. The staging system has been revised to combine both measures of tumor burden and disease biology. Advances in therapy have resulted in a marked improvement in overall survival. New drugs introduced in the past few years include carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab. In this review, we outline the current approach to the diagnosis, prognosis, and management of multiple myeloma. PMID:26763514

  1. Risk Stratification in Multiple Myeloma.

    PubMed

    Ooi, Melissa Gaik-Ming; de Mel, Sanjay; Chng, Wee Joo

    2016-04-01

    There are many prognostic variables in multiple myeloma and the difficulty is in deciding which is truly significant. The widely used International Staging System (ISS) does not incorporate genetics, age, and other important variables in its risk stratification. Although it has its own limitations, the recently published Revised International Staging System (R-ISS) that was built upon the framework of ISS, is a more comprehensive and predictive tool for multiple myeloma patients and should be henceforth utilised. We will review the current prognostic variables and their significance in this paper. PMID:26883334

  2. Non-Hodgkin lymphoma

    MedlinePlus

    ... The cancer may be low grade (slow growing), intermediate grade, or high grade (fast growing). NHL is ... Accessed March 2, 2015. National Cancer Institute: PDQ Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer ...

  3. Non-Hodgkin Lymphoma

    MedlinePlus

    ... Lymphoma? A lymphoma is a cancer of the lymphatic system . The lymphatic system is a part of the body's immune system. ... non-Hodgkin lymphoma, cancer cells form in the lymphatic system and start to grow. Most of the time, ...

  4. Drugs Approved for Multiple Myeloma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  5. New treatments for multiple myeloma.

    PubMed

    Richardson, Paul G; Schlossman, Robert; Hideshima, Teru; Anderson, Kenneth C

    2005-12-01

    In 2004, multiple myeloma was diagnosed in more than 15,000 people in the United States and will account for approximately 20% of deaths due to hematologic malignancies. Although traditional therapies such as melphalan (Alkeran)/prednisone, combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), and high-dose chemotherapy with stem cell transplantation have shown some success, median survival remains between 3 to 5 years. Treatment options for patients with multiple myeloma have increased in recent years, with the promise of improvement in survival. New agents, such as the proteasome inhibitor bortezomib (Velcade), the antiangiogenic and immunomodulator thalidomide (Thalomid) and its analogs, such as lenalidomide (Revlimid), together with other small molecules, including arsenic trioxide (Trisenox), and other targeted therapies, have been studied alone and in combination with other antineoplastic therapies, either as induction therapy prior to stem cell transplantation or in patients with relapsed disease. Bortezomib recently was approved in the United States for the treatment of multiple myeloma in patients who have received at least one prior therapy. The use of bortezomib-based regimens as front-line therapy as well as the use of other agents in multiple myeloma remain under investigation, and approvals for both thalidomide and lenalidomide are hoped for soon, with the overall prospect of patient outcome continuing to be increasingly positive. PMID:16506632

  6. [Mandibular lesions in multiple myeloma].

    PubMed

    Scutellari, P N; Orzincolo, C

    1992-03-01

    A review was made of 237 cases of multiple myeloma seen at the Institute of Radiology and Hematology of the Ferrara University from 1984 through 1990. The results showed skeletal involvement of the mandible to be present in 25 patients (10.54%). The diagnosis of multiple myeloma was based on the following criteria: 1) increased number of abnormal, atypical or immature plasma cells in the bone marrow; 2) the presence of a monoclonal protein in the serum or urine; 3) bone lesions consistent with those of myeloma. Symptoms include pain and swelling of the oral cavity, tooth mobility and loss, numbness along the inferior dental nerve, and paresthesia of the lower lip. The typical radiographic appearance is a well-defined "punched-out" lytic defect, solitary or multiple; sometimes, the defect enlarges and appears "bubbly" or septated. Permeative lytic areas, with blurred outlines, are a rare pattern, which is radiologically indistinguishable from skeletal metastases. The involvement of the oral cavity and jaw in multiple myeloma has been often reported in literature: nevertheless, if radiographs of the jaws had been systematically taken in all the cases, its incidence would probably have been much higher than previously suspected. PMID:1579669

  7. Exposure to Multiple Pesticides and Risk of Non-Hodgkin Lymphoma in Men from Six Canadian Provinces

    PubMed Central

    Hohenadel, Karin; Harris, Shelley A.; McLaughlin, John R.; Spinelli, John J.; Pahwa, Punam; Dosman, James A.; Demers, Paul A.; Blair, Aaron

    2011-01-01

    Non-Hodgkin lymphoma (NHL) has been linked to several agricultural exposures, including some commonly used pesticides. Although there is a significant body of literature examining the effects of exposure to individual pesticides on NHL, the impact of exposure to multiple pesticides or specific pesticide combinations has not been explored in depth. Data from a six-province Canadian case-control study conducted between 1991 and 1994 were analyzed to investigate the relationship between NHL, the total number of pesticides used and some common pesticide combinations. Cases (n = 513) were identified through hospital records and provincial cancer registries and controls (n = 1,506), frequency matched to cases by age and province of residence, were obtained through provincial health records, telephone listings, or voter lists. In multiple logistic regression analyses, risk of NHL increased with the number of pesticides used. Similar results were obtained in analyses restricted to herbicides, insecticides and several pesticide classes. Odds ratios increased further when only ‘potentially carcinogenic’ pesticides were considered (OR[one pesticide] = 1.30, 95% CI = 0.90–1.88; OR[two to four] = 1.54, CI = 1.11–2.12; OR[five or more] = 1.94, CI = 1.17–3.23). Elevated risks were also found among those reporting use of malathion in combination with several other pesticides. These analyses support and extend previous findings that the risk of NHL increases with the number of pesticides used and some pesticide combinations. PMID:21776232

  8. Emerging therapies in multiple myeloma.

    PubMed

    El-Amm, Joelle; Tabbara, Imad A

    2015-06-01

    The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat). PMID:23934133

  9. SnapShot: Multiple Myeloma.

    PubMed

    Braggio, Esteban; Kortüm, K Martin; Stewart, A Keith

    2015-11-01

    Multiple myeloma (MM) is a plasma cell malignancy characterized by a heterogeneous clinical presentation. Genetic abnormalities are not only key events in the origin and progression of the disease but are also useful tools for prognosis, risk stratification, and therapeutic decision making. Although still incurable, a revolution in the treatment of MM is currently ongoing, leading to a significant improvement of clinical outcome and survival. To view this SnapShot, open or download the PDF. PMID:26555176

  10. What Are the Key Statistics about Multiple Myeloma?

    MedlinePlus

    ... factors for multiple myeloma? What are the key statistics about multiple myeloma? Multiple myeloma is a relatively ... in women). Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Last Medical Review: ...

  11. Non-Hodgkin Lymphoma

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 72,580 % of All New Cancer Cases 4.3% Estimated Deaths in 2016 20,150 % of All Cancer ... of This Cancer : In 2013, there were an estimated 569,536 people living with non-Hodgkin lymphoma ...

  12. Oral ixazomib maintenance therapy in multiple myeloma.

    PubMed

    Offidani, Massimo; Corvatta, Laura; Gentili, Silvia; Maracci, Laura; Leoni, Pietro

    2016-01-01

    Continuous therapy has proven to be an effective therapeutic strategy to improve the outcome of both young and elderly multiple myeloma patients. Remarkably, lenalidomide and bortezomib showed to play a crucial role in this setting due to their safety profile allowing long-term exposure. Ixazomib, the first oral proteasome inhibitor to be evaluated in multiple myeloma, exerts substantial anti-myeloma activity as a single agent and particularly in combination with immunomodulatory drugs and it may be an attractive option for maintenance therapy. Here we address the issue of maintenance therapy as part of a therapeutic approach of multiple myeloma patients focusing on the potential role of ixazomib. PMID:26588946

  13. Innovative Agents in Multiple Myeloma

    PubMed Central

    Faiman, Beth; Richards, Tiffany

    2014-01-01

    Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within the past decade. This is due, in part, to newer agents such as immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, MLN9708). These and several other new classes of drugs have arisen from an improved understanding of the complex environment in which genetic changes occur. Improved understanding of genetic events will enable clinicians to better stratify risk before and during therapy, tailor treatment, and test the value of personalized interventions. The ultimate goal in this incurable disease setting is to reduce the impact of cancer- or chemotherapy-related side effects. Nurses and advanced practitioners are integral to the treatment team. Thus, each should be aware of changes to the current drug landscape. Targeted drugs with sophisticated mechanisms of action are currently under investigation. Patients gain access to newer drugs within the context of clinical trials. Awareness of such trials will help accrual and determine if therapeutic benefit exists. In this article, we will describe new agents with unique and targeted mechanisms of action that have activity in patients with relapsed and/or refractory multiple myeloma. PMID:25089218

  14. State of Oral Mucosa as an Additional Symptom in the Course of Primary Amyloidosis and Multiple Myeloma Disease

    PubMed Central

    Czerniuk, Maciej R.; Jurczyszyn, Artur; Charlinski, Grzegorz

    2014-01-01

    Multiple myeloma (myeloma multiplex (MM)) is a malignant non-Hodgkin's lymphoma derived from B cell. Its essence is a malignant clone of plasma cells synthesizing growth of monoclonal immunoglobulin, which infiltrate the bone marrow, destroy the bone structure, and prevent the proper production of blood cells components. The paper presents a case of 62-year-old patient who developed symptoms in addition to neurological and haematological changes in the oral mucosa in the course of multiple myeloma. The treatment resulted in partial improvement. The authors wish to draw attention not only to nonspecificity and rarity of changes in the mouth which can meet the dentist but also to the complexity of the multidisciplinary therapy patients diagnosed with MM. PMID:25013412

  15. Pulmonary hypertension complicating multiple myeloma

    PubMed Central

    Mark, Tomer M.; Niesvizky, Ruben; Sobol, Irina

    2015-01-01

    Abstract Pulmonary hypertension (PH) is an infrequently reported complication of multiple myeloma (MM). PH has been more commonly associated with amyloidosis, myeloproliferative diseases, and the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome. PH in MM is typically mild to moderate and may be secondary to a variety of conditions, which include left ventricular dysfunction, high-output cardiac failure, chronic kidney disease, treatment-related toxicities, and precapillary involvement. We describe 3 patients with MM and severe PH. Each patient underwent right heart catheterization. All patients demonstrated elevated pulmonary pressures, transpulmonary gradients, and pulmonary vascular resistance. Each patient was ultimately treated with pulmonary vasodilator therapy with improvement in cardiopulmonary symptoms. Additional studies are needed to define the prevalence, prognosis, and pathogenesis of PH in this complex population and to help clarify who may benefit from targeted PH therapy. PMID:26401262

  16. Clonal Evolution in Multiple Myeloma.

    PubMed

    Fakhri, Bita; Vij, Ravi

    2016-08-01

    Multiple myeloma (MM) is the second most common hematologic malignancy encountered among patients in the United States. The last decade has seen incremental improvements in the survival of patients with MM. These advances are, to a large extent, attributable to the addition of proteasome inhibitors and immunomodulatory drugs to the armamentarium of treatment options. The adoption of these drug classes was the result of an empiric research paradigm. However, with the application of next generation sequencing technologies, we are now starting to unravel the genomic landscape of MM. It is hoped that this will allow us to better disentangle the biology of the disease and allow for identification of new therapeutic targets. In this article, we review what we have learned to date about the mutational profile, clonal architecture, and evolution of the disease, and discuss the potential clinical implications of these findings. PMID:27521309

  17. Pulmonary hypertension complicating multiple myeloma.

    PubMed

    Krishnan, Udhay; Mark, Tomer M; Niesvizky, Ruben; Sobol, Irina

    2015-09-01

    Pulmonary hypertension (PH) is an infrequently reported complication of multiple myeloma (MM). PH has been more commonly associated with amyloidosis, myeloproliferative diseases, and the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome. PH in MM is typically mild to moderate and may be secondary to a variety of conditions, which include left ventricular dysfunction, high-output cardiac failure, chronic kidney disease, treatment-related toxicities, and precapillary involvement. We describe 3 patients with MM and severe PH. Each patient underwent right heart catheterization. All patients demonstrated elevated pulmonary pressures, transpulmonary gradients, and pulmonary vascular resistance. Each patient was ultimately treated with pulmonary vasodilator therapy with improvement in cardiopulmonary symptoms. Additional studies are needed to define the prevalence, prognosis, and pathogenesis of PH in this complex population and to help clarify who may benefit from targeted PH therapy. PMID:26401262

  18. Cancer stem cells in multiple myeloma.

    PubMed

    Ghosh, Nilanjan; Matsui, William

    2009-05-01

    Several key observations providing evidence for the cancer stem cell hypothesis and insights into the unique biology of these cells have come from the study of multiple myeloma. These include evidence that cancer cells may be functionally heterogeneous in spite of their genetic homogeneity and that malignant progenitors share many biological features with normal adult stem cells including drug resistance and regulatory processes governing self-renewal. We review studies that have examined clonogenic cells in multiple myeloma, highlight controversies regarding the cell of origin in multiple myeloma, and discuss potential targeting strategies. PMID:18809245

  19. Novel therapy in multiple myeloma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Cleto, Sergio; Castañeda, Claudia; González, Martha; Talavera, Alejandra; Huerta-Guzmán, Judith

    2005-10-01

    Treatment in patients with multiple myeloma remain to be defined. Younger patients (defined as a cut-off level < 65 years old) will be treated with chemotherapy and transplant procedures. However, most patients > 65 years old are not candidates for this therapeutic approach and the use of intensive chemotherapy could be associated to severe toxicity. We developed an new, not-cytotoxic regimen with dexamethasone 30 mg/m(2), iv, days 1 to 4, all trans retinoic acid 45 mg/m(2), po, days 5 to 14 and interferon alfa 2a 4.5 MU, sc, daily, days 5 to 14 (DAI regimen) administered every 28 days in number of 6 cycles, at this point patients were restaging, if they showed complete response, objective response or partial response they were conducted to received thalidomide 100-200 mg po, daily and dexamethasone 10 mg/2, po days 1 to 4 at monthly intervals, for 18 months. Forty one patients were enrolled in an Phase II study. In an intent to treat analysis all patients were evaluable. Complete response was observed in 18 cases (43%), objective response in 10 patients (24%) and partial response in 5 patients (12%), overall response rate was 80%. Eight patients were considered failures. At an median of 36 months, no relapse of progression disease has been observed, thus actuarial curves at 3-years showed that event free survival is 100% and overall survival is 91%. Toxicity was mild, all patients received the planned dose in time. This regimen appear to be useful in older patients with multiple myeloma, the response rate is higher and toxicity was mild. Controlled clinical trials comparing with conventional chemotherapy will be conducted to define the role of this therapeutic approach. PMID:16133792

  20. Search for familial clustering of multiple myeloma with any cancer.

    PubMed

    Frank, C; Fallah, M; Chen, T; Mai, E K; Sundquist, J; Försti, A; Hemminki, K

    2016-03-01

    Multiple myeloma (MM) is a disease of immunoglobulin-producing plasma cells, which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM, but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24 137) were identified from the Swedish Cancer Registry from years 1958 to 2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first-degree relatives and compared with individuals whose relatives had no cancer. MM was reliably associated with relative's colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; in addition, MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study. PMID:26449663

  1. Multiple Myeloma Gets Three New Drugs.

    PubMed

    Poh, Alissa

    2016-01-01

    In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively. PMID:26658418

  2. Autologous Stem Cell Transplant Followed By Maintenance Therapy in Treating Elderly Patients With Multiple Myeloma

    ClinicalTrials.gov

    2014-11-18

    Extramedullary Plasmacytoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Primary Systemic Amyloidosis; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma

  3. AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

    ClinicalTrials.gov

    2016-03-16

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large

  4. Drugs Approved for Non-Hodgkin Lymphoma

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Non-Hodgkin Lymphoma This page lists ... non-Hodgkin lymphoma that are not listed here. Drugs Approved for Non-Hodgkin Lymphoma Abitrexate (Methotrexate) Adcetris ( ...

  5. Emerging therapies for multiple myeloma

    PubMed Central

    Podar, Klaus; Tai, Yu-Tzu; Hideshima, Teru; Vallet, Sonia; Richardson, Paul G; Anderson, Kenneth C

    2011-01-01

    Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM. PMID:19249983

  6. Multiple Myeloma and Kidney Disease

    PubMed Central

    Noiri, Eisei

    2013-01-01

    Multiple myeloma (MM) has a high incidence rate in the elderly. Responsiveness to treatments differs considerably among patients because of high heterogeneity of MM. Chronic kidney disease (CKD) is a common clinical feature in MM patients, and treatment-related mortality and morbidity are higher in MM patients with CKD than in patients with normal renal function. Recent advances in diagnostic tests, chemotherapy agents, and dialysis techniques are providing clinicians with novel approaches for the management of MM patients with CKD. Once reversible factors, such as hypercalcemia, have been corrected, the most common cause of severe acute kidney injury (AKI) in MM patients is tubulointerstitial nephropathy, which results from very high circulating concentrations of monoclonal immunoglobulin free light chains (FLC). In the setting of AKI, an early reduction of serum FLC concentration is related to kidney function recovery. The combination of extended high cutoff hemodialysis and chemotherapy results in sustained reductions in serum FLC concentration in the majority of patients and a high rate of independence from dialysis. PMID:24288486

  7. Emerging therapies for multiple myeloma.

    PubMed

    Podar, Klaus; Tai, Yu-Tzu; Hideshima, Teru; Vallet, Sonia; Richardson, Paul G; Anderson, Kenneth C

    2009-03-01

    Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 - 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents - small molecules as well as therapeutic antibodies - that hold promise to further improve outcome in MM. PMID:19249983

  8. Update of thrombosis in multiple myeloma.

    PubMed

    Leebeek, Frank W G

    2016-04-01

    With the introduction of thalidomide and multi-agent chemotherapy in the treatment of multiple myeloma around 15years ago a strongly increased risk of venous thrombosis was observed. The occurrence of venous thrombosis in multiple myeloma is not only determined by the kind of treatment, but also by several other factors, including disease specific factors, patient-specific factors, changes in pro-and anticoagulant factors and fibrinolysis. Studies showed a prevalence of up to 25% in patients with newly diagnosed multiple myeloma. Therefore these patients nowadays receive prophylaxis with aspirin, low molecular weight heparin or warfarin in order to reduce the risk of venous thrombosis. It is however still debatable which patients should receive prophylaxis and what the best kind of prophylaxis is, considering both the risk of thrombosis and the risk of bleeding. In recent years several new anti-myeloma agents have been developed and investigated in large clinical studies. The risk of thrombosis using these new drugs seems less than with thalidomide and lenalidomide-based regimens. In this article an update on prevention and management of thrombotic events in patients with multiple myeloma is given. PMID:27067983

  9. Drugs Approved for Multiple Myeloma and Other Plasma Cell Neoplasms

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Multiple Myeloma and Other Plasma Cell ... plasma cell neoplasms that are not listed here. Drugs Approved for Multiple Myeloma and Other Plasma Cell ...

  10. What's New in Multiple Myeloma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for multiple myeloma What’s new in multiple myeloma research and treatment? Important research ... the disease and how to improve treatment. Many new drugs are being tested. Researchers have found that ...

  11. New approaches to management of multiple myeloma.

    PubMed

    Genadieva-Stavric, Sonja; Cavallo, Federica; Palumbo, Antonio

    2014-06-01

    Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. New antimyeloma drugs such as thalidomide, lenalidomide, and bortezomib have dramatically changed treatment paradigm leading to both tumor reduction and tumor suppression. Much progress has been made, but still many unsolved questions remain. In the mode of sequencing treatment for patients with multiple myeloma, we are still using old drugs such as the alkylating agent melphalan, which continues to play a central role in the transplantation setting. Newer drugs are now emerging and are being tested: monoclonal antibodies, histone deacetylase (romidespsin), MLN9708 (ixazomib) a new oral proteasome inhibitor, carfilzomib, signal transduction modulator perifosine. Many advances have been made, but there is still a long way to go. PMID:24578203

  12. Multiple myeloma and physical activity: a scoping review

    PubMed Central

    Smith, Lee; McCourt, Orla; Henrich, Malgorzata; Paton, Bruce; Yong, Kwee; Wardle, Jane; Fisher, Abigail

    2015-01-01

    Objectives Multiple myeloma is the second most common haematological cancer. A growing body of literature is emerging that investigates the role physical activity plays in all stages of multiple myeloma (prevention and survivorship) and to date no attempt has been made to collate and understand this literature. Therefore, this scoping review aims to (1) outline what is already known about physical activity in all stages of multiple myeloma (2) map the literature on physical activity and multiple myeloma and (3) identify future directions for research. Design Scoping Review. Data Sources Searches were carried out in May 2015. Searchers were conducted in PubMed, Web of Science, SPORTdiscus and MEDLINE. Eligibility criteria for selecting studies To be included studies had to report original data, investigate physical activity per se or physical activity correlates and multiple myeloma or smouldering multiple myeloma. Results A total of 19 papers received full screening, 5 of these papers were excluded. This review identified three journal articles relating to the role of physical activity in the prevention of multiple myeloma, nine papers were identified in the treatment of multiple myeloma and two on smouldering multiple myeloma. Conclusions The search identified that the literature surrounding multiple myeloma and physical activity is very limited. We encourage those designing new cohort studies to allow for future assessment of associations between physical activity and onset of multiple myeloma and smouldering multiple myeloma, as well as the potential role that physical activity plays in the progression from smouldering multiple myeloma to multiple myeloma. Second, we encourage the design and investigation of gender and treatment-specific physical activity interventions in patients with multiple myeloma. Finally, we highlight the need for more randomised controlled trials to evaluate the impact of different types, frequencies and intensities of physical activity

  13. Recent advances in understanding multiple myeloma.

    PubMed

    Dhakal, Binod; Girnius, Saulius; Hari, Parameswaran

    2016-01-01

    There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both. PMID:27610224

  14. Recent advances in understanding multiple myeloma

    PubMed Central

    Dhakal, Binod; Girnius, Saulius; Hari, Parameswaran

    2016-01-01

    There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both. PMID:27610224

  15. Insulin Autoimmune Syndrome Accompanied by Multiple Myeloma.

    PubMed

    Ito, Harumi; Miyake, Takafumi; Nakashima, Kazuo; Ito, Yuji; Tanahashi, Chisato; Uchigata, Yasuko

    2016-01-01

    In 1981, a 48-year old man was diagnosed with insulin autoimmune syndrome. In 2005, he experienced a substantial increase in his monoclonal insulin antibody levels; in 2006 and 2007, serum monoclonal gammopathy and an 11% marrow plasmacyte ratio were confirmed. In 2012, asymptomatic multiple myeloma was diagnosed based on an increased γ-globulin fraction and serum M-protein (IgG) levels. The insulin antibody binding rate was 75.4% in 2005 and 78.8% in 2012. In 2012, he was hospitalized for ileus and died. Autopsy identified multiple myeloma and no endocrinological tumors in the pancreas. PMID:27522998

  16. Mechanisms of multiple myeloma bone disease

    PubMed Central

    Galson, Deborah L; Silbermann, Rebecca; Roodman, G David

    2012-01-01

    Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. Multiple myeloma bone disease (MMBD) is characterized by abnormal bone remodeling with dysfunction of both bone resorption and bone formation, and thus can be used as a paradigm for other inflammatory bone diseases, and the regulation of osteoclasts and osteoblasts in malignancy. Studies of MMBD have identified novel regulators that increase osteoclastogenesis and osteoclast function, repress osteoblast differentiation, increase angiogenesis, or permanently alter stromal cells. This review will discuss the current understanding of mechanisms of osteoclast and osteoblast regulation in MMBD, and therapeutic approaches currently in use and under development that target mediators of bone destruction and blockade of bone formation for myeloma patients, including new anabolic therapies. PMID:23951515

  17. Leukaemia, lymphoma, and multiple myeloma in seamen on tankers

    PubMed Central

    Nilsson, R. I.; Nordlinder, R.; Horte, L. G.; Jarvholm, B.

    1998-01-01

    OBJECTIVES: To investigate the risk of lymphatic and haematopoietic malignancies in deck crew on tankers exposed to cargo vapours. METHODS: The study design was as a nested case-referent study in two cohorts of male Swedish seamen 20-64 years of age at the national census 1960 (n 13,449) and 1970 (n 11,290), respectively. Cases were detected by record linkage with the Swedish Cancer Register 1961-79 and 1971-87, respectively. For each case, three to five age matched referents from the population were selected. Exposure was assessed from data in the Swedish Registry of Seamen and from a register of Swedish ships. RESULTS: Seamen in the 1970 cohort, who had been exposed to cargo vapours for at least one month on chemical or product tankers, had an increased risk of lymphatic and haematopoietic malignancies (Mantel- Haenszel odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.1 to 5.9)) with a significant exposure-response relation (conditional logistic regression analysis, p = 0.04). The ORs were increased for both lymphoma (3.2), multiple myeloma (4.0), and leukaemia (1.6), but the increase was only significant for non-Hodgkin's lymphoma (OR 3.3, 95% CI 1.1 to 10.6). There were no significantly increased risks for the 1960 cohort or for seamen exposed only on crude oil tankers, but these groups had few exposed cases and low cumulative exposure to benzene and other light petroleum products. CONCLUSIONS: Seamen exposed to cargo vapours from gasoline and other light petroleum products on chemical or product tankers had an increased incidence of lymphatic and haematopoietic malignancies. One possible cause is exposure to benzene during loading, unloading, and tank cleaning operations.   PMID:9849537

  18. Bendamustine Hydrochloride, Etoposide, Dexamethasone, and Filgrastim For Peripheral Blood Stem Cell Mobilization in Treating Patients With Refractory or Recurrent Lymphoma or Multiple Myeloma

    ClinicalTrials.gov

    2016-03-08

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  19. Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma

    SciTech Connect

    Boice, J.D. Jr.; Morin, M.M.; Glass, A.G.; Friedman, G.D.; Stovall, M.; Hoover, R.N.; Fraumeni, J.F. Jr. )

    1991-03-13

    Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk (RR), 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays.

  20. Multiple Myeloma, Version 2.2016

    PubMed Central

    Anderson, Kenneth C.; Alsina, Melissa; Atanackovic, Djordje; Biermann, J. Sybil; Chandler, Jason C.; Costello, Caitlin; Djulbegovic, Benjamin; Fung, Henry C.; Gasparetto, Cristina; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kassim, Adetola; Krishnan, Amrita Y.; Kumar, Shaji K.; Liedtke, Michaela; Lunning, Matthew; Raje, Noopur; Singhal, Seema; Smith, Clayton; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P.; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A.; Kumar, Rashmi

    2016-01-01

    Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM. PMID:26553768

  1. Elotuzumab for the treatment of multiple myeloma.

    PubMed

    Wang, Yucai; Sanchez, Larysa; Siegel, David S; Wang, Michael L

    2016-01-01

    Elotuzumab is one of the first two monoclonal antibodies that gained FDA approval for the treatment of multiple myeloma (MM). It targets SLAMF7, which is highly expressed in normal plasma and MM cells as well as natural killer (NK) cells. Elotuzumab demonstrated significant anti-myeloma activity in preclinical studies, and its mechanisms of action include mediating antibody-dependent cell-mediated cytotoxicity, enhancing cytotoxicity of NK cells, and inhibiting MM cell interaction with bone marrow stromal cells. In clinical trials, elotuzumab in combination with immunomodulatory drugs and proteasome inhibitors has demonstrated an excellent efficacy and safety profile in treating MM. PMID:27417553

  2. How I treat smoldering multiple myeloma

    PubMed Central

    Landgren, Ola

    2014-01-01

    Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. PMID:25298034

  3. Immunotherapeutic approaches to treat multiple myeloma

    PubMed Central

    Roeven, Mieke WH; Hobo, Willemijn; Schaap, Nicolaas; Dolstra, Harry

    2014-01-01

    Cellular immunotherapy can be an effective adjuvant treatment for multiple myeloma (MM), as demonstrated by induction of durable remissions after allogeneic stem cell transplantation. However, anti-myeloma immunity is often hampered by suppressive mechanisms in the tumor micro-environment resulting in relapse or disease progression. To overcome this immunosuppression, new cellular immunotherapies have been developed, based on the important effector cells in anti-myeloma immunity, namely T cells and natural killer cells. These effectors can be modulated to improve their functionality, activated by dendritic cell vaccines, or combined with immune stimulating antibodies or immunomodulatory drugs to enhance their efficacy. In this review, we discuss promising pre-clinical and clinical data in the field of cellular immunotherapy in MM. In addition, we address the potential of combining these strategies with other therapies to maximize clinical effects without increasing toxicity. The reviewed therapies might pave the way to effective personalized treatments for MM patients. PMID:24335570

  4. The Role of Immunotherapy in Multiple Myeloma

    PubMed Central

    Kocoglu, Mehmet; Badros, Ashraf

    2016-01-01

    Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies. PMID:26784207

  5. Implications of Heterogeneity in Multiple Myeloma

    PubMed Central

    de Mel, Sanjay; Lim, Su Hong; Tung, Moon Ley; Chng, Wee-Joo

    2014-01-01

    Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated. PMID:25101266

  6. Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies

    PubMed Central

    di Luccio, Eric

    2015-01-01

    Background: Multiple myeloma SET domain (MMSET)/nuclear receptor binding SET domain 2 (NSD2) is a lysine histone methyltransferase (HMTase) and bona fide oncoprotein found aberrantly expressed in several cancers, suggesting potential role for novel therapeutic strategies. In particular, MMSET/NSD2 is emerging as a target for therapeutic interventions against multiple myeloma, especially t(4;14) myeloma that is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma and remains an incurable malignancy. Thus, effective therapeutic strategies are greatly needed. HMTases inhibitors are scarce and no NSDs inhibitors have been isolated. Methods: We used homology modeling, molecular modeling simulations, virtual ligand screening, computational chemistry software for structure-activity relationship and performed in vitro H3K36 histone lysine methylation inhibitory assay using recombinant human NSD2-SET and human H3.1 histone. Results: Here, we report the discovery of LEM-06, a hit small molecule inhibitor of NSD2, with an IC50 of 0.8 mM against H3K36 methylation in vitro. Conclusions: We propose LEM-06 as a hit inhibitor that is useful to further optimize for exploring the biology of NSD2. LEM-06 derivatives may pave the way to specific NSD2 inhibitors suitable for therapeutic efforts against malignancies. PMID:26151044

  7. Multiple myeloma: managing a complex blood cancer.

    PubMed

    Dowling, Maura; Kelly, Mary; Meenaghan, Teresa

    2016-09-01

    This article gives a comprehensive overview of multiple myeloma (MM), a complex blood cancer involving overproduction of plasma cells. Although MM remains incurable, patients are living longer as a result of multiple treatment options. However, MM patients are also living with a higher symptom burden. The overall aims in managing MM are therefore to control disease progression, prolong survival and improve quality of life. PMID:27615537

  8. Multiple myeloma and atopic eczema in an adult.

    PubMed

    Hossain, Mohammad Amir; Nai, Qiang; Zhang, Ping; Luo, Hongxiu; Hossain, Mohammed Amzad; Mahmad, Abdul; Yousif, Abdalla M; Sen, Shuvendu

    2015-01-01

    Multiple myeloma is the fourteenth cause of cancer-related death. The symptoms of myeloma are mostly nonspecific, and there is significant delay between the first symptoms and diagnosis of myeloma. Atopic eczema is a common chronic inflammatory skin disease associated with dysregulation of the immune system. It generally develops in early childhood but can also occur in adults. Eczema is associated with a variety of hematological and solid malignancies, and possibly multiple myeloma. We report a patient with eczema that developed 5 years before the diagnosis of multiple myeloma but was mistaken for psoriasis. PMID:25848353

  9. Multiple Myeloma and Atopic Eczema in an Adult

    PubMed Central

    Hossain, Mohammad Amir; Nai, Qiang; Zhang, Ping; Luo, Hongxiu; Hossain, Mohammed Amzad; Mahmad, Abdul; Yousif, Abdalla M.; Sen, Shuvendu

    2015-01-01

    Multiple myeloma is the fourteenth cause of cancer-related death. The symptoms of myeloma are mostly nonspecific, and there is significant delay between the first symptoms and diagnosis of myeloma. Atopic eczema is a common chronic inflammatory skin disease associated with dysregulation of the immune system. It generally develops in early childhood but can also occur in adults. Eczema is associated with a variety of hematological and solid malignancies, and possibly multiple myeloma. We report a patient with eczema that developed 5 years before the diagnosis of multiple myeloma but was mistaken for psoriasis. PMID:25848353

  10. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001.

    PubMed

    Hsu, Wan-Ling; Preston, Dale L; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Kimura, Akiro; Kamada, Nanao; Dohy, Hiroo; Tomonaga, Masao; Iwanaga, Masako; Miyazaki, Yasushi; Cullings, Harry M; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E; Mabuchi, Kiyohiko

    2013-03-01

    A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This article presents analyses of radiation effects on leukemia, lymphoma and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose-response relationship and, to the extent the data allowed, to investigate variation in the excess risks with gender, attained age, exposure age and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a nonlinear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this nonlinearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence

  11. The incidence of leukemia, lymphoma, and multiple myeloma among atomic bomb survivors: 1950 – 2001

    PubMed Central

    Hsu, Wan-Ling; Preston, Dale L.; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Kimura, Akiro; Kamada, Nanao; Dohy, Hiroo; Tomonaga, Masao; Iwanaga, Masako; Miyazaki, Yasushi; Cullings, Harry M.; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E.; Mabuchi, Kiyohiko

    2013-01-01

    A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This paper presents analyses of radiation effects on leukemia, lymphoma, and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry-based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma, and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose response relationship and, to the extent the data allowed, to investigate variation in the excess risks with sex, attained age, exposure age, and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a non-linear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this non-linearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence

  12. Elotuzumab for the treatment of multiple myeloma.

    PubMed

    Moreau, Philippe; Touzeau, Cyrille

    2014-05-01

    New agents are awaited for the treatment of multiple myeloma and research is ongoing for the development of monoclonal antibodies (MoAbs) targeting the tumor cells. One of the most promising MoAb is elotuzumab, the only humanized IgG1 MoAb specifically targeting CS1 (SLAMF7), a cell surface glycoprotein that is highly expressed in plasma cells. Preclinical and clinical data on elotuzumab will be presented in this article. PMID:24941981

  13. New prognostic biomarkers in multiple myeloma.

    PubMed

    Szudy-Szczyrek, Aneta; Szczyrek, Michał; Soroka-Wojtaszko, Maria; Hus, Marek

    2016-01-01

    Multiple myeloma is a malignant neoplastic disease, characterized by uncontrolled proliferation and accumulation of plasma cells in the bone marrow, which is usually connected with production of a monoclonal protein. It is the second most common hematologic malignancy. It constitutes approximately 1% of all cancers and 10% of hematological malignancies. Despite the huge progress that has been made in the treatment of multiple myeloma in the past 30 years including the introduction of new immunomodulatory drugs and proteasome inhibitors, it is still an incurable disease. According to current data, the five-year survival rate is 45%. Multiple myeloma is a very heterogeneous disease with a very diverse clinical course, which is expressed by differences in effectiveness of therapeutic strategies and ability to develop chemoresistance. This diversity implies the need to define risk stratification factors that would help to create personalized and optimized therapy and thereby improve treatment outcomes. Prognostic markers that aim to objectively evaluate the risk of a poor outcome, relapse and the patient's overall outcome are useful for this purpose. The existing, widely used prognostic classifications, such as the Salmon-Durie classification or ISS, do not allow for individualization of treatment. As a result of the development of diagnostic techniques, especially cytogenetics and molecular biology, we were able to discover a lot of new, more sensitive and specific prognostic factors. The paper presents recent reports on the role of molecular, cytogenetic and biochemical alterations in pathogenesis and prognosis of the disease. PMID:27463592

  14. [Multiple myeloma and other plasma cell dyscrasias].

    PubMed

    Nagy, Zsolt

    2016-06-01

    Multiple myeloma is the most common primary malignant disease of bone marrow. It mainly occurs among elderly people and, according to international databases, it is twice as frequent in men, however in our country this fact cannot be observed because of the high male mortality rate. The presence of this disease increased by more than one and the half times during the last 60 years. The five year survival for multiple myeloma has increased from 25% to 40% since the seventies due to high-dose chemotherapy followed by autologous stem cell transplantation and the new anti-myeloma drugs which were introduced in the last decade, such as immunomodulators (IMiD) like thalidomide, lenalidomide, pomalidomide and proteasome inhibitors (PI) like bortezomib, carfilzomib, ixazomib. The number of treatment options are growing fast, and not only because of using new combinations of medications, but also due to the development of investigational products which are available for the patients by participating in a clinical trial. PMID:27275642

  15. Novel Combination Treatments in Multiple Myeloma.

    PubMed

    Nooka, Ajay K; Lonial, Sagar

    2016-05-01

    The last decade has witnessed the identification of several novel druggable targets in multiple myeloma, leading to identification of novel therapies with clinically proven efficacy, both in the newly diagnosed and relapsed setting. More importantly, a common theme of good outcomes was observed among prospective randomized studies that have utilized combinations of agents with different mechanisms of action. The correlation between achieving a deeper response and the improvement in progression-free survival and overall survival has never been so clear. In this article, we elucidate the rationale for use of novel drug combinations in patients with myeloma, and review current evidence-based data supporting the use of specific combinations in various settings. We also attempt to craft a framework to guide clinicians in optimizing the use of combination therapies, to enable patients to derive maximal benefit. PMID:27188677

  16. Multiple Myeloma: Treatment is Getting Individualized.

    PubMed

    Agarwal, M B

    2016-03-01

    Multiple myeloma (MM) is a heterogeneous disease with varied outcome. The novel agents including two major classes of drugs; the immunomodulatory drugs and the proteasome inhibitors with unprecedented response rates, have replaced conventional chemotherapy. With monoclonal antibodies on the horizon, outcome of this disorder will further improve. Progression in risk stratification systems has made it possible to predict the disease course as well as outcome in myeloma patients with disease categorization into low to high risk. In addition, detection of minimal residual disease by serum free light chain assay, flow cytometry, molecular techniques like polymerase chain reaction and positron emission tomography scan is playing an important role in modifying the treatment. An extensive research in the disease biology has improved our knowledge regarding interplay between myeloma cells and elements of the bone marrow microenvironment which contribute to sustain proliferation and survival as well as de novo drug resistance. Again, insight into the role of genetic and epigenetic interactions in MM has exposed new molecular targets. All these have opened the gateway for novel therapeutic strategies with focus on risk based individualized therapy. PMID:26855501

  17. Heat shock proteins in multiple myeloma

    PubMed Central

    Zhang, Lei; Fok, Jacqueline H.L.; Davies, Faith E.

    2014-01-01

    Heat shock proteins are molecular chaperones with a central role in protein folding and cellular protein homeostasis. They also play major roles in the development of cancer and in recent years have emerged as promising therapeutic targets. In this review, we discuss the known molecular mechanisms of various heat shock protein families and their involvement in cancer and in particular, multiple myeloma. In addition, we address the current progress and challenges in pharmacologically targeting these proteins as anti-cancer therapeutic strategies PMID:24675290

  18. NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

    PubMed

    Anderson, Kenneth C; Alsina, Melissa; Atanackovic, Djordje; Biermann, J Sybil; Chandler, Jason C; Costello, Caitlin; Djulbegovic, Benjamin; Fung, Henry C; Gasparetto, Cristina; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kassim, Adetola; Krishnan, Amrita Y; Kumar, Shaji K; Liedtke, Michaela; Lunning, Matthew; Raje, Noopur; Reu, Frederic J; Singhal, Seema; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A; Kumar, Rashmi

    2016-04-01

    These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options. PMID:27059188

  19. Pleural effusion as a manifestation of multiple myeloma.

    PubMed

    Iqbal, Nousheen; Tariq, Muhammad Usman; Shaikh, Mohammad Usman; Majid, Hashir

    2016-01-01

    Multiple myeloma is a clonal B-cell malignancy, characterised by proliferation of plasma cells and secretion of paraproteins. These plasma cells accumulate predominantly in the bone marrow; rarely, they invade other areas, especially the thorax. Myeloma presenting with a pleural effusion is rare and reported in only 6% of patients with myeloma. Such patients generally present late and have a poor prognosis. Here, we describe a patient presenting with a lung mass, renal failure and a massive unilateral pleural effusion due to multiple myeloma who was treated successfully. PMID:27520995

  20. Clinical and Pathologic Studies in Non-Hodgkin's Lymphoma Patients Receiving Antibody Treatment

    ClinicalTrials.gov

    2011-05-31

    Lymphoma, Non-Hodgkin; Lymphomas: Non-Hodgkin; Lymphomas: Non-Hodgkin Cutaneous Lymphoma; Lymphomas: Non-Hodgkin Diffuse Large B-Cell; Lymphomas: Non-Hodgkin Follicular / Indolent B-Cell; Lymphomas: Non-Hodgkin Mantle Cell; Lymphomas: Non-Hodgkin Marginal Zone; Lymphomas: Non-Hodgkin Peripheral T-Cell; Lymphomas: Non-Hodgkin Waldenstr Macroglobulinemia

  1. Identify multiple myeloma stem cells: Utopia?

    PubMed Central

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-01

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs. PMID:25621108

  2. Improving induction therapy in multiple myeloma.

    PubMed

    Nooka, Ajay; Gleason, Charise; Lonial, Sagar

    2010-07-01

    Significant improvements in induction therapy for multiple myeloma have been seen over the past decade for both transplant-eligible patients and transplant-ineligible patients. The emergence of novel agents in managing myeloma has revealed new directions for clinicians to approach the disease. The first determinant is transplant eligibility. With the recognition of the prognostic impact of postinduction response on overall outcomes, the importance of the choice of optimal regimen has become more important than ever. The preference of induction therapy for transplant-eligible patients has progressively changed from the alkylator-based therapies to doublet therapies to triplet therapies incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors. The role of quadruplet therapies remains unclear, but with appropriate dosage modifications, these regimens were efficacious and had an acceptable toxicity profile. Similar treatment approaches for transplant-ineligible patients resulted in superior outcomes with the triplet therapies. Many challenges remain however, such as achieving greater depth of responses with molecular remissions and more effective use of risk stratification in induction therapy. These are still to be explored. PMID:20449692

  3. Identify multiple myeloma stem cells: Utopia?

    PubMed

    Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

    2015-01-26

    Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs. PMID:25621108

  4. What Are the Key Statistics about Non-Hodgkin Lymphoma?

    MedlinePlus

    ... for non-Hodgkin lymphoma? What are the key statistics about non-Hodgkin lymphoma? Non-Hodgkin lymphoma (NHL) ... coming years. Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Last Medical Review: ...

  5. What's New in Non-Hodgkin Lymphoma Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for non-Hodgkin lymphoma What’s new in non-Hodgkin lymphoma research and treatment? Research ... non-Hodgkin lymphoma is focused on looking at new and better ways to treat this disease. Chemotherapy ...

  6. Dilemmas in Treating Smoldering Multiple Myeloma

    PubMed Central

    Ahn, Inhye E.; Mailankody, Sham; Korde, Neha; Landgren, Ola

    2015-01-01

    Novel therapies hold promise for high-risk smoldering multiple myeloma (SMM). Recent studies suggest that modern combination approaches can be options for high-risk SMM to obtain deep molecular responses with favorable toxicity profiles. Although pioneering treatment trials based on small numbers of patients suggest progression-free and overall survival benefits, application of the data to real-life practice remains to be validated. Therapeutic modulation of disease tempo, disease burden, clonal evolution, and tumor microenvironment in SMM remains to be understood and calls for reliable biomarkers reflective of disease biology. Here, we review studies that open a new management platform for SMM, address ongoing dilemmas in practice and under investigation, and highlight emerging scientific questions in the era of SMM treatment. PMID:25422486

  7. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  8. Development of Novel Immunotherapies for Multiple Myeloma.

    PubMed

    Al-Hujaily, Ensaf M; Oldham, Robyn A A; Hari, Parameswaran; Medin, Jeffrey A

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  9. A patient with Multiple myeloma and Renal cell carcinoma

    PubMed Central

    Shahi, Farhad; Ghalamkari, Marziye; Mirzania, Mehrzad; Khatuni, Mahdi

    2016-01-01

    The coexistence of two malignancies is rarely seen. A little association between hematologic malignancies especially multiple myeloma and renal cell carcinoma has been reported in the recent past. Several case series revealed a bidirectional association between these two malignancies which may be due to the common risk factors, similar cytokine growth requirements and clinical presentation. Here, we aim to describe a patient who had multiple myeloma and in his work up renal cell carcinoma was found out incidentally. We would like to create awareness among clinicians for the coincidence of Renal cell carcinoma and Multiple myeloma. PMID:27047652

  10. Oxidative stress and proteasome inhibitors in multiple myeloma.

    PubMed

    Lipchick, Brittany C; Fink, Emily E; Nikiforov, Mikhail A

    2016-03-01

    Multiple myeloma is a form of plasma cell neoplasm that accounts for approximately 10% of all hematological malignancies. Recently, several novel drugs have been discovered that almost doubled the overall survival of multiple myeloma patients. One of these drugs, the first-in-class proteasome inhibitor bortezomib (Velcade) has demonstrated remarkable response rates in multiple myeloma patients, and yet, currently this disease remains incurable. The major factor undermining the success of multiple myeloma treatment is a rapidly emerging resistance to the available therapy. Thus, the development of stand-alone or adjuvant anti-myeloma agents becomes of paramount importance. Overproduction of intracellular reactive oxygen species (ROS) often accompanies malignant transformation due to oncogene activation and/or enhanced metabolism in tumor cells. As a result, these cells possess higher levels of ROS and lower levels of antioxidant molecules compared to their normal counterparts. Unbalanced production of ROS leads to oxidative stress which, if left unchecked, could be toxic for the cell. In multiple myeloma cells where high rates of immunoglobulin synthesis is an additional factor contributing to overproduction of ROS, further induction of oxidative stress can be an effective strategy to cope with this disease. Here we will review the available data on the role of oxidative stress in the cytotoxicity of proteasome inhibitors and the use of ROS-inducing compounds as anti-myeloma agents. PMID:26827824

  11. [Hematopoietic stem cell transplantation in multiple myeloma].

    PubMed

    Vela-Ojeda, Jorge; Ruiz-Esparza, Miriam A García

    2005-01-01

    Multiple myeloma (MM) is the second most common hematologic malignancy, affecting approximately 14,000 new patients per year in the United States. For over four decades, the standard treatment for MM has been a regimen of melphalan combined with prednisone. Using this treatment modality, complete responses are rare, and 50% of patients have had disease that was resistant to chemotherapy. Attempts have been made to improve the outcome of MM by administering combinations of i.v. poli-chemotherapy, but these treatments are equivalent in terms of overall survival. High-dose therapy with peripheral blood stem cell support can be applied safely in these patients and achieves significantly higher complete remission rates as well as better event-free survival and overall survival. However, neither tumor-cell purging, positive selection, intensification of conditioning with additional chemotherapeutic agents, nor total body irradiation have been shown to improve outcome. The role of tandem transplantation with high-dose melphalan seems to be a good selection of treatment in hospitals having all resources. Future research will include the combination of the best remission-induction regimen with tandem transplants and maintenance treatments (thalidomide, idiotype or dendritic cell vaccination) that will sustain complete remission. Development of non-myeloablative allogeneic transplantation in order to exploit the graft-versus myeloma effect provides an alternative for patients who have a compatible donor. Combining all of these modalities with the new drugs developed few years ago (thalidomide, bortezomib, revlimid), we hope that MM will become a manageable chronic disease and perhaps a curable disease at least for 30% to 40% of the patients. PMID:16524072

  12. Type-B lactic acidosis associated with progressive multiple myeloma

    PubMed Central

    Abdullah, Sameer Y.; Ali, Moaath K.; Sabha, Marwa M.

