250 results on '"Rajkumar, S V"'
Search Results
2. "Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.
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Vaxman I, Abeykoon J, Dispenzieri A, Kumar SK, Buadi F, Lacy MQ, Dingli D, Hwa Y, Fonder A, Hobbs M, Reeder C, Sher T, Hayman S, Kourelis T, Warsame R, Muchtar E, Leung N, Go R, Gonsalves W, Siddiqui M, Kyle RA, Rajkumar SV, Kristen M, Kapoor P, and Gertz MA
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- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological adverse effects, Female, Humans, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively., (© 2021. The Author(s).)
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- 2021
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3. Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial.
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Ailawadhi S, Mikhael JR, LaPlant BR, Laumann KM, Kumar S, Roy V, Dingli D, Bergsagel PL, Buadi FK, Rajkumar SV, Fonseca R, Gertz MA, Kapoor P, Sher T, Hayman SR, Stewart AK, Dispenzieri A, Kyle RA, Gonsalves WI, Reeder CB, Lin Y, Go RS, Leung N, Kourelis T, Lust JA, Russell SJ, Chanan-Khan AA, and Lacy MQ
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- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Dexamethasone administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma genetics, Multiple Myeloma mortality, Retreatment, Survival Analysis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Multiple Myeloma drug therapy
- Abstract
Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.
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- 2018
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4. Natural history of t(11;14) multiple myeloma.
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Lakshman A, Alhaj Moustafa M, Rajkumar SV, Dispenzieri A, Gertz MA, Buadi FK, Lacy MQ, Dingli D, Fonder AL, Hayman SR, Hobbs MA, Gonsalves WI, Hwa YL, Kapoor P, Leung N, Go RS, Lin Y, Kourelis TV, Lust JA, Russell SJ, Zeldenrust SR, Kyle RA, and Kumar SK
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- Adult, Aged, Aged, 80 and over, Chromosome Aberrations, Female, Humans, In Situ Hybridization, Fluorescence methods, Male, Middle Aged, Neoplasm Staging methods, Prognosis, Progression-Free Survival, Translocation, Genetic genetics, Young Adult, Chromosomes, Human genetics, Multiple Myeloma genetics, Multiple Myeloma pathology
- Abstract
Translocation (11;14) on interphase fluorescent in situ hybridization in plasma cells is regarded as a standard risk prognostic marker in multiple myeloma based on studies conducted before introduction of current therapies. We identified 365 patients with t(11;14), and 730 matched controls:132 patients with non-(11;14) translocations and 598 patients with no chromosomal translocation. The median progression-free survival for the three groups were 23.0 (95% confidence interval (CI), 20.8-27.6), 19.0 (95% CI, 15.8-22.7) and 28.3 (95% CI, 25.7-30.6) months, respectively (P<0.01). The median overall survival (OS) for t(11;14), non-(11;14) translocation and no-translocation groups were 74.4 (95% CI, 64.8-89.3), 49.8 (95% CI, 40.0-60.6) and 103.6 (95% CI, 85.2-112.3) months, respectively (P<0.01). Excluding those with 17p abnormality, the median OS in the three groups were 81.7 (95% CI, 67.0-90.7), 58.2 (95% CI, 47.0-76.4) and 108.3 (95% CI, 92.4-140.1) months, respectively (P<0.01). The above relationship held true in patients with age <65 years, international staging system (ISS) I/II stage or those who received novel agent-based induction. Advanced age (hazard ratio (HR): 1.98), 17p abnormality (HR: 2.2) and ISS III stage (HR: 1.59) at diagnosis predicted reduced OS in patients with t(11;14). These results suggest that outcomes of t(11;14) MM are inferior to other standard risk patients.
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- 2018
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5. Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey.