    2015-01-01

    We report a 64-year-old lady with stage II, Immunoglobulin-G lambda multiple myeloma (MM) (standard risk), who presented with type-B lactic acidosis (LA), and multi-organ dysfunction associating myeloma progression, and ending in imminent death. In the context of literature review of all previously reported similar cases, this report highlights and discusses the association of type-B LA and MM (especially progressive disease), and also emphasizes the poor outcome. Early recognition of this condition with intensive supportive care, and treatment of multiple myeloma may improve outcomes. PMID:25719593

  13. General Information about Plasma Cell Neoplasms (Including Multiple Myeloma)

    MedlinePlus

    ... Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  14. Three-Drug Combination for Relapsed Multiple Myeloma

    Cancer.gov

    A summary of Interim results from an international, randomized phase III trial that suggest that adding carfilzomib (Kyprolis®) to a standard treatment improves outcomes for patients with multiple myeloma whose cancer has relapsed.

  15. Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

    PubMed Central

    Morton, Lindsay M.; Slager, Susan L.; Cerhan, James R.; Wang, Sophia S.; Vajdic, Claire M.; Skibola, Christine F.; Bracci, Paige M.; de Sanjosé, Silvia; Smedby, Karin E.; Chiu, Brian C. H.; Zhang, Yawei; Mbulaiteye, Sam M.; Monnereau, Alain; Turner, Jennifer J.; Clavel, Jacqueline; Adami, Hans-Olov; Chang, Ellen T.; Glimelius, Bengt; Hjalgrim, Henrik; Melbye, Mads; Crosignani, Paolo; di Lollo, Simonetta; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Stagnaro, Emanuele; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Cocco, Pierluigi; Foretova, Lenka; Maynadié, Marc; Nieters, Alexandra; Staines, Anthony; Colt, Joanne S.; Cozen, Wendy; Davis, Scott; de Roos, Anneclaire J.; Hartge, Patricia; Rothman, Nathaniel; Severson, Richard K.; Holly, Elizabeth A.; Call, Timothy G.; Feldman, Andrew L.; Habermann, Thomas M.; Liebow, Mark; Blair, Aaron; Cantor, Kenneth P.; Kane, Eleanor V.; Lightfoot, Tracy; Roman, Eve; Smith, Alex; Brooks-Wilson, Angela; Connors, Joseph M.; Gascoyne, Randy D.; Spinelli, John J.; Armstrong, Bruce K.; Kricker, Anne; Holford, Theodore R.; Lan, Qing; Zheng, Tongzhang; Orsi, Laurent; Dal Maso, Luigino; Franceschi, Silvia; La Vecchia, Carlo; Negri, Eva; Serraino, Diego; Bernstein, Leslie; Levine, Alexandra; Friedberg, Jonathan W.; Kelly, Jennifer L.; Berndt, Sonja I.; Birmann, Brenda M.; Clarke, Christina A.; Flowers, Christopher R.; Foran, James M.; Kadin, Marshall E.; Paltiel, Ora; Weisenburger, Dennis D.; Linet, Martha S.; Sampson, Joshua N.

    2014-01-01

    Background Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. Methods We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). Results Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a

  16. Role of osteocytes in multiple myeloma bone disease

    PubMed Central

    Delgado-Calle, Jesus; Bellido, Teresita; Roodman, G. David

    2014-01-01

    Purpose of review Despite the increased knowledge of osteocyte biology, the contribution of this most abundant bone cell to the development and progression of multiple myeloma in bone is practically unexplored. Recent findings Multiple myeloma bone disease is characterized by exacerbated bone resorption and the presence of osteolytic lesions that do not heal because of a concomitant reduction in bone formation. Osteocytes produce molecules that regulate both bone formation and resorption. Recent findings suggest that the life span of osteocytes is compromised in multiple myeloma patients with bone lesions. In addition, multiple myeloma cells affect the transcriptional profile of osteocytes by upregulating the production of pro-osteoclastogenic cytokines, stimulating osteoclast formation and activity. Further, patients with active multiple myeloma have elevated circulating levels of sclerostin, a potent inhibitor of bone formation which is specifically expressed by osteocytes in bone. Summary Understanding the contribution of osteocytes to the mechanisms underlying the skeletal consequences of multiple myeloma bone disease has the potential to provide important new therapeutic strategies that specifically target multiple myeloma–osteocyte interactions. PMID:25289928

  17. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.

    PubMed

    Rajkumar, S Vincent; Dimopoulos, Meletios A; Palumbo, Antonio; Blade, Joan; Merlini, Giampaolo; Mateos, María-Victoria; Kumar, Shaji; Hillengass, Jens; Kastritis, Efstathios; Richardson, Paul; Landgren, Ola; Paiva, Bruno; Dispenzieri, Angela; Weiss, Brendan; LeLeu, Xavier; Zweegman, Sonja; Lonial, Sagar; Rosinol, Laura; Zamagni, Elena; Jagannath, Sundar; Sezer, Orhan; Kristinsson, Sigurdur Y; Caers, Jo; Usmani, Saad Z; Lahuerta, Juan José; Johnsen, Hans Erik; Beksac, Meral; Cavo, Michele; Goldschmidt, Hartmut; Terpos, Evangelos; Kyle, Robert A; Anderson, Kenneth C; Durie, Brian G M; Miguel, Jesus F San

    2014-11-01

    This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition. PMID:25439696

  18. Body mass index, physical activity, and risk of multiple myeloma

    PubMed Central

    Birmann, Brenda M.; Giovannucci, Edward; Rosner, Bernard; Anderson, Kenneth C.; Colditz, Graham A.

    2013-01-01

    Several studies have reported a positive relation of baseline body mass index (BMI) with multiple myeloma, but data on other correlates of energy balance are limited. We undertook the present analyses to further examine the role of energy balance in multiple myeloma etiology in two large prospective cohorts with biennially updated exposure data. We followed members of the Nurses’ Health Study and Health Professionals Follow-up Study cohorts from baseline until multiple myeloma diagnosis, death, or 2002. Adult height and current weight were reported at enrollment, and weight every 2 years thereafter. Physical activity was queried at baseline and updated every 2-4 years. We computed age-adjusted relative risks (RR) of multiple myeloma for categories of BMI and physical activity using Cox proportional hazards regression. We conducted analyses on each cohort separately and on both cohorts combined. We confirmed 215 incident cases of multiple myeloma in the combined cohort of 136,623 individuals (>2.1 million person-years at risk). BMI was positively associated with multiple myeloma in all analyses. The association was strongest in men with BMI ≥30 kg/m2 (v. BMI <22.0 kg/m2; RR=2.4, 95% confidence interval (CI)=1.0-6.0) and modest in overweight (BMI 25-29.9 kg/m2) and obese (BMI ≥30 kg/m2) women (v. BMI <22.0 kg/m2; RR (95% CI)=1.6 (1.0-2.7) and 1.2 (0.7-2.2), respectively). Physical activity was not significantly related to multiple myeloma risk, although an inverse association was suggested in women. In conclusion, obesity appears to have an etiologic role in multiple myeloma, but the role of other correlates of energy balance remains uncertain. PMID:17627013

  19. Pulmonary embolism as the first manifestation of multiple myeloma.

    PubMed

    Vallianou, N; Lazarou, V; Tzangarakis, J; Barounis, R; Sioula, E

    2013-01-01

    Multiple myeloma is considered a hypercoagulable state due to several mechanisms such as the increased IL-6 and immunoglobulins production, the defective fibrinolytic mechanism, and the acquired resistance to activated protein C that are involved in the pathogenesis and clinical futures of the disease. We describe a case of a female patient who presented to the hospital with pulmonary embolism as the first manifestation of the hypercoagulability of multiple myeloma. PMID:24151508

  20. Pulmonary Embolism as the First Manifestation of Multiple Myeloma

    PubMed Central

    Vallianou, N.; Lazarou, V.; Tzangarakis, J.; Barounis, R.; Sioula, E.

    2013-01-01

    Multiple myeloma is considered a hypercoagulable state due to several mechanisms such as the increased IL-6 and immunoglobulins production, the defective fibrinolytic mechanism, and the acquired resistance to activated protein C that are involved in the pathogenesis and clinical futures of the disease. We describe a case of a female patient who presented to the hospital with pulmonary embolism as the first manifestation of the hypercoagulability of multiple myeloma. PMID:24151508

  1. Tretatment Approach of Nontransplant Patients with Multiple Myeloma

    PubMed Central

    Krstevska, Svetlana B.; Sotirova, Tatjana; Balkanov, Trajan; Genadieva-Stavric, Sonja

    2014-01-01

    Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients. PMID:25568637

  2. Tretatment approach of nontransplant patients with multiple myeloma.

    PubMed

    Krstevska, Svetlana B; Sotirova, Tatjana; Balkanov, Trajan; Genadieva-Stavric, Sonja

    2014-10-01

    Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients. PMID:25568637

  3. Cloudy corneas as an initial presentation of multiple myeloma

    PubMed Central

    Sharma, Priyanka; Madi, Haifa A; Bonshek, Richard; Morgan, Stephen J

    2014-01-01

    Summary We report a case of previously unsuspected myeloma, presenting with cornea verticillata due to intracorneal paraprotein deposition. History An 85-year-old female presented via her optician with a 4-month history of cloudy vision. She had undergone an uneventful bilateral phacoemulsification surgery 7 years earlier. Extensive spiraling corneal epithelial opacification was noted on slit-lamp examination. On further investigation, she was found to have a previously unsuspected low-grade multiple myeloma. We established the nature of the corneal deposits with corneal epithelial biopsy histopathology and electron microscopy. It is very rare for multiple myeloma to present in this fashion. Ophthalmologists should be aware that such a presentation may rarely be due to systemic multiple myeloma. PMID:24812487

  4. Quality of Life and Supportive Care in Multiple Myeloma

    PubMed Central

    Cömert, Melda; Güneş, Ajda Ersoy; Şahin, Fahri; Saydam, Güray

    2013-01-01

    Multiple myeloma is the second most common haematological malignancy. Novel therapies have led to improvement in survival. Current myeloma management is matching the progress made in improved survival through disease control while optimising quality of life with effective supportive care. Supportive treatment is an essential part of the therapeutic management of myeloma patients because it is directed towards improving the patient’s quality of life and also can improve survival. The aim of this review is to highlight the relationship among life of quality, supportive care, and improvement in survival. Conflict of interest:None declared. PMID:24385802

  5. Robust isolation of malignant plasma cells in multiple myeloma.

    PubMed

    Frigyesi, Ildikó; Adolfsson, Jörgen; Ali, Mina; Christophersen, Mikael Kronborg; Johnsson, Ellinor; Turesson, Ingemar; Gullberg, Urban; Hansson, Markus; Nilsson, Björn

    2014-02-27

    Molecular characterization of malignant plasma cells is increasingly important for diagnostic and therapeutic stratification in multiple myeloma. However, the malignant plasma cells represent a relatively small subset of bone marrow cells, and need to be enriched prior to analysis. Currently, the cell surface marker CD138 (SDC1) is used for this enrichment, but has an important limitation in that its expression decreases rapidly after sampling. Seeking alternatives to CD138, we performed a computational screen for myeloma plasma cell markers and systematically evaluated 7 candidates. Our results conclusively show that the markers CD319 (SLAMF7/CS1) and CD269 (TNFRSF17/BCMA) are considerably more robust than CD138 and enable isolation of myeloma plasma cells under more diverse conditions, including the samples that have been delayed or frozen. Our results form the basis of improved procedures for characterizing cases of multiple myeloma in clinical practice. PMID:24385542

  6. Acute renal failure in patients with multiple myeloma.

    PubMed

    Cohen, D J; Sherman, W H; Osserman, E F; Appel, G B

    1984-02-01

    In the past, patients with multiple myeloma and acute renal failure have had a poor prognosis. Few patients recovered renal function and fewer still survived for prolonged time periods. This report describes the course of 10 patients with multiple myeloma and true acute renal failure treated during the decade 1970 to 1980, and reviews recent reports concerning this association. The use of radiographic contrast agents is no longer the primary predisposing factor to acute renal failure in the myeloma population. Rather, infection, hypercalcemia, and dehydration in the presence of light chain excretion are the major conditions precipitating the renal failure. Despite severe renal failure requiring dialysis, many patients may regain good renal function. Factors associated with a good or poor prognosis in this population are reviewed. The prognosis in patients with myeloma and acute renal failure has greatly improved in recent years, and prolonged survival may occur. PMID:6695948

  7. Pyoderma gangrenosum due to lenalidomide use for multiple myeloma.

    PubMed

    Dasanu, Constantin A; Bockorny, Bruno; Alexandrescu, Doru T

    2015-12-01

    Pyoderma gangrenosum has been described in association with multiple myeloma and usually affects patients with active/untreated disease. This dermatologic condition was shown to resolve after successful anti-myeloma therapy. We report herein occurrence of pyoderma gangrenosum involving bilateral knees in a patient with multiple myeloma responding to lenalidomide therapy. Previous papers claimed usefulness of thalidomide and its newer derivatives for the therapy of this neutrophilic dermatosis. Occurrence of pyoderma gangrenosum in a myeloma patient responding to lenalidomide would argue against its effectiveness in treating this skin condition. Moreover, the clinical setting suggested that lenalidomide either induced or contributed to the occurrence of pyoderma gangrenosum in our patient. If our hypothesis is correct, we expect more reports of pyoderma gangrenosum with the use of this class of pharmaceuticals. PMID:24986794

  8. Contemporary drug therapies for multiple myeloma.

    PubMed

    de la Puente, P; Azab, A K

    2013-09-01

    Multiple myeloma (MM) is an incurable disease characterized by the proliferation of plasma cells. The survival in MM patients has improved significantly in the past decade due to the introduction of novel agents. In this review, we focus on novel agents used in MM, including immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, marizomib and ixazomib citrate), monoclonal antibodies (elotuzumab, siltuximab, daratumumab and BT-062), and drugs affecting an interaction with the tumor microenvironment (anti-VLA4 monoclonal antibody, chemokine CXCR4 inhibitor AMD-3100 and selectin inhibitor GMI-1070). We discuss their mechanism of action, preclinical and clinical outcome in the treatment of MM. Although the development of novel agents has improved the outcomes of MM treatment, most of the patients will still relapse and become refractory to therapy due to development of drug resistance. A better understanding of the biological mechanisms of MM progression, including cellular and molecular events in the MM cells and in their bone marrow microenvironment, is warranted to provide new therapeutic targets and develop new drugs and therapeutic strategies to treat MM. PMID:24086952

  9. Antibody-Based Therapies in Multiple Myeloma

    PubMed Central

    Tai, Yu-Tzu; Anderson, Kenneth C.

    2011-01-01

    The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases. PMID:22046572

  10. Targeting the Pim kinases in multiple myeloma

    PubMed Central

    Keane, N A; Reidy, M; Natoni, A; Raab, M S; O'Dwyer, M

    2015-01-01

    Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM. PMID:26186558

  11. [Classification and genetic abnormalities of multiple myeloma].

    PubMed

    Hanamura, Ichiro; Iida, Shinsuke

    2015-01-01

    Multiple myeloma (MM) is a malignancy of plasma cells which develops through genetic aberrations, epigenetic changes and the bone marrow microenvironment interaction. Despite recent tremendous progress in treatments for MM, a complete cure remains elusive. Further development of more effective therapeutic strategies is needed. The International Staging System (ISS) reported in 2005 has been used widely as the most simple and powerful prognostic classification in MM, but genetic abnormalities affecting prognosis were not considered in this model. In the past decade, non-random chromosomal aberrations such as t(4;14), t(14;16), t(14;20), amp1q21 and del17p have shown to be poor prognostic value, and moreover, recent progress in genome-wide deep sequencing studies has revealed novel mutations and intra-tumor subclonal heterogeneity which may explain clinical phenotype and therapeutic resistance. Here we review the current understanding of genetic abnormalities in MM for developing better prognostic classification and molecular targeted therapies leading to the stratified or personalized medicine. PMID:25626298

  12. New Cancers after Autotransplants for Multiple Myeloma

    PubMed Central

    Mahindra, Anuj; Raval, Girindra; Mehta, Paulette; Brazauskas, Ruta; Zhang, Mei-Jie; Zhong, Xiaobo; Bird, Jennifer M.; Freytes, César O.; Hale, Gregory A.; Herzig, Roger; Holmberg, Leona A.; Kamble, Rammurti T.; Kumar, Shaji; Lazarus, Hillard M.; Majhail, Navneet S.; Marks, David I.; Moreb, Jan S.; Olsson, Richard; Saber, Wael; Savani, Bipin N.; Schiller, Gary J.; Tay, Jason; Vogl, Dan T.; Waller, Edmund K.; Wiernik, Peter H.; Wirk, Baldeep; Lonial, Sagar; Krishnan, Amrita Y.; Dispenzieri, Angela; Brandenburg, Nancy A.; Gale, Robert Peter; Hari, Parameswaran

    2015-01-01

    We describe baseline incidence and risk-factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma (MM) in the US during 1990- 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13387 person years at-risk. 163 new cancers were observed for a crude incidence rate of 1.2 new cancers per 100 person-years and cumulative incidences of 2.6% (95% CI; 2.09-3.17), 4.2% (95% CI; 3.49-5.00) and 6.1% (95% CI; 5.08-7.24) at 3, 5 and 7 years. The incidence of new cancers in the autotransplant cohort was similar to age- race- and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI; 0.81-1.22). However, acute myeloid leukemia (AML) and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI; 1.67–12.04; P=0.0004), and 3.58 (99% CI, 1.82–6.29; P<0.0001). Obesity, older age and male gender were associated with increased risks of new cancers in multivariate analyses. This large dataset provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving post autotransplant therapies such as maintenance. PMID:25555448

  13. Multiple Myeloma in a Patient with Acromegaly

    PubMed Central

    Kang, Yu Mi; Choi, Jong Han; Lee, Min Jung; Ahn, Ari; Park, Chan-Jeoung; Chang, Kiju; Seo, Seyoung; Hong, Sun In

    2015-01-01

    Acromegaly is a slowly progressing condition resulting from excess growth hormone (GH), generally caused by a GH-secreting pituitary adenoma. Cancer is the third most common cause of mortality in patients with acromegaly, and insulin-like growth factor 1 (IGF-1) is known to influence tumor formation by increasing cell proliferation and inhibiting apoptosis. Multiple myeloma (MM) is a plasma cell neoplasm, and previous studies have suggested the possible role of IGF-1 in its development of MM. However, no cases of acromegaly accompanied with MM have been reported in Asia to date. We here report the case of a 58-year-old woman with acromegaly accompanied with MM who presented with longstanding acromegalic manifestations resulting from a GH-secreting pituitary adenoma and also exhibited anemia, a reversed albumin/globulin ratio, and plasmacytosis on bone marrow examination. Because IGF-1 has been suggested to play an important role in the development and progression of MM, the patient promptly underwent surgical removal of the pituitary adenoma via a transsphenoidal approach. Since there is currently no consensus on therapeutic guidelines and suggested prognosis for MM with acromegaly, long-term follow-up of such cases is needed. PMID:25491781

  14. Revisiting IL-6 antagonism in multiple myeloma.

    PubMed

    Matthes, Thomas; Manfroi, Benoit; Huard, Bertrand

    2016-09-01

    IL-6, a cytokine with broad functions in inflammation and immunity, has been extensively studied for its role on normal antibody-producing plasma cells. In addition, IL-6 is recognized as a proliferative factor for multiple myeloma (MM), a malignant plasma cell tumor developing in the bone marrow. Blocking IL-6 signaling was thus developed into a therapeutic approach for MM already early after its discovery, in 1991. Unfortunately, the first clinical trials did not demonstrate a clear benefit, but despite this apparent failure hopes on IL-6 antagonism are still high and trials ongoing. The cellular source of IL-6 has long been a matter of debate. IL-6 was first recognized as an autocrine factor produced by the malignant plasma cells themselves, but later reports clearly showed that IL-6 was a paracrine factor, produced by the microenvironment, mostly by cells from the myeloid lineage. Recently, we have confirmed that IL-6 originates from myeloid lineage cells, mainly from myeloid precursors. We have also demonstrated that IL-6 amplifies the pool of myeloid cells producing a second key factor for MM, a proliferation inducing ligand (APRIL). These findings form a new rationale for IL-6 inhibition in MM and for new ways to use IL-6 blocking in the clinics. PMID:27497026

  15. Stages of Childhood Non-Hodgkin Lymphoma

    MedlinePlus

    ... Past treatment for cancer and having a weakened immune system affect the risk of having childhood non-Hodgkin ... or human immunodeficiency virus (HIV). Having a weakened immune system after a transplant or from medicines given after ...

  16. Treatment Options for Non-Hodgkin Lymphoma

    MedlinePlus

    ... with HIV infection. Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin ... the cancer cells to normal cells of the immune system. Other tests and procedures may be done depending ...

  17. Stages of Adult Non-Hodgkin Lymphoma

    MedlinePlus

    ... with HIV infection. Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin ... the cancer cells to normal cells of the immune system. Other tests and procedures may be done depending ...

  18. Immunotherapy strategies for multiple myeloma: the present and the future

    PubMed Central

    Locke, Frederick L; Nishihori, Taiga; Alsina, Melissa; Kharfan-Dabaja, Mohamed A

    2015-01-01

    Growing knowledge of the complexities of the immune system have led to a better understanding of how it can be harnessed for the purpose of anticancer therapy. Moreover, recent success with immunotherapies for solid tumors, combined with novel therapeutic strategies against myeloma, heighten excitement at the prospect of improving clinical outcomes for myeloma by improving antitumor immunity. Increased understanding of myeloma tumor-associated antigens, availability of more potent vaccines, expanded immune-modulating therapies, development of agents that block immune-suppressive pathways, increased sophistication of adoptive cell therapy techniques and capitalization upon standard autologous transplant are all important standalone or combination strategies that might ultimately improve prognosis of patients with multiple myeloma. PMID:23998734

  19. Guidelines for supportive care in multiple myeloma 2011.

    PubMed

    Snowden, John A; Ahmedzai, Sam H; Ashcroft, John; D'Sa, Shirley; Littlewood, Timothy; Low, Eric; Lucraft, Helen; Maclean, Rhona; Feyler, Sylvia; Pratt, Guy; Bird, Jennifer M

    2011-07-01

    Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011. PMID:21517805

  20. Prognostic factors and classification in multiple myeloma.

    PubMed Central

    San Miguel, J. F.; Sànchez, J.; Gonzalez, M.

    1989-01-01

    Analyses of prognostic factors have allowed the design of staging systems in different haematological disorders. In a series of 220 patients with multiple myeloma, univariate analysis showed that nine parameters had a significant adverse effect on survival; poor performance status (Karnowsky scaling system less than 70%), infections before diagnosis, renal impairment (assessed either by creatinine clearance greater than 2 mg dl-1 or urea greater than 40 mg dl-1), serum calcium (greater than 10 mg dl-1), severe anaemia (less than 8.5 g dl-1), the presence of Bence-Jones proteinuria, failure to achieve complete remission, more than 40% plasma cells in bone marrow and a low paraprotein index (monoclonal component/% plasma cells: P less than 0.09). In addition, this index correlated significantly with all the other prognostic factors except performance status. The best combination of disease characteristics selected by means of the Cox regression proportional hazards method were performance status and creatinine levels. Additionally, by factor analysis of principal components we obtained a regression equation that included creatinine levels, haemoglobin, performance status and paraprotein index. Using this it was possible to separate the series of patients into three risk categories: A (65 patients), B (69 patients) and C (65 patients) with a median survival of 41, 24 and 12 months, respectively. The model provided similar results to those of the British Medical Research Council, whereas the staging systems proposed by Durie and Salmon, Merlin et al. and Carbone et al. had a lower discriminant value in our series. PMID:2757917

  1. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics

    PubMed Central

    Garcia-Gomez, Antonio; Sanchez-Guijo, Fermin; del Cañizo, M Consuelo; San Miguel, Jesus F; Garayoa, Mercedes

    2014-01-01

    Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented. PMID:25126382

  2. Bone marrow invasion in multiple myeloma and metastatic disease.

    PubMed

    Vilanova, J C; Luna, A

    2016-04-01

    Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. PMID:26767542

  3. [Multiple myeloma and venous thrombosis. Which thromboprophylaxis should be given?].

    PubMed

    de Moreuil, C; Ianotto, J-C; Eveillard, J-R; Carrier, M; Delluc, A

    2016-07-01

    Multiple myeloma is a malignant plasma cells dyscrasia that mainly affects patients older than 65 years. These patients are at a higher risk for venous thromboembolism (VTE) because of cancer status, intrinsic risk factors, and exposure to prothrombotic therapies. The risk for VTE appears higher during the first months of myeloma treatment and decreases over time. Exposure to immunomodulatory drugs (IMIDs) such as thalidomide or lenalidomide in association with high doses of dexamethasone or anthracyclin-based chemotherapy is associated with a four-fold increased risk for VTE. Low-dose aspirin, preventive-dose of low molecular weight heparin (LMWH) or vitamin K antagonists were tested for primary prevention of VTE in myeloma patients receiving chemotherapy. The International Myeloma Working Group (IMWG) suggests stratifying VTE risk to decide which patients should receive VTE prevention. Then, the IMWG suggests giving low-dose aspirin to low VTE risk patients and LMWH or vitamin K antagonists to patients at high risk for VTE. For daily practice, it seems reasonable to start preventive doses of LMWH for 3 to 6 months in ambulatory myeloma patients receiving combined therapy with IMID and in all myeloma patients admitted to hospital. PMID:26833146

  4. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.

    PubMed

    Kumar, Shaji; Paiva, Bruno; Anderson, Kenneth C; Durie, Brian; Landgren, Ola; Moreau, Philippe; Munshi, Nikhil; Lonial, Sagar; Bladé, Joan; Mateos, Maria-Victoria; Dimopoulos, Meletios; Kastritis, Efstathios; Boccadoro, Mario; Orlowski, Robert; Goldschmidt, Hartmut; Spencer, Andrew; Hou, Jian; Chng, Wee Joo; Usmani, Saad Z; Zamagni, Elena; Shimizu, Kazuyuki; Jagannath, Sundar; Johnsen, Hans E; Terpos, Evangelos; Reiman, Anthony; Kyle, Robert A; Sonneveld, Pieter; Richardson, Paul G; McCarthy, Philip; Ludwig, Heinz; Chen, Wenming; Cavo, Michele; Harousseau, Jean-Luc; Lentzsch, Suzanne; Hillengass, Jens; Palumbo, Antonio; Orfao, Alberto; Rajkumar, S Vincent; San Miguel, Jesus; Avet-Loiseau, Herve

    2016-08-01

    Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments. PMID:27511158

  5. Psoriasis induced by thalidomide in a patient with multiple myeloma

    PubMed Central

    Ferrazzi, Anna; Zambello, Renato; Russo, Irene; Alaibac, Mauro

    2014-01-01

    A 54-year-old woman developed psoriasis on the plantar surface of her feet after 2 weeks of thalidomide 100 mg daily for the treatment of multiple IgG myeloma. She did not have any previous history of psoriasis. Thalidomide was immediately stopped and topical treatment with calcipotriol ointment and β-methasone valerate was started. Psoriasis disappeared completely after 2 weeks of topical therapy. This is the first case of de novo psoriasis in a patient with multiple myeloma under treatment with thalidomide. Our observation provides further evidence of the potential paradoxical effect of thalidomide on tumour necrosis factor-α production. PMID:24973347

  6. CD38-Targeted Immunochemotherapy in Refractory Multiple Myeloma: A New Horizon.

    PubMed

    Laubach, Jacob P; Richardson, Paul G

    2015-06-15

    CD38 is a type II transmembrane glycoprotein that is highly expressed in multiple myeloma and is a promising target for immunotherapy. Daratumumab is a human monoclonal antibody that has potent anti-multiple myeloma activity both as monotherapy and in combination with other multiple myeloma treatments, and has breakthrough designation on this basis. PMID:25878332

  7. Concurrent Presentation of Hodgkin Lymphoma and Multiple Myeloma

    PubMed Central

    Simon, Miklos; Spurgeon, Stephen E.

    2013-01-01

    The simultaneous presentation of the Hodgkin lymphoma and multiple myeloma in the absence of prior chemotherapy or radiation is very rare. Here, we discuss a 72-year-old patient who initially presented with generalized pruritis. Workup led to a diagnosis of multiple myeloma which progressed and required treatment. As part of his pretreatment workup, an MRI was performed to evaluate skeletal lesions. This revealed diffuse and bulky adenopathy which was confirmed by PET. A biopsy of an axillary node was consistent with the nodular sclerosing type Hodgkin lymphoma. He was treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy × 6 resulting in complete resolution of his adenopathy and pruritis as well as improvement in his myeloma. PMID:24027647

  8. Listeria monocytogenes brain abscess in a patient with multiple myeloma.

    PubMed

    Al-Khatti, Adil A; Al-Tawfiq, Jaffar A

    2010-12-01

    Listeria monocytogenes is an uncommon cause of illness in the general population. Meningoencephalitis is the most common central nervous system (CNS) manifestation of listeriosis. However, brain abscess represents 1-10% of all CNS listeriosis. To our knowledge, L. monocytogenes brain abscess in multiple myeloma patients has not been previously reported. Thus we report a 58-year-old male patient with multiple myeloma who developed a brain abscess due to L. monocytogenes. Due to a history of penicillin allergy, he was treated with intravenous trimethoprim/sulfamoxazole (TMP-SMX) for a total of 12 weeks, and gentamicin for the first two weeks, followed by oral therapy of TMP-SMX for a total of nine months. He is alive six and a half years after the diagnosis of myeloma with occasional brief seizures despite being on two anticonvulsants. PMID:21252468

  9. Genetics of multiple myeloma: another heterogeneity level?

    PubMed Central

    Corre, Jill; Munshi, Nikhil

    2015-01-01

    Our knowledge of myeloma genetics remained limited and lagged behind many other hematologic malignancies because of the inherent difficulties in generating metaphases within the malignant plasma cell clone. With the development of molecular techniques (microarrays and next-generation sequencing), our understanding has been highly improved in the past 5 years. These studies have not only confirmed the prevalence of wide heterogeneity in myeloma at the molecular level, but has also provided a much clearer picture of the disease pathogenesis and progression. Whether these data will enable improvements in the therapeutic approach is still a matter of debate. The next improvement will come from detailed analyses of these molecular features to try to move from a treatment fitted to every patient to individualized therapies, taking into account the complexity of the chromosomal changes, the mutation spectrum, and subclonality evolution. PMID:25628468

  10. Survivorship Care Guidelines for Patients Living With Multiple Myeloma: Consensus Statements of the International Myeloma Foundation Nurse Leadership Board

    PubMed Central

    Bilotti, Elizabeth; Faiman, Beth M.; Richards, Tiffany A.; Tariman, Joseph D.; Miceli, Teresa S.; Rome, Sandra I.

    2012-01-01

    Novel therapies approved over the past decade for the management of multiple myeloma have contributed to improved overall survival in patients with newly diagnosed and relapsed disease. Nurses play a key role in educating, advocating for, and supporting patients throughout the continuum of care. Identifying potential and actual comorbid conditions associated directly with multiple myeloma and its treatment is important, as is confirming those that are patient specific so that prompt intervention can take place; therefore, the International Myeloma Foundation Nurse Leadership Board identified the most significant needs of patients diagnosed with multiple myeloma as bone health, health maintenance, mobility and safety, sexual dysfunction, and renal health. The Nurse Leadership Board then developed a survivorship care plan to assist healthcare providers and patients with multiple myeloma, their partners, and their caregivers to identify these needs. PMID:21816706

  11. Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association.

    PubMed

    Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

    2016-01-01

    Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

  12. Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

    PubMed Central

    Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

    2016-01-01

    Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

  13. A Case of Multiple Myeloma Following Bladder Cancer

    PubMed Central

    Shafi, Hamid; Vakili Sadeghi, Mohsen; Ghorbani, Hosein; Sharbatdaran, Majid

    2016-01-01

    Second primary malignancy following multiple myeloma (MM) was reported several years ago. There are also rare reports of cases with synchronous MM and other malignancies. To our knowledge, only one case of MM following bladder cancer has been reported in the literature. Here, we report the second case occurred three months after diagnosis of bladder cancer. PMID:27252812

  14. Hypoxia inducible factor-1 alpha and multiple myeloma

    PubMed Central

    Tiwary, Bhupendra Nath

    2016-01-01

    Rapid tumor growth creates a state of hypoxia in the tumor microenvironment and results in release of hypoxia inducible factor-1 alpha (HiF-1α) in the local milieu. Hypoxia inducible factor activity is deregulated in many human cancers, especially those that are highly hypoxic. In multiple myeloma (MM) in initial stages of disease establishment, the hypoxic bone marrow microenvironment supports the initial survival and growth of the myeloma cells. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Therefore, HIF is an attractive, although challenging, therapeutic target in MM directly or indirectly in recent years. PMID:26900575

  15. Nonsecretory Multiple Myeloma Presenting as an Intestinal Tumor

    PubMed Central

    Triantafyllopoulou, Diana; Mellor, Stuart; Cargo, Catherine; Gkikas, Ioannis; Adiyodi, Jagdish; Bin, Ayub Ali; Sahasrabudhe, Neil; Rokicka, Margaret

    2015-01-01

    We report a case of a 43-year-old Caucasian man who presented with colicky abdominal pain and microcytic hypochromic anemia. The patient underwent a colonoscopy where a tumor was seen in the ascending colon; histology showed plasmacytoma of the colon. From the protein electrophoresis, no monoclonal band or free light chains were detected nor was urinary Bence Jones protein present. A bone marrow biopsy showed plasma cell myeloma. To the best of our knowledge, this is the first case of nonsecretory multiple myeloma presenting as plasmacytoma of the colon. PMID:25960896

  16. Preclinical development of hybrid cell vaccines for multiple myeloma.

    PubMed

    Walewska, Renata; Teobald, Iryna; Dunnion, Debbie; Abdulmajed, Hind; Aldred, Micheala; Sadler, Jean; Chapman, Claire; Browning, Michael

    2007-01-01

    Immunotherapy may provide alternative or supplementary treatment of multiple myeloma (MM). We propose that hybrid cells, formed by fusing professional antigen-presenting cells with malignant plasma cells, would induce immune responses capable of mediating tumour regression. The human B-lymphoblastoid cell line, HMy2, was fused in vitro with CD138+ bead-separated myeloma plasma cells from five patients with MM. The hybrid cell lines generated in these studies grew stably in tissue culture, and maintained their phenotypic and functional characteristics, providing self-renewing cell lines with potential for therapeutic vaccination. The hybrid cells stimulated allogeneic and autologous T-cell proliferative responses in vitro to a considerably greater degree than their respective parent myeloma plasma cells, and directly activated both CD4+ and CD8+ T-cell responses. The enhanced T-cell stimulation correlated with expression of CD80 on the hybrid cells, and was inhibited by CTLA4-Ig fusion protein. The hybrid cell lines expressed several tumour-associated antigens known to be expressed in myeloma. These data show that self-replicating cell lines with enhanced immunostimulatory properties and potential for therapeutic vaccination can be generated by in vitro fusion of ex vivo myeloma cells and B-lymphoblastoid cell lines. PMID:17302859

  17. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

    PubMed Central

    Bolli, Niccolo; Avet-Loiseau, Hervé; Wedge, David C.; Van Loo, Peter; Alexandrov, Ludmil B.; Martincorena, Inigo; Dawson, Kevin J.; Iorio, Francesco; Nik-Zainal, Serena; Bignell, Graham R.; Hinton, Jonathan W.; Li, Yilong; Tubio, Jose M.C.; McLaren, Stuart; O' Meara, Sarah; Butler, Adam P.; Teague, Jon W.; Mudie, Laura; Anderson, Elizabeth; Rashid, Naim; Tai, Yu-Tzu; Shammas, Masood A.; Sperling, Adam S.; Fulciniti, Mariateresa; Richardson, Paul G.; Parmigiani, Giovanni; Magrangeas, Florence; Minvielle, Stephane; Moreau, Philippe; Attal, Michel; Facon, Thierry; Futreal, P Andrew; Anderson, Kenneth C.; Campbell, Peter J.; Munshi, Nikhil C.

    2014-01-01

    Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment. PMID:24429703

  18. Multiple myeloma presenting with coexisting severe marrow hypoplasia.

    PubMed

    Medhi, K; Kalita, Dipti; Chopra, Anita; Anand, Mona; Raina, Vinod; Kumar, Rajive

    2008-01-01

    A 68-year-old man was referred to us with clinical and bone marrow (BM) features compatible with aplastic anemia. The correct diagnosis, hypoplasia of the BM coexisting with multiple myeloma, became apparent after noting rouleaux in the peripheral blood (PB) and approximately 50% plasma cells in the touch imprint of one of the two BM biopsies done. As standard therapy was precluded, the patient was put on dexamethasone but died within 4 days. This first case of the coexistence of untreated myeloma with aplastic BM shows that even apparently straightforward hypoplasia seen on the BM biopsy should be interpreted in conjunction with the PB smear and the BM touch imprint findings. Among other things, the BM biopsy and imprint should be repeated if the PB has findings such as rouleaux that do not fit with straightforward aplastic anemia. The combination of myeloma and BM aplasia precludes standard therapy and is rapidly fatal. PMID:19008591

  19. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

    PubMed

    Bolli, Niccolo; Avet-Loiseau, Hervé; Wedge, David C; Van Loo, Peter; Alexandrov, Ludmil B; Martincorena, Inigo; Dawson, Kevin J; Iorio, Francesco; Nik-Zainal, Serena; Bignell, Graham R; Hinton, Jonathan W; Li, Yilong; Tubio, Jose M C; McLaren, Stuart; O' Meara, Sarah; Butler, Adam P; Teague, Jon W; Mudie, Laura; Anderson, Elizabeth; Rashid, Naim; Tai, Yu-Tzu; Shammas, Masood A; Sperling, Adam S; Fulciniti, Mariateresa; Richardson, Paul G; Parmigiani, Giovanni; Magrangeas, Florence; Minvielle, Stephane; Moreau, Philippe; Attal, Michel; Facon, Thierry; Futreal, P Andrew; Anderson, Kenneth C; Campbell, Peter J; Munshi, Nikhil C

    2014-01-01

    Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment. PMID:24429703

  20. General Information about Adult Non-Hodgkin Lymphoma

    MedlinePlus

    ... Non-Hodgkin Lymphoma Treatment (PDQ®)–Patient Version General Information About Adult Non-Hodgkin Lymphoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  1. General Information about Childhood Non-Hodgkin Lymphoma

    MedlinePlus

    ... Non-Hodgkin Lymphoma Treatment (PDQ®)–Patient Version General Information About Childhood Non-Hodgkin Lymphoma Go to Health ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  2. Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium

    PubMed Central

    Neuhouser, Marian L.; Rosner, Bernard; Albanes, Demetrius; Buring, Julie E.; Giles, Graham G.; Lan, Qing; Lee, I-Min; Purdue, Mark P.; Rothman, Nathaniel; Severi, Gianluca; Yuan, Jian-Min; Anderson, Kenneth C.; Pollak, Michael; Rifai, Nader; Hartge, Patricia; Landgren, Ola; Lessin, Lawrence; Virtamo, Jarmo; Wallace, Robert B.; Manson, JoAnn E.; Colditz, Graham A.

    2012-01-01

    Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P = .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma. PMID:23074271

  3. Aberrant glycosylation of Igg heavy chain in multiple myeloma.

    PubMed

    Aurer, Igor; Lauc, Gordan; Dumić, Jerka; Rendić, Dubravko; Matisić, Danica; Milos, Marija; Heffer-Lauc, Marija; Flogel, Mirna; Labar, Boris

    2007-03-01

    Although the majority of eukaryotic proteins are glycosylated, there is a dearth of knowledge regarding protein sugar moieties and their changes in disease. Most multiple myeloma cases are characterized by production of monoclonal immunoglobulins (Ig). We studied galactosylation and sialylation of IgG heavy chains in 16 patients with IgG myeloma using lectin blotting and densitometry. In comparison to age and sex matched controls, galactosylation was reduced in multiple myeloma (median 317 vs. 362, range 153-410 vs. 309-447 relative units, p = 0.015, Student's t-test). Sialylation was stage dependent; samples from patients with stage IIA had lowest amounts of sialic acid, IIIA intermediate and IIIB highest (142.6 vs. 185.9 vs. 248.5 relative units, correlation coefficient r = 0.55). Both galactosylation and sialylation levels were independent of age, sex, treatment type, response to treatment, disease duration and IgG and b2 microglobulin concentration. These data indicate that multiple myeloma is characterized by aberrant immunoglobulin glycosylation. PMID:17598409

  4. Potential role of daratumumab in the treatment of multiple myeloma

    PubMed Central

    Khagi, Yulian; Mark, Tomer M

    2014-01-01

    Multiple myeloma is the second most common hematologic malignancy in the US. Treatments utilizing alkylating agents, corticosteroids, proteasome inhibitors, and immunomodulatory drugs have resulted in significant survival benefits, however, despite the advances, relapse is inevitable. Decreased depth and duration of response obtained with each successive relapse of disease is typical of the disease course, thereby highlighting a continuing need for new treatment options. With the introduction of monoclonal antibodies for multiple myeloma, new options for treatment in the relapsed setting are on the horizon. Among the new immunologic agents is daratumumab (DARA), a humanized antibody to CD38 with potent multifaceted antitumor activity. Phase I and II clinical trials have demonstrated significant reduction in serum M-protein and bone marrow plasma cell percentage in refractory patients, with an acceptable toxicity profile. Moreover, ex vivo studies have shown that DARA may be particularly useful in combination with currently used anti-myeloma agents. With a recent breakthrough drug designation by the US Food and Drug Administration, DARA shows promise as mono- and combination therapy for the treatment of relapsed/refractory multiple myeloma. PMID:24971019

  5. Can Non-Hodgkin Lymphoma Be Prevented?

    MedlinePlus

    ... HIV is spread among adults mostly through unprotected sex and by injection drug users sharing contaminated needles. Blood transfusions are now an extremely rare source of HIV infection. Curbing the spread of HIV would prevent many deaths from non-Hodgkin lymphoma. Treating HIV with anti- ...

  6. European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications

    PubMed Central

    Terpos, Evangelos; Kleber, Martina; Engelhardt, Monika; Zweegman, Sonja; Gay, Francesca; Kastritis, Efstathios; van de Donk, Niels W.C.J.; Bruno, Benedetto; Sezer, Orhan; Broijl, Annemiek; Bringhen, Sara; Beksac, Meral; Larocca, Alessandra; Hajek, Roman; Musto, Pellegrino; Johnsen, Hans Erik; Morabito, Fortunato; Ludwig, Heinz; Cavo, Michele; Einsele, Hermann; Sonneveld, Pieter; Dimopoulos, Meletios A.; Palumbo, Antonio

    2015-01-01

    The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6–8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID:26432383

  7. European Myeloma Network guidelines for the management of multiple myeloma-related complications.

    PubMed

    Terpos, Evangelos; Kleber, Martina; Engelhardt, Monika; Zweegman, Sonja; Gay, Francesca; Kastritis, Efstathios; van de Donk, Niels W C J; Bruno, Benedetto; Sezer, Orhan; Broijl, Annemiek; Bringhen, Sara; Beksac, Meral; Larocca, Alessandra; Hajek, Roman; Musto, Pellegrino; Johnsen, Hans Erik; Morabito, Fortunato; Ludwig, Heinz; Cavo, Michele; Einsele, Hermann; Sonneveld, Pieter; Dimopoulos, Meletios A; Palumbo, Antonio

    2015-10-01

    The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID:26432383

  8. Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Shah, Jatin J.; Orlowski, Robert Z.

    2016-01-01

    Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor bortezomib was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally-designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other anti-myeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically- and molecularly-defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of anti-myeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease. PMID:19741722

  9. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  10. Minimal Change Nephrotic Syndrome Associated With Non-Hodgkin Lymphoid Disorders

    PubMed Central

    Kofman, Tomek; Zhang, Shao-Yu; Copie-Bergman, Christiane; Moktefi, Anissa; Raimbourg, Quentin; Francois, Hélène; Karras, Alexandre; Plaisier, Emmanuelle; Painchart, Bernard; Favre, Guillaume; Bertrand, Dominique; Gyan, Emmanuel; Souid, Marc; Roos-Weil, Damien; Desvaux, Dominique; Grimbert, Philippe; Haioun, Corinne; Lang, Philippe; Sahali, Djillali; Audard, Vincent

    2014-01-01

    Abstract Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenström macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse. PMID:25500704

  11. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma

    PubMed Central

    Arora, Mili; Gowda, Sonia; Tuscano, Joseph

    2016-01-01

    Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID:27493711

  12. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma

    PubMed Central

    Thomas, Alexandra L.; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J.; Rajapakshe, Kimal; Krett, Nancy L.; Gunaratne, Preethi H.; Rosen, Steven T.

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  13. Multiple myeloma presenting with unilateral abducens and trigeminal nerve palsies.

    PubMed

    Thiruvengadam, Sushrut S; Prayson, Richard A

    2016-04-01

    Petrous apex masses can manifest with neurologic symptoms due to their involvement of various structures, including cranial nerves (CN) V and VI. The differential diagnosis of petrous masses is broad and includes a variety of both non-neoplastic and neoplastic lesions. We report a rare case of multiple myeloma confined to the right petrous apex, presenting with ipsilateral abducens and trigeminal nerve palsies. A 63-year-old woman presented with a 6-8 week history of facial numbness and a 2 week history of diplopia, with examination showing right-sided facial hypoesthesia in the CN V1-V3 region and right-sided lateral rectus palsy. MRI of the brain showed a solitary 2.0 cm lesion confined to the right petrous apex involving the right cavernous internal carotid artery and Meckel's cave. A transnasal biopsy showed a proliferation of plasmacytoid cells, which showed diffuse immunoreactivity with antibodies to CD138 and kappa, consistent with a plasma cell dyscrasia. A bone scan subsequently revealed multiple lytic bone lesions involving the skull, left humerus, bilateral femurs and possibly the L4 vertebral body. Bone marrow biopsy and serum laboratory results confirmed the diagnosis of kappa-type multiple myeloma. Although rare, multiple myeloma may initially present with petrous involvement and associated cranial nerve deficits. PMID:26602603

  14. Differential and limited expression of mutant alleles in multiple myeloma

    PubMed Central

    Rashid, Naim U.; Sperling, Adam S.; Bolli, Niccolo; Wedge, David C.; Van Loo, Peter; Tai, Yu-Tzu; Shammas, Masood A.; Fulciniti, Mariateresa; Samur, Mehmet K.; Richardson, Paul G.; Magrangeas, Florence; Minvielle, Stephane; Futreal, P. Andrew; Anderson, Kenneth C.; Avet-Loiseau, Herve; Parmigiani, Giovanni

    2014-01-01

    Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications. PMID:25237203

  15. Initial genome sequencing and analysis of multiple myeloma.

    PubMed

    Chapman, Michael A; Lawrence, Michael S; Keats, Jonathan J; Cibulskis, Kristian; Sougnez, Carrie; Schinzel, Anna C; Harview, Christina L; Brunet, Jean-Philippe; Ahmann, Gregory J; Adli, Mazhar; Anderson, Kenneth C; Ardlie, Kristin G; Auclair, Daniel; Baker, Angela; Bergsagel, P Leif; Bernstein, Bradley E; Drier, Yotam; Fonseca, Rafael; Gabriel, Stacey B; Hofmeister, Craig C; Jagannath, Sundar; Jakubowiak, Andrzej J; Krishnan, Amrita; Levy, Joan; Liefeld, Ted; Lonial, Sagar; Mahan, Scott; Mfuko, Bunmi; Monti, Stefano; Perkins, Louise M; Onofrio, Robb; Pugh, Trevor J; Rajkumar, S Vincent; Ramos, Alex H; Siegel, David S; Sivachenko, Andrey; Stewart, A Keith; Trudel, Suzanne; Vij, Ravi; Voet, Douglas; Winckler, Wendy; Zimmerman, Todd; Carpten, John; Trent, Jeff; Hahn, William C; Garraway, Levi A; Meyerson, Matthew; Lander, Eric S; Getz, Gad; Golub, Todd R

    2011-03-24

    Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. PMID:21430775

  16. Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma without Cryopreservation

    PubMed Central

    Al-Anazi, Khalid Ahmed

    2012-01-01

    High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation is considered the standard of care for multiple myeloma patients who are eligible for transplantation. The process of autografting comprises the following steps: control of the primary disease by using a certain induction therapeutic protocol, mobilization of stem cells, collection of mobilized stem cells by apheresis, cryopreservation of the apheresis product, administration of high-dose pretransplant conditioning therapy, and finally infusion of the cryopreserved stem cells after thawing. However, in cancer centers that treat patients with multiple myeloma and have transplantation capabilities but lack or are in the process of acquiring cryopreservation facilities, alternatively noncryopreserved autologous stem cell therapy has been performed with remarkable success as the pretransplant conditioning therapy is usually brief. PMID:22693672

  17. MicroRNAs in multiple myeloma and related bone disease.

    PubMed

    Rossi, Marco; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2015-12-01

    MicroRNAs (miRNAs) are short non coding RNAs aberrantly expressed in solid and hematopoietic malignancies where they play a pivotal function as post-transcriptional regulators of gene expression. Recent reports have unveiled a central role of miRNAs in multiple myeloma onset and progression and preclinical findings are progressively disclosing their potential therapeutic value as drugs or targets. In this review, we provide the basic insights of miRNA biology and function, showing how these molecules are extensively dysregulated in malignant plasma cells (PC) and related microenvironment, thus favoring clone survival and proliferation. We here describe how these critical activities have recently been evaluated to design miRNA-based therapies against multiple myeloma cells and its surrounding microenvironment. PMID:26734644

  18. MicroRNAs in multiple myeloma and related bone disease

    PubMed Central

    Rossi, Marco; Tagliaferri, Pierosandro

    2015-01-01

    MicroRNAs (miRNAs) are short non coding RNAs aberrantly expressed in solid and hematopoietic malignancies where they play a pivotal function as post-transcriptional regulators of gene expression. Recent reports have unveiled a central role of miRNAs in multiple myeloma onset and progression and preclinical findings are progressively disclosing their potential therapeutic value as drugs or targets. In this review, we provide the basic insights of miRNA biology and function, showing how these molecules are extensively dysregulated in malignant plasma cells (PC) and related microenvironment, thus favoring clone survival and proliferation. We here describe how these critical activities have recently been evaluated to design miRNA-based therapies against multiple myeloma cells and its surrounding microenvironment. PMID:26734644

  19. The hyponatramia of multiple myeloma is true and not pseudohyponatramia.

    PubMed

    Sachs, Jeffrey; Fredman, Brian

    2006-01-01

    The hyponatremia found in multiple myeloma and which is associated with a reduced anion gap (ag) is considered to be pseudohyponatremia due to the displacement of water by the high globulin content in the blood. Serum proteins participate in acid-base balance. Stewart and other authors in their approach to acid-base interpretation acknowledge electrical neutrality as a fundamental characteristic of body fluids. Furthermore, they have shown that both the strong ion difference (SID) and protein, specifically, negatively-charged albumin affect hydrogen ion concentration (H(+)) in the body--i.e., for example an increase in SID leads to a decrease in H(+) and a decrease in albumin leads to a similar effect. The M proteins of multiple myeloma are positively charged. As a result they cause a decrease in sodium levels and the anion gap and thus a true hyponatremia. PMID:16707230

  20. Initial genome sequencing and analysis of multiple myeloma

    PubMed Central

    Chapman, Michael A.; Lawrence, Michael S.; Keats, Jonathan J.; Cibulskis, Kristian; Sougnez, Carrie; Schinzel, Anna C.; Harview, Christina L.; Brunet, Jean-Philippe; Ahmann, Gregory J.; Adli, Mazhar; Anderson, Kenneth C.; Ardlie, Kristin G.; Auclair, Daniel; Baker, Angela; Bergsagel, P. Leif; Bernstein, Bradley E.; Drier, Yotam; Fonseca, Rafael; Gabriel, Stacey B.; Hofmeister, Craig C.; Jagannath, Sundar; Jakubowiak, Andrzej J.; Krishnan, Amrita; Levy, Joan; Liefeld, Ted; Lonial, Sagar; Mahan, Scott; Mfuko, Bunmi; Monti, Stefano; Perkins, Louise M.; Onofrio, Robb; Pugh, Trevor J.; Vincent Rajkumar, S.; Ramos, Alex H.; Siegel, David S.; Sivachenko, Andrey; Trudel, Suzanne; Vij, Ravi; Voet, Douglas; Winckler, Wendy; Zimmerman, Todd; Carpten, John; Trent, Jeff; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.

    2013-01-01

    Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. PMID:21430775

  1. Whole bone marrow irradiation for the treatment of multiple myeloma

    SciTech Connect

    Coleman, M.; Saletan, S.; Wolf, D.; Nisce, L.; Wasser, J.; McIntyre, O.R.; Tulloh, M.

    1982-04-01

    Nine patients with multiple myeloma were treated with whole bone marrow irradiation. Six had heavily pretreated disease refractory to chemotherapy. Three had stable disease lightly pretreated by chemotherapy. A modification of the ''three and two'' total nodal radiation technique was employed. Although varying and often severe treatment related cytopenia occurred, infectious complications, clinical bleeding, and nonhematalogic complications were minimal. Five of nine patients showed a decrease in monoclonal protein components, and one showed an increase during treatment. These preliminary results indicate that a reduction of tumor cell burden may occur in patients following whole bone marrow irradiation and that the technique is feasible. Whole bone marrow irradiation combined with chemotherapy represents a new conceptual therapeutic approach for multiple myeloma.

  2. Differential and limited expression of mutant alleles in multiple myeloma.

    PubMed

    Rashid, Naim U; Sperling, Adam S; Bolli, Niccolo; Wedge, David C; Van Loo, Peter; Tai, Yu-Tzu; Shammas, Masood A; Fulciniti, Mariateresa; Samur, Mehmet K; Richardson, Paul G; Magrangeas, Florence; Minvielle, Stephane; Futreal, P Andrew; Anderson, Kenneth C; Avet-Loiseau, Herve; Campbell, Peter J; Parmigiani, Giovanni; Munshi, Nikhil C

    2014-11-13

    Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications. PMID:25237203

  3. [Preoperative plasmapheresis for lung cancer with multiple myeloma].

    PubMed

    Tagawa, T; Itoh, S; Sano, I; Miwa, N; Ikuta, Y; Ohe, H

    1995-12-01

    A 66-old-male admitted to our hospital was diagnosed multiple myeloma (IgA kappa type, Durie & Salmon stage IIIA) and squamous cell lung cancer (c-T2N0M0 stage I). The function of platelets was within a normal range (11.7 x 10(4)/mm3 and the bleeding time of two minutes), but the function of coagulation was reduced (prothrombin time, 13.1 seconds; activating prothrombin time, 45.1 seconds; and antithrombin III, 65%). The hyperviscosity syndrome was anticipated because of high IgA M protein (6,551 mg/dl). Plasmapheresis with 800 ml of fresh frozen plasma was performed before the left lower pulmonary lobectomy and R1 lymph node dissection. Then the function of coagulation was improved (prothrombin time, 12.6 seconds; activating prothrombin time, 31.3 seconds; and antithrombin III, 75%). IgA M protein was also decreased to 4,696 mg/dl. Postoperative bleeding necessitated a second thoracotomy. The cause of postoperative bleeding was the ablasion of the pleural adhesion due to tuberculous pleuritis as well as bleeding tendency of multiple myeloma. The plasmapheresis performed in this case did not fully improve the bleeding tendency. Cases of cancer complicated with multiple myeloma have been increasing and if an operation is needed, plasmapheresis should be considered. The indication and the extent of hematologic restoration to be achieved should be further investigated. PMID:8551081

  4. Smoldering multiple myeloma requiring treatment: time for a new definition?

    PubMed Central

    Stewart, A. Keith; Chanan-Khan, Asher; Rajkumar, S. Vincent; Kyle, Robert A.; Fonseca, Rafael; Kapoor, Prashant; Bergsagel, P. Leif; McCurdy, Arleigh; Gertz, Morie A.; Lacy, Martha Q.; Lust, John A.; Russell, Stephen J.; Zeldenrust, Steven R.; Reeder, Craig; Roy, Vivek; Buadi, Francis; Dingli, David; Hayman, Suzanne R.; Leung, Nelson; Lin, Yi; Mikhael, Joseph; Kumar, Shaji K.

    2013-01-01

    Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved. PMID:24144641

  5. Sacroplasty for Local or Massive Localization of Multiple Myeloma

    SciTech Connect

    Basile, Antonio; Tsetis, Dimitrios; Cavalli, Maide; Fiumara, Paolo; Raimondo, Francesco Di; Coppolino, Francesco; Coppolino, Carmelo; Mundo, Elena; Desiderio, Carla; Granata, Antonio; Patti, Maria Teresa

    2010-12-15

    The purpose of this study was to assess the efficacy of cementoplasty in the treatment of sacral multiple myelomas. We retrospectively reviewed the records of eight patients (four women and four men; age range 47-68 years; mean age 57.8) who underwent cementoplasty for painful osteolytic localization of multiple myeloma between April 2007 and May 2009. The patients had difficulty walking because of increasing pain. Six patients had persistent pain despite other cementoplasties for vertebral and femoral localization, whereas two patients referred at the time of diagnosis had only sacral lesions. The clinical indication for treatment was (1) a pain intensity score {>=}5 on visual analogue scale (VAS) and (2) pain totally or partially refractory to analgesic treatment in patients with a life expectancy >3 months. Technical planning was based on computed tomography and/or magnetic resonance imaging. Six patients had previously undergone radiotherapy or chemotherapy and were receiving varying doses of analgesics, whereas sacroplasty represented the first treatment for two patients. Five patients had monolateral local involvement, and the other patients had massive involvement of the sacrum; Technical success was achieved in all cases. We had only one small and asymptomatic foraminal leak. All patients experienced improvement in symptoms after the procedure, as demonstrated by improved VAS scores and performance status (PS) and decreased analgesic dose constant during follow-up. In our experience, percutaneous stabilization can be used effectively and safely in patients with focal or extensive involvement of the sacrum by multiple myeloma.

  6. Expression profile of telomere-associated genes in multiple myeloma

    PubMed Central

    de la Guardia, Rafael Díaz; Catalina, Purificación; Panero, Julieta; Elosua, Carolina; Pulgarin, Andrés; López, María Belén; Ayllón, Verónica; Ligero, Gertrudis; Slavutsky, Irma; Leone, Paola E

    2012-01-01

    To further contribute to the understanding of multiple myeloma, we have focused our research interests on the mechanisms by which tumour plasma cells have a higher survival rate than normal plasma cells. In this article, we study the expression profile of genes involved in the regulation and protection of telomere length, telomerase activity and apoptosis in samples from patients with monoclonal gammopathy of undetermined significance, smouldering multiple myeloma, multiple myeloma (MM) and plasma cell leukaemia (PCL), as well as several human myeloma cell lines (HMCLs). Using conventional cytogenetic and fluorescence in situ hybridization studies, we identified a high number of telomeric associations (TAs). Moreover, telomere length measurements by terminal restriction fragment (TRF) assay showed a shorter mean TRF peak value, with a consistent correlation with the number of TAs. Using gene expression arrays and quantitative PCR we identified the hTERT gene together with 16 other genes directly involved in telomere length maintenance: HSPA9, KRAS, RB1, members of the Small nucleolar ribonucleoproteins family, A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins, and 14-3-3 family. The expression levels of these genes were even higher than those in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which have unlimited proliferation capacity. In conclusion, the gene signature suggests that MM tumour cells are able to maintain stable short telomere lengths without exceeding the short critical length, allowing cell divisions to continue. We propose that this could be a mechanism contributing to MM tumour cells expansion in the bone marrow (BM). PMID:22947336

  7. COMPARISON OF TWIN AND AUTOLOGOUS TRANSPLANTS FOR MULTIPLE MYELOMA

    PubMed Central

    Bashey, Asad; Pérez, Waleska S.; Zhang, Mei-Jie; Anderson, Kenneth C.; Ballen, Karen; Berenson, James R.; To, L. Bik; Fonseca, Rafael; Freytes, César O.; Gale, Robert Peter; Gibson, John; Giralt, Sergio A.; Kyle, Robert A.; Lazarus, Hillard M.; Maharaj, Dipnarine; McCarthy, Philip L.; Milone, Gustavo A.; Nimer, Stephen; Pavlovsky, Santiago; Reece, Donna E.; Schiller, Gary; Vesole, David H.; Hari, Parameswaran

    2008-01-01

    Relapse is the overwhelming cause of treatment-failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on post-transplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically-identical twins vs. autotransplants since confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the CIBMTR. Multivariate analysis was performed by fitting a Cox model stratified on matched-pairs. The matched transplant patients studied were similar with respect to subject-, disease- and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower and progression-free survival was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk, RR=0.49, 95% confidence interval (CI) 0.28 – 0.86, p=0.011). Twin transplants have a significantly lower relapse risk than autotransplants in multiple myeloma suggesting that graft composition may impact outcomes following high-dose chemotherapy. PMID:18804041

  8. Three-dimensional Nuclear Telomere Organization in Multiple Myeloma12

    PubMed Central

    Klewes, Ludger; Vallente, Rhea; Dupas, Eric; Brand, Carolin; Grün, Dietrich; Guffei, Amanda; Sathitruangsak, Chirawadee; Awe, Julius A; Kuzyk, Alexandra; Lichtensztejn, Daniel; Tammur, Pille; Ilus, Tiiu; Tamm, Anu; Punab, Mari; Rubinger, Morel; Olujohungbe, Adebayo; Mai, Sabine

    2013-01-01

    Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). Up to date, it is difficult to predict an individual's time to disease progression and the treatment response. To examine whether the nuclear telomeric architecture will unravel some of these questions, we carried out. Three-dimensional (3D) telomere analysis on samples from patients diagnosed with MGUS and MM, as well as from patients who went into relapse. Telomere signal intensity, number of telomere aggregates, nuclear volume, and the overall nuclear telomere distribution (a/c ratio) were analyzed. The telomeric profiles allowed for the differentiation of the disease stages. The telomeric profiles of myeloma cells obtained from blood and bone marrow aspirates were identical. Based on this study, we discuss the use of 3D telomere profiling as a potential future tool for risk stratification and personalized treatment decisions. PMID:24466378

  9. New Frontiers in the Treatment of Multiple Myeloma

    PubMed Central

    Hwang, Janice Jin; Ghobrial, Irene M.; Anderson, Kenneth C.

    2011-01-01

    Recent leaps in elucidating the biology of myeloma, particularly the intracellular pathways and the complex interaction with the bone marrow microenvironment, have resulted in an unprecedented surge of novel, targeted therapies and therapeutic regimens. There are currently over 30 new agents being tested in the treatment of multiple myeloma (MM). Many of these are novel, targeted agents that have demonstrated significant efficacy and prolonged survival. In this review, we summarize the current understanding of the mechanisms of action of novel therapies being tested in the preclinical and clinical settings in MM. These include agents that act directly on the intracellular signaling pathways, cell maintenance processes, and cell surface receptors. Finally, we present the clinical responses to some of these agents when used alone or in combination in clinical trials of patients with MM. Indeed, MM has become a model disease for the development of novel, therapeutic agents. PMID:17160337

  10. IMWG consensus on risk stratification in multiple myeloma.

    PubMed

    Chng, W J; Dispenzieri, A; Chim, C-S; Fonseca, R; Goldschmidt, H; Lentzsch, S; Munshi, N; Palumbo, A; Miguel, J S; Sonneveld, P; Cavo, M; Usmani, S; Durie, B G M; Avet-Loiseau, H

    2014-02-01

    Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies. PMID:23974982

  11. New Approaches to Molecular Imaging of Multiple Myeloma.

    PubMed

    Vij, Ravi; Fowler, Kathryn J; Shokeen, Monica

    2016-01-01

    Molecular imaging plays an important role in detection and staging of hematologic malignancies. Multiple myeloma (MM) is an age-related hematologic malignancy of clonal bone marrow plasma cells characterized by destructive bone lesions and is fatal in most patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolytic lesions manifested in MM. Progressive biomedical imaging technologies such as low-dose CT, molecularly targeted PET, MRI, and the functional-anatomic hybrid versions (PET/CT and PET/MRI) provide incremental advancements in imaging MM. Imaging with PET and MRI using molecularly targeted probes is a promising precision medicine platform that might successfully address the clinical ambiguities of myeloma spectrum diseases. The intent of this focus article is to provide a concise review of the present status and promising developments on the horizon, such as the new molecular imaging biomarkers under investigation that can either complement or potentially supersede existing standards. PMID:26541780

  12. Bone Disease in Multiple Myeloma: Pathophysiology and Management

    PubMed Central

    Hameed, Abdul; Brady, Jennifer J; Dowling, Paul; Clynes, Martin; O’Gorman, Peter

    2014-01-01

    Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD. PMID:25187738

  13. Multiple myeloma: is it time for biomarker-driven therapy?

    PubMed

    Bhutani, Manisha; Landgren, Ola; Usmani, Saad Z

    2015-01-01

    Remarkable strides have been made in understanding the molecular mechanisms by which multiple myeloma develops, leading to more sophisticated classification that incorporates not only the traditional diagnostic criteria, but also immunophenotype, genetic, and molecular features. However, even with this added information, considerable heterogeneity in clinical outcomes exists within the identified subtypes. The present paradigm for myeloma treatment is built on the basic step of defining transplant eligibility versus noneligibility, as determined by age, performance status, and cumulative burden of comorbidities. An incredibly complex heterogeneous disease is, therefore, treated in a generalized way with the result that large interpatient variability exists in the outcome. As antimyeloma therapeutics continue to expand it is becoming even more crucial to personalize treatment approaches that provide the most value to a specific patient. Development of biomarkers, either individually or as larger sets or patterns and ranging from analysis of blood or bone marrow to biomedical imaging, is a major focus in the field. Biomarkers such as involved serum free light chain ratio and MRI focal lesions have been implemented in the new definition of multiple myeloma and guide clinicians to initiate treatment in otherwise asymptomatic individuals. Currently, however, there is not enough evidence to support intensifying the treatment for high-risk disease or reducing the treatment for low-risk disease. Minimal residual disease-negative status is an important biomarker that holds promise for monitoring the effectiveness of response-adapted strategies. This article sheds light on the forward landscape and rear-mirror view of biomarkers in myeloma. PMID:25993214

  14. Multiple Myeloma Treatment (Beyond the Basics)

    MedlinePlus

    ... the Licensed Materials from any location via the Internet. b. STANDALONE WORKSTATION: A standalone subscription permits multiple ... computer. A Standalone Workstation license does not include Internet access to the Licensed Materials. c. INSTITUTIONAL SUBSCRIPTION: ...

  15. Sclerotic multiple myeloma with an unusual sunburst periosteal reaction occurring in the sternum.

    PubMed

    Li, Yuqing; Wu, Wenjuan; Zhang, Zekun; Ding, Yang; Latif, Mahrukh

    2015-05-01

    Multiple myeloma is a disseminated neoplastic monoclonal gammopathy that usually affects the skull, clavicle, rib, pelvis, spinal column, and proximal portions of the humerus and femur. The initial manifestation of multiple myeloma in the sternum is rare. The classic radiological presentations of multiple myeloma are multiple "punched-out" areas of bone destruction, expansile lytic lesions, and generalized osteoporosis. Primary sclerotic presentation is rare and occurs in only 3 % of cases. A sclerotic multiple myeloma with a sunburst periosteal reaction occurring in the sternum has not been reported in the English literature. We report a case of sclerotic multiple myeloma of a 49-year-old woman. In the sternum, the lesion displayed extensive sclerosis mixed with mottled lytic areas with a sunburst periosteal reaction occurring in the periphery, which radiologically mimicked an osteosarcoma. Multiple focal areas of sclerosis were also found in the right clavicle, pelvis, multiple ribs, and vertebrae. PMID:25351419

  16. CYT997 causes apoptosis in human multiple myeloma.

    PubMed

    Monaghan, Katherine; Khong, Tiffany; Smith, Gregg; Spencer, Andrew

    2011-04-01

    Multiple Myeloma (MM) is an incurable malignancy of mature plasma cells. Microtubule targeting agents (MTAs) are an established class of drug that include many conventional and some novel compounds. MTAs function by inhibiting the polymerisation or depolymerisation of microtubules (MTs) within the cell, disrupting various important cellular functions. We have investigated pre-clinically the novel tubulin polymerisation inhibitor CYT997 for the potential treatment of MM. Here we demonstrate the promising anti-myeloma activity of CYT997 as evidenced by tubulin disruption, inhibition of growth and proliferation, cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells using nanomolar drug concentrations. CYT997 also synergises with bortezomib to produce more potent anti-MM activity. These in vitro observations were validated in vivo by the ability of CYT997 to significantly prolong survival in a murine model of aggressive systemic myelomatosis. These findings provide a basis for continuing pre-clinical and clinical investigations into the anti-MM effects of CYT997. PMID:19907921

  17. Recent advances in the mangement of multiple myeloma.

    PubMed

    Kumar, Lalit; Vikram, P; Kochupillai, V

    2006-01-01

    The management of multiple myeloma has undergone a major change during the past decade. Currently, patients < 65 years of age with advanced disease (stage II-III) are best treated with initial chemotherapy (3-4 cycles of vincristine, adriamycin and dexamethasone, or vincristine, adriamycin and methyl prednisolone, or thalidomide and dexamethasone followed by high dose chemotherapy with autologous peripheral blood stem cell transplantation. More than 50% of patients achieve complete response following this approach. The results of a number of nonrandomized and randomized studies indicate that treatment with high dose chemotherapy followed by autologous peripheral blood stem cell transplantation is associated with improved overall and event-free survival compared with conventional chemotherapy. The absence of chromosome 13 abnormalities, serum albumin levels > 3.5 g/dl and low serum b-2 microglobulin are associated with a better outcome. Almost all patients with significant bone disease or osteoporosis are candidates for therapy with bisphosphonates. About one-third of patients with relapsed or refractory myeloma benefit from therapy with thalidomide or bortezomib (a proteosome inhibitor). Recent work in the immunotherapy of myeloma suggests that some novel immune-based approaches might be useful in the management. The application of cytogenetics and molecular genetics, especially gene expression profiling, are likely to be areas of active research in future studies. PMID:16756196

  18. Multiple myeloma among Danish women: employment history and workplace exposures.

    PubMed

    Pottern, L M; Heineman, E F; Olsen, J H; Raffn, E; Blair, A

    1992-09-01

    To investigate the role of employment history and workplace exposures as risk factors for multiple myeloma among women, a population-based case-control study using the Danish Cancer Registry data linkage system was conducted. All cases of myeloma diagnosed in Danish women between 1970 and 1984 (1,010 cases) and 4,040 age-matched women alive at the time of case-diagnosis were identified. Industrial histories from 1964 forward were obtained from the nationwide Pension Fund for 363 cases and 1,517 controls, and the most recent occupation on the tax record was available for 607 cases and 2,596 controls. Using industry/occupational-code combinations for the cases and controls who had industry employment, Danish industrial hygienists assessed the likelihood of exposure to 47 workplace substances. An increased myeloma risk (odds ratio [OR] = 1.2, 95 percent confidence interval [CI] = 1.0-1.5) was seen for women not in the Pension Fund, but who had an occupational title coded as 'Mrs/homemaker.' Nonsignificantly elevated risks of 1.3 or greater were observed for employment in: production of agricultural products; orchards/nurseries; spinning/weaving; other textile and plastics manufacturing; hotel, entertainment, and social services industries. Elevated, but nonsignificant risks were observed for possible and probable exposure to exhaust fumes, formaldehyde, wood dust, animals or animal products, and pesticides. The strongest association with myeloma was employment in the agricultural industry (OR = 1.5, CI = 0.8-2.8), however, the number of women who worked on family farms was unknown and could not be included in this risk estimate. PMID:1525323

  19. Multiple myeloma presenting as an intracranial plasmacytoma: a case report.

    PubMed

    Terada, Tadashi

    2009-01-01

    Multiple myeloma presenting as an intracranial tumor (plasmacytoma) is very rare. An 81-year-old woman was admitted to our hospital because of gait disturbance. A blood laboratory test revealed a mildly increased lactate dehydrogenase (236 IU/L) and glucose (121 mg/dl). Blood protein fractions were normal. Brain computed tomography and magnetic resonance imaging revealed an intracranial mass (5 x 4 x 3 cm) in the brain base next to the clavus, and it was clinically diagnosed as chordoma. An excision of the brain tumor was performed. Imaging modalities including ultrasound, x-ray, computed tomography, magnetic resonance imaging and positron emission tomography did not reveal any tumors other than the brain tumor. The tumor was soft, fragile, and bloody. Microscopically, a monotonous proliferation of atypical plasma cells with hyperchromatic nuclei was recognized. Histochemically, the tumor cells were pyroninophilic and the congo-red stain revealed amyloidosis. Immunohistochemically, the tumor cells were positive for kappa-chain and negative for cytokeratin, epithelial membrane antigen, vimentin, CD45, CD20, CD45RO, lambda-chain, IgM, IgA, IgG, synaptophysin, chromogranin, S100 protein, desmin, alpha-smooth muscle antigen, myoglobin, p53 protein, and glial fibrillary acidic protein. The Ki-67 labeling was 11%. Intracranial plasmacytoma was pathologically diagnosed. The patient was treated by adjuvant chemoradiation, and entered into the complete remission stage. However, multiple metastases emerged in the vertebral bones and ribs six months after the remission. A diagnosis of multiple myeloma was made. The urine revealed Bence-Jones protein of monoclonal IgG kappa-chain type, but blood M protein was not recognized. The patient's condition gradually deteriorated. The patient died of respiratory failure due to bronchopneumonia 18 months after the admission. The present case indicates that multiple myeloma may manifest as an intracranial brain tumor (plasmacytoma). PMID

  20. Adrenal involvement in non-Hodgkin lymphoma

    SciTech Connect

    Paling, M.R.; Williamson, B.R.J.

    1983-08-01

    Adrenal masses are described in seven cases of non-Hodgkin lymphoma in a series of 173 patients. In all seven patients the lymphoma was diffuse rather than nodular. Three patients had adrenal masses at the time of presentation, whereas in four cases the adrenal gland was a site of tumor recurrence after therapy. Three patients had simultaneous bilateral adrenal involvement by tumor. No characteristic features were recognized that might have distinguished these tumors from other adrenal masses. Appropriate therapy successfully resolved the adrenal masses in all but one case. The latter patient was the only one with evidence of adrenal insufficiency.

  1. Panobinostat for the treatment of multiple myeloma: the evidence to date

    PubMed Central

    Bailey, Hanna; Stenehjem, David D; Sharma, Sunil

    2015-01-01

    Multiple myeloma is a malignancy involving plasma cell proliferation within the bone marrow. Survival of patients diagnosed with myeloma has significantly improved in the last decade, following the approval of novel agents. Despite great strides achieved in the management of multiple myeloma, it is still considered an incurable disease as the majority of patients relapse after initiation of therapy. Additionally, the duration of response generally decreases with an increasing number of therapy lines. The need to overcome resistance to therapy dictates research into more potent agents and those with novel mechanisms of action. A therapeutic option for relapsed/refractory myeloma includes histone deacetylase inhibition. Various histone deacetylase inhibitors, including the newly approved panobinostat, are currently under evaluation in this setting. Panobinostat for multiple myeloma is used in combination with other potent therapeutic agents, such as proteasome inhibitors and steroids. Ongoing research evaluating other panobinostat-containing regimens will provide additional insight into its place in myeloma management. PMID:26504410

  2. Veliparib, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory Lymphoma, Multiple Myeloma, or Solid Tumors

    ClinicalTrials.gov

    2015-10-14

    Adult B Acute Lymphoblastic Leukemia; Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Adult Solid Neoplasm; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Hepatosplenic T-Cell Lymphoma; Intraocular Lymphoma; Lymphomatous Involvement of Non-Cutaneous Extranodal Site; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides and Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  3. [Kidney damage in multiple myeloma and other monoclonal gammopathies].

    PubMed

    Adam, Z; Pour, L; Krejcí, M; Stĕpánková, S; Svobodová, I; Veselý, K; Hájek, R

    2008-09-01

    Multiple myeloma typically damages the skeleton in the form of osteolytic lesions or diffuse osteoporosis and causes a decrease in blood production. Renal insufficiency is diagnosed immediately at the onset of illness when establishing diagnosis in up to 20% of patients. Where patients suffer from an advanced form of the illness, it occurs in up to 40%. The predominant cause of damage to the kidneys is the monoclonal light chains. Most frequently, nephropathy is caused by the precipitation of light chains with the Tamm-Horsfall protein in the distal part of the loop of Henle and subsequent tubular ruptures and the creation of fibrous changes in the interstitium. Less frequently, there is clinically serious damage to tubular functions without indication of renal insufficiency. In some patients monoclonal immunoglobulin induces changes in the glomeruli. A rare type of damage is deposits of light chains in the form of AL-amyloid and subsequent nephritic syndrome. A very rare form is the deposition of monoclonal immunoglobulin in the form of amorphous matter (light-chain deposition disease) or in the form of crystals within tissue histiocytes (crystal storing histiocytosis). Both of these disorders cause renal insufficiency and less frequently nephritic syndrome such as AL amyloidosis. With timely and intensive treatment of multiple myeloma, which quickly suppresses the creation of light chains, a significant proportion of patients experience reparative changes and improved kidney function. The benefit of plasmapheresis for patients with severe kidney damage has not been confirmed by randomised studies. At the present time the first positive results are becoming available from tests of the use of pre-emptive haemodialysis with special columns that are permeable for light chains. The aim of the text is to provide information on the various forms of nephropathy whose closer analysis can reveal multiple myeloma and contribute to the timely diagnosis of the cause of the

  4. Radiation therapy for the palliation of multiple myeloma

    SciTech Connect

    Leigh, B.R.; Kurtts, T.A.; Mack, C.F.; Matzner, M.B.; Shimm, D.S. )

    1993-04-02

    This study reviews the experience at the University of Arizona in an effort to define the minimum effective radiation dose for durable pain relief in the majority of patients with symptomatic multiple myeloma. The records of 101 patients with multiple myeloma irradiated for palliation at the University of Arizona between 1975 and 1990 were reviewed. Three hundred sixteen sites were treated. Ten sites were asymptomatic, including six hemibody fields with advanced disease unresponsive to chemotherapy and four local fields with impending pathological fractures. Three hundred six evaluable symptomatic sites remained. The most common symptom was bone pain. Other symptoms included neurological impairment with a palpable mass. Total tumor dose ranged from 3.0 to 60 Gy, with a mean of 25 Gy. Symptom relief was obtained in 297 of 306 evaluable symptomatic sites (97%). Complete relief of symptoms was obtained in 26% and partial relief in 71%. Symptom relief was obtained in 92% of sites receiving a total dose less than 10 Gy (n = 13) and 98% of sites receiving 10 Gy or more (n = 293). No dose-response could be demonstrated. The likelihood of symptom relief was not influenced by the location of the lesion or the use of concurrent chemotherapy. Of the 297 responding sites, 6% (n = 19) relapsed after a median symptom-free interval of 16 months. Neither the probability of relapse nor the time to relapse was related to the radiation dose. Retreatment of relapsing sites provided effective palliation in all cases. Radiation therapy is effective in palliating local symptoms in multiple myeloma. A total dose of 10 Gy should provide durable symptom relief in the majority of patients. 16 refs., 3 figs., 4 tabs.

  5. Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo

    PubMed Central

    Van Valckenborgh, E; De Raeve, H; Devy, L; Blacher, S; Munaut, C; Noël, A; Van Marck, E; Van Riet, I; Van Camp, B; Vanderkerken, K

    2002-01-01

    Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis. British Journal of Cancer (2002) 86, 796–802. DOI: 10.1038/sj/bjc/6600137 www.bjcancer.com © 2002 Cancer Research UK PMID:11875745

  6. HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients.

    PubMed

    Storti, P; Donofrio, G; Colla, S; Airoldi, I; Bolzoni, M; Agnelli, L; Abeltino, M; Todoerti, K; Lazzaretti, M; Mancini, C; Ribatti, D; Bonomini, S; Franceschi, V; Pistoia, V; Lisignoli, G; Pedrazzini, A; Cavicchi, O; Neri, A; Rizzoli, V; Giuliani, N

    2011-03-01

    The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in MM. PMID:21183939

  7. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

    PubMed

    Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

    2016-05-01

    The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM. PMID:26710887

  8. Spotlight on ixazomib: potential in the treatment of multiple myeloma

    PubMed Central

    Muz, Barbara; Ghazarian, Rachel Nicole; Ou, Monica; Luderer, Micah John; Kusdono, Hubert Daniel; Azab, Abdel Kareem

    2016-01-01

    Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib. PMID:26811670

  9. Spotlight on ixazomib: potential in the treatment of multiple myeloma.

    PubMed

    Muz, Barbara; Ghazarian, Rachel Nicole; Ou, Monica; Luderer, Micah John; Kusdono, Hubert Daniel; Azab, Abdel Kareem

    2016-01-01

    Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib. PMID:26811670

  10. [Daratumumab--breakthrough drug in multiple myeloma therapy].

    PubMed

    Jurczyszyn, Artur; Kosmaczewska, Agata; Skotnicki, Aleksander B

    2014-01-01

    Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM. PMID:25531698

  11. Novel targeted agents in the treatment of multiple myeloma.

    PubMed

    Varga, Cindy; Laubach, Jacob; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C; Richardson, Paul G

    2014-10-01

    New, next-generation targeted treatment strategies are required to improve outcomes in patients with multiple myeloma (MM). Monoclonal antibodies, cell signaling inhibitors, and selective therapies targeting the bone marrow microenvironment have demonstrated encouraging results with generally manageable toxicity in therapeutic trials of patients with relapsed and refractory disease, each critically informed by preclinical studies. A combination approach of these newer agents with immunomodulators and/or proteasome inhibitors as part of a treatment platform seems to improve the efficacy of anti-MM regimens, even in heavily pretreated patients. Future studies are required to better understand the complex mechanisms of drug resistance in MM. PMID:25212889

  12. MRI in multiple myeloma: a pictorial review of diagnostic and post-treatment findings.

    PubMed

    Dutoit, Julie C; Verstraete, Koenraad L

    2016-08-01

    Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity.This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message • Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. • Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. • Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. • Combined morphological and functional MRI provides optimal bone marrow assessment for staging. • Combined morphological and functional MRI is of considerable value in treatment follow-up. PMID:27164915

  13. Non-Hodgkin's lymphomas: clinical governance issues.

    PubMed

    Fields, P A; Goldstone, A H

    2002-09-01

    Every patient in every part of the world has the right to expect the best possible quality of care from health care providers. Non-Hodgkin's lymphomas (NHL) are an extremely heterogeneous group of conditions which require important decisions to be taken at many points along the treatment pathway. To get this right every time requires that high-quality standards are instituted and adhered to, so that the best possible outcome is achieved. In the past this has not always been the case because of the failure of clinicians sometimes to adhere to an optimal management plan. In 1995, the UK government commissioned an inquiry into the running of cancer services in the United Kingdom, which culminated in a series of recommendations to improve them. Subsequently, these recommendations were implemented as objectives of the NHS Cancer Plan which is the framework by which the UK government wishes to improve cancer services. Concurrently another general concept has emerged which is designed to ensure that the highest quality standards may be achieved for all patients across the whole National Health Service (NHS). This concept, termed 'clinical governance', brings together a corporate responsibility of all health care workers to deliver high quality standards, in the hope that this will translate into better long-term survival of patients with malignant disease. This chapter focuses on the issues surrounding clinical governance and how the principles of this concept relate to non-Hodgkin's lymphomas. PMID:12468407

  14. Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

    NASA Astrophysics Data System (ADS)

    Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

    2016-03-01

    Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

  15. Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    PubMed

    Stiff, Andrew; Caserta, Enrico; Sborov, Douglas W; Nuovo, Gerard J; Mo, Xiaokui; Schlotter, Sarah Y; Canella, Alessandro; Smith, Emily; Badway, Joseph; Old, Matthew; Jaime-Ramirez, Alena Cristina; Yan, Pearlly; Benson, Don M; Byrd, John C; Baiocchi, Robert; Kaur, Balveen; Hofmeister, Craig C; Pichiorri, Flavia

    2016-05-01

    Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed multiple myeloma confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the multiple myeloma cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with multiple myeloma remain unknown. Here, we report that junctional adhesion molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in multiple myeloma cells. Treatment of multiple myeloma cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Furthermore, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of multiple myeloma cells in vitro and in vivo This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in multiple myeloma. Mol Cancer Ther; 15(5); 830-41. ©2016 AACR. PMID:26809490

  16. EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes.

    PubMed

    Hernando, Henar; Gelato, Kathy A; Lesche, Ralf; Beckmann, Georg; Koehr, Silke; Otto, Saskia; Steigemann, Patrick; Stresemann, Carlo

    2016-02-01

    Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. ©2015 AACR. PMID:26590165

  17. [Meningococcal Septicemia Revealing Multiple Myeloma: A Case Report].

    PubMed

    Arakawa, Risturo; Mori, Nobuaki; Kagawa, Narito; Higuchi, Akiko; Tanaka, Masashi; Aoki, Yasuko; Seki, Shiko; Suzuki, Ryo

    2016-05-01

    Meningococcal infection is among the most devastating diseases. It is rarely seen in Japan. However, several environmental and host factors have been associated with increased risks of Neisseria meningitidis infection. We present a case of invasive N. meningitidis infection that revealed the presence of multiple myeloma. A 55-year-old Japanese man was admitted with fever and altered consciousness. He was sent to the intensive care unit for septic shock and disseminated intravascular coagulation. In addition to standard septic shock and multiple organ failure treatment, polymyxin-B immobilized column direct hemoperfusion was performed. His blood culture was positive for N. meningitidis. The patient gradually improved and was discharged on day 35. We evaluated the risk factors for the development of meningococcal infection. A laboratory examination showed that the patient was negative for human immunodeficiency virus antibody and had a normal total complement function. However, his serum immunoglobulin G level was high, and serum and urine protein electrophoresis detected a monoclonal gammopathy. A bone marrow examination led to the diagnosis of multiple myeloma. Because N. meningitidis bacteria spreads between individuals in close contact through the exchange of oral secretions, droplet precautions and antimicrobial chemoprophylaxis (ciprofloxacin, 500 mg) were implemented to prevent the spread of the meningococcal infection. Sporadic meningococcal infection warrants an evaluation for immunodeficiency and the prevention of secondary infection. PMID:27529971

  18. Prognostic Impact of Cytogenetic Abnormalities in Multiple Myeloma

    PubMed Central

    Jian, Yuan; Chen, Xiaolei; Zhou, Huixing; Zhu, Wanqiu; Liu, Nian; Geng, Chuanying; Chen, Wenming

    2016-01-01

    Abstract The identification of specific cytogenetic abnormalities by interphase fluorescence in situ hybridization (i-FISH) has become a routine procedure for prognostic stratification of multiple myeloma (MM) patients. In this study, the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in 229 newly diagnosed multiple myeloma patients was retrospectively analyzed. Results showed that del (17p), t(4;14), and 1q21 gain were adverse predictors of progression-free survival (PFS). Patients who carried these cytogenetic abnormalities were more likely to have more adverse biological parameters and lower response rate. Multivariate analysis showed that del (17p), t(4;14), and 1q21 gain were statistically independent predictors of PFS, whereas del (17p) was also adverse predictor of overall survival. Multiple coexisting cytogenetic abnormalities also had a negative correlation with PFS. Bortezomib-based therapy could improve the rate and depth of response in patients with t(4;14) translocation and 1q21 gain. Autologous stem cell transplantation could improve, but not overcome the adverse prognostic effect of high-risk cytogenetic abnormalities. These results demonstrate that MM patients with iFISH abnormalities, especially del (17p), are more likely to have a poor prognosis. PMID:27175647

  19. Multiple myeloma: from front-line to relapsed therapies.

    PubMed

    Moreau, Philippe; Touzeau, Cyrille

    2015-01-01

    Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade has been the introduction of the novel agents thalidomide, bortezomib, and lenalidomide as part of front-line treatment in both the transplant and nontransplant settings. However, disease relapse is inevitable for the majority of patients and myeloma typically recurs more aggressively with each relapse, eventually leading to the development of treatment-refractory disease. Several phase II and III trials have demonstrated the efficacy of recently approved agents in the setting of relapsed and relapsed and refractory MM, including pomalidomide and carfilzomib. Ixazomib, an oral proteasome inhibitor, and multiple other novel classes of agents are being investigated. These include monoclonal antibodies and histone deacetylase inhibitors, which may further add to the therapeutic armamentarium for this malignancy. Therefore, in a disease characterized by multiple relapses, the optimal sequencing of the different effective options is an important consideration in attempting to prolong survival. PMID:25993216

  20. Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma

    PubMed Central

    Yang, Ye; Shi, Jumei; Gu, Zhimin; Salama, Mohamed E; Das, Satyabrata; Wendlandt, Erik; Xu, Hongwei; Huang, Junwei; Tao, Yi; Hao, Mu; Franqui, Reinaldo; Levasseur, Dana; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2015-01-01

    Ibrutinib (Imbruvica®), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma (MM), yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population (SP) cells from human myeloma cell lines (HMCLs) and MM primary samples as surrogate fort the elusive multiple myeloma stem cell (MMSC), we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent up-regulation of key stemness genes (OCT4, SOX2, NANOG, MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, over-expression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered SP-derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than SP-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma. PMID:25589346

  1. The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective.

    PubMed

    Caers, Jo; Fernández de Larrea, Carlos; Leleu, Xavier; Heusschen, Roy; Zojer, Niklas; Decaux, Olivier; Kastritis, Efstathios; Minnema, Monique; Jurczyszyn, Artur; Beguin, Yves; Wäsch, Ralph; Palumbo, Antonio; Dimopoulos, Meletios; Mateos, Maria Victoria; Ludwig, Heinz; Engelhardt, Monika

    2016-03-01

    Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in

  2. Monoclonal antibody therapy in multiple myeloma: where do we stand and where are we going?

    PubMed

    Thanendrarajan, Sharmilan; Davies, Faith E; Morgan, Gareth J; Schinke, Carolina; Mathur, Pankaj; Heuck, Christoph J; Zangari, Maurizio; Epstein, Joshua; Yaccoby, Shmuel; Weinhold, Niels; Barlogie, Bart; van Rhee, Frits

    2016-01-01

    Multiple myeloma is a plasma cell malignancy that is characterized by refractory and relapsing course of disease. Despite the introduction of high-dose chemotherapy in combination with autologous stem cell transplantation and innovative agents such as proteasome inhibitors and immunomodulatory drugs, achieving cure in multiple myeloma is a challenging endeavor. In the last couple of years, enormous advances were made in implementing monoclonal antibody therapy in multiple myeloma. A large number of preclinical and clinical studies have been introduced successfully, demonstrating a safe and efficient administration of monoclonal antibodies in multiple myeloma. In particular, the application of monoclonal antibodies in combination with immunomodulatory drugs, proteasome inhibitors, corticosteroids or conventional chemotherapy seem to be promising and will expand the treatment arsenal for patients with multiple myeloma. PMID:26888183

  3. The effects of proteasome inhibitors on bone remodeling in multiple myeloma.

    PubMed

    Zangari, Maurizio; Suva, Larry J

    2016-05-01

    Bone disease is a characteristic feature of multiple myeloma, a malignant plasma cell dyscrasia. In patients with multiple myeloma, the normal process of bone remodeling is dysregulated by aberrant bone marrow plasma cells, resulting in increased bone resorption, prevention of new bone formation, and consequent bone destruction. The ubiquitin-proteasome system, which is hyperactive in patients with multiple myeloma, controls the catabolism of several proteins that regulate bone remodeling. Clinical studies have reported that treatment with the first-in-class proteasome inhibitor bortezomib reduces bone resorption and increases bone formation and bone mineral density in patients with multiple myeloma. Since the introduction of bortezomib in 2003, several next-generation proteasome inhibitors have also been used clinically, including carfilzomib, oprozomib, ixazomib, and delanzomib. This review summarizes the available preclinical and clinical evidence regarding the effect of proteasome inhibitors on bone remodeling in multiple myeloma. PMID:26947893

  4. Myeloma

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 30,330 % of All New Cancer Cases 1.8% Estimated Deaths in 2016 12,650 % of All Cancer ... of This Cancer : In 2013, there were an estimated 95,688 people living with myeloma in the ...

  5. Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment.

    PubMed

    Magen, Hila; Muchtar, Eli

    2016-08-01

    Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof. PMID:27493709

  6. Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

    PubMed Central

    Rajkumar, S. Vincent

    2014-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage. PMID:20425398

  7. A Very Rare Presentation of Multiple Myeloma: Unilateral Raccoon Eye

    PubMed Central

    Varım, Ceyhun; Ergenc, Hasan; Uyanık, Mehmet Sevki; Kaya, Tezcan; Nalbant, Ahmet; Karacaer, Cengiz; Sunu, Cenk; Tamer, Ali

    2015-01-01

    Multiple myeloma (MM), the second most common hematological malignancy, is caused by the accumulation of monoclonal plasma cells in bone marrow. It accounts for 10–15% of deaths from hematological malignancies and approximately 2% of deaths from cancer. The median age at presentation is 70 years old. The diagnosis is incidental in 30% of cases. MM is often discovered through routine blood screening with a large gap between the total protein and the albumin levels. Two thirds of patients complain of bone pain, especially lower back pain. MM could be diagnosed after a pathologic fracture occurs in one third of patients. Presentation with symptoms related to hyperviscosity, hypercalcemia and bleeding tendency could also be observed. A rare presentation of MM is peri-orbital ecchymotic lesion (raccoon eye). Here, we report a 64 years old, male patient presented with unilateral raccoon eye and high erythrocyte sedimentation rate (ESR) to internal medicine outpatient. The patient was referred to hematology outpatient and was diagnosed with multiple myeloma. PMID:27275266

  8. Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment

    PubMed Central

    Magen, Hila; Muchtar, Eli

    2016-01-01

    Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof. PMID:27493709

  9. New Strategies in the Treatment of Multiple Myeloma

    PubMed Central

    Munshi, Nikhil C.; Anderson, Kenneth C.