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Landgren O, Graubard BI, Kumar S, Kyle RA, Katzmann JA, Murata K, Costello R, Dispenzieri A, Caporaso N, Mailankody S, Korde N, Hultcrantz M, Therneau TM, Larson DR, Cerhan JR, and Rajkumar SV
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- Adolescent, Adult, Child, Female, Humans, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance pathology, Multiple Myeloma pathology, Nutrition Surveys, Prevalence, Risk Factors, Young Adult, Monoclonal Gammopathy of Undetermined Significance diagnosis, Multiple Myeloma diagnosis
- Abstract
We studied the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in younger individuals, age 10-49 years, using samples from the National Health and Nutritional Examination Survey (NHANES) III. NHANES prevalence rates were standardized to the 2000 US total population. Among 12 372 individuals (4073 blacks, 4146 Mexican-Americans, 3595 whites, and 558 others), MGUS was identified in 63 persons (0.34%, 95% CI 0.23-0.50). The prevalence of MGUS was significantly higher in blacks (0.88%, 95% CI 0.62-1.26) compared with whites (0.22%, 95% CI 0.11-0.45), P=0.001. The prevalence of MGUS in Mexican-Americans was at an intermediate level (0.41%, 95% CI 0.23-0.73). The disparity in prevalence of MGUS between blacks and whites was most striking in the 40-49 age-group; 3.26% (95% CI 2.04-5.18) versus 0.53% (95% CI 0.20-1.37), P=0.0013. There was a trend to earlier age of onset of MGUS in blacks compared with whites. MGUS was seen in only two persons in the 10-19 age-group (both Mexican-American), and in three persons in the 20-29-year age-group (all of whom were black). In persons less than 50 years of age, MGUS is significantly more prevalent, with up to 10 years earlier age of onset, in blacks compared with whites.
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- 2017
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6. Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma.
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Binder M, Rajkumar SV, Ketterling RP, Greipp PT, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Hayman SR, Hwa YL, Zeldenrust SR, Lust JA, Russell SJ, Leung N, Kapoor P, Go RS, Gonsalves WI, Kyle RA, and Kumar SK
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- Adult, Aged, Female, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma therapy, Retrospective Studies, Risk Factors, Chromosomes, Human, Pair 13 genetics, Multiple Myeloma genetics, Multiple Myeloma mortality, Translocation, Genetic
- Abstract
Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors.
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- 2017
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7. Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.
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Hillengass J, Moulopoulos LA, Delorme S, Koutoulidis V, Mosebach J, Hielscher T, Drake M, Rajkumar SV, Oestergaard B, Abildgaard N, Hinge M, Plesner T, Suehara Y, Matsue K, Withofs N, Caers J, Waage A, Goldschmidt H, Dimopoulos MA, Lentzsch S, Durie B, and Terpos E
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- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Male, Middle Aged, Retrospective Studies, Survival Rate, Multiple Myeloma diagnostic imaging, Multiple Myeloma mortality, Osteolysis diagnostic imaging, Osteolysis mortality, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.
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- 2017
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8. Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma.
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Ravi P, Kumar S, Gonsalves W, Buadi F, Lacy MQ, Go RS, Dispenzieri A, Kapoor P, Lust JA, Dingli D, Lin Y, Russell SJ, Leung N, Gertz MA, Kyle RA, Bergsagel PL, and Rajkumar SV
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Remission Induction, Treatment Outcome, Multiple Myeloma drug therapy
- Abstract
Little is known about the impact of multiple myeloma (MM) treatment on uninvolved immunoglobulins (Ig). We identified 448 patients who received high-dose dexamethasone (HD-DEX), lenalidomide and dexamethasone (RD), bortezomib and dexamethasone (VD), bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD) for newly diagnosed MM at our institution between 2000 and 2013, and who had available data on absolute lymphocyte count (ALC) and quantitative uninvolved Ig at baseline and at the end of four cycles of therapy. Changes in ALC and uninvolved Ig were significantly different across treatments, with VCD and HD-DEX producing reductions in uninvolved Ig, and RD, VD and VRD leading to increases in uninvolved Ig. In addition, treatment with RD, VD and VRD was independently associated with higher odds of achieving a ⩾25% increase in or normalization of the primary uninvolved Ig on multivariate analysis. Although achievement of a humoral response in the primary uninvolved Ig was associated with a higher odds of achieving VGPR or better after four cycles of therapy, it was not associated with improved overall survival. These data highlight the different mechanisms of action of MM drugs and point toward a possible role for the use of VCD in treating antibody-mediated autoimmune disease.
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- 2017
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9. Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma.
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Tandon N, Rajkumar SV, LaPlant B, Pettinger A, Lacy MQ, Dispenzieri A, Buadi FK, Gertz MA, Hayman SR, Leung N, Go RS, Dingli D, Kapoor P, Lin Y, Hwa YL, Fonder AL, Hobbs MA, Zeldenrust SR, Lust JA, Gonsalves WI, Russell SJ, and Kumar SK
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Prognosis, Young Adult, Multiple Myeloma diagnosis, Neoplasm Staging methods
- Abstract
We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III (P<0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III (P<0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.