    2014-01-01

    Multiple myeloma (MM) is the second most common hematologic malignancy affecting terminally differentiated plasma cells. Although high-dose chemotherapy and autologous stem cell transplantation improved survival in younger patients, the natural history of MM has been changed with the availability of five new agents approved in last 10 years (thalidomide, bortezomib, lenalidomide, liposomal doxorubicin and carfilzomib). Despite this significant improvement in overall outcome, MM remains incurable in majority of patients prompting continued search for additional therapeutic options. Extensive molecular and genomic characterization of MM cells in its bone marrow milieu, which affects myeloma cell growth and survival, has provided number of novel drugable targets and pathways. Perturbation of protein catabolism at multiple levels has become an important target in MM. Similarly with improvements in monoclonal antibody generation and vaccine development along with identification of number of cell surface and cellular targets have led to development of various strategies including antibodies and antibody-drug conjugates which are under investigation both preclinically as well as in early clinical studies. We propose that eventually, molecularly-informed multi-agent combination therapies will be required to eliminate the MM cell clone for a long-term disease control. PMID:23515406

  10. Immunotherapy in Multiple Myeloma Using Cancer-Testis Antigens

    PubMed Central

    Ghafouri-Fard, Soudeh; Seifi-Alan, Mahnaz; Shamsi, Roshanak; Esfandiary, Ali

    2015-01-01

    Context: Multiple myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion of abnormal plasma cells in the bone marrow. It accounts for 10% of hematological malignancies. Although patients respond to a wide range of anticancer modalities, relapse occurs in a significant number of the cases. Immunotherapeutic approaches have been evolved to tackle this problem. Cancer-testis antigens CTAs as a group of tumor-associated antigens are appropriate targets for cancer immunotherapy as they have restricted expression pattern in normal tissues except for testis which is an immune-privileged site. Expression of these antigens has been assessed in different malignancies including MM. Evidence Acquisition: We performed a computerized search of the MEDLINE/PubMed databases with key words: multiple myeloma, cancer-testis antigen, and cancer stem cell and immunotherapy. Results: Several CTAs including NY-ESO-1, MAGE and GAGE family have been shown to be expressed in MM patients. Cellular and humoral immune responses against these antigens have been detected in MM patients. Conclusions: The frequent and high expression level of CTAs in MM patients shows that these antigens can be applied as cancer biomarkers as well as targets for immunotherapy in these patients. PMID:26634107

  11. A Very Rare Presentation of Multiple Myeloma: Unilateral Raccoon Eye.

    PubMed

    Varım, Ceyhun; Ergenc, Hasan; Uyanık, Mehmet Sevki; Kaya, Tezcan; Nalbant, Ahmet; Karacaer, Cengiz; Sunu, Cenk; Tamer, Ali

    2015-09-15

    Multiple myeloma (MM), the second most common hematological malignancy, is caused by the accumulation of monoclonal plasma cells in bone marrow. It accounts for 10-15% of deaths from hematological malignancies and approximately 2% of deaths from cancer. The median age at presentation is 70 years old. The diagnosis is incidental in 30% of cases. MM is often discovered through routine blood screening with a large gap between the total protein and the albumin levels. Two thirds of patients complain of bone pain, especially lower back pain. MM could be diagnosed after a pathologic fracture occurs in one third of patients. Presentation with symptoms related to hyperviscosity, hypercalcemia and bleeding tendency could also be observed. A rare presentation of MM is peri-orbital ecchymotic lesion (raccoon eye). Here, we report a 64 years old, male patient presented with unilateral raccoon eye and high erythrocyte sedimentation rate (ESR) to internal medicine outpatient. The patient was referred to hematology outpatient and was diagnosed with multiple myeloma. PMID:27275266

  12. Leukaemic Transformation of Multiple Myeloma in Post Chemotherapy Remission Phase.

    PubMed

    Agarwal, Palak; Nayak, Prachi; Singh, Premala Anthony; Mishra, Bal Krishna

    2016-04-01

    Plasma cell leukaemia is diagnosed when plasma cells are >20% in the peripheral blood. Plasma cell leukaemia may be present at the time of diagnosis (primary plasma cell leukaemia) or may evolve from multiple myeloma (secondary plasma cell leukaemia). We report case of a 62-year-old male who was diagnosed with multiple myeloma. He was treated with combination of prednisolone, melphalan and thalidomide. After 6 years he had Worsening of symptoms and also developed a scalp swelling. The swelling was diagnosed as plasmacytoma on fine needle aspiration cytology and confirmed on histopathology. Complete haemogram showed-Haemoglobin - 8g/dl, Total Leucocyte Count - 4300/μl, Differential leucocyte count - Neutrophil-40%, Lymphocyte-28%, Eosinophil-01%, Monocyte-10%, Atypical cells-21%, Platelet count- 1.5 lacs/μl. Peripheral blood showed rouleaux formation and plasma cells. Serum protein electrophoresis revealed an M spike (3.26 g/dl). So, patient was diagnosed as secondary plasma cell leukaemia. Weekly bortezomib and dexamethasone combination chemotherapy was given to the patient. Patient is on monthly follow up. Here we present a detailed case history of this patient. PMID:27190822

  13. Leukaemic Transformation of Multiple Myeloma in Post Chemotherapy Remission Phase

    PubMed Central

    Nayak, Prachi; Singh, Premala Anthony; Mishra, Bal Krishna

    2016-01-01

    Plasma cell leukaemia is diagnosed when plasma cells are >20% in the peripheral blood. Plasma cell leukaemia may be present at the time of diagnosis (primary plasma cell leukaemia) or may evolve from multiple myeloma (secondary plasma cell leukaemia). We report case of a 62-year-old male who was diagnosed with multiple myeloma. He was treated with combination of prednisolone, melphalan and thalidomide. After 6 years he had Worsening of symptoms and also developed a scalp swelling. The swelling was diagnosed as plasmacytoma on fine needle aspiration cytology and confirmed on histopathology. Complete haemogram showed-Haemoglobin - 8g/dl, Total Leucocyte Count – 4300/μl, Differential leucocyte count - Neutrophil-40%, Lymphocyte-28%, Eosinophil-01%, Monocyte-10%, Atypical cells-21%, Platelet count- 1.5 lacs/μl. Peripheral blood showed rouleaux formation and plasma cells. Serum protein electrophoresis revealed an M spike (3.26 g/dl). So, patient was diagnosed as secondary plasma cell leukaemia. Weekly bortezomib and dexamethasone combination chemotherapy was given to the patient. Patient is on monthly follow up. Here we present a detailed case history of this patient. PMID:27190822

  14. Emergence of therapy resistance in multiple myeloma in heterogeneous microenvironment

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Zhang, Qiucen; Lambert, Guillaume; Khin, Zayar; Silva, Ariosto; Gatenby, Robert; Kim, Hyungsung; Pourmand, Nader; Austin, Robert; Sturm, James

    2014-03-01

    Cancer chemotherapy resistance is always a problem that is not clear considering spatial heterogeneity in the tumor microenvironment. We culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region in a microfluidic device which mimics the tumor microenvironment with a chemotherapy drug gradient and microhabitats. Resistance of the multiple myeloma cells to doxorubicin emerged within two weeks. For the resistant cells evolved from the devices, the doxorubicin concentration that inhibits 50% of the controlled population increased by 16-fold than the parental cells. Whole transcriptome sequencing revealed that 39% of newly acquired mutational hotspots (the genes with more than 3 non-synonymous point mutation) of the resistant cells are involved in apoptosis and DNA repair. On the other hand, 40% of the non-mutated genes that are abnormally regulated in the resistant cells, are involved in metabolism, biosynthesis, and biomolecular transport. Among them, metabolic drug efflux pumps and oxidative stress scavengers are up-regulated to reduce the cytotoxicity of doxorubicin and further result in the resistance. The roles of the spatial drug gradients and microhabitats in rapid emergence of cancer resistance will be discussed. The project described was supported by the National Science Foundation and the National Cancer Institute.

  15. Multiple myeloma in a dog with multiple concurrent infectious diseases and persistent polyclonal gammopathy.

    PubMed

    Geigy, Caroline; Riond, Barbara; Bley, Carla Rohrer; Grest, Paula; Kircher, Patrick; Lutz, Hans

    2013-03-01

    A 12-year-old, spayed female, mixed-breed dog was presented for acute hematuria, stranguria, polyuria, and polydipsia, as well as lameness for 8 days. Previous medical history included treatment for infection with Ehrlichia canis, Anaplasma phagocytophilum, Leishmania infantum, and Dirofilaria immitis 6.5 years prior to presentation. Besides persistently increased antibody titers to E canis and A phagocytophilum, polyclonal gammopathy with a monoclonal spike and moderate hypercalcemia were observed. There was marked hematuria, and Staphylococcus aureus was cultured from urine. Two weeks after successful treatment of the urinary tract infection, radiographs showed an extensive destructive monostotic lesion of the right humerus. Cytologic examination of fine-needle aspirates of this lesion revealed a neoplastic round cell population suggestive of multiple myeloma. The dog was treated with melphalan and prednisolone for suspected multiple myeloma and doxycycline for suspected ehrlichiosis and anaplasmosis. Treatments lead to resolution of the clinical signs, hypercalcemia, and monoclonal gammopathy, and there was radiographic improvement of bone lesions; polyclonal gammopathy persisted. About one year after presentation the dog was still in clinical remission. This is a rare report of a dog with suspected multiple myeloma and a history of multiple chronic infectious diseases, suggesting that chronic infection and uncontrolled long-term stimulation of the immune system could contribute to the pathogenesis of multiple myeloma. PMID:23278475

  16. Non-Hodgkins lymphoma of maxilla: A rare entity

    PubMed Central

    Agrawal, M. G.; Agrawal, S. M.; Kambalimath, Deepashri H.

    2011-01-01

    Non-Hodgkin's lymphomas are a group of neoplasms that originate from the cells of the lymphoreticular system. Forty percent of non-Hodgkin's lymphomas arise from extra nodal sites. Non-Hodgkin's lymphomas detected primarily in the bone are quite rare, but among jaw lesions, they are more frequently present in the maxilla than in the mandible. There are no classical characteristic clinical features of lymphomas involving the jaw bones. Swelling, ulcer or discomfort may be present in the region of the lymphoma, or it may mimic a periapical pathology or a benign condition. Extranodal non-Hodgkins lymphoma of the maxilla could present as one of the early manifestation of detrimental diseases. Clinically these types of lymphoma can mimic an inflammatory endo-periodontal lesion with symptoms of pain and local discomfort. The greater the delay in diagnosis subsequently worsens the prognosis. A case of maxillary non-Hodgkin's lymphoma with an unusual presentation is discussed. PMID:22639517

  17. Immunoglobulin D Multiple Myeloma With Rapidly Progressing Renal Failure.

    PubMed

    Modi, Jwalant; Kamal, Jeanne; Eter, Ahmad; El-Sayegh, Suzanne; El-Charabaty, Elie

    2015-08-01

    Immunoglobulin D (IgD) multiple myeloma (MM) is a very rare form of myeloma affecting less than 2% of all myeloma patients. It has a multiorgan involvement with renal failure being the key feature. We present here a case of IgD MM in a 62-year-old white male, smoker with past medical history of hypertension, who presented to emergency department with complaints of lower abdominal pain, constipation and decreased urination. Physical exam was unremarkable. Laboratory investigation showed S.Cr 5.99 mg/dL, hemoglobin 8.7 g/dL and corrected S.Ca 10.6 mg/dL. Urine dipstick showed 100 protein and TP/Cr ratio was 23. Serology was positive for serum free lambda chain level of 8,947.6 mg/L as well with free κ/λ ratio < 0.01. The results of serum and urine electrophoresis and immunofixation were also supportive of diagnosis of IgD MM. IgD level was remarkably elevated (27,300 mg/L) too. CT scan of abdomen/pelvis was negative for obstructive uropathy. Skeletal survey showed a solitary lytic lesion in the iliac crest. His kidney function deteriorated next day requiring hemodialysis. The bone marrow biopsy was positive for plasma cell hypercellularity (70-80%) and flow cytometry showed 8% monoclonal IgD lambda plasma cells. The patient was started on bortezomib and dexamethasone and he underwent bone marrow transplant 6 months later. He is doing well hematologically now but he remains dialysis-dependent. IgD MM is a very rare disease affecting younger population with poor prognosis; patients often end up on hemodialysis despite better control of the hematological component. PMID:26124916

  18. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

    PubMed Central

    Abdi, Jahangir; Chen, Guoan; Chang, Hong

    2013-01-01

    In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma. PMID:24327604

  19. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

    PubMed

    Lohr, Jens G; Stojanov, Petar; Carter, Scott L; Cruz-Gordillo, Peter; Lawrence, Michael S; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A; Straussman, Ravid; Levy, Joan; Perkins, Louise M; Keats, Jonathan J; Schumacher, Steven E; Rosenberg, Mara; Getz, Gad; Golub, Todd R

    2014-01-13

    We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. PMID:24434212

  20. Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma

    PubMed Central

    Cagnetta, Antonia; Lovera, Davide; Grasso, Raffaella; Colombo, Nicoletta; Canepa, Letizia; Ballerini, Filippo; Calvio, Marino; Miglino, Maurizio; Gobbi, Marco; Lemoli, Roberto; Cea, Michele

    2015-01-01

    Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients. Here we will review mechanisms mediating genomic instability in MM cells with an emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair, telomere function and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the mechanisms by which genetic aberrations give rise to multiple pathogenic events required for myelomagenesis and conclude with a discussion of the clinical applications of these findings in MM patients. PMID:26579543

  1. Input of DNA microarrays to identify novel mechanisms in multiple myeloma biology and therapeutic applications

    PubMed Central

    Mahtouk, Karène; Hose, Dirk; De Vos, John; Moreaux, Jérôme; Jourdan, Michel; Rossi, Jean François; Rème, Thierry; Goldschmidt, Harmut; Klein, Bernard

    2007-01-01

    Multiple myeloma (MM) is a B cell neoplasia characterized by the proliferation of a clone of malignant plasma cells in the bone marrow. We review here the input of gene expression profiling (GEP) of myeloma cells and of their tumor microenvironment to develop new tumor classifiers, to better understand the biology of myeloma cells, to identify some mechanisms of drug sensitivity and resistance, to identify new myeloma growth factors, and to depict the complex interactions between tumor cells and their microenvironment. We discuss how these findings may improve the clinical outcome of this still incurable disease. PMID:18094409

  2. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

    PubMed Central

    Engelhardt, Monika; Terpos, Evangelos; Kleber, Martina; Gay, Francesca; Wäsch, Ralph; Morgan, Gareth; Cavo, Michele; van de Donk, Niels; Beilhack, Andreas; Bruno, Benedetto; Johnsen, Hans Erik; Hajek, Roman; Driessen, Christoph; Ludwig, Heinz; Beksac, Meral; Boccadoro, Mario; Straka, Christian; Brighen, Sara; Gramatzki, Martin; Larocca, Alessandra; Lokhorst, Henk; Magarotto, Valeria; Morabito, Fortunato; Dimopoulos, Meletios A.; Einsele, Hermann; Sonneveld, Pieter; Palumbo, Antonio

    2014-01-01

    Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B). PMID:24497560

  3. Recent advances in multiple myeloma: a Korean perspective.

    PubMed

    Hong, Junshik; Lee, Jae Hoon

    2016-09-01

    Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration's approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea's trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea. PMID:27604794

  4. Recent advances in multiple myeloma: a Korean perspective

    PubMed Central

    Hong, Junshik; Lee, Jae Hoon

    2016-01-01

    Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration’s approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea’s trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea. PMID:27604794

  5. Evaluation of immunomodulatory drugs in multiple myeloma: single center experience

    PubMed Central

    Ozkan, Melda Comert; Tombuloglu, Murat; Sahin, Fahri; Saydam, Guray

    2015-01-01

    Objective: Multiple myeloma (MM) comprises 1% of all cancers and 10% of hematologic malignancies and known as an incurable disease. The introduction of immunomodulatory drugs (IMiDs) has brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and relapsed/refractory MM patients. The aim of this study was to evaluate the relationship between response status and hematological parameters in patients with MM treated with thalidomide or lenalidomide. Methods: Sixty-eight patients who were treated with IMiDs in Ege University, School of Medicine, Department of Hematology, between 2005 and 2012, were evaluated, retrospectively. Results and Conclusion: We could not find any difference between the hematological parameters before and after the treatment neither with thalidomide nor lenalidomide. However, the heterogenity of our groups, the difference in treatment strategies and potential side effects would have an impact on this result. It is needed to perform prospective clinical trials to prove that whether correction of hematological parameters would reflect the response status in patients with myeloma that treated with IMiDs. PMID:27069758

  6. Updated Diagnostic Criteria and Staging System for Multiple Myeloma.

    PubMed

    Rajkumar, S Vincent

    2016-01-01

    There has been remarkable progress made in the diagnosis and treatment of multiple myeloma (MM). The median survival of the disease has doubled as a result of several new active drugs. These advances have necessitated a revision of the disease definition and staging of MM. Until recently, MM was defined by the presence of end-organ damage, specifically hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the clonal process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add three specific biomarkers that can be used to diagnose the disease in patients who did not have CRAB features: clonal bone marrow plasma cells greater than or equal to 60%, serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/L or higher, or more than one focal lesion on MRI. In addition, the definition was revised to allow CT and PET-CT to diagnose MM bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development of end-organ damage for patients who are at the highest risk. A new staging system has been developed that incorporates high-risk cytogenetic abnormalities in addition to standard laboratory markers of prognosis. PMID:27249749

  7. Clonal competition with alternating dominance in multiple myeloma

    PubMed Central

    Keats, Jonathan J.; Chesi, Marta; Egan, Jan B.; Garbitt, Victoria M.; Palmer, Stephen E.; Braggio, Esteban; Van Wier, Scott; Blackburn, Patrick R.; Baker, Angela S.; Dispenzieri, Angela; Kumar, Shaji; Rajkumar, S. Vincent; Carpten, John D.; Barrett, Michael; Fonseca, Rafael; Stewart, A. Keith

    2012-01-01

    Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection. PMID:22498740

  8. Nephrogenic diabetes insipidus--prodromal phase of multiple myeloma.

    PubMed

    Goranov, S; Hristova, I; Pencheva, K

    1994-01-01

    We report on a 65-year-old female patient with an A-kappa multiple myeloma diagnosed on the grounds of bone pain, anemia and extremely elevated erythrocyte sedimentation rate (ESR). Eight years prior to admission to the Clinic of Haematology the patient started to excrete a considerable amount of urine (4-6 liters per 24 hrs) with low specific gravity and to experience hardly controllable thirst. The disorder was specified in a specialised endocrinologic clinic as diabetes inspidus with ambiguous aetiology. The administered treatment with adiuretin had a small effect. A course of cyclophosphamide and glucocorticosteroids was started after myeloma was diagnosed--this had a considerable effect on the polyuria and polydipsia; the specific gravity of the urine increased. This effect, as well as the proven light chain proteinuria in the patient, leads to the interpretation of the early complaints of the patient as onset of the underlying disease in the form of nephrogenic diabetes insipidus--a rare light chain tubular syndrome. PMID:7601396

  9. Immunosurveillance and therapy of multiple myeloma are CD226 dependent.

    PubMed

    Guillerey, Camille; Ferrari de Andrade, Lucas; Vuckovic, Slavica; Miles, Kim; Ngiow, Shin Foong; Yong, Michelle C R; Teng, Michele W L; Colonna, Marco; Ritchie, David S; Chesi, Marta; Chesi, Martha; Bergsagel, P Leif; Hill, Geoffrey R; Smyth, Mark J; Martinet, Ludovic

    2015-05-01

    Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226-dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and CD8+ T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM. PMID:25893601

  10. Nuances in the Management of Older People With Multiple Myeloma.

    PubMed

    Pawlyn, Charlotte; Gay, Francesca; Larocca, Alessandra; Roy, Vivek; Ailawadhi, Sikander

    2016-06-01

    Multiple myeloma is a disease of the elderly, with about a third of patients at diagnosis older than 75 years of age. Yet, the population of elderly patients is heterogeneous: older patients are more likely to have comorbidities and frailties complicating both their initial diagnosis and subsequent management, but these are not consistent across the group. Furthermore, patients with comorbidities and frailty are generally underrepresented in clinical trials. Despite the survival of myeloma patients increasing following the introduction of novel agents, older patients continue to have worse outcomes with increased treatment-related toxicity. Treatment tolerability is not defined by age alone, rather a combination of age, physical function, cognitive function, and comorbidities. These factors all influence patients' tolerability of treatment and therefore treatment efficacy and should also be considered when reviewing the results of clinical trials. It is the nuances of determining how these factors interact that should influence initial treatment and ongoing management decisions and these will be discussed here. PMID:27038805

  11. IMWG consensus on maintenance therapy in multiple myeloma

    PubMed Central

    Durie, Brian G. M.; McCarthy, Philip; Palumbo, Antonio; San Miguel, Jésus; Barlogie, Bart; Morgan, Gareth; Sonneveld, Pieter; Spencer, Andrew; Andersen, Kenneth C.; Facon, Thierry; Stewart, Keith A.; Einsele, Hermann; Mateos, Maria-Victoria; Wijermans, Pierre; Waage, Anders; Beksac, Meral; Richardson, Paul G.; Hulin, Cyrille; Niesvizky, Ruben; Lokhorst, Henk; Landgren, Ola; Bergsagel, P. Leif; Orlowski, Robert; Hinke, Axel; Cavo, Michele; Attal, Michel

    2012-01-01

    Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established. PMID:22271445

  12. Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation

    PubMed Central

    Kirushnan, B.; Subbarao, B.; Prabhu, P.

    2016-01-01

    ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft. PMID:27512301

  13. Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation.

    PubMed

    Kirushnan, B; Subbarao, B; Prabhu, P

    2016-01-01

    ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft. PMID:27512301

  14. The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group.

    PubMed

    Terpos, E; Dimopoulos, M A; Sezer, O; Roodman, D; Abildgaard, N; Vescio, R; Tosi, P; Garcia-Sanz, R; Davies, F; Chanan-Khan, A; Palumbo, A; Sonneveld, P; Drake, M T; Harousseau, J-L; Anderson, K C; Durie, B G M

    2010-10-01

    Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future. PMID:20811404

  15. Clinical roundtable monograph. Emerging treatment options for relapsed and refractory multiple myeloma.

    PubMed

    Siegel, David S; Vij, Ravi; Jakubowiak, Andrzej J

    2011-04-01

    Multiple myeloma is a major hematologic malignancy, with an incidence of over 20,000 new diagnoses in the United States each year. Historically, a lack of effective therapies led to a poor patient prognosis. However, the introduction of new agents over the past decade has improved the treatment landscape for these patients, resulting in improved responses and prolonged progression-free and overall survival. Unfortunately, though, nearly all multiple myeloma patients go on to experience relapsed disease. The definition of this progression has also evolved with a growing understanding of the biology of multiple myeloma as well how the disease responds to these newer agents. While refractory multiple myeloma is considered to be a disease that does not respond to a particular therapy, the new definition of relapsed and refractory multiple myeloma includes patients who show disease progression within 60 days of discontinuing therapy. These new definitions are an important consideration when interpreting both previously reported and ongoing clinical trial data. Another major issue in the management of relapsed and refractory multiple myeloma is how to treat patients after they no longer respond to thalidomide, lenalidomide, and bortezomib. Regarding this issue, a number of novel agents are now in clinical trial development; many of them show indications of significant activity, even in heavily pretreated patients. Thus, the introduction of these newer agents has the potential to again make a major impact on multiple myeloma patient outcomes. PMID:21928467

  16. Does benzene cause multiple myeloma? An analysis of the published case-control literature

    SciTech Connect

    Bezabeh, S.; Engel, A.; Morris, C.B.; Lamm, S.H.

    1996-12-01

    Two case series and two epidemiological studies in the 1970s and 1980s suggested that benzene exposure might be a risk factor for multiple myeloma. An analysis has now been conducted of the published population-based and hospital-based case-control studies published through mid-1995 that permit examination of the relationship between multiple myeloma and benzene exposure or surrogates for benzene exposure. No increased association was found between multiple myeloma and benzene exposure or exposure to chemical groups that included benzene. The odds ratios from these analyses approximated 1.0. Exposures to petroleum products and employment in petroleum-related occupations did not appear to be risk factors for multiple myeloma. Cigarette smoking, as a surrogate of benzene exposure, was not found to be associated with multiple myeloma, while some studies of products of combustion described as {open_quotes}engine exhaust{close_quotes} did show a significant association with multiple myeloma. In toto, the population-based and hospital-based case-control literature indicated that benzene exposure was not a likely causal factor for multiple myeloma. 28 refs., 3 figs., 1 tab.

  17. Biclonal gammopathy in multiple myeloma: a case report.

    PubMed

    Bakta, I M; Sutarka, I N

    2000-05-01

    Monoclonal gammopathy is a group of B-cell disorders which result in the production of a specific and unique monoclonal immunoglobulin (M-component). Biclonal gammopathy is characterized by the simultaneous appearance of two different M-components. The incidence is about 1% of all monoclonal gammopathy. This paper reports on a 48-year-old male who had a chief complaint of back-pain beginning 7 months earlier. A physical examination was unremarkable, except for anemia and tenderness in the back. Hemoglobin was 5.4 g/dl, white blood cells 4.5 x 10(3)/microliter, platelets 157 x 10(3)/microliter, and reticulocytes 0.9%. Serum iron was 79 mg/dl, and total iron-binding capacity was 210 mg/dl. A blood smear showed the formation of rouleaux, but no plasma cells were found. Serum creatinine was 5.4 mg/dl, with a creatinine clearance of 18.1 ml/min. Serum electrolytes were normal except for serum calcium which was 14.4 mg/dl. The urinalysis showed strongly positive proteinuria (+2), with negative Bence Jones protein. Serum protein electrophoresis showed an increase and a spike pattern of beta-2 globulin (2.8 g/dl) and alpha-2 globulin (1.5 g/dl), with normal gamma globulin. By nephelometry technique, serum IgG was normal (1388 mg/dl), IgA was high (900 mg/dl), and IgM was also high (517 mg/dl). Advanced and extensive osteolytic lesions were found in the clavicle, ribs, skull, humerus, femur, and columna vertebralis. Plasma cells (myeloma cells) in bone marrow were 32%. The clinical diagnosis was multiple myeloma (biclonal gammopathy) stage IIIB (Durie and Salmon staging system). Clinical response was good after two series of conventional chemotherapy, with normal serum electrophoresis, decreasing serum creatinine and serum calcium. Based on the above data, the diagnosis of multiple myeloma with biclonal gammopathy was confirmed. This is a rare case with a combination of IgA and IgM M-components. PMID:10895208

  18. Abdominal actinomycosis with multiple myeloma: A case report

    PubMed Central

    ERCOLAK, VEHBI; PAYDAS, SEMRA; ERGIN, MELEK; ATES, BERNA T.; DUMAN, BERNA B.; GUNALDI, MERAL; AFSAR, CIGDEM U.

    2014-01-01

    Actinomycosis is a chronic suppurative infection, for which immune suppression is a predisposing factor. In unusual cases, this disease may present as an abdominal wall involvement simulating a soft tissue tumor as seen in the present case. The presented patient had no signs of trauma or surgical approach and the pathology was considered to be a primary abdominal wall actinomycosis. Preoperative diagnosis is difficult due to the nonspecific nature of clinical presentation, radiographic and laboratory findings. Surgery combined with antibiotic treatment is a curative approach for this relatively rare infection. Surgeons must be aware of this disease in order to ensure correct diagnosis and to prevent performing any unnecessary procedures. The present study describes a case of abdominal actinomycosis with multiple myeloma, together with a review of important points related to this disease. PMID:25202429

  19. Multiple myeloma developing in a patient with immune thrombocytopenia.

    PubMed

    Itoh, Toshio

    2016-05-01

    A female diagnosed as having immune thrombocytopenic purpura (ITP) was found to be simultaneously suffering from monoclonal gammopathy of undetermined significance (IgGλ). Urine Bence-Jones protein was negative. During the course, plasma cells accounted for 21.6% of the bone marrow. Based on these clinical features in our case, the second disease was diagnosed as multiple myeloma (MM). Both ITP and MM were successfully treated with corticosteroids, bortezomib, lenalidomide with dexamethasone and eltrombopag olamine. MM with ITP may show the following features: 1) the great majority are IgG types, 2) λ chain types show marked light chain predominance when these two diseases appear simultaneously, 3) κ chain types are predominant in the cases with MM followed by ITP, and 4) MM cases with ITP are more often seen in Japan. PMID:27263790

  20. Targeting SDF-1 in multiple myeloma tumor microenvironment.

    PubMed

    Bouyssou, Juliette M C; Ghobrial, Irene M; Roccaro, Aldo M

    2016-09-28

    Multiple myeloma (MM) is a type of B-cell malignancy that remains incurable to date. The bone marrow (BM) microenvironment plays a crucial role in MM progression. The chemokine SDF-1 (CXCL12) is an important actor of the BM microenvironment that has the ability to regulate numerous processes related to its malignant transformation during MM development. The activity of SDF-1 is mainly mediated by its specific receptor CXCR4, which is expressed at the surface of MM cells and various other BM cell types. Current treatments available for MM patients mainly target tumor cells but have limited effects on the BM microenvironment. In this context, SDF-1 and CXCR4 represent ideal targets for the normalization of the MM-supportive BM microenvironment. The present review focuses on the activity of SDF-1 in the MM BM microenvironment and the current efforts carried out to target the SDF-1/CXCR4 axis for treatment of MM. PMID:26655999

  1. A rare case of listeriosis, acute cholecystitis and multiple myeloma.

    PubMed

    Polanco, Thais O; Alothman, Sara; Depaz, Hector; Ramcharan, Alexius

    2016-01-01

    Listeria monocytogenes (LM) is an aerobic, motile, intracellular gram-positive bacterium. Most invasive systemic infections caused by LM are commonly seen in patients at both extremes of age, during pregnancy or in immunocompromised hosts. Common clinical manifestations of LM infection in immunocompromised adults are bacteremia, infections of central nervous system, such as meningitis, and self-limiting febrile gastroenteritis. Focal infections of listeria are rare, especially cholecystitis, with only few cases reported in the last 33 years. A 62-year-old man presented with multiple myeloma, cholecystitis and LM bacteremia. Due to prompt surgical treatment and antibiotics (amoxicillin plus clavulanic acid and gentamycin), this high-risk patient recovered without any complications. PMID:27170703

  2. Salvage Therapy of Multiple Myeloma: The New Generation Drugs

    PubMed Central

    Romano, Alessandra; Conticello, Concetta; Di Raimondo, Cosimo; Schinocca, Elena; La Fauci, Alessia; Parrinello, Nunziatina Laura; Chiarenza, Annalisa

    2014-01-01

    During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways. PMID:24967371

  3. Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma.

    PubMed

    Kubiczkova, Lenka; Pour, Ludek; Sedlarikova, Lenka; Hajek, Roman; Sevcikova, Sabina

    2014-06-01

    Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics. PMID:24712303

  4. Current strategies for treatment of relapsed/refractory multiple myeloma.

    PubMed

    Laubach, Jacob P; Voorhees, Peter M; Hassoun, Hani; Jakubowiak, Andrzej; Lonial, Sagar; Richardson, Paul G

    2014-02-01

    In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat. PMID:24471924

  5. A rare case of listeriosis, acute cholecystitis and multiple myeloma

    PubMed Central

    Polanco, Thais O.; Alothman, Sara; Depaz, Hector; Ramcharan, Alexius

    2016-01-01

    Listeria monocytogenes (LM) is an aerobic, motile, intracellular gram-positive bacterium. Most invasive systemic infections caused by LM are commonly seen in patients at both extremes of age, during pregnancy or in immunocompromised hosts. Common clinical manifestations of LM infection in immunocompromised adults are bacteremia, infections of central nervous system, such as meningitis, and self-limiting febrile gastroenteritis. Focal infections of listeria are rare, especially cholecystitis, with only few cases reported in the last 33 years. A 62-year-old man presented with multiple myeloma, cholecystitis and LM bacteremia. Due to prompt surgical treatment and antibiotics (amoxicillin plus clavulanic acid and gentamycin), this high-risk patient recovered without any complications. PMID:27170703

  6. Deep Response in Multiple Myeloma: A Critical Review

    PubMed Central

    Fulciniti, Mariateresa; Munshi, Nikhil C.; Martinez-Lopez, Joaquin

    2015-01-01

    Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged as one of the most relevant prognostic factors in MM and should be included in a new definition of complete response (CR). Although further standardization is still required, MRD monitoring should be applied in prospective clinical trials as a sensitive tool to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings, and implement individualized therapy-monitoring approaches. Here, we review current definition of deep response in MM, advantages and limitations of current MRD assessment assays, clinical evidences for MRD monitoring as a prognostic tool for therapeutic decisions in MM, and challenges to develop uniform criteria for MRD monitoring. PMID:26783530

  7. Mesenteric amyloid deposition as the initial presentation of multiple myeloma

    PubMed Central

    Asadi, Mehrnaz

    2011-01-01

    Despite many recent progresses in diagnostic modalities, occasionally the initial manifestation of the diseases may be misleading. Therefore, to consider the uncommon presentations of prevalent diseases may be of help. Plasma-cell dyscrasia is one of the most well-known haematological malignancies. Clonal expansion of plasma cells results in diverse clinical findings, such as renal failure, lytic bone lesion, anaemia, hyperviscosity syndrome and so forth. However, this disease entity rarely presents with abdominal mass due to mesenteric amyloid deposition. Here we report a case of a 53-year-old Iranian woman who presented with a 4-month history of abdominal pain and fullness; she was finally found to suffer from small bowel mesenteric amyloidosis in the context of multiple myeloma. PMID:22714598

  8. [Molecular Mechanism and Malignant Clonal Evolution of Multiple Myeloma].

    PubMed

    Ding, Fei; Zhu, Ping; Wu, Xue-Qiang

    2015-10-01

    Almost all patients with multiple myeloma (MM) have chromosomal translocation which can result in genetic variation. There are mainly five types of chromosomal translocations, involving the IGH gene translocation to 11q13 (CCND1), 4p16 (FGFR/MMSET), 16q23 (MAF), 6p21 (CCND3) and 20q11 (MAFB). It is possible that all IGH translocations converge on a common cell cycle signal pathway. Some MM develops through a multistep transformation from monoclonal gammopathy of undetermined significance (MGUS) to smoldering MM (SMM) and eventually to MM and plasma cell leukemia (PCL). Similarly to what Darwin proposed in the mid-19th century-random genetic variation and natural selection in the context of limited resources, MM clonal evolution follow branching and nonlinear mode. The failure of MM treatment is usually related with the minimal subclone which is hardly found at newlydiagnosed. PMID:26524068

  9. Monoclonal antibody-based immunotherapy for multiple myeloma.

    PubMed

    Danylesko, Ivetta; Beider, Katia; Shimoni, Avichai; Nagler, Arnon

    2012-09-01

    Multiple myeloma (MM) is a life-threatening hematological malignancy. High-dose chemotherapy followed by autologous stem cell transplantation is a relatively effective treatment, but disease recurrence remains a major obstacle. Allogeneic transplantation may result in durable responses and cure due to antitumor immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. This review will focus on MM antigens and their specific antibodies. These monoclonal antibodies are an attractive therapeutic tool for MM humoral immunotherapy, with most promising preclinical results. PMID:23046236

  10. A practical review on carfilzomib in multiple myeloma.

    PubMed

    Muchtar, Eli; Gertz, Morie A; Magen, Hila

    2016-06-01

    Carfilzomib, a second-generation proteasome inhibitor, has been increasingly used in relapsed/refractory multiple myeloma (MM) since its approval by the American food and drug administration (FDA) in the summer of 2012. The drug is active as a single agent and in combination with other antimyeloma agents. As a result of its efficacy and safety in the relapsed/refractory setting, carfilzomib is being evaluated in patients with newly diagnosed MM as well as in high-risk smoldering MM. This review will give a comprehensive summary of the drug, including its mechanism of action, the evaluated doses and schedules as well as a summary of the main clinical trials in the relapsed/refractory and newly diagnosed settings. A focus will be placed upon certain subgroups of interest as well as a description of the toxicity associated with carfilzomib use and a clinical perspective on toxicity management. PMID:26893241

  11. A rare case of multiple myeloma initially presenting with pseudoachalasia.

    PubMed

    Lazaraki, Georgia; Nakos, Andreas; Katodritou, Eirini; Pilpilidis, Ioannis; Tarpagos, Anestis; Katsos, Ioannis

    2009-01-01

    Pseudoachalasia is a rare clinical entity with clinical, radiographic, and manometric features often indistinguishable from achalasia. Primary adenocarcinomas arising at the gastroesophageal junction or a tumor of the distal esophagus are the most frequent causes of pseudoachalasia. Rarely, processes other than esophagogastric cancers including chronic idiopathic intestinal pseudo-obstruction, amyloidosis, sarcoidosis, Chagas' disease, vagotomy, antireflux surgery, pancreatic pseudocysts, von Recklinghausen's neuroinomatosis, gastrointestinal stromal tumor, and other malignancies and rare genetic syndromes, may lead to the development of pseudoachalasia. Secondary achalasia is extremely rare, with less than 100 cases reported in the literature so far. Gastrointestinal manifestations in primary or secondary amyloidosis include abdominal pain, diarrhea, constipation, malabsorption, obstruction, motility disturbance, intestinal infarction, perforation, and hemorrhage; however, gastrointestinal tract involvement is asymptomatic in most instances. We present here a rare case of multiple myeloma initially presenting with dysphagia because of esophageal amyloidosis and manometric findings typical of achalasia. PMID:19207546

  12. Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib.

    PubMed

    Mitsiades, Constantine S; Hideshima, Teru; Chauhan, Dharminder; McMillin, Douglas W; Klippel, Steffen; Laubach, Jacob P; Munshi, Nikhil C; Anderson, Kenneth C; Richardson, Paul G

    2009-04-01

    The successful clinical development of thalidomide, bortezomib, and lenalidomide not only transformed the therapeutic management of multiple myeloma (MM) but also catalyzed a renewed interest in the development of additional classes of novel agents for this disease. This review focuses on a series of new therapeutics that have shown promising preclinical results, as well as encouraging safety profiles and early evidence of anti-MM activity in clinical studies, either alone or in combination with other, conventional or novel, anti-MM treatments. These agents include second-generation proteasome inhibitors and immunomodulatory agents, as well as members of other therapeutic classes, such as histone deacetylase inhibitors (HDAC), heat shock protein 90 (Hsp90) inhibitors, and the alkylphospholipid Akt inhibitor perifosine. PMID:19389500

  13. Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

    PubMed Central

    Yang, Wen-Chi; Lin, Sheng-Fung

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID:26649299

  14. Image-Guided Total-Marrow Irradiation Using Helical Tomotherapy in Patients With Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C. Rosenthal, Joseph; Liu An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

    2009-01-01

    Purpose: Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Methods and Materials: Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. Results: For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. Conclusions: This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.

  15. RBQ3 participates in multiple myeloma cell proliferation, adhesion and chemoresistance.

    PubMed

    Liu, Hong; Ding, Linlin; Shen, Yaodong; Zhong, Fei; Wang, Qiru; Xu, Xiaohong

    2016-10-01

    Cell adhesion mediated drug resistance (CAM-DR) is a major factor that impedes the effect of chemotherapy in multiple myeloma (MM). RBQ3, which is a RB-binding protein, played a crucial role in cell cycle process. Here, we reported that RBQ3 expression was increased gradually during the proliferation process of myeloma cells. Knocking down of RBQ3 resulted in cell cycle arrest in G1 phase and increased myeloma cells adherent to fibronectin or bone marrow stromal cells (BMSCs). Furthermore, silencing of RBQ3 reduced sensitivity to chemotherapeutic drugs in myeloma cell lines adherent to BMSCs and reduced two apoptotic marker proteins cleaved caspase-3 and cleaved PARP expression. Besides, we also found that RBQ3 participated in MAPK/ERK signal transduction pathway. In summary, these results may shed new insights into the role of RBQ3 in the development of multiple myeloma. PMID:27189701

  16. Risk of multiple myeloma in a case-spouse study.

    PubMed

    Andreotti, Gabriella; Katz, Michael; Hoering, Antje; Van Ness, Brian; Crowley, John; Morgan, Gareth; Hoover, Robert N; Baris, Dalsu; Durie, Brian

    2016-06-01

    This study examined lifestyle, occupation, medical history and medication use with multiple myeloma risk in a case-spouse study (481 patients, 351 spouses). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using logistic regression. Compared to spouse controls, cases were more likely to have a family history of multiple myeloma (OR = 2.8, 95% CI = 1.2-6.4) and smoked cigarettes (OR = 1.7, 95% CI = 1.2-2.5), but less likely to have consumed alcohol (OR = 0.6, 95% CI = 0.4-0.9). Nurse/health practitioners (OR = 2.8, 95% CI = 1.3-6.2) and production workers (OR = 3.7, 95% CI = 1.0-13.7) had significantly increased risks; and some occupations linked to diesel exhaust had elevated, but non-significant, risks. History of herpes simplex (OR = 1.7, 95% CI = 1.2-2.4), shingles (OR = 1.7, 95% CI = 1.1-2.7), sexually transmitted diseases (OR = 2.0, 95% CI = 1.0-3.7) and medication allergies (OR = 1.7, 95% CI = 1.2-2.4) were associated with higher risks. Use of angiotensin-converting enzyme inhibitors, anti-convulsants, antidepressants, statins and diuretics were associated with reduced risks. The results are consistent with previous population-based studies and support the utility of patient databanks and spouse controls as a resource in epidemiologic research. PMID:26422532

  17. A preclinical assay for chemosensitivity in multiple myeloma

    PubMed Central

    Khin, Zayar P.; Ribeiro, Maria L. C.; Jacobson, Timothy; Hazlehurst, Lori; Perez, Lia; Baz, Rachid; Shain, Kenneth; Silva, Ariosto S.

    2013-01-01

    Accurate preclinical predictions of the clinical efficacy of experimental cancer drugs are highly desired but often haphazard. Such predictions might be improved by incorporating elements of the tumor microenvironment in preclinical models by providing a more physiological setting. In generating improved xenograft models, it is generally accepted that the use of primary tumors from patients are preferable to clonal tumor cell lines. Here we describe an interdisciplinary platform to study drug response in multiple myeloma (MM), an incurable cancer of the bone marrow. This platform uses microfluidic technology to minimize the number of cells per experiment, while incorporating 3D extracellular matrix and mesenchymal cells derived from the tumor microenvironment. We used sequential imaging and a novel digital imaging analysis algorithm to quantify changes in cell viability. Computational models were used convert experimental data into dose-exposure-response "surfaces" which offered predictive utility. Using this platform, we predicted chemosensitivity to bortezomib and melphalan, two clinical MM treatments, in 3 MM cell lines and 7 patient-derived primary MM cell populations. We also demonstrated how this system could be used to investigate environment-mediated drug resistance and drug combinations that target it. This interdisciplinary preclinical assay is capable of generating quantitative data that can be used in computational models of clinical response, demonstrating its utility as a tool to contribute to personalized oncology. Major Findings By designing an experimental platform with the specific intent of generating experimental parameters for a computational clinical model of personalized therapy in multiple myeloma, while taking in consideration the limitations of working with patient primary cells, and the need to incorporate elements of the tumor microenvironment, we have generated patient-individualized estimations of initial response and time to relapse

  18. Immunohistochemical evaluation of CD20 expression in patients with multiple myeloma

    PubMed Central

    Yavasoglu, Irfan; Sargin, Gokhan; Kadikoylu, Gurhan; Doger, Firuzan Kacar; Bolaman, Zahit

    2014-01-01

    Objective CD20 expression was reported at different rates in patients with multiple myeloma. The importance of this B-cell antigen for plasma cells is still unknown. This study aimed to investigate CD20 expression of myeloma cells in bone marrow, and any relationship between the stage of disease, isotype and clinical features. Methods Sixty-one patients who were admitted to the hematology clinic of the Adnan Menderes Medical School with the diagnosis of multiple myeloma according to the criteria of the “International Myeloma Working Group” were enrolled in this study. Age, gender, Durie–Salmon stage, history of autologous hematopoietic stem cell transplantation, and the distribution pattern and positivity of CD20 expression on multiple myeloma cells in bone marrow were evaluated. The Mann–Whitney U and chi-square tests were used for statistical analysis with a p-value < 0.05 being accepted as statistically significant. Results Thirty patients (48.9%) had positive scores for CD20 with the distribution pattern being most likely interstitial in 55.6% of the cases. There was no statistically significant difference between immunohistochemical positivity for CD20 expression on multiple myeloma cells, immunoglobulin type, and the stage of disease. Conclusion The combination of immunohistochemical studies with flow cytometry may reveal the importance of CD20 positivity in patients with multiple myeloma more clearly. PMID:25638765

  19. Genetic events in the pathogenesis of multiple myeloma.

    PubMed

    Chng, W J; Glebov, O; Bergsagel, P L; Kuehl, W M

    2007-12-01

    The genetics of myeloma has been increasingly elucidated in recent years. Recurrent genetic events, and also biologically distinct and clinically relevant genetic subtypes of myeloma have been defined. This has facilitated our understanding of the molecular pathogenesis of the disease. In addition, some genetic abnormalities have proved to be highly reproducible prognostic factors. With the expanding therapeutic armamentarium, it is time to include genetic assessment as part of clinical evaluation of myeloma patients to guide management. In this review we examine the role of various genetic abnormalities in the molecular pathogenesis of myeloma, and the use of such abnormalities in disease classification, prognosis and clinical management. PMID:18070707

  20. Genetic events in the pathogenesis of multiple myeloma

    PubMed Central

    Chng, W. J.; Glebov, O.; Bergsagel, P.L.; Kuehl, W. M.

    2007-01-01

    The genetics of myeloma has been increasingly elucidated in recent years. Recurrent genetic events, and also biologically distinct and clinically relevant genetic subtypes of myeloma have been defined. This has facilitated our understanding of the molecular pathogenesis of the disease. In addition, some genetic abnormalities have proved to be highly reproducible prognostic factors. With the expanding therapeutic armamentarium, it is time to include genetic assessment as part of clinical evaluation of myeloma patients to guide management. In this review we examine the role of various genetic abnormalities in the molecular pathogenesis of myeloma, and the use of such abnormalities in disease classification, prognosis and clinical management. PMID:18070707

  1. Association of response endpoints with survival outcomes in multiple myeloma

    PubMed Central

    Lonial, S; Anderson, K C

    2014-01-01

    Since the introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, more patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. These improvements have afforded more robust analyses of the relationship between response and survival. Generally, these studies have demonstrated that improvements in the quality of response across all stages of treatment are associated with better disease control and longer survival. Thus, achievement of maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, quality of life and patient preferences. In select patients, achievement of a lesser response may be adequate to prolong survival, and attempts to treat these patients to a deeper response may place them at unnecessary risk without significant benefit. Maintenance therapy has been shown to improve the quality of response and disease control and, in some studies, survival. Studies support maintenance therapy for high-risk patients as a standard of care, and there are emerging data supporting maintenance therapy in standard-risk patients to improve progression-free and possibly overall survival. Multidrug regimens combining a proteasome inhibitor and an IMiD have shown exceptional response outcomes with acceptable increases in toxicity in both the frontline and salvage settings, and are becoming a standard treatment approach. Moving forward, the use of immunophenotypic and molecular response criteria will be essential in better understanding the impact of highly active and continuous treatment regimens across myeloma patient populations. Future translational studies will help to develop antimyeloma agents to their fullest potential. The introduction of novel targeted therapies, including the IMiD pomalidomide and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), will provide

  2. Association of response endpoints with survival outcomes in multiple myeloma.

    PubMed

    Lonial, S; Anderson, K C

    2014-02-01

    Since the introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, more patients with multiple myeloma are achieving deep, durable responses and disease control, and are living longer. These improvements have afforded more robust analyses of the relationship between response and survival. Generally, these studies have demonstrated that improvements in the quality of response across all stages of treatment are associated with better disease control and longer survival. Thus, achievement of maximal response should be strongly considered, particularly in the frontline setting, but must also be balanced with tolerability, quality of life and patient preferences. In select patients, achievement of a lesser response may be adequate to prolong survival, and attempts to treat these patients to a deeper response may place them at unnecessary risk without significant benefit. Maintenance therapy has been shown to improve the quality of response and disease control and, in some studies, survival. Studies support maintenance therapy for high-risk patients as a standard of care, and there are emerging data supporting maintenance therapy in standard-risk patients to improve progression-free and possibly overall survival. Multidrug regimens combining a proteasome inhibitor and an IMiD have shown exceptional response outcomes with acceptable increases in toxicity in both the frontline and salvage settings, and are becoming a standard treatment approach. Moving forward, the use of immunophenotypic and molecular response criteria will be essential in better understanding the impact of highly active and continuous treatment regimens across myeloma patient populations. Future translational studies will help to develop antimyeloma agents to their fullest potential. The introduction of novel targeted therapies, including the IMiD pomalidomide and the proteasome inhibitors carfilzomib and ixazomib (MLN9708), will provide

  3. European Perspective on Multiple Myeloma Treatment Strategies in 2014

    PubMed Central

    Sonneveld, Pieter; Davies, Faith; Bladé, Joan; Boccadoro, Mario; Cavo, Michele; Morgan, Gareth; de la Rubia, Javier; Delforge, Michel; Dimopoulos, Meletios; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Moreau, Philippe; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Hajek, Roman; Sondergeld, Pia; Palumbo, Antonio

    2014-01-01

    The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on “fitness,” with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results. PMID:25063227

  4. European perspective on multiple myeloma treatment strategies in 2014.

    PubMed

    Ludwig, Heinz; Sonneveld, Pieter; Davies, Faith; Bladé, Joan; Boccadoro, Mario; Cavo, Michele; Morgan, Gareth; de la Rubia, Javier; Delforge, Michel; Dimopoulos, Meletios; Einsele, Hermann; Facon, Thierry; Goldschmidt, Hartmut; Moreau, Philippe; Nahi, Hareth; Plesner, Torben; San-Miguel, Jesús; Hajek, Roman; Sondergeld, Pia; Palumbo, Antonio

    2014-08-01

    The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results. PMID:25063227

  5. Treatment Options for Childhood Non-Hodgkin Lymphoma

    MedlinePlus

    ... Past treatment for cancer and having a weakened immune system affect the risk of having childhood non-Hodgkin ... or human immunodeficiency virus (HIV). Having a weakened immune system after a transplant or from medicines given after ...

  6. Treatment Option Overview (Childhood Non-Hodgkin Lymphoma)

    MedlinePlus

    ... Past treatment for cancer and having a weakened immune system affect the risk of having childhood non-Hodgkin ... or human immunodeficiency virus (HIV). Having a weakened immune system after a transplant or from medicines given after ...

  7. Treatment Option Overview (Adult Non-Hodgkin Lymphoma)

    MedlinePlus

    ... with HIV infection. Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin ... the cancer cells to normal cells of the immune system. Other tests and procedures may be done depending ...

  8. What Are the Risk Factors for Non-Hodgkin Lymphoma?

    MedlinePlus

    ... suggested that chemicals such as benzene and certain herbicides and insecticides (weed- and insect-killing substances) may ... higher risk of developing non-Hodgkin lymphoma. The human immunodeficiency virus (HIV) can also weaken the immune ...

  9. [Histone deacetylase inhibitors: new synergistic third-line option in multiple myeloma].

    PubMed

    Stegmann, Danielle A

    2016-04-01

    Despite advances in drug therapy of the orphan disease multiple myeloma, patients relapse or become refractory to first-line therapy, and the disease remains incurable. Therefore, histone deacetylase inhibitors have emerged as a new class of anti-myeloma drugs, with synergistic results on progression free survival when given in combination to current first-line therapy. Histone deacetylase inhibitors influence gene expression of target genes. Based on results of an extensive multicenter phase III trial, panobinostat was approved by the FDA in February 2015 as the first histone deacetylase inhibitor for the treatment of multiple myeloma. In Europe, panobinostat received marketing authorization by August 2015. PMID:27209894

  10. Second cancers following non-Hodgkin's lymphoma

    SciTech Connect

    Travis, L.B.; Curtis, R.E.; Boice, J.D. Jr.; Hankey, B.F.; Fraumeni, J.F. Jr. )

    1991-04-01

    The risk of second malignancies following non-Hodgkin's lymphoma (NHL) was estimated in 29,153 patients diagnosed with NHL between 1973 and 1987 in one of nine areas participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Compared with the general population, NHL patients were at a significantly increased risk of developing second cancers (observed/expected (O/E) = 1.18; O = 1231). The O/E ratio increased significantly with time to reach 1.77 in 10-year survivors. Significant excesses were noted for acute nonlymphocytic leukemia (O/E = 2.88), cancers of the bladder (O/E = 1.30), kidney (O/E = 1.47), and lung (O/E = 1.57), malignant melanoma (O/E = 2.44), and Hodgkin's disease (O/E = 4.16). Chemotherapy appeared related to subsequent acute nonlymphocytic leukemia (ANLL) and bladder cancer. Radiation therapy was associated with ANLL and possibly cancers of the lung, bladder, and bone. Malignant melanoma was not clearly related to initial NHL treatment.

  11. Cellular telephones and non-Hodgkin lymphoma.

    PubMed

    Linet, Martha S; Taggart, Theresa; Severson, Richard K; Cerhan, James R; Cozen, Wendy; Hartge, Patricia; Colt, Joanne

    2006-11-15

    Dramatic increase in hand-held cellular telephone use since the 1980s and excess risk of lymphoproliferative malignancies associated with radio-frequency radiation (RFR) exposures in epidemiological and experimental studies motivated assessment of cellular telephones within a comprehensive US case-control investigation of non-Hodgkin lymphoma (NHL). A questionnaire ascertained cellular telephone use in 551 NHL cases and 462 frequency-matched population controls. Compared to persons who had never used cellular telephones, risks were not increased among individuals whose lifetime use was fewer than 10 (odds ratio (OR) = 0.9, 95% confidence intervals (CI): 0.6, 1.3), 10-100 (OR = 1.0, 95 % CI: 0.7, 1.5) or more than 100 times (e.g., regular users, OR = 0.9, 95% CI: 0.6, 1.4). Among regular users compared to those who had never used hand-held cellular telephones, risks of NHL were not significantly associated with minutes per week, duration, cumulative lifetime or year of first use, although NHL was non-significantly higher in men who used cellular telephones for more than 8 years. Little evidence linked use of cellular telephones with total, diffuse large B-cell lymphoma or follicular NHL. These findings must be interpreted in the context of less than 5% of the population reporting duration of use of 6 or more years or lifetime cumulative use of 200 or more hours. PMID:16894556

  12. Non-Hodgkin Lymphoma in Children.

    PubMed

    Sandlund, John T

    2015-09-01

    The non-Hodgkin lymphomas (NHLs) of childhood include high-grade mature B cell lymphoma [Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphoma (PMLBCL)], anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma (LL). The prognosis for children with NHL is generally excellent, although there are some higher risk groups. In this regard, PMLBCL is generally associated with a poorer outcome than BL or DLBCL of comparable stage. The long-term event-free survival for children with ALCL is approximately 70 %. Novel biological agents, including those that target CD-30 or ALK, may hold promise for improving treatment results. Children with LL are treated with regimens derived from those used to treat acute lymphoblastic leukemia (ALL). Recent biological study of LL may provide insights into revising treatment stratification. The challenge in pediatric NHL, a group that already has a relatively good prognosis, is to improve treatment outcome without increasing concerning late effects. PMID:26174528

  13. Endogenous Panophthalmitis in a case of Multiple Myeloma and Diabetes Mellitus

    PubMed Central

    Nayak, Madhurima K.

    2016-01-01

    Multiple myeloma cripples the human body in many ways, one of them being decreased immunity. Infections occurring spontaneously can increase the morbidity. We report a case of an elderly lady with multiple myeloma on treatment and uncontrolled diabetes, who developed loss of vision, swelling and redness of left eye of 4 days duration. There was no history of injury or entry of a foreign body. She also had left arm cellulitis. Ocular examination revealed visual acuity of 6/36 in right eye and no perception of light in left eye. Anterior segment of the right eye was insignificant while the left eye showed features suggestive of panophthalmitis. B scan revealed choroidal detachment and confirmed panophthalmitis. She underwent evisceration of the left eye. The cause of spontaneous infections is an immunocompromised state due to multiple myeloma and uncontrolled diabetes. This case report highlights the propensity of multiple myeloma to cause infections of the eye debilitating enough to cause severe visual morbidity.

  14. Simultaneous bilateral spontaneous pneumothorax in a patient with recurrent, extraosseous multiple myeloma

    PubMed Central

    Peters, F; Cathomas, G; Rothen, M; Thurnheer, R; Rutishauser, J

    2003-01-01

    SBSP is a rare condition and may be caused by trauma, parenchymal lung disease, infections, or neoplasms. This is the first report of SBSP caused by pleuropulmonary infiltration of multiple myeloma. PMID:12612329

  15. Pomalidomide Plus Low-Dose Dexamethasone Improves Survival for Patients with Multiple Myeloma

    MedlinePlus

    ... Patients with Multiple Myeloma Summary Results from a randomized phase III trial show that the combination of ... condition of accelerated approval for the drug. That randomized phase III clinical trial ( CC-4047-MM-007 ) ...

  16. Comparison of bone scintigraphy and radiography in multiple myeloma. [/sup 99m/Tc-phosphate complexes

    SciTech Connect

    Woolfenden, J.M.; Pitt, M.J.; Durie, B.G.M.; Moon, T.E.

    1980-03-01

    Radionuclide images and skeletal radiographs of 51 patients with multiple myeloma were compared to assess the sensitivity of scintigraphy in detecting radiographically evident disease. Comparable studies were available for 562 sites. The radionuclide image was relatively insensitive in detecting myeloma; it failed to show radiographically evident disease or underestimated its extent at 27% of the sites. On a limited number of serial images there were 7 sites at which a scintigraphic abnormality preceded the radiographic abnormality. No definite correlation was found between scintigraphic findings and hematologic parameters of myeloma activity. Although the radionuclide image may demonstrate a few sites of myeloma before the radiograph, radiography remains the primary method of evaluating skeletal involvement by myeloma.

  17. Incidence rates of classical Kaposi's sarcoma and multiple myeloma do not correlate.

    PubMed

    Hjalgrim, H; Frisch, M; Melbye, M

    1998-08-01

    We compared population-based incidence rates for classical Kaposi's sarcoma and multiple myeloma. Neither for men (Spearman's rank correlation coefficient (r) = 0.01, P = 0.97, 13 pairs) nor for women (r = 0.24, P = 0.42, 13 pairs) did the incidences of the two conditions correlate. This absence of correlation does not support the hypothesis that Kaposi's sarcoma and multiple myeloma share a common aetiology, such as HHV-8. PMID:9703293

  18. ESRD due to Multiple Myeloma in the United States, 2001-2010.

    PubMed

    Reule, Scott; Sexton, Donal J; Solid, Craig A; Chen, Shu-Cheng; Foley, Robert N

    2016-05-01

    Although management of multiple myeloma has changed substantially in the last decade, it is unknown whether the burden of ESRD due to multiple myeloma has changed, or whether survival of patients with multiple myeloma on RRT has improved. Regarding ESRD due to multiple myeloma necessitating RRT in the United States, we evaluated temporal trends between 2001 and 2010 for demography-adjusted incidence ratios, relative to rates in 2001-2002, and mortality hazards from RRT initiation, relative to hazards in 2001-2002. In this retrospective cohort study, we used the US Renal Data System database (n=1,069,343), 2001-2010, to identify patients with ESRD due to multiple myeloma treated with RRT (n=12,703). Demography-adjusted incidence ratios of ESRD from multiple myeloma decreased between 2001-2002 and 2009-2010 in the overall population (demography-adjusted incidence ratio 0.82; 95% confidence interval, 0.79 to 0.86) and in most demographic subgroups examined. Mortality rates were 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of RRT, respectively, compared with 32.3, 20.6, and 21.3 in matched controls without multiple myeloma. Unadjusted mortality hazards ratios declined monotonically after 2004 to a value of 0.72; 95% confidence interval, 0.67 to 0.77 in 2009-2010, and declines between 2001-2002 and 2008-2009 were observed (P<0.05) in most demographic subgroups examined. Findings were similar when adjustment was made for demographic characteristics, comorbidity markers, and laboratory test values. These data suggest the incidence of RRT from multiple myeloma in the United States has decreased in the last decade, and clinically meaningful increases in survival have occurred for these patients. PMID:26516209

  19. Multiple myeloma in the very elderly patient: challenges and solutions

    PubMed Central

    Willan, John; Eyre, Toby A; Sharpley, Faye; Watson, Caroline; King, Andrew J; Ramasamy, Karthik

    2016-01-01

    Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life. PMID:27143866

  20. NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

    PubMed Central

    Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) – not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma. PMID:25230277

  1. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

    PubMed Central

    Rosean, Timothy R.; Tompkins, Van S.; Tricot, Guido; Holman, Carol J.; Olivier, Alicia K.; Zhan, Fenghuang; Janz, Siegfried

    2014-01-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM. PMID:24845460

  2. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis.

    PubMed

    Bouchnita, Anass; Eymard, Nathalie; Moyo, Tamara K; Koury, Mark J; Volpert, Vitaly

    2016-06-01

    Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of nonerythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with nonerythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients. Am. J. Hematol. 91:371-378, 2016. © 2016 Wiley Periodicals, Inc. PMID:26749142

  3. Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma.

    PubMed

    Vatolin, Sergei; Phillips, James G; Jha, Babal K; Govindgari, Shravya; Hu, Jennifer; Grabowski, Dale; Parker, Yvonne; Lindner, Daniel J; Zhong, Fei; Distelhorst, Clark W; Smith, Mitchell R; Cotta, Claudiu; Xu, Yan; Chilakala, Sujatha; Kuang, Rebecca R; Tall, Samantha; Reu, Frederic J

    2016-06-01

    Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR. PMID:27197150

  4. A Rare Case of Nonsecretory Multiple Myeloma in Lagos, Nigeria: A Case Report and Literature Review.

    PubMed

    Uche, Ebele; Akinbami, Akinsegun; John-Olabode, Sarah; Dosunmu, Adedoyin; Odesanya, Majeed

    2015-01-01

    Multiple myeloma (MM) is a plasma cell disorder associated with clonal proliferation of plasma cells. Nonsecretory multiple myeloma (NSMM) is a rare variant of MM and accounts for approximately 1% to 5% of all cases. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin on serum or urine electrophoresis. This variant usually poses a diagnostic challenge to the clinician. We present a 60-year-old Nigerian man who was investigated extensively for bone pain, weight loss, and anaemia. He was eventually diagnosed as having nonsecretory multiple myeloma based on histology and immunohistochemistry results of bone marrow trephine biopsy. He is currently being managed with bortezomib, doxorubicin, and thalidomide, as well as zoledronic acid. He is also on anticoagulation. He continues to show remarkable clinical improvement. We describe this case report and literature review for better awareness amongst medical practitioners and pathologists. PMID:26649043

  5. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

    PubMed

    Miceli, Teresa S; Colson, Kathleen; Faiman, Beth M; Miller, Kena; Tariman, Joseph D

    2011-08-01

    About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. PMID:21816707

  6. Maintaining Bone Health in Patients With Multiple Myeloma: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board

    PubMed Central

    Miceli, Teresa S.; Colson, Kathleen; Faiman, Beth M.; Miller, Kena; Tariman, Joseph D.

    2014-01-01

    About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. PMID:21816707

  7. Immunophenotyping in multiple myeloma and related plasma cell disorders

    PubMed Central

    Kumar, Shaji; Kimlinger, Teresa; Morice, William

    2010-01-01

    SUMMARY Plasma cell disorders form a spectrum ranging from the asymptomatic presence of small monoclonal populations of plasma cells to conditions like plasma cell leukemia and multiple myeloma, in which the bone marrow can be replaced by the accumulation of neoplastic plasma cells. Immunophenotyping has become an invaluable tool in the management of hematological malignancies and is increasingly finding a role in the diagnosis and monitoring of plasma cell disorders. Multiparameter flow cytometry has evolved considerably during the past decade with an increasing ability to screen large numbers of events and to detect multiple antigens at the same time. This, along with a better understanding of the phenotypic heterogeneity of the clonal plasma cells in different disorders, has made immunophenotyping an indispensible tool in the diagnosis, prognostic classification and management of plasma cell disorders. This book chapter addresses the approaches taken to evaluate monoclonal plasma cell disorders, and the different markers and techniques that are important for the study of these diseases. PMID:21112041

  8. Advances in the pathogenesis and diagnosis of multiple myeloma.

    PubMed

    Chesi, M; Bergsagel, P L

    2015-05-01

    Multiple myeloma (MM) is a tumor of indolent, bone marrow (BM) localized, isotype-switched plasma cells. Recently, the diagnostic criteria have been amended to include some patients who would previously have been diagnosed with ultra-high-risk smoldering MM and benefit from immediate treatment. Genetically it can be divided into tumors with different recurrent immunoglobulin heavy chain gene translocations (4p16, 11q13, 6p21, 16q23, 20q11) and tumors characterized by hyperdiploidy with multiple trisomies. Recent genomic studies have shown that almost half of untreated patients have a genetic rearrangements of the MYC locus that result in juxtaposition of ectopic super-enhancers adjacent to MYC, as well as somatic mutations that activate the RAS/MAPK pathway (NRAS, KRAS, BRAF, FGFR3). Mutations that result in constitutive activation of the NFkB pathway and that inactivate TP53, CDKN2C, KDM6A, FAM46C, and DIS3 are also recurrent. A major insight from these studies has been the recognition of the high degree of subclonal heterogeneity in MM, which is more frequent in patients with high-risk genetics. The subclones may alternate in dominance under alternating therapeutic pressure, a phenomenon known as 'clonal tides'. The identification of marked subclonal heterogeneity argues in those patients for the use of therapeutic strategies to maximize response, and long-term suppressive therapies to prevent tumor regrowth and development of additional subclones. PMID:25976968

  9. New orally active proteasome inhibitors in multiple myeloma.

    PubMed

    Allegra, Alessandro; Alonci, Andrea; Gerace, Demetrio; Russo, Sabina; Innao, Vanessa; Calabrò, Laura; Musolino, Caterina

    2014-01-01

    Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM. PMID:24239172

  10. Total cost comparison in relapsed/refractory multiple myeloma

    PubMed Central

    Durie, Brian; Binder, Gary; Pashos, Chris; Khan, Zeba; Hussein, Mohamad; Borrello, Ivan

    2013-01-01

    Objectives Advances in survival in multiple myeloma have focused payer attention on the cost of care. An assessment was conducted to compare the costs of two recent treatments for relapsed/refractory multiple myeloma (rrMM), from the perspective of a US payer. Methods An economic model estimated the total costs of care for two guideline-recommended therapies in rrMM patients: bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX). To evaluate total treatment costs, the costs associated with drug treatment, medical resource utilization, and adverse event (AE) management were determined for each regimen over a common 1-year period. Medical costs and grade 3/4 AE costs were based on rates from published literature, package inserts, and fee schedules (US dollars). To evaluate cost per outcome, assessments determined the monthly costs without disease progression based on pivotal clinical trials (APEX [BORT] and MM-009/MM-010 [LEN/DEX]). Univariate sensitivity analyses and alternative scenarios were also conducted. Results Drug costs for the treatments were very similar, differing by under $10 per day. Medical and AE management costs for BORT were higher by more than $40 per day. Treatment with BORT had annual excess total costs of >$17,000 compared with LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses. Total cost per month without progression was 11% lower with LEN/DEX. Limitations This analysis relied on separate studies having similar comparators, populations, and end-points. Actual treatment patterns and costs pre- and post-relapse may vary from the base scenario and sensitivities modeled. The 12-month time frame captures the preponderance of costs for a relapse line of therapy, yet may not reflect the entirety of costs. There is insufficient evidence to determine whether, or how, a difference in the lifetime costs of the two regimens would vary from the 1-year cost difference. Conclusion While rrMM treatment with

  11. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group

    PubMed Central

    Palumbo, Antonio; Avet-Loiseau, Hervé; Oliva, Stefania; Lokhorst, Henk M.; Goldschmidt, Hartmut; Rosinol, Laura; Richardson, Paul; Caltagirone, Simona; Lahuerta, Juan José; Facon, Thierry; Bringhen, Sara; Gay, Francesca; Attal, Michel; Passera, Roberto; Spencer, Andrew; Offidani, Massimo; Kumar, Shaji; Musto, Pellegrino; Lonial, Sagar; Petrucci, Maria T.; Orlowski, Robert Z.; Zamagni, Elena; Morgan, Gareth; Dimopoulos, Meletios A.; Durie, Brian G.M.; Anderson, Kenneth C.; Sonneveld, Pieter; San Miguel, Jésus; Cavo, Michele; Rajkumar, S. Vincent; Moreau, Philippe

    2015-01-01

    Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Patients and Methods Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. Conclusion The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival. PMID:26240224

  12. Non-Hodgkin's lymphoma by immunohistochemistry.

    PubMed

    Akhter, A; Saleheen, M S; Hussain, M; Majid, N; Rahman, M R; Shermin, S; Rajib, R C; Huda, M M; Haque, N

    2015-01-01

    Non Hodgkin's lymphomas (NHL) constitute a heterogeneous group of neoplasm of the lymphoid system. There are many histological subtype of NHL based on WHO classification of hematopoietic and lymphoid neoplasm. This cross-sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka from January 2009 to December 2010 to observe the different subtypes of NHL using immunohistochemistry (IHC) with CD3. A total of 50 microscopically diagnosed case of NHL irrespective of age and sex were included in the study. The diagnostic morphologic criteria of each lymphoma subcategory were compiled and diagnosis was made. Mean age of the study subjects were 42.0±19.7 years with range 3-75 years and male female ratio was 1.8:1. Nodal NHL was 66% and extranodal cases were 34%. Maximum number of histolgic subtypes belonged to diffuse large B-cell lymphoma (DLBCL) and male was predominant in all histological subtypes, except peripheral T-cell lymphoma (PTCL). DLBCL was predominant in all B-cell NHL whereas PTCL was predominant in all T-cell NHL. The most childhood patients belonged to lymphoblastic lymphoma. Regarding cell lineage B-cell NHL was more common than T-cell NHL (88% vs. 12%), but high grade pattern was more predominant in T-cell type (83.3% vs. 65.9%). Among 50 study subjects histological (H & E) diagnosis reveals 46 cases as B-cell NHL and 4 as T-cell NHL but IHC confirms 6 cases as T-cell NHL. PMID:25725676

  13. Ileocecal Obstruction Due to B-cell Non-Hodgkin Lymphoma.

    PubMed

    Negrean, Vasile; Graur, Florin; Moiş, Emil; Al-Hajjar, Nadim

    2016-01-01

    We report a rare case of non-Hodgkin lymphoma presented as an ileocecal mass. The patient was a 77-year-old man with history of symptoms of partial bowel obstruction, intermittent right iliac fossa pain, loss of weight, vomiting and fatigue. Clinical signs included moderate abdominal tenderness with a palpable mass in the right iliac fossa at the physical examination. Colonoscopy revealed an intussusception of the right colon causing a complete stenosis. The patient developed complete bowel obstruction during hospitalization that required emergent surgical intervention. Intraoperatively an ileocecal mass was found measuring 10-12 cm in diameter, causing complete stenosis at its level and bowel dilatation proximally. Multiple nodules were found in the liver and the parietal peritoneum as well. An ileotransverso-anastomosis was performed and biopsies of the nodules were taken. Pathological evaluation revealed a diffuse large B cell non-Hodgkin'™s lymphoma of the ileocecum and the parietal peritoneum. PMID:26988544

  14. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

    PubMed Central

    Fonseca, R; Bergsagel, PL; Drach, J; Shaughnessy, J.; Gutierrez, N; Stewart, AK; Morgan, G; Van Ness, B; Chesi, M; Minvielle, S; Neri, A; Barlogie, B; Kuehl, WM; Liebisch, P; Davies, F; Chen-Kiang, S; Durie, BGM; Carrasco, R; Sezer, Orhan; Reiman, Tony; Pilarski, Linda; Avet-Loiseau, H

    2010-01-01

    Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinico-pathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor- B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials. PMID:19798094

  15. What Are the Risk Factors for Multiple Myeloma?

    MedlinePlus

    ... a person’s risk of developing myeloma. Having other plasma cell diseases Many people with monoclonal gammopathy of ... American Cancer Society is a qualified 501(c)(3) tax-exempt organization. Cancer.org is provided courtesy ...

  16. Systemic Mastocytosis with Smoldering Multiple Myeloma: Report of a Case

    PubMed Central

    Garcia, Gwenalyn; Ying, Liu; Hurford, Matthew; Odaimi, Marcel

    2016-01-01

    Systemic mastocytosis (SM) is a disease characterized by a clonal infiltration of mast cells affecting various tissues of the body. It is grouped into six different subtypes according to the World Health Organization classification. It is called indolent systemic mastocytosis (ISM) when there is no evidence of end organ dysfunction, while the presence of end organ dysfunction defines aggressive systemic mastocytosis (ASM). When SM coexists with a clonal hematological disorder, it is classified as systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD). Over 80% of SM-AHNMD cases involve disorders of the myeloid cell lines. To our knowledge, there are only 8 reported cases to date of SM associated with a plasma cell disorder. We report a patient with ISM who was found to have concomitant smoldering multiple myeloma. His disease later progressed to ASM. We discuss this rare association between SM and a plasma cell disorder, and potential common pathophysiologic mechanisms linking the two disorders will be reviewed. We also discuss prognostic factors in SM as well as the management options considered during the evolution of the patient's disease. PMID:27293930

  17. Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma.

    PubMed

    Moreau, Philippe; Facon, Thierry; Touzeau, Cyrille; Benboubker, Lotfi; Delain, Martine; Badamo-Dotzis, Julie; Phelps, Charles; Doty, Christopher; Smit, Hans; Fourneau, Nele; Forslund, Ann; Hellemans, Peter; Leleu, Xavier

    2016-07-01

    The maximum tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/week) plus subcutaneous bortezomib (1.3 mg/m(2)) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was determined. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clinically significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 months, respectively. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone. PMID:26758913

  18. A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma

    PubMed Central

    Xuan, Yang; Li, Xiao-Hong; Hu, Zhong-Qian; Teng, Zhi-Mei; Hu, Dao-Jun

    2016-01-01

    Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID:27126524

  19. Multiple myeloma in the marrow: pathogenesis and treatments.

    PubMed

    Fairfield, Heather; Falank, Carolyne; Avery, Lindsey; Reagan, Michaela R

    2016-01-01

    Multiple myeloma (MM) is a B cell malignancy resulting in osteolytic lesions and fractures. In the disease state, bone healing is limited owing to increased osteoclastic and decreased osteoblastic activity, as well as an MM-induced forward-feedback cycle where bone-embedded growth factors further enhance tumor progression as bone is resorbed. Recent work on somatic mutation in MM tumors has provided insight into cytogenetic changes associated with this disease; the initiating driver mutations causing MM are diverse because of the complexity and multitude of mutations inherent in MM tumor cells. This manuscript provides an overview of MM pathogenesis by summarizing cytogenic changes related to oncogenes and tumor suppressors associated with MM, reviewing risk factors, and describing the disease progression from monoclonal gammopathy of undetermined significance to overt MM. It also highlights the importance of the bone marrow microenvironment (BMM) in the establishment and progression of MM, as well as associated MM-induced bone disease, and the relationship of the bone marrow to current and future therapeutics. This review highlights why understanding the basic biology of the healthy and diseased BMM is crucial in the quest for better treatments and work toward a cure for genetically diverse diseases such as MM. PMID:27002787

  20. Genetic factors influencing the risk of multiple myeloma bone disease

    PubMed Central

    Johnson, D C; Weinhold, N; Mitchell, J; Chen, B; Stephens, O W; Försti, A; Nickel, J; Kaiser, M; Gregory, W A; Cairns, D; Jackson, G H; Hoffmann, P; Noethen, M M; Hillengass, J; Bertsch, U; Barlogie, B; Davis, F E; Hemminki, K; Goldschmidt, H; Houlston, R S; Morgan, G J

    2016-01-01

    A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10–9) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10–7). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM. PMID:26669972

  1. Development of chimeric antigen receptors for multiple myeloma.

    PubMed

    Martínez-Cingolani, Carolina; Bories, Jean Christophe

    2016-04-15

    Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to MM is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate MM plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of MM to circumvent current problems of toxicity. PMID:27068946

  2. The osteoblastic niche in the context of multiple myeloma.

    PubMed

    Toscani, Denise; Bolzoni, Marina; Accardi, Fabrizio; Aversa, Franco; Giuliani, Nicola

    2015-01-01

    The osteoblastic niche has a critical role in the regulation of hemopoietic stem cell (HSC) quiescence and self-renewal and in the support of hematopoiesis. Several mechanisms are involved in the crosstalk between stem cells and osteoblasts, including soluble cytokines, adhesion molecules, and signal pathways such as the wingless-Int (Wnt), Notch, and parathyroid hormone pathways. According to the most recent evidence, there is an overlap between osteoblastic and perivascular niches that affects HSC function involving mesenchymal stromal and endothelial cells and a gradient of oxygen regulated by hypoxia inducible factor (HIF)-1α. Derived from plasma cells, multiple myeloma (MM) is a hematopoietic malignancy characterized by a peculiar dependency on the bone microenvironment. Quiescent MM cells may reside in the osteoblastic niche for protection from apoptotic stimuli; in turn, MM cells suppress osteoblast formation and function, leading to impairment of bone formation and the development of osteolytic lesions. Several recent studies have investigated the mechanisms involved in the relationship between osteoblasts and MM cells and identified potential therapeutic targets in the osteoblastic niche, including the HIF-1α, Runx2, and Wnt (both canonical and noncanonical) signaling pathways. PMID:25424768

  3. Plasma fatty acid profile in multiple myeloma patients.

    PubMed

    Jurczyszyn, Artur; Czepiel, Jacek; Gdula-Argasińska, Joanna; Paśko, Paweł; Czapkiewicz, Anna; Librowski, Tadeusz; Perucki, William; Butrym, Aleksandra; Castillo, Jorge J; Skotnicki, Aleksander B

    2015-04-01

    New membrane formation in the proliferating tumor cells consequently results in hypermetabolism of fatty acids (FA), as seen in many cancer patients, including multiple myeloma (MM). The FA composition of plasma reflects both endogenous synthesis as well as the dietary supply of these compounds. Additionally, obesity is a risk factor for the development of MM. The aim of this study was to compare the FA composition of plasma in 60 MM patients and 60 healthy controls. We noted significant differences in the FA profile of plasma from patients with MM when compared to the control group. Increased levels of saturated and n-6 polyunsaturated fatty acids in MM patients suggest that there may be increased endogenous synthesis of these fatty acids, likely due to increased expression of desaturase and elongase. Furthermore, cluster analysis showed differences in the distribution of FA in plasma from MM patients compared to controls. Dietary fat and a deranged endogenous FA metabolism may contribute to cancer-associated inflammation through an abnormal arachidonic acid metabolism, caused by pro-inflammatory derivatives. Our study supports further research on the biochemistry of lipids in patients with MM. PMID:25666255

  4. Quantification of Clonal Circulating Plasma cells in Relapsed Multiple Myeloma

    PubMed Central

    Gonsalves, Wilson I; Morice, William G; Rajkumar, S. Vincent; Gupta, Vinay; Timm, Michael M; Dispenzieri, Angela; Buadi, Francis K; Lacy, Martha Q; Singh, Preet P; Kapoor, Prashant; Gertz, Morie A; Kumar, Shaji K

    2014-01-01

    The presence of clonal circulating plasma cells (cPCs) remains a marker of high-risk disease in newly diagnosed multiple myeloma (MM) patients. However, its prognostic utility in MM patients with previously treated disease is unknown. We studied 647 consecutive patients with previously treated MM seen at the Mayo Clinic, Rochester who had their peripheral blood evaluated for cPCs by multi-parameter flow cytometry. Of these patients, 145 had actively relapsing disease while the remaining 502 had disease that was in a plateau and included 68 patients in complete remission (CR) and 434 patients with stable disease. Patients with actively relapsing disease were more likely to have clonal cPCs than those in a plateau (P < 0.001). None of the patients in CR had any clonal cPCs detected. Among patients whose disease was in a plateau, the presence of clonal cPCs predicted for a worse median survival (22 months vs. not reached; P=0.004). Among actively relapsing patients, the presence of ≥100 cPCs predicted for a worse survival after flow cytometry analysis (12 months vs. 33 months; P<0.001). Future studies are needed to determine the role of these findings in developing a risk-adapted treatment approach in MM patients with actively relapsing disease. PMID:25113422

  5. Model of translational cancer research in multiple myeloma

    PubMed Central

    Yasui, Hiroshi; Ishida, Tadao; Maruyama, Reo; Nojima, Masanori; Ikeda, Hiroshi; Suzuki, Hiromu; Hayashi, Toshiaki; Shinomura, Yasuhisa; Imai, Kohzoh

    2012-01-01

    Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in multiple myeloma (MM). The introduction of novel agents such as the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, which were rapidly translated from preclinical studies at the Dana-Farber Cancer Institute into clinical trials, has changed the treatment paradigm and markedly extended overall survival; MM has therefore become a remarkable example of translational cancer research in new drug development. In this article, with the aim of determining the key factors underlying success in translational research, we focus on our studies of MM at Dana-Farber Cancer Institute as well as at our institutes. The identification of these key factors will help to promote translational cancer research not only in MM but also in other hematologic malignancies and solid tumors, to develop novel therapies, to overcome drug resistance, and to thereby improve the prognosis of cancer patients. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02384.x, 2012) PMID:22809142

  6. Multiple myeloma in the very old: an IASIA conference report.

    PubMed

    Tuchman, Sascha A; Shapiro, Gary R; Ershler, William B; Badros, Ashraf; Cohen, Harvey J; Dispenzieri, Angela; Flores, Irene Q; Kanapuru, Bindu; Jurivich, Donald; Longo, Dan L; Nourbakhsh, Ali; Palumbo, Antonio; Walston, Jeremy; Yates, Jerome W

    2014-05-01

    Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population. PMID:24700806

  7. Systemic Mastocytosis with Smoldering Multiple Myeloma: Report of a Case.

    PubMed

    Ghanem, Sassine; Garcia, Gwenalyn; Ying, Liu; Hurford, Matthew; Odaimi, Marcel

    2016-01-01

    Systemic mastocytosis (SM) is a disease characterized by a clonal infiltration of mast cells affecting various tissues of the body. It is grouped into six different subtypes according to the World Health Organization classification. It is called indolent systemic mastocytosis (ISM) when there is no evidence of end organ dysfunction, while the presence of end organ dysfunction defines aggressive systemic mastocytosis (ASM). When SM coexists with a clonal hematological disorder, it is classified as systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD). Over 80% of SM-AHNMD cases involve disorders of the myeloid cell lines. To our knowledge, there are only 8 reported cases to date of SM associated with a plasma cell disorder. We report a patient with ISM who was found to have concomitant smoldering multiple myeloma. His disease later progressed to ASM. We discuss this rare association between SM and a plasma cell disorder, and potential common pathophysiologic mechanisms linking the two disorders will be reviewed. We also discuss prognostic factors in SM as well as the management options considered during the evolution of the patient's disease. PMID:27293930

  8. Functional Analysis of microRNA in Multiple Myeloma.

    PubMed

    Di Martino, Maria Teresa; Amodio, Nicola; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

    2016-01-01

    MicroRNAs (miRNAs) are short non coding RNAs that regulate the gene expression and play a relevant role in physiopathological mechanisms such as development, proliferation, death, and differentiation of normal and cancer cells. Recently, abnormal expression of miRNAs has been reported in most of solid or hematopoietic malignancies, including multiple myeloma (MM), where miRNAs have been found deeply dysregulated and act as oncogenes or tumor suppressors. Presently, the most recognized approach for definition of miRNA portraits is based on microarray profiling analysis. We here describe a workflow based on the identification of dysregulated miRNAs in plasma cells from MM patients based on Affymetrix technology. We describe how it is possible to search miRNA putative targets performing whole gene expression profile on MM cell lines transfected with miRNA mimics or inhibitors followed by luciferase reporter assay to analyze the specific targeting of the 3'untranslated region (UTR) sequence of a mRNA by selected miRNAs. These technological approaches are suitable strategies for the identification of relevant druggable targets in MM. PMID:25971914

  9. Multiple Myeloma in the Very Old: An IASIA Conference Report

    PubMed Central

    Shapiro, Gary R.; Ershler, William B.; Badros, Ashraf; Cohen, Harvey J.; Dispenzieri, Angela; Flores, Irene Q.; Kanapuru, Bindu; Jurivich, Donald; Longo, Dan L.; Nourbakhsh, Ali; Palumbo, Antonio; Walston, Jeremy; Yates, Jerome W.

    2014-01-01

    Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population. PMID:24700806

  10. Multiple Myeloma Mortality in Relation to Obesity Among African Americans.

    PubMed

    Sonderman, Jennifer S; Bethea, Traci N; Kitahara, Cari M; Patel, Alpa V; Harvey, Chinonye; Knutsen, Synnøve F; Park, Yikyung; Park, Song-Yi; Fraser, Gary E; Teras, Lauren R; Purdue, Mark P; Stolzenberg-Solomon, Rachael Z; Gillanders, Elizabeth M; Palmer, Julie R; Kolonel, Laurence N; Blot, William J

    2016-10-01

    Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m(2)), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m(2) or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States. PMID:27147231

  11. MUC1-C drives MYC in multiple myeloma.

    PubMed

    Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey; Alam, Maroof; Gali, Reddy; Bailey, Shannon; Tai, Yu-Tzu; Hideshima, Teru; Anderson, Kenneth; Avigan, David; Kufe, Donald

    2016-05-26

    Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein. The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a β-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases β-catenin occupancy on the MYC promoter, (2) forms a complex with β-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives MYC expression in MM. PMID:26907633

  12. Fact or fiction - identifying the elusive multiple myeloma stem cell

    PubMed Central

    2013-01-01

    Multiple Myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM has introduced confusion toward this hypothesis. However, recent evidence has suggested that MM originates from the B cell lineage with memory-B cell like features, allowing for self-renewal of the progenitor-like status and differentiation to a monoclonal plasma cell population. Furthermore, this tumor-initiating cell uses signaling pathways and microenvironment similar to the hematopoietic stem cell, though hijacking these mechanisms to create and favor a more tumorigenic environment. The bone marrow niche allows for pertinent evasion, either through avoiding immunosurveillance or through direct interaction with the stroma, inducing quiescence and thus drug resistance. Understanding the interaction of the MM stem cell to the microenvironment and the mechanisms utilized by various stem cell-like populations to allow persistence and therapy-resistance can enable for better targeting of this cell population and potential eradication of the disease. PMID:24314019

  13. A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma.

    PubMed

    Xuan, Yang; Li, Xiao-Hong; Hu, Zhong-Qian; Teng, Zhi-Mei; Hu, Dao-Jun

    2016-01-01

    Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID:27126524

  14. Multiple myeloma in the United States, 1950--1975

    SciTech Connect

    Blattner, W.A.; Blair, A.; Mason, T.J.

    1981-12-01

    A total of 68,400 whites and 10,533 nonwhites were reported to have died from multiple myeloma (MM) in the continental United States between 1950 and 1975 (excluding 1972 because of incomplete case ascertainment). Age-adjusted mortality rates for nonwhites were approximately twice as high as for whites. During the 25-year period of this survey, there was a twofold to threefold increase in MM mortality. The increase was seen in both races, but was greater in nonwhites than whites and primarily occurred in people over 55 years of age. The increases were uniform in all geographic regions and urban/rural categories. MM mortality from 1950--1969 was correlated with geographic, demographic, and occupational factors at the county level. The rates were highest in the far west and mid-central regions for whites and in the northeast for nonwhites. Urban areas had the highest rates and rural areas had the lowest, and positive associations were seen with indices of socioeconomic level and the percentage of residents with Scandinavian ancestry. For white males, MM mortality rates were elevated in areas with high petroleum and paper production, and a slight increase was seen in furniture manufacturing areas.

  15. Immunotherapy for multiple myeloma: Current status and future directions.

    PubMed

    Ayed, Ayed O; Chang, Lung-Ji; Moreb, Jan S

    2015-12-01

    Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies and has been in the limelight of fast-track development of novel drugs that have contributed to the transformation of a rapidly lethal disease into a chronic illness with significant improvement in quality of life. Nonetheless, MM remains an incurable disease in many patients. Immunotherapy has been one of the approaches that had the highest hope for curing this disease. More than two decades of research and clinical trials in immunotherapy for MM have however resulted in very little impact on patient survival. The various immunotherapy approaches that have been attempted over the last two decades but were fraught with failure have already been extensively summarized in many published reviews. Nevertheless, in view of better understanding of the immune checkpoints, the innate immune system, and improved biotechnology, there is renewed hope. In this review, we will briefly discuss the unsuccessful approaches and emphasize the lessons learned, highlight the challenges that lie ahead, and discuss the more promising approaches, that already exist or being developed such as use of allogeneic stem cell transplants (allo-SCT) as a form of cellular immunotherapy, new monoclonal antibodies, chimeric antigen receptor (CAR) T-cell adoptive therapy, and NK cell therapy. PMID:26153389

  16. The treatment of multiple myeloma patients not eligible for asct.

    PubMed

    Richardson, Paul; Laubach, Jacob; Mahindra, Anuj; Mitsiades, Constantine; Schlossman, Robert; Ghobrial, Irene; Hideshima, Teru; Raje, Noopur; Munshi, Nikhil; Anderson, Kenneth

    2010-01-01

    Advances in therapies for younger patients with multiple myeloma have resulted in significant improvements in outcome over recent years, on the contrary the progress in treatments for elderly patients has remained more modest. Traditionally, patients who are not eligible for transplantation, like the older patients, have been treated with the combination of melphalan plus prednisone (MP), which leads to responses in approximately 50% of patients; however, patients rarely achieve a complete response (CR) and long-term outcomes are disappointing, with a relapse-free survival of approximately 18 months and an overall survival (OS) of approximately 3 years.With the arrival of novel agents, including the first-in-class proteasome inhibitor, bortezomib, and the immunomodulatory agents, thalidomide and lenalidomide, a shift in the management of older patients and/or those not eligible for transplantation has taken place. Increasingly, novel agents are now being incorporated into therapy, based on the positive findings from clinical trials in this setting, and outcomes have improved accordingly. PMID:21415962

  17. Multiple myeloma with hypercalcemia and chloride resistant metabolic alkalosis.

    PubMed

    Alshayeb, Hala; Patel, Vikul; Naseer, Adnan; Mangold, Therese A; Wall, Barry M

    2011-10-01

    This report describes a novel presentation of chloride resistant metabolic alkalosis in a patient with hypercalcemia related to Multiple Myeloma (MM). A 51-year-old male with newly diagnosed MM presented with widespread skeletal involvement, calcium (Ca(+2)) of 18 mg/dL, phosphorous (PO4) of 6 mg/dL, serum bicarbonate (HCO3) of 37 mEq/L, and serum creatinine (Cr) of 2.6 mg/dL Other causes of metabolic alkalosis such as vomiting, diuretics, alkali ingestion, mineralocorticoid excess and hypokalemia were excluded. Hypercalcemia and metabolic alkalosis were only partially corrected after rehydration, calcitonin and steroids. Subsequent treatment with zoledronic acid resulted in resolution of hypercalcemia and correction of metabolic alkalosis.The chloride resistant component of metabolic alkalosis was most likely related to extensive release of Ca(+2), carbonate and phosphate from bone by activated osteoclasts with inhibited osteoblastic activity. The additional reduction in glomerular filtration rate due to MM, contributed to a triad mimicking Calcium-Alkali syndrome. PMID:22073517

  18. [Clinical characteristics and therapeutic efficacy of immunoglobin D multiple myeloma].

    PubMed

    Liu, Yan; Ke, Xiao-Yan; Wang, Jing; Jing, Hong-Mei; Wang, Ji-Jun; Dong, Fei; Wan, Wen-Li; Zhang, Wei

    2014-12-01

    This study was aimed to evaluate the clinical characteristics of immunoglobin D multiple myeloma (IgD MM) and its curative efficacy. The clinical data of 15 cases of newly diagnosed IgD MM from April 1993 to June 2013 were analyzed retrospectively. Among 15 cases received induction treatment, the traditional chemotherapy was carried out in 9 cases, bortezomib-based therapy was performed in 6 cases. The diagnostic criteria and disease response criteria of MM were based on International Myeloma Working Group (IMWG) criteria,survival time was analyzed by using Kaplan-Meier method, the median age of patients was 57 years (range 40-72), the ratio of male to female was 2:1, the MM patients in Durie-Salmon stage III accounted for 100% (15/15) , the MM patients with λ light chain accounts for 80% (12/15) , with bone lesion 86.7% (13/15), with pleural effusion 26.7% (4/15) , with renal impairment (RI) 86.7% (13/15) ,with anemia 93.3% (14/15) , with serum album<35 g/L 26.7% (4/15). The median creatinine clearance rate (Ccr) of patients was 23.1 (6-44) ml/min, and median hemoglobin level was 82 (43-131) g/L. The results showed that in followed-up 11 cases, 8 cases died, 3 cases survived; the average duration of follow-up for these cases was 20 (0.5-138) months, the median progression-free survival time (PFS) was 7 (95%CI4.6-9.4) months, and the median overall survival (OS) time was 15 (95%CI6.6-27.4 ) months. Compared traditional chemotherapy with bortezomib regimen therapy,median OS time was 17 (95%CI6.1-28.0) months vs 15 (95%CI 0.0-33.3) months (P = 0.90) . Assessable curative effect of 14 cases was as follows: CR 33.3% (5/15); VGPR 13.3% (2/15); PR 20% (3/15); SD 20% (3/15); PD 6.7% (1/15). It is concluded that IgD MM is a rare type of MM and has a poor prognosis. Bortezomib may be beneficial for some patients with extramedullary infiltration. Autologous hematopoietic stem cell transplantation may improve survival time. PMID:25543487

  19. The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma

    PubMed Central

    Andreu-Vieyra, Claudia V.

    2014-01-01

    Panobinostat is an investigational and potent histone deacetylase inhibitor (HDACi) that has shown promise as an antimultiple myeloma agent in the preclinical setting. In this review, we discuss the rationale for the use of panobinostat as a combination therapy for multiple myeloma and provide an overview of recent and ongoing clinical trials testing the safety and efficacy of panobinostat for the treatment of the disease. PMID:25469210

  20. Extensive skeletal involvement detected by gallium-67 citrate in a patient with multiple myeloma

    SciTech Connect

    Nishiyama, H.; Morand, T.M.; Seiwert, V.J.

    1988-03-01

    Extensive skeletal involvement of multiple myeloma was detected by Ga-67 citrate imaging while searching for infectious foci. The case was unique in that a radiographic skeletal survey showed typical lytic lesions only in the skull, and extensive myeloma involvement in the skeletal system was an incidental finding. A high tumor cell burden was presumed to be present, which led to a rapid and fulminant clinical course in this patient.