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- 2017
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10. Second primary malignancies in multiple myeloma: an overview and IMWG consensus.
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Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, Comenzo R, Du J, Durie BGM, San Miguel J, Einsele H, Chen WM, Garderet L, Pietrantuono G, Hillengass J, Kyle RA, Moreau P, Lahuerta JJ, Landgren O, Ludwig H, Larocca A, Mahindra A, Cavo M, Mazumder A, McCarthy PL, Nouel A, Rajkumar SV, Reiman A, Riva E, Sezer O, Terpos E, Turesson I, Usmani S, Weiss BM, and Palumbo A
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- Humans, Incidence, Multiple Myeloma epidemiology, Multiple Myeloma pathology, Neoplasms, Second Primary epidemiology, Risk Factors, Multiple Myeloma therapy, Neoplasms, Second Primary etiology
- Abstract
Background: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians., Design: A Panel of International Myeloma Working Group members reviewed the most relevant data published in the literature as full papers, or presented at meetings of the American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, or International Myeloma Workshops, up to June 2016. Here, we present the recommendations of the Panel, based on this literature review., Results: Overall, the risk of SPMs in MM is low, multifactorial, and partially related to the length of patients' survival and MM intrinsic susceptibility. Studies suggest a significantly increased incidence of SPMs when lenalidomide is administered either following, or concurrently with, oral melphalan. Increased SPM incidence has also been reported with lenalidomide maintenance following high-dose melphalan, albeit to a lesser degree. In both cases, the risk of death from MM was significantly higher than the risk of death from SPMs, with lenalidomide possibly providing a survival benefit. No increase in SPM incidence was reported with lenalidomide plus dexamethasone (without melphalan), or with bortezomib plus oral melphalan, dexamethasone, or thalidomide., Conclusion: In general, the risk of SPMs should not alter the current therapeutic decision-making process in MM. However, regimens such as lenalidomide plus dexamethasone should be preferred to prolonged exposure to lenalidomide plus oral melphalan. SPM risk should be carefully discussed with the patient in the context of benefits and risks of different treatment options., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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11. Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression.
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Gonsalves WI, Rajkumar SV, Dispenzieri A, Dingli D, Timm MM, Morice WG, Lacy MQ, Buadi FK, Go RS, Leung N, Kapoor P, Hayman SR, Lust JA, Russell SJ, Zeldenrust SR, Hwa L, Kourelis TV, Kyle RA, Gertz MA, and Kumar SK
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- Adult, Aged, Aged, 80 and over, Cell Count, Clone Cells pathology, Disease Progression, Early Diagnosis, Female, Flow Cytometry methods, Humans, Male, Middle Aged, Multiple Myeloma pathology, Multiple Myeloma diagnosis, Neoplastic Cells, Circulating pathology, Plasma Cells pathology
- Abstract
The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ⩾150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ⩾150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage., Competing Interests: Conflict-of-interest disclosure: S.K.K., S.V.R., M.A.G., A.D., M.Q.L., W.G.M., M.M.T., F.K.B., Y.L., D.D., R.S.G, S.R.H., J.A.L., N.L., R.A.K., S.R.Z., S.R. and P.K.: These authors declare no competing financial interests.
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- 2017
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12. Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents.
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Majithia N, Rajkumar SV, Lacy MQ, Buadi FK, Dispenzieri A, Gertz MA, Hayman SR, Dingli D, Kapoor P, Hwa L, Lust JA, Russell SJ, Go RS, Kyle RA, and Kumar SK
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- Adult, Aged, Aged, 80 and over, Cytogenetics, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma therapy, Prognosis, Recurrence, Serum Albumin, Survival Rate, Time Factors, Transplantation, Autologous, Treatment Outcome, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy
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Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.
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- 2016
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13. Autologous stem cell transplant for multiple myeloma patients 70 years or older.