  1. Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma.

    PubMed

    Kurup, Ravi Kumar; Kurup, Paramesware Achutha

    2003-12-01

    This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with

  2. Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo

    SciTech Connect

    Cheong, Chee Man; Chow, Annie W.S.; Fitter, Stephen; Hewett, Duncan R.; Martin, Sally K.; Williams, Sharon A.; To, L. Bik; and others

    2015-03-01

    Background: Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. Methods: We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. Results: TSPAN7 was found to be highly expressed at the RNA and protein level in CD138{sup +} MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. Conclusion: These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients. - Highlights: • TSPAN7 expression is upregulated in newly-diagnosed patients with active multiple myeloma. • Overexpression of TSPAN7 inhibits myeloma tumour development in vivo. • TSPAN7 interacts with calnexin at the plasma membrane in a myeloma cell line.

  3. [Gastric non-Hodgkin lymphoma associated with heavy metal exposures].

    PubMed

    Garavito Rentería, Jorge; Araujo Banchón, William Javier; Quesada Ríos, María Pía; Ponce de León, Diego

    2012-01-01

    Primary extranodal Non-Hodgkin lymphoma (NHL) is a non epithelial tumours that accounts for 40% of cases of NHL. Spread of nodal lymphomas to the gastrointestinal tract (GIT) is the most common location. Within the GIT is the stomach the most affected organ (60%). We report the case of 52-year- old man , mining company worker for over 10 years, which is derived to the Service of Gastroenterology with history of epigastric pain, nausea, vomiting and weight loss. Upper gastrointestinal endoscopic examination revealed an ulcerated lesion on greater curve of stomach and histopathological examination and subsequent immunohistochemical analysis showed diffuse large B cell gastric NHL. Also, the patient had multiple organ involvement in relation to chronic exposure to heavy metals, which was found in the mineralograma, with the highest concentration of uranium, thallium, arsenic, lead and mercury. The literature has described the association of chronic occupational exposure to uranium and arsenic with NHL presenting gastrointestinal involvement. Therefore, gastric commitment can not be considered as an isolated injury, but rather part of systemic involvement associated with elevated concentrations of metals. Mining is a key driver of income for Peru; however, there are no reports to date of the association of gastrointestinal NHL commitment regarding occupational exposure to heavy metals. PMID:23307094

  4. Malignant non-Hodgkin's lymphomas in children.

    PubMed

    Magrath, I T

    1987-12-01

    The spectrum of non-Hodgkin's lymphomas (NHL) that occurs in children differs markedly from that in adults. This is probably a consequence of differences in the proportions of precursor and mature lymphoid cells in the immune systems of children and adults, and the greater emphasis on the development of an immunologic repertoire in the child. Childhood NHL can be classified into three main types based on histology, all of them diffuse: lymphoblastic, small noncleaved cell, and large cell. The majority of lymphoblastic lymphomas are of immature T cell (thymocyte) origin, although a few have a B cell precursor phenotype. All express the enzyme terminal transferase. Small noncleaved lymphomas express B cell characteristics, as do the majority do the majority of large cell lymphomas, although a small proportion of the latter express T cell characteristics. Very few are of true histiocytic origin. Little is known of the epidemiology of lymphoblastic and large cell lymphomas. However, using histology as a diagnostic criterion, both occur throughout the world and occur primarily, as do all childhood NHL, in the first two decades of life. There appear to be at least two types of small noncleaved cell lymphomas, both of which are associated with specific chromosomal translocations. An endemic form occurs at high frequency in equatorial Africa, and a sporadic form occurs at low frequency throughout the world. The endemic tumor is associated with the Epstein-Barr virus, it has a high incidence of jaw tumors, and has a breakpoint on chromosome 8 that is usually some distance upstream of the c-myc oncogene. The sporadic tumor is only occasionally associated with EBV, it often involves the bone marrow, particularly at relapse, and has a breakpoint on chromosome 8 that is usually very close to or within the c-myc oncogene. Childhood NHL is rarely truly localized, and treatment regimens are always based on chemotherapy. There is no evidence that radiation is beneficial when modern

  5. Cranio-maxillofacial non-Hodgkin's lymphoma: clinical and histological presentation.

    PubMed

    Scherfler, Sebastian; Freier, Kolja; Seeberger, Robin; Bacon, Claire; Hoffmann, Jürgen; Thiele, Oliver C

    2012-10-01

    Non-Hodgkin's lymphoma represents about 5% of all malignant lesions of the head and neck. In this study we retrospectively evaluated clinical presentation, histological subtype and long-term prognosis of 42 patients with non-Hodgkin's lymphoma involving the craniofacial area. The mean age at diagnosis was 64 years. More than half of the patients presented with disseminated disease at multiple sites (55%, n=23). In 62% (n=26) the first manifestation was extranodal. The most common affected region was the oral cavity (65%, n=17). Treatment consisted of local therapy, including surgical resection and radiation, as well as chemotherapy with or without local therapy. Recurrence occurred in 31% (n=13) of the treated patients. Mean survival after first diagnosis varied from 17 months in patients presenting with diffuse large B-cell lymphoma (DLBCL), to 8.5 years in patients with follicular lymphoma. The most common histological subtype is DLBCL. Standard treatment for DLBCL consists of chemotherapy combined with CD 20 monoclonal antibody, even after total resection of the tumour. There is high risk of systemic disease in patients presenting with non-Hodgkin's lymphoma and high risk of post therapy recurrence. PMID:22093243

  6. Non Secretory Multiple Myeloma With Extensive Extramedullary Plasmacytoma: A Diagnostic Dilemma

    PubMed Central

    Low, Soo Fin; Mohd Tap, Nor Hanani; Kew, Thean Yean; Ngiu, Chai Soon; Sridharan, Radhika

    2015-01-01

    Multiple myeloma (MM) is characterized by progressive proliferation of malignant plasma cells, usually initiating in the bone marrow. MM can affect any organ; a total of 7 - 18% of patients with MM demonstrate extramedullary involvement at diagnosis. Non-secretory multiple myeloma (NSMM) is a rare variant that accounts for 1 - 5% of all cases of multiple myeloma. The disease is characterized by the absence of monoclonal gammopathy in serum and urine electrophoresis. Our case report highlights the diagnostic challenge of a case of NSMM with extensive extramedullary involvement in a young female patient who initially presented with right shoulder pain and bilateral breasts lumps. Skeletal survey showed multiple lytic bony lesions. The initial diagnosis was primary breast carcinoma with osseous metastases. No monoclonal gammopathy was found in the serum or urine electrophoresis. Bone marrow and breast biopsies revealed marked plasmacytosis. The diagnosis was delayed for a month in view of the lack of clinical suspicion of multiple myeloma in a young patient and scant biochemical expression of non-secretory type of multiple myeloma. PMID:26528383

  7. A transplant "immunome" screening platform defines a targetable epitope fingerprint of multiple myeloma.

    PubMed

    Schieferdecker, Aneta; Oberle, Anna; Thiele, Benjamin; Hofmann, Fabian; Göthel, Markus; Miethe, Sebastian; Hust, Michael; Braig, Friederike; Voigt, Mareike; von Pein, Ute-Marie; Koch-Nolte, Friedrich; Haag, Friedrich; Alawi, Malik; Indenbirken, Daniela; Grundhoff, Adam; Bokemeyer, Carsten; Bacher, Ulrike; Kröger, Nicolaus; Binder, Mascha

    2016-06-23

    Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and next-generation sequencing-assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy. PMID:27034429

  8. Non-Hodgkin Lymphoma Risk and Insecticide, Fungicide and Fumigant Use in the Agricultural Health Study

    PubMed Central

    Alavanja, Michael C. R.; Hofmann, Jonathan N.; Lynch, Charles F.; Hines, Cynthia J.; Barry, Kathryn H.; Barker, Joseph; Buckman, Dennis W.; Thomas, Kent; Sandler, Dale P.; Hoppin, Jane A.; Koutros, Stella; Andreotti, Gabriella; Lubin, Jay H.; Blair, Aaron; Beane Freeman, Laura E.

    2014-01-01

    Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were

  9. Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities.

    PubMed

    Shay, G; Hazlehurst, L; Lynch, C C

    2016-01-01

    Multiple myeloma is a plasma cell skeletal malignancy. While therapeutic agents such as bortezomib and lenalidomide have significantly improved overall survival, the disease is currently incurable with the emergence of drug resistance limiting the efficacy of chemotherapeutic strategies. Failure to cure the disease is in part due to the underlying genetic heterogeneity of the cancer. Myeloma progression is critically dependent on the surrounding microenvironment. Defining the interactions between myeloma cells and the more genetically stable hematopoietic and mesenchymal components of the bone microenvironment is critical for the development of new therapeutic targets. In this review, we discuss recent advances in our understanding of how microenvironmental elements contribute to myeloma progression and, therapeutically, how those elements can or are currently being targeted in a bid to eradicate the disease. PMID:26423531

  10. Concomitant multiple myeloma spectrum diagnosis in a central retinal vein occlusion: a case report and review.

    PubMed

    Borgman, Christopher J

    2016-07-01

    Multiple myeloma is a neoplastic plasma-cell disorder resulting from malignant plasma cells in the bone marrow. It can cause a hyperviscosity syndrome secondary to the paraproteinaemia associated with the disease. The increased hyperviscosity can lead to retinal vein occlusions and other ocular problems that may challenge clinicians. In patients with multiple myeloma and hypertension and/or diabetes mellitus, retinal changes appear similar and changes due to one disease or the other may be difficult to determine. A 48-year-old white female presented to the clinic with a complaint of blurry vision in her left eye. A full comprehensive ocular examination revealed a central retinal vein occlusion presumably from the patient's history of hypertension, diabetes mellitus and hypercholesterolaemia. Further bloodwork revealed monoclonal protein in the patient's serum and an increased percentage of plasma cells in the bone marrow. She was diagnosed with monoclonal gammopathy of undetermined significance, part of the multiple myeloma disease spectrum. She was referred to a retinal specialist for initiation of intravitreal injections of anti-vascular endothelial growth factor. Multiple myeloma has been implicated in younger patients as an underlying cause of retinal vein occlusions. Multiple myeloma should be considered as a differential diagnosis in young patients with retinal vein occlusions, even if other risk factors for venous occlusion like hypertension, diabetes mellitus and hypercholesterolaemia are present. Timely referral to the patient's primary care physician and haematologist is important for appropriate treatment and control of underlying systemic conditions. PMID:27079282

  11. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    SciTech Connect

    Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

    2014-05-02

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

  12. MR imaging and PET/CT in diagnosis and management of multiple myeloma.

    PubMed

    Ferraro, Regan; Agarwal, Ankit; Martin-Macintosh, Erica L; Peller, Patrick J; Subramaniam, Rathan M

    2015-01-01

    Multiple myeloma is a common hematologic malignancy among the elderly population. Although there have been many advances in treatment over the past few decades, the overall prognosis for the disease remains poor. Conventional radiography has long been the standard of reference for the imaging of multiple myeloma. However, 10%-20% of patients with multiple myeloma do not have evidence of disease at conventional radiography. There is a growing body of evidence supporting use of magnetic resonance (MR) imaging and 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) in diagnosis and management of multiple myeloma. MR imaging is useful in detection of bone marrow infiltration, a finding often missed at conventional radiography. FDG PET/CT is especially sensitive for the detection of extramedullary disease and can help detect the metabolically active lesions that often precede evidence of osseous destruction at conventional radiography. MR imaging and FDG PET/CT are useful tools that can provide essential information for diagnosis and management of patients with multiple myeloma. Both modalities allow accurate localization of disease after chemotherapy or autologous stem cell transplantation and can provide important prognostic information that can influence further clinical decision making regarding therapy, particularly when tumor serum markers may be a less reliable indicator of disease burden after repeated treatments. PMID:25763728

  13. Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

    PubMed Central

    Tosi, Patrizia

    2013-01-01

    Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation of vertebral alterations, as it allows to detect not only the exact morphology of the lesions, but also the pattern of bone marrow infiltration by the disease. Multiple treatment modalities can be used to manage multiple myeloma-related vertebral lesions. Surgery or radiotherapy is mainly employed in case of spinal cord compression, impending fractures, or intractable pain. Percutaneous vertebroplasty or balloon kyphoplasty can reduce local pain in a significant fraction of treated patients, without interfering with subsequent therapeutic programs. Systemic antimyeloma therapy with conventional chemotherapy or, more appropriately, with combinations of conventional chemotherapy and compounds acting on both neoplastic plasma cells and bone marrow microenvironment must be soon initiated in order to reduce bone resorption and, possibly, promote bone formation. Bisphosphonates should also be used in combination with antimyeloma therapy as they reduce bone resorption and prolong patients survival. A multidisciplinary approach is thus needed in order to properly manage spinal involvement in multiple myeloma. PMID:24381787

  14. Anti-galectin-3 therapy: a new chance for multiple myeloma and ovarian cancer?

    PubMed

    Mirandola, Leonardo; Nguyen, Diane D; Rahman, Rakhshanda L; Grizzi, Fabio; Yuefei, Yu; Figueroa, José A; Jenkins, Marjorie R; Cobos, Everardo; Chiriva-Internati, Maurizio

    2014-10-01

    Here we review the role of Galectins in the molecular pathogenesis of multiple myeloma and ovarian cancer, with a special focus on Glectin-3. Multiple myeloma is the second most common hematologic malignancy worldwide. Because the pathogenesis of multiple myeloma is still incompletely understood, there is no ultimately effective cure, and this cancer results fatal. Ovarian cancer is the most lethal gynecologic malignancy worldwide. Due to the lack of screening techniques for early detection, patients are mostly diagnosed with advanced disease, which results ultimately fatal. Multiple myeloma and ovarian cancer have different biologies, but they share a strong dependence on adhesion with extracellular matrix and other cells. Galectin-3 plays a key role in regulating such adhesive abilities of tumor cells. Here we discuss the outcomes and possible mechanism of action of a truncated, dominant negative form of Galectin-3, Galectin-3C, in these malignancies. Overall, we report that Galectin-3C is a promising new compound for effective adjuvant therapies in advanced, refractory multiple myeloma and ovarian cancer. PMID:24801755

  15. Bortezomib in multiple myeloma: systematic review and clinical considerations

    PubMed Central

    Kouroukis, T.C.; Baldassarre, F.G.; Haynes, A.E.; Imrie, K.; Reece, D.E.; Cheung, M.C.

    2014-01-01

    We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival. PMID

  16. [Retrospective analysis of 71 cases of multiple myeloma].

    PubMed

    Yang, Ping; Zhang, Wen-Juan; Jing, Hong-Mei; Ke, Xiao-Yan

    2009-12-01

    The aim of this study was to investigate the efficacy of different chemotherapy regimens in patients with multiple myeloma (MM). The therapeutic effects of 71 MM patients receiving standard chemotherapy regimens were retrospectively analyzed and evaluated. The results showed that 44 out of 71 new-diagnosed MM patients gained remission in varying degree, total effective rate was 61.9%, in which the rate of complete remission (CR) plus nearly complete remission (nCR) was 21.1%. 21 MM patients received M2 regimen gained total effective rate of 57.1%, in which the CR plus nCR were found in 5 MM patients, and partial remission (PR) was observed in 7 MM patients. 8 MM patients received MP chemotherapy regimen gained total effective rate of 37.5%, in which the CR + nCR was not found, but the PR was observed in 3 MM patients. 30 MM patients received VAD regimen gained total effective rate of 63.3%, in which CR + nCR and PR were found in 6 and 13 MM patients respectively, 12 MM patients received combined bortezomib regimen gained total effective rate of 83.3%, in which CR + nCR and PR were found in 4 and 6 MM patients respectively. The median time of progression and the median time of survival in 72 MM patients were 22.1 and 29.5 months respectively. The 3 and 5 year survival rates in 72 MM patients were 41.2% and 20.6% respectively. In conclusion, the chemotherapy regimen for new-diagnosed MM patients should be selected according to their clinical features and subtypes, the bortezomib-combined regimen may be considered as a new and effective regimen for MM patients. PMID:20030950

  17. Multiple Myeloma and lifetime occupation: results from the EPILYMPH study

    PubMed Central

    2012-01-01

    Background The EPILYMPH study applied a detailed occupational exposure assessment approach to a large multi-centre case–control study conducted in six European countries. This paper analysed multiple myeloma (MM) risk associated with level of education, and lifetime occupational history and occupational exposures, based on the EPILYMPH data set. Methods 277 MM cases and four matched controls per each case were included. Controls were randomly selected, matching for age (+/− 5 years), centre and gender. Lifetime occupations and lifetime exposure to specific workplace agents was obtained through a detailed questionnaire. Local industrial hygienists assessed likelihood and intensity for specific exposures. The odds ratio and 95% confidence intervals (OR, 95% CI) were calculated for level of education, individual occupations and specific exposures. Unconditional logistic regression models were run for individual occupations and exposures. Results A low level of education was associated with MM OR=1.68 (95% CI 1.02-2.76). An increased risk was observed for general farmers (OR=1.77; 95% CI 1.05-2.99) and cleaning workers (OR=1.69; 95% CI 1.04-2.72) adjusting for level of education. Risk was also elevated, although not significant, for printers (OR=2.06; 95% CI 0.97-4.34). Pesticide exposure over a period of ten years or more increased MM risk (OR=1.62; 95% CI 1.01-2.58). Conclusion These results confirm an association of MM with farm work, and indicate its association with printing and cleaning. While prolonged exposure to pesticides seems to be a risk factor for MM, an excess risk associated with exposure to organic solvents could not be confirmed. PMID:23241100

  18. Effects of survivin on FVADT chemotherapy for refractory multiple myeloma

    PubMed Central

    Yang, Hua; Du, Xingjun; Xi, Yuren

    2016-01-01

    The present study aimed to investigate the effects of survivin, an apoptosis inhibitor protein, on the efficacy of the fludarabine, vincristine, epirubicin, dexamethasone and thalidomide (FVADT) chemotherapy regime for the treatment of refractory multiple myeloma (MM). A total of 82 patients with MM were selected from the Hematology Inpatient Department at The Second Affiliated Hospital of Zhengzhou University (Zhengzhou, China). The initial treatment group consisted of 40 patients with MM, who received the vincristine, epirubicin and dexamethasone (VAD) chemotherapy regime. The refractory group consisted of 42 patients with refractory MM, who received the FVADT chemotherapy regime. Bone marrow biopsies were collected via marrow aspirations, and the protein expression of survivin was analyzed by immunohistochemistry. In addition, the Kaplan-Meier method was used for survival analyses. Intergroup differences in the protein expression levels of survivin were compared, and the association between survivin expression and the short- and long-term effects of FVADT chemotherapy were analyzed. The positive expression rate of survivin was significantly higher in the refractory group, as compared with the initial treatment group (P<0.05). Furthermore, the complete remission rate and the effective rate were significantly lower in the survivin-positive group, as compared with the survivin-negative group (P<0.05). The overall survival, progression free survival and 1 and 3 year survival rates of the survivin-positive group were significantly higher, as compared with the survivin-negative group (P<0.05). The results of the present study suggested that the protein expression of survivin was upregulated in refractory MM tissues, which was indicative of a poor short- and long-term efficacy for FVADT chemotherapy. PMID:27446274

  19. Molecular sequelae of proteasome inhibition in human multiple myeloma cells

    PubMed Central

    Mitsiades, Nicholas; Mitsiades, Constantine S.; Poulaki, Vassiliki; Chauhan, Dharminder; Fanourakis, Galinos; Gu, Xuesong; Bailey, Charles; Joseph, Marie; Libermann, Towia A.; Treon, Steven P.; Munshi, Nikhil C.; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

    2002-01-01

    The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM. PMID:12391322

  20. Study of specific genetic and epigenetic variables in multiple myeloma.

    PubMed

    Hatzimichael, Eleftheria; Dasoula, Aggeliki; Benetatos, Leonidas; Syed, Nelofer; Dranitsaris, George; Crook, Tim; Bourantas, Konstantinos

    2010-12-01

    Few studies have examined the association between methylenetetrahydrofolate reductase (MTHFR) SNPs, epigenetic changes, and multiple myeloma (MM). We wished to determine genotype distributions for MTHFR 1298AC SNP in cases of MM and healthy controls and to examine whether there is any correlation between the methylation status of the CpG island of CDKN2A and Snk/Plk2 and MTHFR genotypes and with overall survival (OS) and other relevant clinical parameters. Bone marrow and peripheral blood were obtained from 45 patients with MM and 77 controls, respectively. The frequencies of the MTHFR 1298AA, 1298AC, and 1298CC genotypes were 53.3%, 40%, and 6.7% for the patient population and 50.6%, 41.6%, and 7.8% for the controls. No statistically significant difference was found in genotype distribution between cases and controls. No correlation was noted between MTHFR genotypes and OS, disease stage, bone disease, anemia, and extramedullary disease. Regarding CDKN2A and Snk/Plk2 CpG island methylation analysis, we found 12 of 45 patients and 27 of 45, respectively, to be methylated. CDKN2A and Snk/Plk2 methylation did not correlate with MTHFR genotypes. Herein, we report the identification of Snk/Plk2 as a novel methylated gene in MM and show that methylation is not influenced in this CpG island or in that of a previously described methylated gene, CDKN2A, in MM. Further evaluation in a larger sample of patients is needed in order to better define the prognostic and clinical value, if any, of MTHFR 1298 polymorphisms and CDKN2A and Snk/Plk2 methylation in the pathogenesis of MM. PMID:21067440

  1. Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma

    PubMed Central

    Saha, Manujendra N; Jiang, Hua

    2010-01-01

    Multiple myeloma (MM) is an incurable plasma cell malignancy in which p53 is rarely mutated. Thus, activation of the p53 pathway by a small molecule inhibitor of the p53-MDM2 interaction, nutlin, in MM cells retaining wild type p53 is an attractive therapeutic strategy. Recently we reported that nutlin plus velcade (a proteasome inhibitor) displayed a synergistic response in MM. However, the mechanism of the p53-mediated apoptosis in MM has not been fully understood. Our data show that nutlin-induced apoptosis correlated with reduction in cell viability, upregulation of p53, p21 and MDM2 protein levels with a simultaneous increase in pro-apoptotic targets PUMA, Bax and Bak and downregulation of anti-apoptotic targets Bcl2 and survivin and activation of caspase in MM cells harboring wild type p53. Nutlin-induced apoptosis was inhibited when activation of caspase was blocked by the caspase inhibitor. Nutlin caused mitochondrial translocation of p53 where it binds with Bcl2, leading to cytochrome C release. Moreover, blocking the transcriptional arm of p53 by the p53-specific transcriptional inhibitor, pifithrin-α, not only inhibited nutlin-induced upregulation of p53-transcriptional targets but also augmented apoptosis in MM cells, suggesting an association of transcription-independent pathway of apoptosis. However, inhibitor of mitochondrial translocation of p53, PFT-µ, did not prevent nutlin-induced apoptosis, suggesting that the p53 transcription-dependent pathway was also operational in nutlin-induced apoptosis in MM. Our study provides the evidence that nutlin-induced apoptosis in MM cells is mediated by transcription-dependent and -independent pathways and supports further clinical evaluation of nutlin as a novel therapeutic agent in MM. PMID:20595817

  2. Correlation of proliferative and clonogenic tumor cells in multiple myeloma

    SciTech Connect

    Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

    1984-09-01

    To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell (/sup 3/H)thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by (/sup 3/H)thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by (/sup 3/H)thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity.

  3. Simultaneous bilateral spontaneous pneumothorax in a patient with recurrent, extraosseous multiple myeloma.

    PubMed

    Peters, F; Cathomas, G; Rothen, M; Thurnheer, R; Rutishauser, J

    2003-02-01

    A patient with simultaneous bilateral spontaneous pneumothorax (SBSP) due to pulmonary and pleural manifestations of recurrent multiple myeloma is presented. The patient died in shock of unknown cause. The diagnosis was suspected from pleural fluid examination showing an exudate with numerous plasmocytes. Macroscopically and histologically, the visceral organs and the bone marrow were infiltrated with multiple monoclonal proliferations of plasma cells staining positively for IgG and lambda chains. SBSP is a rare condition and may be caused by trauma, parenchymal lung disease, infections, or neoplasms. This is the first report of SBSP caused by pleuropulmonary infiltration of multiple myeloma. PMID:12612329

  4. Paediatric non-Hodgkin lymphoma - perspectives in translational biology.

    PubMed

    Shiramizu, Bruce; Mussolin, Lara; Woessmann, Wilhelm; Klapper, Wolfram

    2016-05-01

    Exciting advances have been achieved for infants, children and adolescents diagnosed with, and treated for, non-Hodgkin lymphoma (NHL). In spite of these successes, new frontiers are being paved to improve the prognosis for those who relapse or have resistant disease. This review summarizes some of the novel approaches and ideas in NHL monitoring, diagnosis and treatment as discussed at the 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on October 22nd-24th 2015 in Varese, Italy. PMID:27009921

  5. Non-Hodgkin's Malignant Lymphoma with Aggressive Development

    PubMed Central

    DANCIU, Cezara Elisabeta; HEROIU (CATALOIU), Adriana-Daniela; POPESCU, Cristian Radu

    2014-01-01

    Non-Hodgkin's malignant lymphoma is a hematologic malignant disease which usually responds to the polychemotherapy. We present a clinical case report of a 50 years old patient who develops an aggressive type of lymphoma. Patient develops a nodal Non-Hodgkin's malignant lymphoma who present at hospital admission as a huge tumor at the right side of the neck. Any type of treatment was a failure, the patient having a particularly aggressive form of lymphoma, resistant to all three chemotherapy regimens tested. Death occurs quickly, about one year after diagnosis and initiation of therapy. PMID:25553129

  6. An Unusual Cause of Altered Mental Status in Multiple Myeloma: An Extraosseous Manifestation.

    PubMed

    Jaruvongvanich, Veeravich; Spanuchart, Ittikorn; O-Charoen, Pichaya; Kitamura, Christian; Sumida, Lauren; Roytman, Marina

    2016-04-01

    Multiple myeloma typically presents as lytic bony lesions, hypercalcemia, anemia, and renal failure. Extraosseous manifestations are rare. We report on a patient who was recently diagnosed with multiple myeloma and completed the first cycle of bortezomib, dexamethasone, and palliative radiation therapy with good response. Two weeks after discharge, she became confused and was re-admitted. Despite treatment with lactulose and rifaximin, altered mental status worsened. Computer tomographic scan of abdomen showed hepatomegaly and numerous ill-defined small hyperdense nodules scattered throughout the liver. Liver biopsy demonstrated aggregation of plasma cell myeloma. Magnetic resonance imaging of brain revealed dural thickening. Patient's altered mental status was likely from leptomeningeal myelomatosis and hyperammonemic encephalopathy. Although extraosseous manifestations in multiple myeloma including liver and leptomeningeal involvement are rare, its incidence has increased. This condition portends a poor prognosis. The non-specific manifestations of extraosseous myeloma can be confused with complications of multiple sclerosis and lead to incorrect management, thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however bortezomib and thalidomide show promise. PMID:27099806

  7. An Unusual Cause of Altered Mental Status in Multiple Myeloma: An Extraosseous Manifestation

    PubMed Central

    Spanuchart, Ittikorn; O-charoen, Pichaya; Kitamura, Christian; Sumida, Lauren; Roytman, Marina

    2016-01-01

    Multiple myeloma typically presents as lytic bony lesions, hypercalcemia, anemia, and renal failure. Extraosseous manifestations are rare. We report on a patient who was recently diagnosed with multiple myeloma and completed the first cycle of bortezomib, dexamethasone, and palliative radiation therapy with good response. Two weeks after discharge, she became confused and was re-admitted. Despite treatment with lactulose and rifaximin, altered mental status worsened. Computer tomographic scan of abdomen showed hepatomegaly and numerous ill-defined small hyperdense nodules scattered throughout the liver. Liver biopsy demonstrated aggregation of plasma cell myeloma. Magnetic resonance imaging of brain revealed dural thickening. Patient's altered mental status was likely from leptomeningeal myelomatosis and hyperammonemic encephalopathy. Although extraosseous manifestations in multiple myeloma including liver and leptomeningeal involvement are rare, its incidence has increased. This condition portends a poor prognosis. The non-specific manifestations of extraosseous myeloma can be confused with complications of multiple sclerosis and lead to incorrect management, thus clinicians should be aware of these pathologies and perform proper diagnostic tests including imaging and tissue pathology. The most effective treatment is unknown, however bortezomib and thalidomide show promise. PMID:27099806

  8. Multiple myeloma: Updates for pharmacists in the treatment of relapsed and refractory disease.

    PubMed

    Ashjian, Emily; Redic, Kimberly

    2016-04-01

    There have been a number of recent advances in the treatment of patients with relapsed and refractory multiple myeloma. However, despite additional FDA-approved therapies including carfilzomib and pomalidomide as well as clinical trials investigating new combinations of existing treatments, multiple myeloma remains an incurable disease. New therapies currently in the drug development pipeline for relapsed and refractory disease include additional proteasome inhibitors (oprozomib, marizomib, ixazomib), histone deacetylase inhibitors (panobinostat, ricolinostat, quisinostat), monoclonal antibodies (daratumumab, elotuzumab, SAR650984), Bruton's tyrosine kinase inhibitors (ibrutinib), a selective inhibitor of nuclear export, and others. This review will focus on these newly developing therapies as well as the ever expanding role of the pharmacist in supportive care for patients with relapsed and refractory multiple myeloma. PMID:25694345

  9. Imaging Findings of Plasmacytoma of Both Breasts as a Preceding Manifestation of Multiple Myeloma

    PubMed Central

    Park, Young Mi

    2016-01-01

    Breast plasmacytoma is an extremely rare tumor. It can occur as a primary isolated tumor or as an extramedullary manifestation in multiple myeloma. This report describes the unusual case of a primary extramedullary plasmacytoma that progressed to multiple myeloma within 15 months in a 35-year-old woman. The patient had been initially diagnosed with a primary extramedullary plasmacytoma of the epidural soft tissue at the cervical 6-thoracic 1 spine level and the stomach. The patient had received chemotherapy and the disease had been in remission. One year later, the disease recurred, affecting both breasts, right clavicle, and orbit. Three months later, the disease had progressed to multiple myeloma. I report this case, focusing on the findings of mammography, ultrasonography, magnetic resonance imaging, and positron emission tomography of bilateral breast plasmacytoma, and provide a review of the literature. PMID:26925106

  10. Gallium-67 demonstration of extensive soft-tissue involvement of multiple myeloma.

    PubMed

    Hosono, Makoto; Machida, Kikuo; Inoue, Yusuke; Honda, Norinari; Takahashi, Takeo; Kashimada, Akio; Ohtawa, Nobuyuki; Ohno, Hitoshi; Yamano, Takafumi

    2003-02-01

    A 46-year-old woman with multiple myeloma presented with neurological symptoms in the right upper extremity. After MR imaging of the cervical spine failed to show the cause of her symptoms, Ga-67 scintigraphy demonstrated increased uptake in multiple areas including the right supraclavicular region and bilateral lower extremities. Histology of the specimen obtained from the left thigh proved soft-tissue involvement of myeloma, and extensive extramedullary involvement was diagnosed. Radiotherapy to the right supraclavicular mass relieved her symptoms. Although Ga-67 scintigraphy is generally considered of limited value in multiple myeloma, this modality contributed to the development of an appropriate strategy in this patient with extensive extramedullary involvement. PMID:12691134

  11. Acquired von Willebrand disease and multiple myeloma: a case report of a breast cancer survivor.

    PubMed

    Jin, Ning; Salahuddin, Farah F; Nesbitt, John A

    2014-12-01

    Acquired von Willebrand disease (aVWD) is rare disease and is associated with a variety of underlying diseases. We report a case of aVWD in the setting of multiple myeloma. The patient was a 63-year-old female with breast cancer in remission who was admitted for symptomatic anemia. She was diagnosed with multiple myeloma. She also had subcutaneous bleeding before admission. Laboratory studies revealed isolated prolongation of the activated partial thromboplastin time, which corrected in a mixing study. Her factor VIII activity, von Willebrand factor (VWF) Ag, and VWF activity were low. VWF multimer study confirmed the patient had aVWD. The treatment of aVWD is discussed in this article, including the treatment of underlying diseases, and acute management in emergent situations. An intriguing question in this case is whether the patient's multiple myeloma is a chemotherapy-induced hematological malignancy or a second primary malignancy. PMID:24911454

  12. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  13. miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression

    PubMed Central

    Seckinger, Anja; MeiΔner, Tobias; Moreaux, Jérôme; Benes, Vladimir; Hillengass, Jens; Castoldi, Mirco; Zimmermann, Jürgen; Ho, Anthony D.; Jauch, Anna; Goldschmidt, Hartmut; Klein, Bernard; Hose, Dirk

    2015-01-01

    Purpose microRNAs regulate gene-expression in biological and pathophysiological processes, including multiple myeloma. Here we address i) What are the number and magnitude of changes in miRNA-expression between normal plasma cells and myeloma- or MGUS-samples, and the latter two? ii) What is the biological relevance and how does miRNA-expression impact on gene-expression? iii) Is there a prognostic significance, and what is its background? Experimental design Ninety-two purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line-samples were investigated using miChip-arrays interrogating 559 human miRNAs. Impact on gene-expression was assessed by Affymetrix DNA-microarrays in two cohorts of myeloma patients (n = 677); chromosomal aberrations were assessed by iFISH, survival for 592 patients undergoing up-front high-dose chemotherapy. Results Compared to normal plasma cells, 67/559 miRNAs (12%) with fold changes of 4.6 to −3.1 are differentially expressed in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS and myeloma. Expression of miRNAs is associated with proliferation, chromosomal aberrations, tumor mass, and gene expression-based risk-scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free and overall survival, as do respective target-gene signatures. Conclusions The myeloma-miRNome confers a pattern of small changes of individual miRNAs impacting on gene-expression, biological functions, and survival. PMID:26472281

  14. Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients.

    PubMed

    Bianco, Mimma; Gasparri, Anna Maria; Colombo, Barbara; Curnis, Flavio; Girlanda, Stefania; Ponzoni, Maurilio; Bertilaccio, Maria Teresa Sabrina; Calcinotto, Arianna; Sacchi, Angelina; Ferrero, Elisabetta; Ferrarini, Marina; Chesi, Marta; Bergsagel, P Leif; Bellone, Matteo; Tonon, Giovanni; Ciceri, Fabio; Marcatti, Magda; Caligaris-Cappio, Federico; Corti, Angelo

    2016-04-01

    Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target. Cancer Res; 76(7); 1781-91. ©2016 AACR. PMID:26869462

  15. Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.

    PubMed

    Amodio, Nicola; Stamato, Maria Angelica; Gullà, Anna Maria; Morelli, Eugenio; Romeo, Enrica; Raimondi, Lavinia; Pitari, Maria Rita; Ferrandino, Ida; Misso, Gabriella; Caraglia, Michele; Perrotta, Ida; Neri, Antonino; Fulciniti, Mariateresa; Rolfo, Christian; Anderson, Kenneth C; Munshi, Nikhil C; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2016-06-01

    Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. ©2016 AACR. PMID:27196750

  16. Iodine I 131 Monoclonal Antibody BC8 Before Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma or Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-06-10

    Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent T-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma

  17. Nonsecretory Multiple Myeloma and AL Amyloidosis Presenting with Nephrotic Range Proteinuria

    PubMed Central

    Beyler Kilic, Ozlem; Oguz, Ali Kemal; Ergun, Ihsan; Baydar, Dilek Ertoy; Ayli, Meltem

    2015-01-01

    Nonsecretory multiple myeloma (NSMM) is the absence of a detectable monoclonal protein in serum and urine of a multiple myeloma (MM) patient and immunoglobulin light chain (AL) amyloidosis is a significantly rare complication. A case of NSMM with AL amyloidosis and nephrotic range proteinuria is presented. Sharing clinical, therapeutic, and prognostic characteristics with MM, real challenge may be during initial diagnosis of NSMM and assessment of treatment response. In elderly patients with unexplained renal dysfunction, MM should be in the differential diagnosis and the absence of a monoclonal protein should not rule out MM but should remind us of the possibility of NSMM. PMID:26090243

  18. Advances in targeted therapy for the treatment of patients with relapsed/refractory multiple myeloma.

    PubMed

    Le Ray, Emmanuelle; Jagannath, Sundar; Palumbo, Antonio

    2016-01-01

    The development of proteasome inhibitors (PIs) and immunomodulatory drugs has significantly improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM); however, not all patients benefit from treatment with these agents and some patients can become drug refractory over time. Due to the largely incurable nature of multiple myeloma, the development of newer agents is ongoing and includes new oral PIs (ixazomib), immunotherapies (e.g., CD38- or SLAMF7-targeted antibodies), and small molecules. This review provides an overview of the advances in targeted therapy for patients with RRMM, including recently approved agents, with a focus on monotherapy and combined targeted therapies. PMID:26558304

  19. Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome

    PubMed Central

    Lippi, I.; Perondi, F.; Ross, S.J.; Marchetti, V.; Lubas, G.; Guidi, G.

    2015-01-01

    A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05) reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma. PMID:26623375

  20. [Clinical study on the effect of human lymphoblastoid interferon in multiple myeloma].

    PubMed

    Takeyama, H; Yano, K; Kataoka, T; Yamamoto, M; Emi, N; Kodera, Y; Kawashima, K; Ohno, R; Yokomaku, S; Kobayashi, M

    1983-09-01

    Ten patients with multiple myeloma were treated with human lymphoblastoid interferon (HLBI). The dosages used were 3 X 10(6) IU to 6 X 10(6) IU of HLBI intramuscularly daily. Out of eight evaluable patients, one partial remission and 3 minor response were observed. More than half patients experienced fever exceeding 38 degrees C and mild myelosuppression. Other toxic effects consisted of anorexia, malaise, liver dysfunction and skin rash. On the basis of our preliminary study, we conclude that HLBI is an effective agent against multiple myeloma. PMID:6614939

  1. Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenströms Macroglobulinemia.

    PubMed

    Laubach, Jacob P; Mitsiades, Constantine S; Roccaro, Aldo M; Ghobrial, Irene M; Anderson, Kenneth C; Richardson, Paul G

    2009-05-01

    Rapid development of the small molecule proteasome inhibitor bortezomib has yielded important clinical benefit for patients with multiple myeloma. Early phase clinical trials suggest the agent has similar efficacy in Waldenströms Macroglobulinemia. Optimization of bortezomib-based therapy, though, requires an understanding of the various challenges associated with use of the drug. This review highlights the rationale for bortezomib therapy in patients with multiple myeloma and Waldenströms Macroglobulinemia, mechanisms of bortezomib resistance, important therapy-related side effects, and new directions for the use of proteasome inhibitors in these disorders. PMID:19452315

  2. The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease

    PubMed Central

    Brandl, Andreas; Müller, Marc; Hofbauer, Lorenz C.; Beilhack, Andreas; Ebert, Regina; Glüer, Claus C.; Tiwari, Sanjay; Schütze, Norbert; Jakob, Franz

    2016-01-01

    Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment. PMID:27158817

  3. Mesenchymal stem cells secretomes' affect multiple myeloma translation initiation.

    PubMed

    Marcus, H; Attar-Schneider, O; Dabbah, M; Zismanov, V; Tartakover-Matalon, S; Lishner, M; Drucker, L

    2016-06-01

    Bone marrow mesenchymal stem cells' (BM-MSCs) role in multiple myeloma (MM) pathogenesis is recognized. Recently, we have published that co-culture of MM cell lines with BM-MSCs results in mutual modulation of phenotype and proteome (via translation initiation (TI) factors eIF4E/eIF4GI) and that there are differences between normal donor BM-MSCs (ND-MSCs) and MM BM-MSCs (MM-MSCs) in this crosstalk. Here, we aimed to assess the involvement of soluble BM-MSCs' (ND, MM) components, more easily targeted, in manipulation of MM cell lines phenotype and TI with specific focus on microvesicles (MVs) capable of transferring critical biological material. We applied ND and MM-MSCs 72h secretomes to MM cell lines (U266 and ARP-1) for 12-72h and then assayed the cells' (viability, cell count, cell death, proliferation, cell cycle, autophagy) and TI (factors: eIF4E, teIF4GI; regulators: mTOR, MNK1/2, 4EBP; targets: cyclin D1, NFκB, SMAD5, cMyc, HIF1α). Furthermore, we dissected the secretome into >100kDa and <100kDa fractions and repeated the experiments. Finally, MVs were isolated from the ND and MM-MSCs secretomes and applied to MM cell lines. Phenotype and TI were assessed. Secretomes of BM-MSCs (ND, MM) significantly stimulated MM cell lines' TI, autophagy and proliferation. The dissected secretome yielded different effects on MM cell lines phenotype and TI according to fraction (>100kDa- repressed; <100kDa- stimulated) but with no association to source (ND, MM). Finally, in analyses of MVs extracted from BM-MSCs (ND, MM) we witnessed differences in accordance with source: ND-MSCs MVs inhibited proliferation, autophagy and TI whereas MM-MSCs MVs stimulated them. These observations highlight the very complex communication between MM and BM-MSCs and underscore its significance to major processes in the malignant cells. Studies into the influential MVs cargo are underway and expected to uncover targetable signals in the regulation of the TI/proliferation/autophagy cascade

  4. Recreational physical activity, leisure sitting time and risk of non-Hodgkin lymphoid neoplasms in the American Cancer Society Cancer Prevention Study II Cohort.

    PubMed

    Teras, Lauren R; Gapstur, Susan M; Diver, W Ryan; Birmann, Brenda M; Patel, Alpa V

    2012-10-15

    Results of studies that examined the relationship between physical activity and non-Hodgkin lymphoid neoplasms (NHL) are inconsistent, and only one study to date examined time spent sitting in relation to NHL. We examined recreational physical activity and leisure-time sitting in relation to risk of NHL in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Between 1992 and 2007, 2,002 incident cases were identified among 146,850 participants who were cancer-free at enrollment. Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) while adjusting for potential confounders. Women who sat for at least 6 hr/day were at 28% higher risk of NHL compared to women who sat for fewer than 3 hr/day. In analyses of specific subtypes, sitting time was associated with risk of multiple myeloma only (6+ vs. 3 hr/day sitting: HR = 2.40, 95% CI: 1.45-3.97). Women who engaged in any recreational physical activity had a nonsignificant 20%-30% lower risk of NHL (p-trend = 0.05) compared to women who reported no recreational physical activity. Neither leisure-time sitting nor recreational physical activity was associated with risk of NHL or major NHL subtype in men. There was no evidence of statistical interaction between physical activity and sitting time, or between body mass index and physical activity or sitting time. Further research is needed to confirm an association between sitting time and multiple myeloma and explore a possible association between physical activity and NHL. PMID:22275172

  5. Vulvar amyloidosis mimicking giant condylomata acuminata in a patient with multiple myeloma.

    PubMed

    Konig, A; Wennemuth, G; Soyer, H P; Hoffmann, R; Happle, R; Krause, W

    1999-01-01

    We report a case of unusual cutaneous amyloidosis involving the vulva in a patient with multiple myeloma. Genital examination revealed a dense agglomeration of verrucous papules and pedunculated condyloma-like tumors. The correct diagnosis was established by immunohistochemical examinations that visualized large amounts of lambda light chains, whereas no reaction was detected for kappa light chains or human papilloma virus. In this way, the differential diagnosis of condylomata acuminata could be ruled out. Condyloma-like lesions have been described in patients suffering from multiple myeloma, but the present case is unusual because of the extensive involvement. Vulvar amyloidosis should be added to the list of possible presentations of myeloma-associated systemic amyloidoses. PMID:9920983

  6. Exposure to hair-coloring products and the risk of multiple myeloma.

    PubMed

    Herrinton, L J; Weiss, N S; Koepsell, T D; Daling, J R; Taylor, J W; Lyon, J L; Swanson, G M; Greenberg, R S

    1994-07-01

    An interview study of persons diagnosed with multiple myeloma between 1977 and 1981 and suitable control subjects was conducted to test the hypothesis that exposure to hair dyes increases the risk of multiple myeloma. Among women, there was little evidence that prior regular use of hair dyes (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.70, 1.4) or prior employment as a hairdresser (OR = 1.1; 95% CI = 0.43, 2.7) increased risk; however, the former comparison was limited by the lack of detailed information concerning the exposure. Among men, there was a modest association of regular use of hair dyes (OR = 1.5; 95% CI = 0.75, 2.9) with myeloma, but this was based on a small number of exposed persons. PMID:8017540

  7. Exploration for the multi-effect of cardamom in's resistance to multiple myeloma.

    PubMed

    Zhihua, Zhao; Jianping, Yang; Miaomiao, Sun; Kuisheng, Chen

    2014-11-01

    This paper aimed to probe the cardamom in effect on the viability, proliferation, apoptosis and periodic function of the multiple myeloma, and explore its mechanism. We used CCK-8 method to evaluate the effect of cardamom in on the viability of PBMNCs (Persom Blood Mononuclear Normal Cells). EdU can test the influence of small cell proliferation. We used the method of PI single-staining flow cytometry, in order to test the influence of tumor cell cycle. AO (Acridine Orange), EB (Ethidium Bromide) double staining fluorescene microscope was applied to observe the influence of tumor apoptotic morphology. It can be concluded that cardamom in can inhibit the viability and proliferation of MM (Multiple Myeloma) cells and cardamom in is the anti-myeloma drug with strong viability. PMID:25410063

  8. Incidental Discovery of a Testicular Plasmacytoma at Initial Presentation of Multiple Myeloma

    PubMed Central

    Hathaway, Amanda R.

    2013-01-01

    Testicular plasmacytomas are a rare phenomenon reported in the literature and they can occur as a solitary plasmacytoma, as a recurrence of multiple myeloma, or concurrently in an active myeloma. We report the case of a 43-year-old man who presented with back pain and was diagnosed with multiple myeloma. A CT scan performed to determine the extent of disease revealed an incidental mass in the testicle. Immunohistochemical staining of the mass revealed monoclonal cytolpasmic IgA in the tumor cells and serum studies showed this same immunoglobulin. Following orchiectomy, radiotherapy to the vertebra, chemotherapy with bortezomib, dexamethasone, and doxorubicin, and an autologous bone marrow transplant, the patient is alive twelve months after diagnosis and is in complete remission. PMID:23738163

  9. The use of novel agents in multiple myeloma patients with hepatic impairment.

    PubMed

    Stansfield, Lindsay C; Gonsalves, Wilson I; Buadi, Francis K

    2015-01-01

    Novel drugs such as immunomodulators and proteasome inhibitors have improved the survival of patients with multiple myeloma. Like all therapeutic agents, appropriate dosing based on metabolism and clearance is important to maintain efficacy while avoiding toxicity. Hepatic impairment (HI) in multiple myeloma patients is rare but well described either due to disease or therapy-related factors. However, limited data are available on the appropriate use and dosing of the novel agent therapeutics in myeloma patients with HI. Furthermore, data on HI secondary to the novel agent toxicity are also sparse. This systematic review highlights the evidence on the use of novel agents like thalidomide, lenalidomide, pomalidomide, bortezomib and carfilzomib in patients with HI as well as their associated hepatic toxicities. PMID:25675129

  10. The use of novel agents in multiple myeloma patients with hepatic impairment

    PubMed Central

    Stansfield, Lindsay C; Gonsalves, Wilson I; Buadi, Francis K

    2015-01-01

    Novel drugs such as immunomodulators and proteasome inhibitors have improved the survival of patients with multiple myeloma. Like all therapeutic agents, appropriate dosing based on metabolism and clearance is important to maintain efficacy while avoiding toxicity. Hepatic impairment (HI) in multiple myeloma patients is rare but well described either due to disease or therapy-related factors. However, limited data are available on the appropriate use and dosing of the novel agent therapeutics in myeloma patients with HI. Furthermore, data on HI secondary to the novel agent toxicity are also sparse. This systematic review highlights the evidence on the use of novel agents like thalidomide, lenalidomide, pomalidomide, bortezomib and carfilzomib in patients with HI as well as their associated hepatic toxicities. PMID:25675129

  11. [Clinical effect of human lymphoblastoid interferon in patients with multiple myeloma].

    PubMed

    Yoshida, M; Ohta, M; Muroi, K; Takeda, K; Kitagawa, S; Tsuboyama, A; Sakamoto, S; Miura, Y; Mutoh, Y

    1984-07-01

    Five patients with multiple myeloma were treated with human lymphoblastoid interferon (HLBI). HLBI, 3 X 10(6) IU/day, was administered daily for more than two weeks by intramuscular injection. Out of four evaluable patients, a minor response was obtained in 3 patients. In these responders, one patient developed pleural effusion due to the infiltration of myeloma cells during the administration of HLBI, and drug resistance was observed in another patient during the re-administration of HLBI. Therefore, out of six evaluable courses, a minor response was obtained in 3 courses of HLBI treatment. No severe side effects were observed. Thrombocytopenia, general malaise, liver dysfunction and anorexia were the main reasons for discontinuation of HLBI administration. On the basis of the preliminary study, it is concluded that HLBI is worth trying in the management of refractory multiple myeloma. PMID:6742866

  12. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group

    PubMed Central

    Avet-Loiseau, Hervé; Lonial, Sagar; Usmani, Saad; Siegel, David; Anderson, Kenneth C.; Chng, Wee-Joo; Moreau, Philippe; Attal, Michel; Kyle, Robert A.; Caers, Jo; Hillengass, Jens; San Miguel, Jesús; van de Donk, Niels W. C. J.; Einsele, Hermann; Bladé, Joan; Durie, Brian G. M.; Goldschmidt, Hartmut; Mateos, María-Victoria; Palumbo, Antonio; Orlowski, Robert

    2016-01-01

    The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification. PMID:27002115

  13. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group.

    PubMed

    Sonneveld, Pieter; Avet-Loiseau, Hervé; Lonial, Sagar; Usmani, Saad; Siegel, David; Anderson, Kenneth C; Chng, Wee-Joo; Moreau, Philippe; Attal, Michel; Kyle, Robert A; Caers, Jo; Hillengass, Jens; San Miguel, Jesús; van de Donk, Niels W C J; Einsele, Hermann; Bladé, Joan; Durie, Brian G M; Goldschmidt, Hartmut; Mateos, María-Victoria; Palumbo, Antonio; Orlowski, Robert

    2016-06-16

    The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification. PMID:27002115

  14. Association between simian virus 40 and non-Hodgkin lymphoma

    NASA Technical Reports Server (NTRS)

    Vilchez, Regis A.; Madden, Charles R.; Kozinetz, Claudia A.; Halvorson, Steven J.; White, Zoe S.; Jorgensen, Jeffrey L.; Finch, Chris J.; Butel, Janet S.

    2002-01-01

    BACKGROUND: Non-Hodgkin lymphoma has increased in frequency over the past 30 years, and is a common cancer in HIV-1-infected patients. Although no definite risk factors have emerged, a viral cause has been postulated. Polyomaviruses are known to infect human beings and to induce tumours in laboratory animals. We aimed to identify which one of the three polyomaviruses able to infect human beings (simian virus 40 [SV40], JC virus, and BK virus) was associated with non-Hodgkin lymphoma. METHODS: We analysed systemic non-Hodgkin lymphoma from 76 HIV-1-infected and 78 HIV-1-uninfected patients, and non-malignant lymphoid samples from 79 HIV-1-positive and 107 HIV-1-negative patients without tumours; 54 colon and breast carcinoma samples served as cancer controls. We used PCR followed by Southern blot hybridisation and DNA sequence analysis to detect DNAs of polyomaviruses and herpesviruses. FINDINGS: Polyomavirus T antigen sequences, all of which were SV40-specific, were detected in 64 (42%) of 154 non-Hodgkin lymphomas, none of 186 non-malignant lymphoid samples, and none of 54 control cancers. This difference was similar for HIV-1-infected patients and HIV-1-uninfected patients alike. Few tumours were positive for both SV40 and Epstein-Barr virus. Human herpesvirus type 8 was not detected. SV40 sequences were found most frequently in diffuse large B-cell and follicular-type lymphomas. INTERPRETATION: SV40 is significantly associated with some types of non-Hodgkin lymphoma. These results add lymphomas to the types of human cancers associated with SV40.

  15. Prediagnostic immunoglobulin E levels and risk of chronic lymphocytic leukemia, other lymphomas and multiple myeloma-results of the European Prospective Investigation into Cancer and Nutrition.

    PubMed

    Nieters, Alexandra; Łuczyńska, Anna; Becker, Susen; Becker, Nikolaus; Vermeulen, Roel; Overvad, Kim; Aleksandrova, Krasimira; Boeing, Heiner; Lagiou, Pagona; Trichopoulos, Dimitrios; Trichopoulou, Antonia; Krogh, Vittorio; Masala, Giovanna; Panico, Salvatore; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, Bas; Jeurnink, Suzanne M; Weiderpass, Elisabete; Ardanaz, Eva; Chirlaque, Maria-Dolores; Sánchez, María-José; Sánchez, Soledad; Borgquist, Signe; Butt, Salma; Melin, Beatrice; Späth, Florentin; Rinaldi, Sabina; Brennan, Paul; Kelly, Rachel S; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolf

    2014-12-01

    Previous epidemiological studies suggest an inverse association between allergies, marked by elevated immunoglobulin (Ig) E levels, and non-Hodgkin lymphoma (NHL) risk. The evidence, however, is inconsistent and prospective data are sparse. We examined the association between prediagnostic total (low: <20; intermediate: 20-100; high >100 kU/l) and specific IgE (negative: <0.35; positive ≥0.35 kU/I) concentrations against inhalant antigens and lymphoma risk in a study nested within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 1021 incident cases and matched controls of NHL, multiple myeloma (MM) and Hodgkin lymphoma with a mean follow-up time of 7 years were investigated. Multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CI) were calculated by conditional logistic regression. Specific IgE was not associated with the risk of MM, B-cell NHL and B-cell NHL subtypes. In contrast, total IgE levels were inversely associated with the risk of MM [high level: OR = 0.40 (95% CI = 0.21-0.79)] and B-cell NHL [intermediate level: OR = 0.68 (95% CI = 0.53-0.88); high level: OR = 0.62 (95% CI = 0.44-0.86)], largely on the basis of a strong inverse association with chronic lymphocytic leukemia [CLL; intermediate level: OR = 0.49 (95% CI = 0.30-0.80); high level: OR = 0.13 (95% CI = 0.05-0.35)] risk. The inverse relationship for CLL remained significant for those diagnosed 5 years after baseline. The findings of this large prospective study demonstrated significantly lower prediagnostic total IgE levels among CLL and MM cases compared with matched controls. This corresponds to the clinical immunodeficiency state often observed in CLL patients prior to diagnosis. No support for an inverse association between prediagnostic levels of specific IgE and NHL risk was found. PMID:25269801

  16. Spinal focal lesion detection in multiple myeloma using multimodal image features

    NASA Astrophysics Data System (ADS)

    Fränzle, Andrea; Hillengass, Jens; Bendl, Rolf

    2015-03-01

    Multiple myeloma is a tumor disease in the bone marrow that affects the skeleton systemically, i.e. multiple lesions can occur in different sites in the skeleton. To quantify overall tumor mass for determining degree of disease and for analysis of therapy response, volumetry of all lesions is needed. Since the large amount of lesions in one patient impedes manual segmentation of all lesions, quantification of overall tumor volume is not possible until now. Therefore development of automatic lesion detection and segmentation methods is necessary. Since focal tumors in multiple myeloma show different characteristics in different modalities (changes in bone structure in CT images, hypointensity in T1 weighted MR images and hyperintensity in T2 weighted MR images), multimodal image analysis is necessary for the detection of focal tumors. In this paper a pattern recognition approach is presented that identifies focal lesions in lumbar vertebrae based on features from T1 and T2 weighted MR images. Image voxels within bone are classified using random forests based on plain intensities and intensity value derived features (maximum, minimum, mean, median) in a 5 x 5 neighborhood around a voxel from both T1 and T2 weighted MR images. A test data sample of lesions in 8 lumbar vertebrae from 4 multiple myeloma patients can be classified at an accuracy of 95% (using a leave-one-patient-out test). The approach provides a reasonable delineation of the example lesions. This is an important step towards automatic tumor volume quantification in multiple myeloma.

  17. Lenalidomide for the treatment of relapsed and refractory multiple myeloma

    PubMed Central

    van de Donk, Niels WCJ; Görgün, Güllü; Groen, Richard WJ; Jakubikova, Jana; Mitsiades, Constantine S; Hideshima, Teru; Laubach, Jacob; Nijhof, Inger S; Raymakers, Reinier A; Lokhorst, Henk M; Richardson, Paul G; Anderson, Kenneth C

    2012-01-01

    Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy. PMID:22956884

  18. The use of animal models in multiple myeloma.

    PubMed

    Libouban, H

    2015-06-01

    In myeloma, the understanding of the tissular, cellular and molecular mechanisms of the interactions between tumor plasma cells and bone cells have progressed from in vitro and in vivo studies. However none of the known animal models of myeloma reproduce exactly the human form of the disease. There are currently three types of animal models: (1) injection of pristane oil in BALB/c mice leads to intraperitoneal plasmacytomas but without bone marrow colonization and osteolysis; (2) injection of malignant plasma cell lines in immunodeficient mice SCID or NOD/SCID; the use of the SCID-hu or SCID-rab model allows the use of fresh plasma cells obtained from MM patients; (3) injection of allogeneic malignant plasma cells (5T2MM, 5T33) in the C57BL/KalwRij mouse induces bone marrow proliferation and osteolytic lesions. These cells did not grow in vitro and can be propagated by injection of plasma cells isolated from bone marrow of a mouse at end stage of the disease into young recipient mice. The 5TGM1 is a subclone of 5T33MM cells and can grow in vitro. Among the different models, the 5TMM models and SCID-hu/SCID-rab models were extensively used to test pathophysiological hypotheses and to assess anti-osteoclastic, anti-osteoblastic or anti-tumor therapies in myeloma. In the present review, we report the different types of animal models of MM and describe their interests and limitations. PMID:25898798

  19. Cord Blood Transplantation for Multiple Myeloma: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    PubMed

    Kawamura, Koji; Takamatsu, Hiroyuki; Ikeda, Takashi; Komatsu, Tsunehiko; Aotsuka, Nobuyuki; Amano, Itsuto; Yamamoto, Go; Watanabe, Kentaro; Ohno, Yuju; Matsue, Kosei; Kouzai, Yasuji; Tsukada, Nobuhiro; Ishiyama, Ken; Anzai, Naoyuki; Kato, Koji; Suzuki, Ritsuro; Sunami, Kazutaka; Kanda, Yoshinobu

    2015-07-01

    Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC-CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC-CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies. PMID:25708214

  20. Primary extra nodal non-Hodgkin's lymphoma of the oral cavity in a young girl

    PubMed Central

    Vinoth, Ponnurangam N.; Selvan, Sathyamoorthi Muthamil; Sahni, Latika; Krishnaratnam, Kannan; Rajendiran, Swaminathan; Anand, Chidambaram Vishwanath; Scott, Julius X.

    2012-01-01

    Primary Non Hodgkin s Lymphoma (NHL) usually arises within the lymphnodes, but 20-30% account for extra nodal sites. Oral cavity, as a primary extra nodal site for NHL, is relatively rare and diverse in presentation, response to therapy and prognosis. We report a 14 year old adolescent girl who presented with multiple gingival swellings, the most prominent one being in the right anterior maxilla. Gingival biopsy showed NHL- diffuse large B cell type. Child was completely cured with chemotherapy and now she is in complete remission and under regular follow up. PMID:23833495

  1. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | Office of Cancer Genomics

    Cancer.gov

    In a recent Nature article, Morin et al. uncovered a novel role for chromatin modification in driving the progression of two non-Hodgkin lymphomas (NHLs), follicular lymphoma and diffuse large B-cell lymphoma. Through DNA and RNA sequencing of 117 tumor samples and 10 assorted cell lines, the authors identified and validated 109 genes with multiple mutations in these B-cell NHLs. Of the 109 genes, several genes not previously linked to lymphoma demonstrated positive selection for mutation including two genes involved in histone modification, MLL2 and MEF2B.

  2. The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

    PubMed Central

    Walz, Simon; Kowalewski, Daniel Johannes; Schuster, Heiko; Weisel, Katja; Backert, Linus; Kahn, Stefan; Nelde, Annika; Stroh, Tatjana; Handel, Martin; Kohlbacher, Oliver; Kanz, Lothar; Salih, Helmut Rainer; Rammensee, Hans-Georg; Stevanović, Stefan

    2015-01-01

    Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM. PMID:26138685

  3. The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy.

    PubMed

    Walz, Simon; Stickel, Juliane S; Kowalewski, Daniel Johannes; Schuster, Heiko; Weisel, Katja; Backert, Linus; Kahn, Stefan; Nelde, Annika; Stroh, Tatjana; Handel, Martin; Kohlbacher, Oliver; Kanz, Lothar; Salih, Helmut Rainer; Rammensee, Hans-Georg; Stevanović, Stefan

    2015-09-01

    Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM. PMID:26138685

  4. A virtual approach to evaluate therapies for management of multiple myeloma induced bone disease

    PubMed Central

    Genever, Paul G.; Fagan, Michael J.

    2015-01-01

    Summary Multiple myeloma bone disease is devastating for patients and a major cause of morbidity. The disease leads to bone destruction by inhibiting osteoblast activity while stimulating osteoclast activity. Recent advances in multiple myeloma research have improved our understanding of the pathogenesis of multiple myeloma‐induced bone disease and suggest several potential therapeutic strategies. However, the effectiveness of some potential therapeutic strategies still requires further investigation and optimization. In this paper, a recently developed mathematical model is extended to mimic and then evaluate three therapies of the disease, namely: bisphosphonates, bortezomib and TGF‐β inhibition. The model suggests that bisphosphonates and bortezomib treatments not only inhibit bone destruction, but also reduce the viability of myeloma cells. This contributes to the current debate as to whether bisphosphonate therapy has an anti‐tumour effect. On the other hand, the analyses indicate that treatments designed to inhibit TGF‐β do not reduce bone destruction, although it appears that they might reduce the viability of myeloma cells, which again contributes to the current controversy regarding the efficacy of TGF‐β inhibition in multiple myeloma‐induced bone disease. © 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd. PMID:26198466

  5. Pancytopenia in Multiple Myeloma- An Enigma: Our Experience from Tertiary Care Hospital

    PubMed Central

    Sridevi, Hanaganahalli B; Rai, Sharada; Somesh, Meludurgamutt S; Minal, Jessica

    2015-01-01

    Introduction Multiple myeloma is a plasma cell neoplasm that is characterized by clonal proliferation of malignant plasma cell in the bone marrow along with M-protein in the serum and/or urine. Pancytopenia as a initial presentation of multiple myeloma is quite unusual. We are presenting a case series having pancytopenia as the presenting complaint. Materials and Methods A retrospective study was conducted for a period of 30 months, wherein all the cases of multiple myeloma presenting with pancytopenia were included. The complete blood picture, peripheral smear examination, bone marrow aspirate & protein electrophoresis of all the cases were reviewed & analysed. Results During the study period, 10 cases presented with pancytopenia with a mean age of 66.3 years (range: 59-72 years) at presentation with male: female ratio being 8:2. Fatigue and weakness was the most common symptom (100%) & average ESR was 104 mm/hour. High-resolution serum electrophoresis, showed a dense, sharp to wide M band in the gamma globulin region. Bone marrow plasma cell percentage was increased with an average of 63.1%. Bone marrow biopsy correlation was obtained in 100% cases. Conclusion Diagnosing multiple myeloma, presenting as pancytopenia requires a high degree of suspicion to avoid delay in initiation of treatment. PMID:26673280

  6. C/EBPβ regulates transcription factors critical for proliferation and survival of multiple myeloma cells

    PubMed Central

    Pal, Rekha; Janz, Martin; Galson, Deborah L.; Gries, Margarete; Li, Shirong; Jöhrens, Korinna; Anagnostopoulos, Ioannis; Dörken, Bernd; Mapara, Markus Y.; Borghesi, Lisa; Kardava, Lela; Roodman, G. David; Milcarek, Christine

    2009-01-01

    CCAAT/enhancer-binding protein β (C/EBPβ), also known as nuclear factor–interleukin-6 (NF-IL6), is a transcription factor that plays an important role in the regulation of growth and differentiation of myeloid and lymphoid cells. Mice deficient in C/EBPβ show impaired generation of B lymphocytes. We show that C/EBPβ regulates transcription factors critical for proliferation and survival in multiple myeloma. Multiple myeloma cell lines and primary multiple myeloma cells strongly expressed C/EBPβ, whereas normal B cells and plasma cells had little or no detectable levels of C/EBPβ. Silencing of C/EBPβ led to down-regulation of transcription factors such as IRF4, XBP1, and BLIMP1 accompanied by a strong inhibition of proliferation. Further, silencing of C/EBPβ led to a complete down-regulation of antiapoptotic B-cell lymphoma 2 (BCL2) expression. In chromatin immunoprecipitation assays, C/EBPβ directly bound to the promoter region of IRF4, BLIMP1, and BCL2. Our data indicate that C/EBPβ is involved in the regulatory network of transcription factors that are critical for plasma cell differentiation and survival. Targeting C/EBPβ may provide a novel therapeutic strategy in the treatment of multiple myeloma. PMID:19717648

  7. Discovery – Velcade®: A New Tool in the Fight against Multiple Myeloma

    Cancer.gov

    Velcade® represents a new type of anticancer drug called proteasome inhibitors. It has shown promise in the treatment of multiple myeloma, a cancer of the white blood cells. Velcade® is being studied for use in a variety of blood cancers and solid tumors.

  8. Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

    PubMed Central

    Mussap, Michele; Merlini, Giampaolo

    2014-01-01

    The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function. PMID:24877060

  9. Effectiveness of percutaneous vertebroplasty in patients with multiple myeloma having vertebral pain

    PubMed Central

    Nas, Ömer Fatih; İnecikli, Mehmet Fatih; Hacıkurt, Kadir; Büyükkaya, Ramazan; Özkaya, Güven; Özkalemkaş, Fahir; Ali, Rıdvan; Erdoğan, Cüneyt; Hakyemez, Bahattin

    2016-01-01

    PURPOSE We aimed to assess the effectiveness, benefits, and reliability of percutaneous vertebroplasty (PV) in patients with vertebral involvement of multiple myeloma. METHODS PV procedures performed on 166 vertebrae of 41 patients with multiple myeloma were retrospectively evaluated. Most of our patients were using level 3 (moderate to severe pain) analgesics. Magnetic resonance imaging was performed before the procedure to assess vertebral involvement of multiple myeloma. The following variables were evaluated: affected vertebral levels, loss of vertebral body height, polymethylmethacrylate (PMMA) cement amount applied to the vertebral body during PV, PMMA cement leakages, and pain before and after PV as assessed by a visual analogue scale (VAS). RESULTS Median VAS scores of patients decreased from 9 one day before PV, to 6 one day after the procedure, to 3 one week after the procedure, and eventually to 1 three months after the procedure (P < 0.001). During the PV procedure, cement leakage was observed at 68 vertebral levels (41%). The median value of PMMA applied to the vertebral body was 6 mL. CONCLUSION Being a minimally invasive and easily performed procedure with low complication rates, PV should be preferred for serious back pain of multiple myeloma patients. PMID:26912107

  10. The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

    PubMed Central

    Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

    2015-01-01

    Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

  11. Case report: gallium study showing a rare form of multiple myeloma

    SciTech Connect

    Meyers, E.; Kasner, J.R.

    1981-12-01

    A case study is presented in which a rare form of multiple myeloma with soft tissue involvememt was diagnosed by a gallium scan using 3 mCi of Ga-67 citrate. Subsequent resting cardiac blood pool images suggested pericardial rather than myocardial involvement. (JMT)

  12. In anemia of multiple myeloma hepcidin is induced by increased bone-morphogenetic protein-2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hepcidin is the principal iron-regulatory hormone and pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contrib...

  13. Autophagy in multiple myeloma: what makes you stronger can also kill you.

    PubMed

    Carroll, Richard G; Martin, Seamus J

    2013-04-15

    Autophagy, a process for recycling cellular constituents, is normally associated with cell survival and is thought to be beneficial for tumor maintenance. However, in this issue of Cancer Cell, Lamy and colleagues report that multiple myeloma utilizes caspase-10 to restrain autophagy and undergoes autophagic cell death upon its removal or inhibition. PMID:23597558

  14. American Society of Hematology Annual Meeting 2014: highlights in multiple myeloma.

    PubMed

    Glavey, Siobhan V; Ghobrial, Irene M

    2015-06-01

    Multiple myeloma (MM) had a major presence at this meeting with 855 abstracts related to MM, 24 oral presentations and 106 posters. This, coupled with the record attendance at this year’s meeting, made it a positive year for patients and clinicians alike as much of the presented data are likely to lead to major advances in the field of myeloma. Key areas of focus included: high-risk smoldering disease, minimal residual disease for monitoring response to therapy, novel therapies in clinical trials, including carfilzomib and daratumumab, and imaging modalities for MM. PMID:25804827

  15. Endocarditis due to Gemella haemolysans in a newly diagnosed multiple myeloma patient.

    PubMed

    Liu, Dongyan; Bateman, Thomas; Carr, Elisabeth; Foster, Paul

    2016-01-01

    An 87-year-old Caucasian woman with hypertension, diabetes mellitus type 2, and COPD was admitted with 1-week duration of back pain and weight gain. The physical examination revealed jugular venous distention, rales in the left lower lung field, and severe pitting edema over lower extremities. As workup for leukocytosis, blood cultures grew Gemella haemolysans. Subsequently, a transthoracic echocardiogram revealed vegetation on the non-coronary aortic leaflet and mild aortic stenosis. She was treated with ampicillin and gentamicin. After further investigation, the patient was diagnosed with plasma cell myeloma, the monoclonal lambda type. This is the first reported case of G. haemolysans endocarditis in a multiple myeloma patient. PMID:27609731

  16. Dendritic Cell-Based Cancer Immunotherapy against Multiple Myeloma: From Bench to Clinic

    PubMed Central

    Hoang, My-Dung; Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Nguyen-Pham, Thanh-Nhan; Choi, Nu-Ri; Vo, Manh-Cuong; Lee, Seung-Shin; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon

    2015-01-01

    Although the introduction of stem cell transplantation and novel agents has improved survival, multiple myeloma (MM) is still difficult to cure. Alternative approaches are clearly needed to prolong the survival of patients with MM. Dendritic cell (DC) therapy is a very promising tool immunologically in MM. We developed a method to generate potent DCs with increased Th1 polarization and migration ability for inducing strong myeloma-specific cytotoxic T lymphocytes. In this review, we discuss how the efficacy of cancer immunotherapy using DCs can be improved in MM. PMID:25914874

  17. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    PubMed

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  18. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

    PubMed Central

    Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.

    2008-01-01

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  19. The RAG Model: A New Paradigm for Genetic Risk Stratification in Multiple Myeloma

    PubMed Central

    Prideaux, Steven M.; Conway O'Brien, Emma; Chevassut, Timothy J.

    2014-01-01

    Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based “traffic-light” risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient. PMID:25295194

  20. Plasma cell maturity as a predictor of prognosis in multiple myeloma.

    PubMed

    Iriyama, Noriyoshi; Miura, Katsuhiro; Hatta, Yoshihiro; Uchino, Yoshihito; Kurita, Daisuke; Takahashi, Hiromichi; Sakagami, Hitomi; Sakagami, Masashi; Kobayashi, Yujin; Nakagawa, Masaru; Ohtake, Shimon; Iizuka, Yoshikazu; Takei, Masami

    2016-08-01

    In this study, the impact of plasma cell maturity on the prognoses of multiple myeloma (MM) patients in the era of novel agents was investigated. Myeloma cell maturity was classified via immunophenotyping: myeloma cells showing mature plasma cell 1 (MPC-1)-positive and CD49e-positive cells were considered mature type; MPC-1-positive and CD49e-negative cells were considered intermediate type; and MPC-1-negative cells were considered immature type. This study included 87 newly diagnosed MM patients who were initially treated with bortezomib and/or chemotherapy. Myeloma cell maturity was a critical factor affecting overall survival (OS) in the cohort, with median OS not reached in mature-type, 50 months in intermediate-type, and 20 months in immature-type cells. Multivariate analysis showed that immature type and stage III according to the International Staging System were both independent prognostic factors affecting OS. The findings of this study demonstrate the clinical importance of myeloma cell classification according to immunophenotyping using MPC-1 and CD49e antibodies to determine patient prognosis in this era of novel therapeutic agents. PMID:27383407

  1. High incidence of intact or fragmented immunoglobulin in urine of patients with multiple myeloma.

    PubMed

    Kraj, Maria; Kruk, Barbara; Lech-Marańda, Ewa; Warzocha, Krzysztof; Prochorec-Sobieszek, Monika

    2015-01-01

    In this prospective study we determined the incidence of intact/fragmented immunoglobulin and Bence Jones protein in urine immunofixation using Sebia reagents and HydrasysTM 2 apparatus and compared the results to concentrations of serum free light chains (FLC) assessed using Siemens BNTM II nephelometer and the immunoassay Freelite (Binding Site) in 289 patients with multiple myeloma at diagnosis. It was found that in one third of IgG, IgA and IgD myeloma patients, intact/fragmented immunoglobulin can be detected in urine and is connected with impaired renal function and reduced survival. Urine immunofixation detects monoclonal protein (FLC and intact/fragmented immunoglobulin) in 66-79% of IgG and IgA myeloma patients while serum FLC immunoassay detect it in 82-94% of IgG and IgA myeloma patients. However, the latter method is inadequate for detection of intact/fragmented immunoglobulin in urine. Serum FLC immunoassay and urine immunofixation are complementary methods in diagnosing and monitoring monoclonal protein in patients with myeloma. PMID:25860239

  2. The RAG Model: A New Paradigm for Genetic Risk Stratification in Multiple Myeloma.

    PubMed

    Prideaux, Steven M; Conway O'Brien, Emma; Chevassut, Timothy J

    2014-01-01

    Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based "traffic-light" risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient. PMID:25295194

  3. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

    PubMed

    Franqui-Machin, Reinaldo; Wendlandt, Erik B; Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

    2015-12-01

    Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID:26415231

  4. Therapeutic monoclonal antibodies for multiple myeloma: an update and future perspectives

    PubMed Central

    Yang, Jing; Yi, Qing

    2011-01-01

    Multiple myeloma (MM) still remains incurable in most of the patients. Despite of treatments with high-dose chemotherapy, stem cell transplantation and other novel therapies, most patients will become refractory to the therapies and relapse. Thus, it is urgent to develop new approaches for MM treatment. Currently, antibody-targeted therapy has been extensively utilized in hematological malignancies, including MM. Several novel monoclonal antibodies (mAbs) against MM have been generated and developed over the past several years. These mAbs aim to target not only tumor cells alone but also tumor microenvironment, including interaction of tumor-bone marrow stromal cells and the components of bone marrow milieu, such as cytokines or chemokines that support myeloma cell growth and survival. These include mAbs specific for CD38, CS1, CD40, CD74, CD70, HM1.24, interleukin-6 and β2-microglobulin (β2M). We have shown that anti-β2M mAbs may be a potential antitumor agent for MM therapy due to their remarkable efficacy to induce myeloma cell apoptosis in tumor cell lines and primary myeloma cells from patients in vitro and in established myeloma mouse models. In this article, we will review advances in the development and mechanisms of MM-targeted mAbs and especially, anti-β2M mAbs. We will also discuss the potential application of the mAbs as therapeutic agents to treat MM. PMID:22065141

  5. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

    PubMed Central

    Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

    2015-01-01

    Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains – just like many other cancers – a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138−, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma “stemness”, the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID:26415231

  6. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma.

    PubMed

    de la Puente, Pilar; Azab, Feda; Muz, Barbara; Luderer, Micah; Arbiser, Jack; Azab, Abdel Kareem

    2016-07-01

    Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma. PMID:26421357

  7. Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry.

    PubMed

    Pessoa de Magalhães, Roberto J; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F; Orfao, Alberto

    2013-01-01

    Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8(+) T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes

  8. Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

    PubMed Central

    Pessoa de Magalhães, Roberto J.; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C.; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M.; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F.; Orfao, Alberto

    2013-01-01

    Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes

  9. A Rare Case of Multple Myeloma (Mm) Presented With Pancytopaenia in A Patient of HIV – At Very Early Age

    PubMed Central

    Soren, Manoj; Das, Anjan Kumar; Mangal, Srishtidhar

    2015-01-01

    Non-hodgkin`s lymphoma (NHL) is the most common haematological malignancy which is seen in HIV infected patients. Among NHLs, immunoblastic lymphomas are most common and a majority of these are diffuse large B-cell lymphomas. Multiple myeloma is a disease of the elderly. It is extremely rare below 30 years of age. On the other hand, in HIV infected individuals, the average age of presentation with plasma cell disorders is 33 years, which is far younger than the average age of presentation in general population. The incidence of AIDS defining malignancies has declined markedly, whereas non-AIDS defining cancers are being increasingly diagnosed in patients with HIV infection during the HAART-era and they may be the presenting manifestations of AIDS. Multiple myeloma, however, usually is not a first presenting feature of AIDS. The usual clinical presentation of multiple myeloma is bone pain and pallor. Pancytopaenia is a rare presenting feature of multiple myeloma. Here, we are reporting a case of pancytopaenia which occurred in a 28-year-old, newly diagnosed, HIV-1 positive female, who with the help of bone marrow examination and further investigations, was subsequently diagnosed as multiple myeloma. PMID:25737998

  10. Multiple Myeloma and Glyphosate Use: A Re-Analysis of US Agricultural Health Study (AHS) Data

    PubMed Central

    Sorahan, Tom

    2015-01-01

    A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993–2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use. PMID:25635915

  11. Establishment of stable multiple myeloma cell line with overexpressed PDCD5 and its proapoptosis mechanism

    PubMed Central

    Feng, Wenchang; Fu, Yunfeng; Zhang, Yanan; Lv, Ben; Li, Xin; Zhang, Fan; Gui, Rong; Liu, Jing

    2015-01-01

    Objective: The transfected multiple myeloma cell line showing a stable doxycycline (DOX)-induced expression of PDCD5 was established. PDCD5 overexpression in the transfected cell line was analyzed for its effect on the dexamethasone (DXM)-induced apoptosis along with a discussion on the mechanism. Methods: (1) Lentiviral plasmid was used for the transfection of PDCD5 gene into the multiple myeloma cells. The screening was done by applying puromycin, and PDCD5 expression was induced by DOX. Real-time fluorescence quantitative PCR and Western Blot were performed to detect the expression levels of the target gene in the stable transfection group and the empty vector group; (2) The cell apoptosis rates of stable transfection group, blank group and empty vector group were measured by Annexin-APC/PI double staining flow cytometry; (3) Real-time fluorescence quantitative PCR and Western Blot were carried out to detect the expression levels of survivin, casepase-3 and Bcl-2 genes and proteins. Results: PDCD5 expression was significantly increased in the stably tranfected multiple myeloma cells compared with blank group and empty vector group. The cells in the transfection group were more sensitive to DXM, and the proportion of apoptotic cells was obviously higher than that of the blank group and the empty vector group (P<0.05). Survivin and Bcl-2 were considerably downregulated in U266/PDCD5 cells and combined DXM group than in the single agent group. However, caspase-3 was significantly upregulated. Conclusion: Multiple myeloma cell line transfected with endogenous PDCD5 gene was established. The endogenous PDCD5 overexpression accelerated the cell apoptosis under DXM induction. The proapoptotic action of PDCD5 gene had the effect of activating casepase-3 and downregulating survivin and Bcl-2, which further promoted the apoptosis of multiple myeloma cells. PMID:26617773

  12. Update on the initial therapy of multiple myeloma.

    PubMed

    Reece, Donna

    2013-01-01

    Advances in myeloma biology and the identification of new anti-myeloma agents have resulted in improved management of younger, transplant-eligible, and older patients. The first novel agents-thalidomide, bortezomib, and lenalidomide-have been integrated into induction therapy before autologous stem cell transplant (ASCT) as well as into first-line therapy in elderly individuals; phase III trials have established the superiority of these approaches in terms of better response rates, progression-free survival (PFS), and, in some studies, overall survival. With more experience, improvements in dosing have decreased the toxicity of these regimens. Before ASCT, four phase III studies have shown that bortezomib-based regimens confer better outcomes than older regimens. Posttransplant consolidation and maintenance strategies with novel agents provide additional benefit, particularly in terms of a longer PFS. In the elderly population, novel agents can be combined with melphalan plus prednisone (MP). MP plus thalidomide and MP plus bortezomib are commonly utilized, and the regimen of MP plus lenalidomide with lenalidomide maintenance (MPR + R) produces superior response rates and longer PFS compared with MP alone. Prolonged maintenance with bortezomib plus thalidomide also appears to extend PFS when given following combinations of MP plus bortezomib. Treatment of very elderly patients, however, remains challenging due to comorbidities and side effects. Lenalidomide plus weekly dexamethasone is also effective in elderly patients, and results of a trial comparing this regimen with MP plus thalidomide should be available soon. Finally, better methods of risk stratification and the availability of even newer drugs will allow future refinements in myeloma treatment. PMID:23714532

  13. Identification of malignant plasma cell precursors in the bone marrow of multiple myeloma.

    PubMed Central

    Caligaris-Cappio, F; Bergui, L; Tesio, L; Pizzolo, G; Malavasi, F; Chilosi, M; Campana, D; van Camp, B; Janossy, G

    1985-01-01

    Precursors of plasma cells were studied in the bone marrow of 28 patients with multiple myeloma, plasma cell leukemia, and benign monoclonal gammopathy. Pre-B and B cell populations were analyzed with anti-B monoclonal antibodies corresponding to the clusters standardized at the Leucocyte Typing Workshops in Paris and Boston (CD9, CD10, CD19-22, CD24). In advanced forms of plasma cell malignancies, such as cases of multiple myeloma in stages II and III and of plasma cell leukemia, some cells of lymphoid morphology expressed common acute lymphoblastic leukemia antigen (CALLA, CD10) and HLA-DR, but contained no detectable terminal deoxynucleotidyl transferase enzyme. These CALLA+ cells were absent in benign monoclonal gammopathies. In multiple myeloma, the CALLA+ cells were negative for surface and cytoplasmic immunoglobulins (Ig), and, unlike CALLA+, terminal deoxynucleotidyl transferase (TdT+) pre-B cells in the normal bone marrow also failed to react with antibodies to B cell-associated antigens such as CD9, CD19, CD22, and CD24. The CALLA+, Ig- cells could be regarded as preplasmacytic since, after having been separated and stimulated with the phorbol ester 12-0-tetradecanoyl-phorbol-13 acetate in vitro, they transformed into plasma cells and synthesized the same heavy and light chains as myeloma cells. Images PMID:2931452

  14. [C/EBPα in multiple myeloma patients may lead to increased hepcidin].

    PubMed

    Han, Xiao; Zhou, Dao-Bin; Duan, Ming-Hui; Hua, Bao-Lai; Wang, Xuan; Zhang, Jie-Ping; Zhao, Yong-Qiang; Shen, Ti; Wu, Yong-Ji

    2014-10-01

    This study was aimed to explore the possible mechanisms of hepcidin increase in multiple myeloma patients. The clinical information and peripheral venous blood of eligible patients with previously untreated multiple myeloma were collected. Serum concentration of IL-6 was detected by ELISA. Peripheral blood monocytes were isolated by CD14⁺ magnetic beads. The expression of hepcidin, IL-6 and C/EBPα mRNA of monocytes were detected by real time quantitative PCR. The results indicated that the hemoglobin level was reduced in 17 multiple myeloma patients enrolled in study (97.8 ± 27.5 g/L), showing the characteristics of anemia of chronic disease. The hepcidin and C/EBPα expression of peripheral blood monocytes significantly increased (P < 0.01), serum IL-6 was also higher than that in normal controls (P < 0.01). Serum IL-6 positively correlated with monocyte hepcidin and C/EBPα expression (P < 0.05); monocyte C/EBPα expression positively correlated with monocyte hepcidin expression (P < 0.05). It is concluded that the elevated IL-6 may induce hepcidin expression through up-regulating C/EBPα in untreated myeloma patients. PMID:25338580

  15. Post-Autologous (ASCT) Stem Cell Transplant Therapy in Multiple Myeloma

    PubMed Central

    Al-Mansour, Zeina

    2014-01-01

    Autologous stem cell transplant (ASCT) is the standard of care in transplant-eligible multiple myeloma patients and is associated with significant improvement in progression-free survival (PFS), complete remission rates (CR), and overall survival (OS). However, majority of patients eventually relapse, with a median PFS of around 36 months. Relapses are harder to treat and prognosis declines with each relapse. Achieving and maintaining “best response” to initial therapy is the ultimate goal of first-line treatment and sustained CR is a powerful surrogate for extended survival especially in high-risk multiple myeloma. ASCT is often followed by consolidation/maintenance phase to deepen and/or maintain the response achieved by induction and ASCT. Novel agents like thalidomide, lenalidomide, and bortezomib have been used as single agents or in combination. Thalidomide use has been associated with a meaningful improvement in PFS and EFS, however, with substantial side effects. Data with lenalidomide maintenance after-ASCT is favorable, but the optimal duration of lenalidomide maintenance is still unclear. Bortezomib use has been associated with superior outcomes, predominantly in high-risk myeloma patients. Combination regimens utilizing a proteasome inhibitor (i.e., bortezomib) with an immunomodulatory drug (thalidomide or lenalidomide) have provided the best outcomes. This review article serves as a review of the best available evidence in post-ASCT approaches in multiple myeloma. PMID:25525435

  16. Incidence and clinical background of hepatitis B virus reactivation in multiple myeloma in novel agents' era.

    PubMed

    Tsukune, Yutaka; Sasaki, Makoto; Odajima, Takeshi; Isoda, Atsushi; Matsumoto, Morio; Koike, Michiaki; Tamura, Hideto; Moriya, Keiichi; Ito, Shigeki; Asahi, Maki; Imai, Yoichi; Tanaka, Junji; Handa, Hiroshi; Koiso, Hiromi; Tanosaki, Sakae; Hua, Jian; Hagihara, Masao; Yahata, Yuriko; Suzuki, Satoko; Watanabe, Sumio; Sugimori, Hiroki; Komatsu, Norio

    2016-09-01

    There are some reports regarding hepatitis B virus (HBV) reactivation in patients with myeloma who are HBV carriers or who have had a resolved HBV infection, and there is no standard prophylaxis strategy for these patients. We performed a retrospective multicenter study to determine the incidence and characteristics of HBV reactivation in patients with multiple myeloma. We identified 641 patients with multiple myeloma who had been treated using novel agents and/or autologous stem cell transplantation with high-dose chemotherapy between January 2006 and June 2014 at nine Japanese hospitals. The patients' characteristics, laboratory data, and clinical courses were retrieved and statistically analyzed. During a median follow-up of 101 weeks, one of eight (12.5 %) HBV carriers developed hepatitis and 9 of 99 (9.1 %) patients with resolved HBV infection experienced HBV reactivation; the cumulative incidences of HBV reactivation at 2 years (104 weeks) and 5 years (260 weeks) were 8 and 14 %, respectively. The nine cases of reactivation after resolved HBV infection had received entecavir as preemptive therapy or were carefully observed by monitoring their HBV DNA levels, and none of these cases developed hepatitis. Among patients with multiple myeloma, HBV reactivation was not rare. Therefore, long-term monitoring of HBV DNA levels is needed to prevent hepatitis that is related to HBV reactivation in these patients. PMID:27358178

  17. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders.

    PubMed

    Rawstron, Andy C; Orfao, Alberto; Beksac, Meral; Bezdickova, Ludmila; Brooimans, Rik A; Bumbea, Horia; Dalva, Klara; Fuhler, Gwenny; Gratama, Jan; Hose, Dirk; Kovarova, Lucie; Lioznov, Michael; Mateo, Gema; Morilla, Ricardo; Mylin, Anne K; Omedé, Paola; Pellat-Deceunynck, Catherine; Perez Andres, Martin; Petrucci, Maria; Ruggeri, Marina; Rymkiewicz, Grzegorz; Schmitz, Alexander; Schreder, Martin; Seynaeve, Carine; Spacek, Martin; de Tute, Ruth M; Van Valckenborgh, Els; Weston-Bell, Nicky; Owen, Roger G; San Miguel, Jesús F; Sonneveld, Pieter; Johnsen, Hans E

    2008-03-01

    The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases. PMID:18268286

  18. Where we were, where we are, where we are going: progress in multiple myeloma.

    PubMed

    Bergsagel, P Leif

    2014-01-01

    The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators. PMID:24857077

  19. Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma

    PubMed Central

    Ghosh, Nilanjan; Tucker, Noah; Zahurak, Marianna; Wozney, Jocelyn; Borrello, Ivan; Huff, Carol Ann

    2015-01-01

    The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1–8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1–13.6 months) and the median duration of response was 6.9 months (range 3–52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses. PMID:24723438

  20. Autologous transplant in multiple myeloma with an augmented conditioning protocol.

    PubMed

    Abu Zaid, Badran; Abdul-Hai, Ali; Grotto, Itamar; Dray, Lillian; Resnick, Igor B; Tsirigotis, Panagiotis D; Samuel, Simcha; Or, Reuven; Shapira, Michael Y

    2013-11-01

    We compared the tolerability and anti-myeloma effect of two conditioning regimens for autologous stem cell transplant (auto-SCT) in consecutive groups of patients. Protocol 1 was the earlier, and consisted of the combination of three agents in a sequential manner, including etoposide, thiotepa and melphalan (n = 29), while protocol 2 employed melphalan alone (n = 34). The two groups were comparable (other than younger age in protocol 1). Conditioning with protocol 1 seemed more toxic, as expressed by the higher number of febrile days and higher demand for parenteral nutrition. This was not expressed with longer admission time. With 108 and 60 months' median follow-up, respectively, the median survival in patients treated by protocol 2 (melphalan 200 mg/m(2)) was reached at 59 months, while the median survival was not yet reached in patients treated with protocol 1 (p = 0.039). The time to progression was significantly longer with protocol 1 (median 44 months vs. 17 months with protocol 2, p = 0.033). Confounded by the small number of patients, conditioning with melphalan augmented by etoposide and thiotepa in a sequential manner is slightly more toxic than melphalan alone and may benefit patients with myeloma undergoing auto-SCT. PMID:23469964

  1. Association of HHV-6 with Hodgkin and non Hodgkin lymphoma

    PubMed Central

    Kiani, Hadis; Samarbafzadeh, Alireza; Teimoori, Ali; Nisi, Niloofar; Mehravaran, Hamide; Radmehr, Hashem; Hosseini, Zeinab; Haghi, Azadeh; Shahani, Toran; Varnaseri, Mehran; Ranjbari, Nastran

    2016-01-01

    Background and Objectives: Human Herpes 6 virus (HHV-6) could remain latent and chronic in the host cells after primary infection. HHV-6 genome encodes certain transactivation proteins which may results in development of malignant lymphoma. The association of human herpes six virus (HHV-6) infection and Hodgkin and Non-Hodgkin lymphomas is strongly supported by epidemiological studies. The aim of this study was to determine the prevalence of HHV-6 among the patients with Hodgkin, Non-Hodgkin‘s lymphoma. Materials and Methods: Overall 44 blocks of formalin-fixed, paraffin-embedded of the patients including 22(50%) Hodgkin and 22(50%) Non-Hodgkin Lymphoma were collected. Initially the section of 5μm-thickness were prepared from the formalin-fixed, paraffin-embedded tissue blocks. Then the deparaphinazation was carried out for each sample. The DNA was extracted, followed by nested PCR for detection of HHV-6. Based on PCR product size and sequencing, the HHV-6 A or B subtypes were characterized. Results: 12/22(54.54%) cases of Hodgkin and 8/22 (36.36%) Non-Hodgkin’s lymphoma were shown as positive for HHV-6. Out of 12 positive HHV-6 in Hodgkin lymphoma, 10 patients (45.45%) belonged to variant A while 2 cases (9.09%) were found positive for both HHV-6A and HHV-6B. All the Non Hodgkin samples (n=8, 36.36%) showed positive for HHV-6 variant A. Conclusion: High prevalence of HHV-6 was found among the patients with Hodgkin and Non-Hodgkin’s lymphoma. Two patients with Hodgkin lymphoma had mixed HHV-6A and HHV-6B infections. It is recommended patients with Hodgkin and Non-Hodgkin should be screened for HHV-6 detection before chemotherapy. PMID:27307982

  2. Can pregnancy aggravate the course of non-Hodgkin's lymphoma?

    PubMed

    Giovannini, M; Saccucci, P; Cannone, D; Damiani, G; Pomini, P

    1989-01-01

    The Authors present three cases of Non-Hodgkin's Lymphoma (NHL) in pregnancy and discuss about problem of diagnosis and management of NHL in this condition. They stress that the diagnosis of NHL in pregnancy is delayed and the clinical progression of lymphoma is probably influenced by hormonal and immunological changes occurring during pregnancy. On the other hand the management of NHL is problematic because radiotherapy is potentially teratogenic. (By editorial staff). PMID:2776787

  3. C-MAF oncogene dysregulation in multiple myeloma: frequency and biological relevance.

    PubMed

    Rasmussen, Thomas; Knudsen, Lene Meldgaard; Dahl, Inger Marie S; Johnsen, Hans Erik

    2003-10-01

    To investigate the frequency and possible biological consequences of c-maf dysregulation, we designed c-maf and IL-4 real-time RT-PCR assays for determination of c-maf and IL-4 mRNA levels. Using the c-maf real-time RT-PCR assay, we tested a panel of 14 B-cell lines, 135 diagnostic bone marrow (BM) samples from patients with multiple myeloma and 10 BM samples from normal donors. In B cell lines and flowsorted CD38++/CD19-/CD56++ myeloma plasma cells (N = 14) the c-maf/GAPDH and IL-4/GAPDH ratios were determined simultaneously using real time RT-PCR. All B cell lines used in the study were characterized by flow cytometry and tested for the presence of Ebstein-Barr virus (EBV). B-cell lines, that were PCR negative for EBV and had a phenotype typical for primary myeloma cells, expressed medium to high levels of c-maf mRNA. However, all EBV PCR positive cell lines, showed a more immature phenotype, lacked expression of aberrant surface markers and contained very low levels of c-maf mRNA. In 4.4% (6/135) of MM patients tested, a c-maf mRNA level comparable to the cell line RPMI 8226 containing at (16:22), translocation was found. In addition, all c-maf positive myeloma cell lines and CD38++/CD19-/CD56++ myeloma plasma cells tested were IL-4 negative. In conclusion, high levels of c-maf mRNA were observed in "true MM cell lines" and 4.4% of MM patients. Further, c-maf dysregulation in myeloma plasma cells did not cause induction of IL-4 transcription. PMID:14692531

  4. Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma.