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Muchtar E, Dingli D, Kumar S, Buadi FK, Dispenzieri A, Hayman SR, Wolf RC, Gastineau DA, Chakraborty R, Hogan WJ, Leung N, Kapoor P, Lacy MQ, Rajkumar SV, and Gertz MA
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- Age Factors, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Female, Hematopoietic Stem Cell Mobilization methods, Hospitalization, Humans, Length of Stay, Male, Survival Analysis, Transplantation Conditioning methods, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma mortality, Multiple Myeloma therapy
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Autologous stem cell transplant (Auto-SCT) is increasingly used in older patients with multiple myeloma (MM), despite lack of phase 3 trials in this age-defined population. For 207 consecutive MM patients who underwent Auto-SCT and were 70 years or older at transplant (study cohort), data were analyzed and compared with a younger cohort (1764 Auto-SCT patients <70 years old). The proportion of Auto-SCT in the older patients increased from 7.8% of all transplants in 1998-2006 to 12.9% in 2007-2015. Sixty percent of patients required stem cell mobilization with chemotherapy or plerixafor. Full-dose melphalan conditioning was given to 55% of the older patients compared with 93% of the younger patients (P<0.001). Older patients were more likely to be hospitalized (64% vs 55%; P=0.01), but hospitalization duration was comparable. For newly diagnosed patients, median PFS was 33.5 months for the older cohort and 33.8 months for the younger cohort (P=0.91), and median overall survival was 6.1 and 7.8 years, respectively (P=0.11). Presumably, a smaller fraction of patients, age 70-76, is selected for Auto-SCT, but the benefits are comparable to those seen for younger patients. Reduced-dose melphalan was given to approximately half the patients to avoid excessive toxicity.
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- 2016
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14. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.
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Biran N, Jacobus S, Vesole DH, Callander NS, Fonseca R, Williams ME, Abonour R, Katz MS, Rajkumar SV, Greipp PR, and Siegel DS
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- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Clinical Trials, Phase III as Topic, Combined Modality Therapy, Dexamethasone administration & dosage, Follow-Up Studies, Humans, Lenalidomide, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Neoplasm Staging, Proportional Hazards Models, Randomized Controlled Trials as Topic, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Multiple Myeloma therapy
- Abstract
In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density., Competing Interests: NB, Celgene speaker's bureau; DHV, Celgene speaker's bureau; MEW, Celgene clinical research funding and consulting fees; RF, Celgene consulting fees; DSS, Celgene consulting fees and speaker's bureau. All other authors declare no conflict of interest.
- Published
- 2016
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15. Clinical course and outcomes of patients with multiple myeloma who relapse after autologous stem cell therapy.
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Gonsalves WI, Rajkumar SV, Gertz MA, Dispenzieri A, Lacy MQ, Buadi FK, Dingli D, Go RS, Leung N, Kapoor P, Hayman SR, Lust JA, Russell SJ, Zeldenrust SR, Hwa YL, Kourelis TV, Kyle RA, and Kumar SK
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- Adult, Aged, Disease Progression, Humans, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Prognosis, Recurrence, Stem Cell Transplantation mortality, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Multiple Myeloma therapy, Stem Cell Transplantation methods
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- 2016
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16. Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma.
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Ravi P, Kumar S, Larsen JT, Gonsalves W, Buadi F, Lacy MQ, Go R, Dispenzieri A, Kapoor P, Lust JA, Dingli D, Lin Y, Russell SJ, Leung N, Gertz MA, Kyle RA, Bergsagel PL, and Rajkumar SV
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- Adult, Aged, Aged, 80 and over, Bone Marrow pathology, Disease Progression, Female, Hemoglobins, Humans, Male, Middle Aged, Multiple Myeloma blood, Multiple Myeloma pathology, Myeloma Proteins, Odds Ratio, Plasma Cells pathology, Risk Assessment, Risk Factors, Biomarkers, Multiple Myeloma diagnosis
- Abstract
We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30-8.77), P=0.013), eMP (OR=8.20 (3.19-21.05), P<0.001) and eHb (OR=5.86 (2.12-16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0-3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors., Competing Interests: SK has obtained research support for clinical trials from Celgene, Millennium, Novartis, Janssen and Sanofi. AD has received research support for clinical trials from Pfizer, Janssen, Millennium, Alnylam and Celgene. MAG has received research support from ISIS and Prothena, and honoraria from Celgene, Millennium Pharmaceuticals and Novartis. PLB has obtained research support for clinical trials from Millennium, Novartis, Constellation Pharmaceuticals and MundiPharma, and honoraria from Amgen and Incyte. The other authors declare no conflict of interest.
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- 2016
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17. Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide-Dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen.
- Author
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Jacobus SJ, Rajkumar SV, Weiss M, Stewart AK, Stadtmauer EA, Callander NS, Dreosti LM, Lacy MQ, and Fonseca R
- Subjects
- Aged, Bortezomib adverse effects, Dexamethasone adverse effects, Female, Humans, Lenalidomide, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Salvage Therapy, Survival Analysis, Thalidomide administration & dosage, Thalidomide adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bortezomib administration & dosage, Consolidation Chemotherapy adverse effects, Consolidation Chemotherapy methods, Dexamethasone administration & dosage, Induction Chemotherapy methods, Multiple Myeloma drug therapy, Thalidomide analogs & derivatives
- Abstract
Competing Interests: Dr Stadtmauer has been a consultant for Celgene, Takeda and Amgen. Dr Stewart has received honoraria for consulting from Celgene. Dr Dreosti has received speaker honorarium from Janssen Pharmaceuticals and congress sponsorship from Janssen Pharmaceuticals. Dr Fonseca has received consulting fees from Celgene and Takeda. The remaining authors declare no conflict of interest.
- Published
- 2016
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18. Treatment outcomes, health-care resource utilization and costs of bortezomib and dexamethasone, with cyclophosphamide or lenalidomide, in newly diagnosed multiple myeloma.
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Kumar SK, Ma E, Engebretson AE, Buadi FK, Lacy MQ, Dispenzieri A, Duh MS, Lafeuille MH, Lefebvre P, Cheng WY, Dea K, Rembert D, Patt D, Niculescu L, Quick M, and Rajkumar SV
- Subjects
- Bortezomib administration & dosage, Cyclophosphamide administration & dosage, Dexamethasone administration & dosage, Follow-Up Studies, Humans, Lenalidomide, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Neoplasm Staging, Prognosis, Survival Rate, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols economics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Health Care Costs statistics & numerical data, Health Resources statistics & numerical data, Multiple Myeloma drug therapy, Multiple Myeloma economics
- Published
- 2016
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19. Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma.
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Binder M, Rajkumar SV, Ketterling RP, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Hayman SR, Hwa YL, Zeldenrust SR, Lust JA, Russell SJ, Leung N, Kapoor P, Go RS, Gonsalves WI, Kyle RA, and Kumar SK
- Subjects
- Adult, Aged, Aged, 80 and over, Bone Marrow metabolism, Bone Marrow pathology, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Karyotype, Male, Middle Aged, Multiple Myeloma mortality, Polyploidy, Prognosis, Proportional Hazards Models, Young Adult, Cell Transformation, Neoplastic genetics, Chromosome Aberrations, Clonal Evolution genetics, Multiple Myeloma diagnosis, Multiple Myeloma genetics
- Abstract
Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09-0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37-6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73-6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification.
- Published
- 2016
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20. Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma.
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Kaufman GP, Gertz MA, Dispenzieri A, Lacy MQ, Buadi FK, Dingli D, Hayman SR, Kapoor P, Lust JA, Russell S, Go RS, Hwa YL, Kyle RA, Rajkumar SV, and Kumar SK
- Subjects
- Adult, Aged, Bortezomib therapeutic use, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 17, Cytogenetic Analysis, Dexamethasone therapeutic use, Humans, In Situ Hybridization, Fluorescence, Induction Chemotherapy methods, Lenalidomide, Male, Melphalan therapeutic use, Middle Aged, Multiple Myeloma genetics, Multiple Myeloma mortality, Prognosis, Remission Induction, Retrospective Studies, Survival Analysis, Thalidomide analogs & derivatives, Thalidomide therapeutic use, Translocation, Genetic, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Multiple Myeloma diagnosis, Multiple Myeloma therapy
- Abstract
Early high-dose therapy (HDT), consisting of high-dose melphalan and autologous stem cell transplantation following doublet or triplet novel agent induction, is a preferred management strategy for transplant-eligible myeloma patients. We set out to examine the utility of the current fluorescence in situ hybridization (FISH)-based risk stratification in a homogenously treated population of transplant-eligible myeloma patients receiving novel induction regimens and early HDT with or without posttransplant maintenance therapy. FISH was available in 409 patients at the time of diagnosis for patients receiving HDT within 12 months of diagnosis. We present comprehensive outcomes for chromosome 14 translocations and 17p abnormalities that both support and refute current risk stratification models. In contrast to its current classification as a marker of 'standard risk' (SR), t(11;14) was associated with inferior overall survival (OS) when compared with the classical SR cohort. The use of novel agent maintenance therapy (bortezomib or lenalidomide) following early HDT ameliorates the negative prognostic value of high-risk (HR) cytogenetic markers. HR patients who received maintenance following early HDT had similar OS compared with the SR cohort at 5 years.