    PubMed

    Li, Shirong; Fu, Jing; Lu, Caisheng; Mapara, Markus Y; Raza, Shahzad; Hengst, Ulrich; Lentzsch, Suzanne

    2016-04-01

    eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap-dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on-inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions, such as c-MYC and C/EBPβ, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711-9. ©2016 AACR. PMID:26939700

  5. Novel agents and new therapeutic approaches for treatment of multiple myeloma

    PubMed Central

    Ria, Roberto; Reale, Antonia; Vacca, Angelo

    2014-01-01

    This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials. PMID:25332907

  6. [Infectious pleurisy as first sign of multiple myeloma in a young 28 years old].

    PubMed

    Benali, A; Kahouli, S; El Ouazzani, H; Souhi, H; Abderrahmani Rhorfi, I; Abid, A; Yahyaoui, A; Zahid, H; Messaoudi, N

    2015-10-01

    Multiple myeloma is a malignant proliferation of plasma cells, mainly affecting the bone marrow. It rarely occurs in young patients. The medical observation study reveals multiple myeloma discovered through a purulent pleurisy in a 28-year-old subject. This patient was admitted to the pneumology service of the Mohamed V military hospital in Rabat for a fever and dyspnea evolving into a context of poor general condition. Clinical examination found a right pleural fluid effusion syndrome. The pleural puncture reveals a germ-free exudative purulent fluid without plasma cells. The myeloma diagnosis was suspected due to the combination of an aplastic normochromic normocytic anemia at 4.5g/dL of hemoglobin, an accelerated erythrocyte sedimentation rate, hypercalcemia, renal failure and osteolytic lesions located mainly in the skull and pelvis area, oriented by electrophoresis and serum protein immunosubstraction revealing a narrow peak in monoclonal beta-2 globulin at 70.56g/L with a lambda monoclonal gammopathy with immunoglobulin G, and confirmed by the myelogram showing a 74% rate of bone marrow plasma cells. The occurrence of myeloma at a young age is rare and the purulent pleurisy without plasma cells is a rare form of presentation and represents a poor prognosis. PMID:25727663

  7. Three Cases of Multiple Myeloma in which the Preclinical Asymptomatic Phases Persisted Throughout 15 to 24 Years

    PubMed Central

    Nøorgaard, O.

    1971-01-01

    During the period from 1950 to 1952, three patients were studied by electrophoresis according to Tiselius on account of anticomplementary activity at WR; the presence of an M-component was demonstrated. On several later occasions it was observed that this component at first seemed to remain unchanged, later it was slightly increased; repeated examinations did not give evidence of multiple myeloma. At intervals ranging from 15 to 24 years after the primary demonstration of the M-component, all three patients presented with symptoms of multiple myeloma and died within less than one year after the disease had been diagnosed. The following conclusions are drawn: (1) The preclinical phase of multiple myeloma may cover up to 24 years. (2) A presence of multiple myeloma cannot be precluded, even after follow-up throughout 24 years, in cases of the so-called “benign monoclonal gammopathy”. PMID:4111430

  8. NF-Kappa B Modulation Is Involved in Celastrol Induced Human Multiple Myeloma Cell Apoptosis

    PubMed Central

    Ni, Haiwen; Zhao, Wanzhou; Kong, Xiangtu; Li, Haitao; Ouyang, Jian

    2014-01-01

    Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation. PMID:24755677

  9. Scavenger receptor class A member 3 (SCARA3) in disease progression and therapy resistance in multiple myeloma

    PubMed Central

    Brown, Charles O.; Schibler, Jeanine; Fitzgerald, Matthew P.; Singh, Neeraj; Salem, Kelley; Zhan, Fenghuang; Goel, Apollina

    2013-01-01

    This study evaluates the role of scavenger receptor class A member 3 (SCARA3) in multiple myeloma (MM). SCARA3 expression was induced upon treatment with oxidative stressors (ionizing radiation and chemotherapeutic drugs). An epigenetic inactivation of SCARA3 was noted in MM.1S myeloma cells. Myeloma cell killing by dexamethasone and bortezomib was inhibited by up-regulation of SCARA3 while SCARA3 knockdown sensitized myeloma cells to the drugs. Clinical samples showed an inverse correlation between SCARA3 gene expression, myeloma progression, and favorable clinical prognosis. In MM, SCARA3 protects against oxidative stress-induced cell killing and can serve as predictor of MM progression and therapeutic response. PMID:23537707

  10. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma.

    PubMed

    Furukawa, Yusuke; Kikuchi, Jiro

    2016-09-01

    Multiple myeloma cells acquire the resistance to anti-cancer drugs through physical and functional interactions with the bone marrow microenvironment via two overlapping mechanisms. First, bone marrow stromal cells (BMSCs) produce soluble factors, such as interleukin-6 and insulin-like growth factor-1, to activate signal transduction pathways leading to drug resistance (soluble factor-mediated drug resistance). Second, BMSCs up-regulate the expression of cell cycle inhibitors, anti-apoptotic members of the Bcl-2 family and ABC drug transporters in myeloma cells upon direct adhesion [cell adhesion-mediated drug resistance (CAM-DR)]. Elucidation of the mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. Recent investigations, including ours, have revealed the involvement of epigenetic alterations in drug resistance especially CAM-DR. For example, we found that class I histone deacetylases (HDACs) determine the sensitivity of proteasome inhibitors and the histone methyltransferase EZH2 regulates the transcription of anti-apoptotic genes during the acquisition of CAM-DR by myeloma cells. In addition, another histone methyltransferase MMSET was shown to confer drug resistance to myeloma cells by facilitating DNA repair. These findings provide a rationale for the inclusion of epigenetic drugs, such as HDAC inhibitors and histone methylation modifiers, in combination chemotherapy for MM patients to increase the therapeutic index. PMID:27411688

  11. [The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma].

    PubMed

    Jurczyszyn, Artur; Gdula-Argasińska, Joanna; Kosmaczewska, Agata; Skotnicki, Aleksander B

    2015-01-01

    Multiple myeloma (MM) is one of the most common hematologic malignancies. It remains an incurable disease, so far. The mainstay of treatment for decades was pointless therapy with cytostatic agents and immunosuppressant's. Because myeloma is most common in the elderly population, vulnerable to aggressive therapy, non-specific treatment approaches led to poor patient survival. Intensive study of MM, allowed identification of the molecular interactions between myeloma cells and bone marrow tumour microenvironment, responsible for the development of the disease and associated complications, such as osteolytic bone lesions. Understanding the molecular mechanisms of action of adhesion molecules, cytokines and signalling pathways involved in the development of myeloma, has led to develop of novel, targeted therapies to improve the quality of patients life and significantly prolong the median survival time. This paper discusses the current state of knowledge of signalling pathways involved in the progression of cancer and the destruction of bone tissue, with particular emphasis on interactions with the bone marrow microenvironment of the tumour. PMID:25983291

  12. Insulin-like growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma

    PubMed Central

    Birmann, Brenda M.; Tamimi, Rulla M.; Giovannucci, Edward; Rosner, Bernard; Hunter, David J.; Kraft, Peter; Mitsiades, Constantine; Anderson, Kenneth C.; Colditz, Graham A.

    2009-01-01

    Insulin-like growth factor (IGF)-1 and interleukin (IL)-6 promote the proliferation and survival of multiple myeloma cells. Variation in genes related to IGF-1 and IL-6 signaling may influence susceptibility to multiple myeloma. To assess their etiologic role, we examined the association of 70 tagging single nucleotide polymorphisms (SNP) in seven IGF-1 and three IL-6 pathway genes with multiple myeloma risk in two prospective cohorts, the Nurses' Health Study and Health Professionals Follow-up Study. Among participants who provided DNA specimens, we identified 58 women and 24 men with multiple myeloma and matched two controls per case. We used multivariable logistic regression models to assess the association of the SNPs or tagged haplotypes with multiple myeloma risk. Several SNPs had suggestive associations with multiple myeloma based on large odds ratios (OR), although corresponding omnibus p-values were not more than nominally significant (i.e., at p<0.05). These SNPs included rs1801278 in the gene encoding insulin receptor substrate-1 (IRS1; C/T v. C/C genotypes; OR=4.3, 95% confidence interval (CI)=1.5-12.1), and three IL-6 receptor SNPs: rs6684439 (T/T v. C/C: 2.9, 1.2-7.0), rs7529229 (C/C v. T/T; 2.5, 1.1-6.0), and rs8192284 (C/C v. A/A; 2.5, 1.1-6.0). Additional SNPs in genes encoding IGF-1, IGF binding protein-2, IRS2, and gp130 also demonstrated suggestive associations with multiple myeloma risk. We conducted a large number of statistical tests, and the findings may be due to chance. Nonetheless, the data are consistent with the hypothesis that IGF-1- and IL-6-related gene variation influences susceptibility to multiple myeloma and warrant confirmation in larger populations. PMID:19124510

  13. Pulmonary Nocardiosis in a Multiple Myeloma Patient Treated with Proteasome Inhibitors

    PubMed Central

    Mendonca, Nikolai P.; Kadayakkara, Deepak K.; Forde, Inga C.; Rudkovaskaia, Anastasiia; Saul, Zane K.; Lobo, David J.

    2016-01-01

    Patient: Male, 71 Final Diagnosis: Pulmonary nocardiosis Symptoms: Cough • dyspnea • fever Medication: Carfillzomib Clinical Procedure: Bronchoscopy Specialty: Infectious Diseases Objective: Rare co-existance of disease or pathology Background: The use of proteasome inhibitors like Bortezomib to treat multiple myeloma has been associated with increased rates of opportunistic infections, including Nocardia, especially when lymphopenia is present. The prevalence or association of such infections with newer agents like Carfilzomib is not known. Case Report: A 71-year-old man with multiple myeloma presented with a 6-week history of respiratory symptoms and cyclic fevers. He was undergoing chemotherapy with Carfilzomib. Work-up revealed severe lymphopenia and a CT chest showed multiple lung nodules and a mass-like consolidation. He underwent a bronchoscopy, and respiratory cultures grew Nocardia species. He responded well to intravenous antibiotics with resolution of symptoms and CT findings. Conclusions: With the introduction of newer agents like Carfilzomib for the treatment of multiple myeloma, clinicians must maintain a high degree of suspicion for opportunistic infections to achieve early diagnosis and treatment. PMID:26861506

  14. Bone involvement in young patients with non-Hodgkin's lymphoma: efficacy of chemotherapy without local radiotherapy.

    PubMed

    Haddy, T B; Keenan, A M; Jaffe, E S; Magrath, I T

    1988-10-01

    Of 95 young non-Hodgkin's lymphoma patients entered consecutively on the National Cancer Institute (NCI) Protocol 7704, 26 (27.4%) had involvement of one or more bones. The mean age of these 26 patients was 16.6 years, and the male to female ratio was 3.3:1. Tumor histology included undifferentiated Burkitt's lymphoma in 12, undifferentiated non-Burkitt's lymphoma in two, undifferentiated, unspecified lymphoma in one, diffuse large cell lymphoma in three, and lymphoblastic lymphoma in eight patients. Most had extensive disease; two patients had isolated bone lesions, one had lesions of two bones without involvement of other tissues, and 23 had either multiple bone lesions or single bone lesions with involvement of other tissues. Eight of the 26 patients had bone marrow involvement. Of a subgroup of 12 patients with jaw disease, 11 had undifferentiated lymphoma and one had diffuse large cell lymphoma. Only one had primary a jaw tumor, with two quadrants of the jaw involved. All 26 patients were treated with chemotherapy; only two received radiotherapy initially for bone lesions. Predicted survival of the 26 patients at 5 years is 53.2%. The 12 patients who remain disease free have a mean survival of 62.1 months (range, 22 to 100 months). Our results call into question the role of radiotherapy in the treatment of bone lesions in non-Hodgkin's lymphoma. PMID:3167201

  15. A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.

    PubMed

    Alagpulinsa, David A; Ayyadevara, Srinivas; Yaccoby, Shmuel; Shmookler Reis, Robert J

    2016-02-01

    PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci. Dinaciclib treatment reduces expression of HR repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Cotreatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of multiple myeloma cells, but not normal CD19(+) B cells, and slowed growth of multiple myeloma xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for multiple myeloma therapy. Mol Cancer Ther; 15(2); 241-50. ©2015 AACR. PMID:26719576

  16. Non-osseous incidental findings in low-dose whole-body CT in patients with multiple myeloma

    PubMed Central

    Bach, A G; Tcherkes, A; Schramm, D

    2014-01-01

    Objective: The purpose of this study was to identify the frequency and grading of non-osseous incidental findings (NOIF) in non-contrast whole-body low-dose CT (LDCT) in patients with multiple myeloma. Methods: In the time period from 2010 to 2013, 93 patients with multiple myeloma were staged by non-contrast whole-body LDCT at our radiological department. LDCT images were analysed retrospectively for NOIF, which also included unsuspected extramedullary manifestation of multiple myeloma. All NOIF were classified as major or clinically significant, moderate or possibly clinically significant and minor or not clinically significant. Medical records were analysed regarding further investigation and follow-up of the identified NOIF. Results: In the 93 patients, 295 NOIF were identified (on average, 3.2 NOIF per patient). Most of the NOIF (52.4%) were not clinically significant, 25.8% of the NOIF were possibly clinically significant and 21.8% of the NOIF were clinically significant. Clinically significant NOIF were investigated further by CT after intravenous administration of contrast medium and/or by ultrasound or MRI. In 34 of these cases, extramedullary relapse of myeloma, occult carcinoma or infectious/septic incidental findings were diagnosed (11.5% of all NOIF). In the remaining 10.3% of the NOIF classified as clinically significant, various benign lesions were diagnosed. Conclusion: LDCT detected various non-osseous lesions in patients with multiple myeloma. 36.6% of the patients had clinically significant NOIF. Therefore, LDCT examinations in patients with multiple myeloma should be evaluated carefully for the presence of NOIF. Advances in knowledge: LDCT identified several NOIF. A total of 36.6% of patients with multiple myeloma had clinically significant NOIF. Radiologists should analyse LDCT examinations in patients with multiple myeloma not only for bone lesions, but also for lesions in other organs. PMID:25004949

  17. Rare Strain of Vibrio cholerae Septicemia in a Patient with Multiple Myeloma

    PubMed Central

    Daniel, Deepu; Kumar, Sunil

    2015-01-01

    Introduction. Non-O1/non-O139 is a rare strain of Vibrio cholera that has been documented to cause significant morbidity and mortality in the immunosuppressed population. Case Presentation. A patient with multiple myeloma develops non-O1/non-O139 Vibrio cholera septicemia, leading to multiorgan failure and ultimately death. Discussion. An exceedingly rare strain of Vibrio cholera, non-O1/non-O139, may be an important factor of morbidity and mortality in certain immunosuppressed populations, such as patients with multiple myeloma and malignancies. Conclusion. Bacteremia involving generally noninvasive microbes, such as non-O1/non-O139 Vibrio cholerae, can have significant deleterious effects in the immunosuppressed patients as shown by this case report. Physicians need to be more diligent when treating these patients. PMID:26257967

  18. Lactate dehydrogenase and its isoenzymes in serum from patients with multiple myeloma.

    PubMed

    Copur, S; Kus, S; Kars, A; Renda, N; Tekuzman, G; Firat, D

    1989-09-01

    Concentrations of total lactate dehydrogenase (LDH; EC 1.1.1.27) and LDH isoenzyme patterns were studied in serum of 19 patients with multiple myeloma and in 19 healthy controls. Patients were divided into three groups (pretreatment, nonresponders, and responders to treatment), based on their clinical status at the time of blood sampling for LDH. The LDH values were found to be significantly higher (P less than 0.05) in the pretreatment group and in the nonresponders than in the responders and the control group, the mean +/- SE values being 445 +/- 35 and 532 +/- 75 units/mL vs 349 +/- 75 and 190 +/- 7.1 units/mL, respectively. Compared with responders and healthy controls, newly diagnosed patients and nonresponders had slight diminutions in LDH-1 and LDH-2, but increased LDH-3. We conclude that determination of LDH and its isoenzymes in serum can be of value as prognostic factors in patients with multiple myeloma. PMID:2776328

  19. Massive Retroperitoneal Hemorrhage as an Initial Presentation of a Rare and Aggressive Form of Multiple Myeloma

    PubMed Central

    Alawadhi, Aydah; Leb, Laszlo

    2016-01-01

    Multiple myeloma, a plasma cell neoplasm, presents most commonly with anemia, hypercalcemia, renal failure, and bone pain. Only few cases of clinical aggressive presentation associated with bleeding were reported in the medical literature. The reported cases included gastrointestinal bleeding and cardiac tamponade. Spontaneous retroperitoneal haemorrhage as initial presentation has not been so far reported. We hereby report a case of a 64-year-old female who was found to have catastrophic hemorrhage in the retroperitoneal region that extended into intrathecal space causing cord compression. The case posed a significant diagnostic and management dilemma. This case emphasizes the need to think broadly and include multiple myeloma in the diagnosis of unexplained massive retroperitoneal bleeding. PMID:26885415

  20. [Diagnosis of multiple myeloma in primary care. Suspicion with an appropriate clinical history].

    PubMed

    Alvarez-Cordovés, M M; Mirpuri-Mirpuri, P G; Pérez-Monje, A

    2013-09-01

    Monoclonal gammopathies are a group of disorders characterized by stable or progressive clonal proliferation of plasma cells producing similar immunoglobulins. Multiple myeloma is characteristic of the presence of bone marrow infiltration by plasma cells, osteolytic lesions, and M component in serum or urine. As cancer cells multiply, they can cause pain and destruction of bone, and if affecting the spine, they can press on nerves causing pain and paresthesias. In patients of advanced age (average 69 years) with bone pain not associated with trauma, and which does not improve with treatment, a differential diagnosis should be performed with multiple myeloma. This should include, at least, a full blood count, biochemistry, total protein, protein electrophoresis, immunofixation, and radiographs of painful areas. PMID:24034763

  1. Promiscuous Mutations Activate the Non-Canonical NF-kB Pathway in Multiple Myeloma

    PubMed Central

    Keats, Jonathan J.; Fonseca, Rafael; Chesi, Marta; Schop, Roelandt; Baker, Angela; Chng, Wee-Joo; Van Wier, Scott; Tiedemann, Rodger; Shi, Chang-Xin; Sebag, Michael; Braggio, Esteban; Henry, Travis; Zhu, Yuan-Xiao; Fogle, Homer; Price-Troska, Tammy; Ahmann, Gregory; Mancini, Catherine; Brents, Leslie A.; Kumar, Shaji; Greipp, Philip; Dispenzieri, Angela; Bryant, Barb; Mulligan, George; Bruhn, Laurakay; Barrett, Michael; Valdez, Riccardo; Trent, Jeff; Stewart, A. Keith; Carpten, John; Bergsagel, P. Leif

    2007-01-01

    Summary Activation of NF-kB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kB pathway in the pathogenesis of multiple myeloma. PMID:17692805

  2. Malignancy: Case Report: Muscle Involvement in Multiple Myeloma: Report of a Patient Presenting Clinically as Polymyositis.

    PubMed

    Islam, ANWARUL; Myers, KEITH; Cassidy, D. M.; Ho, S. F.; De Silva, M.

    1999-01-01

    Although bone pain is common in multiple myeloma (MM), muscular symptoms, especially myalgias, may be rare. We describe a patient who presented with generalised myopathy and elevated creatine kinase (CK) suggestive of polymyositis. Routine blood tests showed raised viscosity and marked rouleaux formation in the peripheral blood film. A serum protein electrophoresis showed IgG Lambda paraproteinemia with immunoparesis. A sternal bone marrow aspirate and a bone marrow biopsy concurrently obtained from the right posterior iliac crest showed considerable (15-20%) marrow infiltration with plasma cells confirming a diagnosis of multiple myeloma. A review of the literature suggests that generalised myopathy and elevated CK associated with MM have not been reported in the past. We believe this is the first reported case of MM presenting as polymyositis. PMID:11399558

  3. Lung Postmortem Autopsy Revealing Extramedullary Involvement in Multiple Myeloma Causing Acute Respiratory Distress Syndrome

    PubMed Central

    Ravinet, Aurélie; Perbet, Sébastien; Guièze, Romain; Guérin, Renaud; Gayraud, Guillaume; Aliane, Jugurtha; Tremblay, Aymeric; Pascal, Julien; Ledoux, Albane; Chaleteix, Carine; Dechelotte, Pierre; Bay, Jacques-Olivier; Bazin, Jean-Etienne; Constantin, Jean-Michel

    2014-01-01

    Pulmonary involvement with multiple myeloma is rare. We report the case of a 61-year-old man with past medical history of chronic respiratory failure with emphysema, and a known multiple myeloma (Durie and Salmon stage III B and t(4;14) translocation). Six months after diagnosis and first line of treatment, he presented acute dyspnea with interstitial lung disease. Computed tomography showed severe bullous emphysema and diffuse, patchy, multifocal infiltrations bilaterally with nodular character, small bilateral pleural effusions, mediastinal lymphadenopathy, and a known lytic lesion of the 12th vertebra. He was treated with piperacillin-tazobactam, amikacin, oseltamivir, and methylprednisolone. Finally, outcome was unfavourable. Postmortem analysis revealed diffuse and nodular infracentimetric infiltration of the lung parenchyma by neoplastic plasma cells. Physicians should be aware that acute respiratory distress syndrome not responding to treatment of common causes could be a manifestation of the disease, even with negative BAL or biopsy and could be promptly treated with salvage therapy. PMID:25165587

  4. [Advances Research on C-MYC Proto-oncogene in Multiple Myeloma -Review].

    PubMed

    Huang, He; Guo, Wen-Jian; Yao, Ron-Xin

    2016-08-01

    Multiple myeloma(MM) as one of the most common tumors of hmatologic system, is characterized by malignant proliferation of plasma cells, and the chemotherapy is the main therapeutic method. MM is an incurable disease because of drug-resistance of MM cells. Although the pathogenesis of MM remains unknown, the chromosome abnormalities exit in half of the patients, particularly the highly expressed gene C-MYC. Furthermore, plenty of clinical researches indicated a high expression level of C-MYC implied worse progression and/or poor prognosis of MM. Recently, the work exploiting the compounds targeting MYC has made substantial progress, even in the MM therapy. In this article, briefly the recent advances of the research on C-MYC proto-oncogene in multiple myeloma are reviewed. PMID:27531809

  5. Bilateral synchronous testicular involvement in multiple myeloma. Case report and review of the literature.

    PubMed

    Castagna, M; Gaeta, P; Cecchi, M; Pagni, G L; Pingitore, R

    1997-01-01

    The authors describe a case of synchronous bilateral involvement of the testes in a 70-year-old patient seven years after the onset of an IgG k IIIA multiple myeloma. Ultrasonographic and postoperative immunohistochemical studies were performed. A complete review of the literature shows the rarity of testicular plasmacytoma. The present one is the second reported case of syncronous involvement of the testes. PMID:9349319

  6. Patient-specific 3D microfluidic tissue model for multiple myeloma.

    PubMed

    Zhang, Wenting; Lee, Woo Y; Siegel, David S; Tolias, Peter; Zilberberg, Jenny

    2014-08-01

    In vitro culturing of primary multiple myeloma cells (MMC) has been a major challenge as this plasma cell malignancy depends on the bone marrow environment for its survival. Using a microfluidic platform to emulate the dynamic physiology of the bone marrow microenvironment, we report here a new approach for culturing difficult to preserve primary human MMC. The system uses a three-dimensional ossified tissue to mimic the tumor niche and recapitulate interactions between bone marrow cells and osteoblasts (OSB). To this end, the human fetal OSB cell line hFOB 1.19 was cultured in an eight-chamber microfluidic culture device to facilitate the seeding of mononuclear cells from bone marrow aspirates from three multiple myeloma patients. Optical microscopy, used for real-time monitoring of mononuclear cell interactions with the ossified tissue, confirmed that these are drawn toward the OSB layer. After 3 weeks, cocultures were characterized by flow cytometry to evaluate the amount of expansion of primary MMC (with CD138(+) and CD38(+)CD56(+) phenotypes) in this system. For each of the three patients analyzed, bone marrow mononuclear cells underwent, on an average, 2 to 5 expansions; CD38(+)CD56(+) cells underwent 1 to 3 expansions and CD138(+) cells underwent 2.5 to 4.6 expansions. This approach is expected to provide a new avenue that can facilitate: (1) testing of personalized therapeutics for multiple myeloma patients; (2) evaluation of new drugs without the need for costly animal models; and (3) studying the biology of multiple myeloma, and in particular, the mechanisms responsible for drug resistance and relapse. PMID:24294886

  7. Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Merin, Noah M.; Kelly, Kevin R.

    2014-01-01

    Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. PMID:25545164

  8. The shaping and functional consequences of the dosage effect landscape in multiple myeloma

    PubMed Central

    2013-01-01

    Background Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. Results We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. Conclusions Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and

  9. Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

    ClinicalTrials.gov

    2015-08-18

    Adult B Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Cutaneous B-Cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; HIV Infection; Intraocular Lymphoma; Multicentric Angiofollicular Lymphoid Hyperplasia; Nodal Marginal Zone Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Plasma Cell Myeloma; Small Intestinal Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  10. Renal complications in multiple myeloma and related disorders: Survivorship care plan of the IMF Nurse Leadership Board

    PubMed Central

    Faiman, Beth; Tariman, Joseph D.; Mangan, Patricia A.; Spong, Jacy

    2012-01-01

    Kidney dysfunction is a common clinical feature of symptomatic multiple myeloma. Some degree of renal insufficiency or renal failure is present at diagnosis or will occur during the course of the disease, and which, if not reversed, will adversely effect overall survival and quality of life. Chronic insults to the kidneys from other illnesses, treatment, or multiple myeloma itself can further damage renal function and increase the risk for additional complications, such as anemia. Patients with multiple myeloma who have light chain (Bence Jones protein) proteinuria may experience renal failure or progress to end-stage renal disease (ESRD) and require dialysis due to light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma may also result from amyloidosis, light chain deposition disease, or acute tubular necrosis caused by nephrotoxic agents; therefore identification of patients at risk for kidney damage is essential. The International Myeloma Foundation’s Nurse Leadership Board have developed these practice recommendations for screening for renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD and dialysis, and reducing and managing renal complications in patients with multiple myeloma. PMID:21816711

  11. Obstructive Jaundice as Initial Presentation of Multiple Myeloma: Case Presentation and Literature Review

    PubMed Central

    Khan, Yasir; Mansour, Iyad; Ong, Eric; Shrestha, Manish

    2015-01-01

    Multiple myeloma is a malignant plasma-cell disorder that primarily involves the bone marrow, but extramedullary involvement is becoming increasingly common (Bladé et al., 2012) both at initial presentation and follow-up. Most common initial presentations for multiple myeloma include generalized fatigue, renal insufficiency, bone pain, and recurrent bacterial infections. We present a case of a healthy 55-year-old man that presented to the emergency department with a three-week history of anorexia and jaundice without any past medical history. Patient's initial labs were significant for hyperbilirubinemia and elevated liver function enzymes (AST, ALT, ALP, and GGT). Additional laboratory workup was significant for mild hypercalcemia and increased protein gap. MRI and ERCP suggested primary sclerosing cholangitis but were not diagnostic. Liver biopsy illustrated plasma-cell infiltration and bone marrow biopsy diagnosed multiple myeloma with extramedullary disease. Patient was started on dexamethasone, bortezomib, and cyclophosphamide, but, despite this aggressive regimen, the patient continued to decline. We take this opportunity to present this atypical presentation of a common hematological malignancy and review the associated literature. PMID:26221143

  12. Immunoglobulin G kappa biclonal gammopathy associated with multiple myeloma, plasmacytoma and cast nephropathy.

    PubMed

    Pradhan, Dinesh; Arora, Prerna; Gami, Ashmita; Kaur, Neeraj

    2015-01-01

    Biclonal gammopathies are characterized by simultaneous appearance of two different monoclonal proteins. Multiclonal gammopathies may be the result of a neoplastic transformation of a cell clone undergoing immunoglobulin (Ig) class switching or due to an independent neoplastic transformation event yielding proliferation of unrelated plasma cell clones. This in turn has implication on the disease manifestation, progression, prognosis and response to therapy. The prevalence of biclonal gammopathy is approximately 1% of all gammopathies and the most common combinations are IgG and IgA (33%), followed by IgM and IgG (24%). Multiple myeloma with biclonal gammopathy is very uncommon. The present case corresponds to an extremely rare occurrence of multiple myeloma with biclonal gammopathy revealing expression of two distinct monoclonal gammaglobulins both of IgG and kappa (κ) subtype in a 56-year-old diabetic man who presented with lower back pain and renal failure. To the best of our knowledge, only one case of IgG κ biclonal gammopathy associated with multiple myeloma have been reported in English literature. This case interestingly also had paraspinal plasmacytoma and cast nephropathy. PMID:26458669

  13. Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells.

    PubMed

    Ghosh, N; Gyory, I; Wright, G; Wood, J; Wright, K L

    2001-05-01

    The major histocompatibility complex (MHC) class II transactivator (CIITA) acts as a master switch to activate expression of the genes required for MHC-II antigen presentation. During B-cell to plasma cell differentiation, MHC-II expression is actively silenced, but the mechanism has been unknown. In plasma cell tumors such as multiple myeloma the repression of MHC-II is associated with the loss of CIITA. We have identified that positive regulatory domain I binding factor 1 (PRDI-BF1), a transcriptional repressor, inhibits CIITA expression in multiple myeloma cell lines. Repression of CIITA depends on the DNA binding activity of PRDI-BF1 and its specific binding site in the CIITA promoter. Deletion of a histone deacetylase recruitment domain in PRDI-BF1 does not inhibit repression of CIITA nor does blocking histone deacetylase activity. This is in contrast to PRDI-BF1 repression of the c-myc promoter. Repression of CIITA requires either the N-terminal acidic and conserved PR motif or the proline-rich domain. PRDI-BF1 has been shown to be a key regulator of B-cell and macrophage differentiation. These findings now indicate that PRDI-BF1 has at least two mechanisms of repression whose function is dependent on the nature of the target promoter. Importantly, PRDI-BF1 is defined as the key molecule in silencing CIITA and thus MHC-II in multiple myeloma cells. PMID:11279146

  14. Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

    PubMed

    Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

    2016-02-01

    Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts. PMID:26318303

  15. Severe resistant hypocalcemia in multiple myeloma after zoledronic acid administration: a case report

    PubMed Central

    2014-01-01

    Introduction Hypercalcemia is one of the most common metabolic abnormalities encountered in any form of malignancy. Hypocalcemia, however, is a rare manifestation, especially in cancers with bone involvement. Here we present a case of hypocalcemia in a patient with multiple myeloma that was refractory to treatment. Case presentation A 73-year-old African American woman recently diagnosed with multiple myeloma, presented with a 2-day history of fever, vomiting and hypocalcemia. Ten days prior to admission she received zoledronic acid, Velcade® (bortezomib), Revlimid® (lenalidomide) and dexamethasone. Treatment was started with intravenous antibiotics and calcium gluconate boluses. After 24 hours of treatment her calcium level became undetectable (<5mg/dL). Continuous intravenous calcium gluconate infusions in addition to boluses were started. She remained persistently hypocalcemic and eventually developed tonic–clonic seizures. Vitamin D levels were found to be low and intravenous paricalcitol was initiated, which improved her calcium level. Conclusions Underlying vitamin D deficiency can precipitate severe hypocalcemia in patients with multiple myeloma receiving bisphosphonates. This warrants baseline screening for vitamin D deficiency in these patients. PMID:25342294

  16. Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma

    PubMed Central

    2014-01-01

    Background Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies. Methods Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient. Patients received six intradermal immunizations with phage idiotype vaccines in three different dose groups. Results Phage idiotype was well tolerated by all study participants. A subset of patients (80% in the middle dose group) displayed a clinical response indicated by decrease or stabilization of paraprotein levels. Patients exhibiting a clinical response to phage vaccines also raised idiotype-specific immunoglobulins. Induction of a cellular immune response was demonstrated by a cytotoxicity assay and delayed type hypersensitivity tests. Conclusion We present a simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible patient-specific therapy for patients with advanced multiple myeloma and produced promising anti-tumor activity in a subset of patients. PMID:24885819

  17. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies.

    PubMed

    Caltagirone, Simona; Ruggeri, Marina; Aschero, Simona; Gilestro, Milena; Oddolo, Daniela; Gay, Francesca; Bringhen, Sara; Musolino, Caterina; Baldini, Luca; Musto, Pellegrino; Petrucci, Maria T; Gaidano, Gianluca; Passera, Roberto; Bruno, Benedetto; Palumbo, Antonio; Boccadoro, Mario; Omedè, Paola

    2014-10-01

    Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19(+)/CD117(-) immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19(+)/CD117(-) bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179. PMID:25015938

  18. Prediction of patients with multiple myeloma eligible for second- or third-line treatment in France.

    PubMed

    Rondeau, Virginie; Cornet, Edouard; Moreau, Philippe; Troussard, Xavier

    2016-08-01

    Multiple myeloma (MM) is one of the most common hematological malignancies, with an estimated 4888 incident cases in France in 2012. The management of patients with MM has changed considerably in recent years. We proposed an approach to predict the number of patients with multiple myeloma eligible for second- and third-line treatment for the period 2012-2020. The input parameters of this model were incident cases of multiple myeloma from the Basse-Normandie French Regional Registry of Hematological Malignancies (RRHMBN) for the period 2000-2012 and survival rates among patients under and over age 65 from the French National Institute of Statistics and Economic Studies (INSEE). In addition, data on mortality rates and progression-free survival (PFS) were extracted from the literature. Our analyses showed that the total incidence of MM in France is predicted to increase by 29 % between 2012 and 2020. We used the proposed approach to predict that at least 47.8 % of first-line MM patients will be eligible for second-line treatment (and 45.6 % will be eligible for third-line treatment). Predicting the number of patients with MM eligible for a new treatment is a prerequisite to planning healthcare and calculating treatment costs. PMID:27165088

  19. CD10 positive thyroid marginal zone non-Hodgkin lymphoma.

    PubMed Central

    Millar, E K; Waldron, S; Spencer, A; Braye, S

    1999-01-01

    A 72 year old woman presented with swelling of the right lobe of her thyroid gland. Fine needle aspiration and flow cytometry showed a clonal population of B cells expressing CD10 and a diagnosis of follicle centre cell lymphoma was made. Subsequent excision of the thyroid showed the typical histological features of a marginal zone non-Hodgkin lymphoma. Polymerase chain reaction showed no evidence of t (14;18). Immunohistochemistry confirmed CD10 positivity and LN1 (CDw75) expression. This is only the second report of aberrant expression of CD 10 by a marginal zone lymphoma. Images PMID:10690178

  20. Texture analysis on MRI images of non-Hodgkin lymphoma.

    PubMed

    Harrison, L; Dastidar, P; Eskola, H; Järvenpää, R; Pertovaara, H; Luukkaala, T; Kellokumpu-Lehtinen, P-L; Soimakallio, S

    2008-04-01

    The aim here is to show that texture parameters of magnetic resonance imaging (MRI) data changes in lymphoma tissue during chemotherapy. Ten patients having non-Hodgkin lymphoma masses in the abdomen were imaged for chemotherapy response evaluation three consecutive times. The analysis was performed with MaZda texture analysis (TA) application. The best discrimination in lymphoma MRI texture was obtained within T2-weighted images between the pre-treatment and the second response evaluation stage. TA proved to be a promising quantitative means of representing lymphoma tissue changes during medication follow-up. PMID:18342845

  1. SNPs Array Karyotyping in Non-Hodgkin Lymphoma

    PubMed Central

    Etebari, Maryam; Navari, Mohsen; Piccaluga, Pier Paolo

    2015-01-01

    The traditional methods for detection of chromosomal aberrations, which included cytogenetic or gene candidate solutions, suffered from low sensitivity or the need for previous knowledge of the target regions of the genome. With the advent of single nucleotide polymorphism (SNP) arrays, genome screening at global level in order to find chromosomal aberrations like copy number variants, DNA amplifications, deletions, and also loss of heterozygosity became feasible. In this review, we present an update of the knowledge, gained by SNPs arrays, of the genomic complexity of the most important subtypes of non-Hodgkin lymphomas.

  2. Non-Hodgkin's lymphoma originating in the spermatic cord.

    PubMed

    Lands, R H

    1996-03-01

    An otherwise healthy 57-year-old man was found to have an early stage, high-grade, non-Hodgkin's lymphoma (NHL) of the spermatic cord. A plan of treatment involving surgery, radiation therapy, combination chemotherapy, and central nervous system prophylaxis was recommended. He did not complete the recommended treatment plan, and subsequently returned with recurrent tumor in his brain. This case highlights the similarity of spermatic cord NHL to primary NHL of the testicle, and the propensity of both to progress or relapse in nodal and extranodal patterns. PMID:8604473

  3. The evolving role of lenalidomide in non-Hodgkin lymphoma.

    PubMed

    Galanina, Natalie; Petrich, Adam; Nabhan, Chadi

    2016-07-01

    Recent advances in the treatment of patients with non-Hodgkin lymphoma have driven a paradigm shift from standard chemotherapy to an ever-expanding choice of targeted agents and combinations. As an orally bioavailable immunomodulator with antineoplastic, immunologic, and antiproliferative activity in B-cell lymphoma, lenalidomide has emerged as one such option. Lenalidomide demonstrates clinically significant activity with a favorable safety profile as a single agent, as well as in combination therapy. Herein, we review accumulated clinical data on lenalidomide, with particular reference to patients with first-line and relapsed/refractory mantle cell lymphoma, indolent lymphoma, and diffuse large B-cell lymphoma. PMID:26902680

  4. Unusual case of pulmonary rickettsiosis in non-Hodgkin's lymphoma.

    PubMed

    Pugliese, C; Parigi, P C; Bamberga, M; Perani, V; Moioli, F; Delvecchio, G; Lorenzi, N; Cottini, M; Michetti, G

    1997-06-01

    A case report of boutonneuse fever with pulmonary complications in a patient with non-Hodgkin's lymphoma (NHL) is described. The patient was hospitalized for persistent hypertermia and marked dyspnea, with radiographic findings of bilateral involvement of the lungs. The confirmation of the diagnosis was obtained by means of serum analyses (Weil-Felix serodiagnosis and IFA); the patient responded to doxycycline with progressive improvement of her general health condition. In this case the occurrence of a NHL could justify the lower reactivity and the facilitated diffusion of rickettsiosis in the patient. PMID:9250284

  5. The management of adult aggressive non-Hodgkin's lymphomas.

    PubMed

    Couderc, B; Dujols, J P; Mokhtari, F; Norkowski, J L; Slawinski, J C; Schlaifer, D

    2000-07-01

    Aggressive non-Hodgkin's lymphona include diffuse large B-cell lymphoma, anaplastic large cell lymphona, and different peripheral T-cell lymphomas. An international prognostic index has been developed including age, serum LDH, performance status, and extranodal involvement. For localized aggressive lymphoma, the preferred treatment is 3-4 CHOP and radiation therapy, with a cure rate of 70-80%. For disseminated aggressive lymphoma, current regimens have a cure rate of less than 40%. Innovative strategies, including dose escalation, autologus stem cell support, new drugs, and immunotherapy are being explored to improve these results. PMID:10863150

  6. FPA micro spectral imaging of non-Hodgkin lymphomas

    NASA Astrophysics Data System (ADS)

    Burattini, E.; Malvezzi-Campeggi, F.; Chilosi, M.; Conti, C.; Ferraris, P.; Monti, F.; Sabbatini, S.; Tosi, G.; Zamò, A.

    2007-05-01

    A FT-IR microspectroscopy study on reactive lymph nodes and non-Hodgkin lymphomas is reported. Mid infrared absorption spectra collected at diffraction limit spatial resolution from reactive and neoplastic lymph nodes resulted sufficiently different once analysed by multivariate pattern recognition analysis to distinguish tumoral from non tumoral samples. The potential of infrared spectroscopy as a post-operative screening is gained by the use of a multielement Focal Plane Array detector. Spectral differences between normal and malignant spectra were mainly in the methyl stretching and in the low frequency region.

  7. Yttrium Y 90 Basiliximab and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With Mature T-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2016-06-29

    Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma

  8. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

    PubMed Central

    Mitchell, Jonathan S.; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C.; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F.; Kuiper, Rowan; Stephens, Owen W.; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A.; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H.; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y.; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M.; Rafnar, Thorunn; Ross, Fiona M.; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A.; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E.; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J.; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S.

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  9. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma.

    PubMed

    Mitchell, Jonathan S; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F; Kuiper, Rowan; Stephens, Owen W; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M; Rafnar, Thorunn; Ross, Fiona M; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  10. Mass cytometry analysis shows that a novel memory phenotype B cell is expanded in multiple myeloma

    PubMed Central

    Hansmann, Leo; Blum, Lisa; Ju, Chia-Hsin; Liedtke, Michaela; Robinson, William H.; Davis, Mark M.

    2015-01-01

    It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals and thus high resolution technologies are likely required. We used cytometry by time-of-flight (CyTOF) and next generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related pre-cancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 pre-cancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T, B, and natural killer cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0±0.7% (mean±SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27+) and naïve (CD24loCD38+) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. PMID:25711758

  11. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation.

    PubMed

    Weinstock, Mathew; Aljawai, Yosra; Morgan, Elizabeth A; Laubach, Jacob; Gannon, Muriel; Roccaro, Aldo M; Varga, Cindy; Mitsiades, Constantine S; Paba-Prada, Claudia; Schlossman, Robert; Munshi, Nikhil; Anderson, Kenneth C; Richardson, Paul P; Weller, Edie; Ghobrial, Irene M

    2015-06-01

    Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation. PMID:25833301

  12. Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations.

    PubMed

    Dănciulescu Miulescu, R; Carşote, M; Trifănescu, R; Ferechide, D; Poiană, C

    2013-09-15

    Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves' disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug's withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy. PMID:24155785

  13. Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations

    PubMed Central

    Dănciulescu Miulescu, R; Carșote, M; Trifănescu, R; Ferechide, D; Poiană, C

    2013-01-01

    Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves’ disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug’s withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy. PMID:24155785

  14. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

    PubMed Central

    Kikuchi, Jiro; Koyama, Daisuke; Wada, Taeko; Izumi, Tohru; Hofgaard, Peter O.; Bogen, Bjarne; Furukawa, Yusuke

    2015-01-01

    Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3–lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion–mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion–dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug–induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index. PMID:26517694

  15. Comparative Effectiveness on Survival of Zoledronic Acid versus Pamidronate in Multiple Myeloma

    PubMed Central

    Sanfilippo, KM; Gage, B; Luo, S; Weilbaecher, K; Tomasson, M; Vij, R; Colditz, G; Carson, K

    2015-01-01

    Zoledronic acid and pamidronate are the two bisphosphonates approved to reduce multiple myeloma skeletal complications in the United States. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal related events and overall survival in myeloma patients treated with zoledronic acid versus pamidronate using a cohort of 1,018 United States Veterans. At median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio (HR) 0.78; 95% CI, 0.67–0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate. PMID:24844358

  16. Chalazia Development in Multiple Myeloma: A New Complication Associated with Bortezomib Therapy

    PubMed Central

    Yun, Charles; Mukhi, Nikhil; Kremer, Valerie; Shinder, Roman; Verma, Vaibhav; Olcay, Batuman

    2015-01-01

    Multiple myeloma (MM) is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia – which caused intolerable discomfort – started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia. PMID:26330998

  17. New approaches to targeting the bone marrow microenvironment in multiple myeloma.

    PubMed

    Gooding, Sarah; Edwards, Claire M

    2016-06-01

    Multiple myeloma is a tumour with a remarkably destructive effect on its host organ, the bone marrow. Through expression or secretion of adhesion molecules, growth factors, exosomes, miRNAs, chemokines and inhibitors, the tumour substantially alters its microenvironment, promoting both tumour survival and osteolytic bone disease. This altered niche is ideally suited to the sustenance of its proliferating compartment and the protection and immune evasion of its dormant, drug resistant fraction. The possibility of deepening response to a drug treatment regime, maintaining remission or even eradicating resistant stem cells by pharmacologically manipulating the tumour's interactions with this niche is a major driving force in current myeloma research. Examples of promising therapies include CXCR4 antagonists, RANKL inhibitors, HIF1α pathway inhibitors, and inhibitors of Notch, Wnt and TGFβ family pathways. PMID:27018230

  18. Myelomatous pleural effusion involvement in 23 patients with multiple myeloma: A single-center clinical analysis.

    PubMed

    Zhong, Yuping; Zhang, Jiajia; Wang, Huan

    2015-05-01

    We investigated the treatment and prognosis of pleural effusion (PE) in multiple myeloma (MM) patients. From June 2005 to December 2013, 296 MM patients participated in this study. There were 23 PE patients, including 11 men and 12 women, with a median age of 56.8 years (range 37-68 years). A diagnosis of PE was based on physical examination, chest X-ray or computed tomography, and pleural fluid analysis. All patients demonstrated myeloma cells in the pleural fluid, and six patients were positive for PE M protein. PE patients received bortezomib combined with other drugs. Only one patient demonstrated a complete response; 10 patients showed partial responses, and 12 patients developed progressive disease and died. MM linked with myelomatous PE is associated with a poor prognosis. Myelomatous PE is likely a late manifestation of the natural history of MM or an expression of the aggressive behavior of the disease. PMID:26273384

  19. Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

    PubMed Central

    Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

    2014-01-01

    Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

  20. Clinical course of light-chain smouldering multiple myeloma (idiopathic Bence Jones proteinuria): a retrospective cohort study

    PubMed Central

    Kyle, Robert A; Larson, Dirk R; Therneau, Terry M; Dispenzieri, Angela; Melton, L Joseph; Benson, Joanne T; Kumar, Shaji; Rajkumar, S Vincent

    2014-01-01

    Summary Background Bence Jones proteinuria is a disorder that is defined by the excretion of monoclonal light-chain protein. About 15–20% of patients with multiple myeloma secrete monoclonal light chains only, without expression of the normal immunoglobulin heavy chain, which constitutes light-chain multiple myeloma. The definition, prevalence, and progression of these premalignant phases of light-chain multiple myeloma have not been fully characterised. We aimed to identify a subset of patients with idiopathic Bence Jones proteinuria who had a high risk of progression to light-chain multiple myeloma analogous to that seen in patients with smouldering multiple myeloma. Methods In this retrospective cohort study, we studied all patients seen at the Mayo Clinic (Rochester, MN, USA) within 30 days of diagnosis of idiopathic Bence Jones proteinuria between Jan 1, 1960, and June 30, 2004. Inclusion criteria were monoclonal light chain in the urine (≥0·2 g/24 h), absence of intact monoclonal immunoglobulin (M protein) in the serum, and no evidence of multiple myeloma, light-chain amyloidosis, or other related plasma-cell proliferative disorders. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis. We examined the cumulative probability of progression and the association of potential risk factors on progression rates to identify patients with a high risk of progression to multiple myeloma or light-chain amyloidosis. Findings We identified 101 patients with idiopathic Bence Jones proteinuria. During 901 total person-years of follow-up, 27 (27%) patients developed multiple myeloma and seven (7%) developed light-chain amyloidosis. The major risk factors for progression were amount of urinary excretion of M protein per 24 h, proportion of bone marrow plasma cells, presence of a markedly abnormal free-light-chain ratio (<0·01 or >100), and reduction of all three uninvolved immunoglobulins. Based on the risk of progression