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- 2016
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21. Clarification of the definition of complete response in multiple myeloma.
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Durie BG, Miguel JF, Blade J, and Rajkumar SV
- Subjects
- Humans, Antibodies, Monoclonal therapeutic use, Multiple Myeloma drug therapy
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- 2015
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22. Interpretation of cytogenetic results in multiple myeloma for clinical practice.
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Rajan AM and Rajkumar SV
- Subjects
- Humans, Chromosome Aberrations, Cytogenetic Analysis methods, Multiple Myeloma genetics
- Abstract
The interpretation of cytogenetic abnormalities in multiple myeloma (MM) is often a challenging task. MM is characterized by several cytogenetic abnormalities that occur at various time points in the disease course. The interpretation of cytogenetic results in MM is complicated by the number and complexity of the abnormalities, the methods used to detect them and the disease stage at which they are detected. Specific cytogenetic abnormalities affect clinical presentation, progression of smoldering multiple myeloma (SMM) to MM, prognosis of MM and management strategies. The goal of this paper is to provide a review of how MM is classified into specific subtypes based on primary cytogenetic abnormalities and to provide a concise overview of how to interpret cytogenetic abnormalities based on the disease stage to aid clinical practice and patient management.
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- 2015
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23. Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma.
- Author
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Vu T, Gonsalves W, Kumar S, Dispenzieri A, Lacy MQ, Buadi F, Gertz MA, and Rajkumar SV
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Dexamethasone administration & dosage, Female, Hematopoietic Stem Cell Transplantation, Humans, Lenalidomide, Male, Middle Aged, Multiple Myeloma genetics, Remission Induction, Thalidomide therapeutic use, Treatment Outcome, Multiple Myeloma drug therapy, Thalidomide analogs & derivatives
- Abstract
We studied all patients at our institution with a diagnosis of multiple myeloma (MM), from 1 January 2004 to 1 July 2009, who received lenalidomide-dexamethasone (Rd) as initial therapy and had a time to progression of 72 months or longer. Of 240 patients, we identified 33 exceptional responders. Twenty-five patients received primary therapy with Rd and eight patients received Rd induction followed by early stem cell transplantation (SCT). Seven of the eight patients who received SCT did not receive maintenance therapy; one patient received 9 months of lenalidomide post transplant. Fifteen (45%) patients had known clonal plasma cell disorder before the diagnosis of MM. The dominant mode of clinical presentation was with lytic lesions in 28 patients. Of those with informative cytogenetics (n=24), trisomies were present in 19 (79%), including one patient with concurrent trisomies and t(11;14). Overall, 21 of 24 patients (88%) had either trisomies or t(11;14). None of these exceptional responders had high-risk cytogenetic features at baseline. Twenty-five patients (76%) had a complete response (CR), whereas eight patients (24%) achieved the exceptional response state without ever achieving a CR. We identify a cohort of exceptional responders to Rd-based therapy, representing ~10-15% newly diagnosed MM patients with normal renal function.
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- 2015
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24. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy.
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Siontis B, Kumar S, Dispenzieri A, Drake MT, Lacy MQ, Buadi F, Dingli D, Kapoor P, Gonsalves W, Gertz MA, and Rajkumar SV
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Multiple Myeloma mortality, Positron-Emission Tomography, Survival Analysis, Tomography, X-Ray Computed, Multimodal Imaging, Multiple Myeloma diagnosis
- Abstract
We studied 188 patients with a suspected smoldering multiple myeloma (MM) who had undergone a positron emission tomography-computed tomography (PET-CT) scan as part of their clinical evaluation. PET-CT was positive (clinical radiologist interpretation of increased bone uptake and/or evidence of lytic bone destruction) in 74 patients and negative in 114 patients. Of these, 25 patients with a positive PET-CT and 97 patients with a negative PET-CT were observed without therapy and formed the study cohort (n=122). The probability of progression to MM within 2 years was 75% in patients with a positive PET-CT observed without therapy compared with 30% in patients with a negative PET-CT; median time to progression was 21 months versus 60 months, respectively, P=0.0008. Of 25 patients with a positive PET-CT, the probability of progression was 87% at 2 years in those with evidence of underlying osteolysis (n=16) and 61% in patients with abnormal PET-CT uptake but no evidence of osteolysis (n=9). Patients with positive PET-CT and evidence of underlying osteolysis have a high risk of progression to MM within 2 years when observed without therapy. These observations support recent changes to imaging requirements in the International Myeloma Working Group updated diagnostic criteria for MM.
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- 2015
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25. Utility of serum free light chain measurements in multiple myeloma patients not achieving complete response to therapy.
- Author
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Alhaj Moustafa M, Rajkumar SV, Dispenzieri A, Gertz MA, Lacy MQ, Buadi FK, Hwa YL, Dingli D, Kapoor P, Hayman SR, Lust JA, Kyle RA, and Kumar SK
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma mortality, Neoplasm Recurrence, Local mortality, Neoplasm Staging, Prognosis, Remission Induction, Retrospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunoglobulin Light Chains blood, Multiple Myeloma blood, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local blood, Neoplasm Recurrence, Local drug therapy
- Abstract
Normalization of the serum-free light-chain ratio (FLCr) with the absence of bone marrow monoclonal plasma cells following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma (MM), and is associated with improved overall survival (OS). However, its value in patients achieving
- Published
- 2015
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26. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.
- Author
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Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, and Dispenzieri A
- Subjects
- Aged, Aged, 80 and over, Boron Compounds adverse effects, Dexamethasone administration & dosage, Disease-Free Survival, Female, Glycine administration & dosage, Glycine adverse effects, Humans, Male, Middle Aged, Multiple Myeloma mortality, Recurrence, Treatment Outcome, Antineoplastic Agents therapeutic use, Boron Compounds administration & dosage, Glycine analogs & derivatives, Multiple Myeloma drug therapy
- Abstract
This phase 2 trial was designed to evaluate ixazomib, an orally bioavailable proteasome inhibitor, in patients with myeloma who have limited prior exposure to bortezomib. Thirty-three patients with relapsed multiple myeloma were enrolled. Ixazomib was given at 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added for lack of a minor response (MR) by end of cycle 2 or lack of a partial response (PR) by end of cycle 4 or for disease progression at any time. Median age was 69 years; patients had a median of two prior therapies (range 1-7). A grade 3 or 4 adverse event considered at least possibly related to drug was seen in 19 (59%) and 6 (19%) patients, respectively. The most common adverse events were thrombocytopenia, fatigue, nausea and diarrhea. Dexamethasone was initiated in 22 (67%) patients, 17 for not reaching the desired response and 5 for progression. Response (⩾PR) to single agent was seen in five patients within four cycles of therapy including three patients with PR, one patient with complete response (CR) and one patient with stringent CR. Six additional patients with either an MR (2) or SD (4) achieved a PR after addition of dexamethasone, translating to an overall response rate of 34%.
- Published
- 2015
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27. Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma.
- Author
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Gonsalves WI, Leung N, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Dingli D, Kapoor P, Go RS, Lin Y, Russell SJ, Lust JA, Zeldenrust S, Kyle RA, Gertz MA, and Kumar SK
- Subjects
- Adult, Aged, Aged, 80 and over, Cytogenetics, Female, Glomerular Filtration Rate, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma blood, Multiple Myeloma complications, Multiple Myeloma pathology, Neoplasm Staging, Renal Insufficiency blood, Renal Insufficiency complications, Renal Insufficiency pathology, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Multiple Myeloma drug therapy, Neoadjuvant Therapy, Renal Insufficiency drug therapy, Renal Insufficiency epidemiology
- Abstract
Renal impairment (RI) is seen in over a quarter of patients with newly diagnosed multiple myeloma (NDMM). It is not clear if reversal of RI improves the outcome to that expected for NDMM patients without RI. We evaluated 1135 consecutive patients with NDMM seen at the Mayo Clinic between January 2003 and December 2012. RI was defined as having a creatinine clearance (CrCl) <40ml/min. The median overall survival (OS) for patients with RI at diagnosis receiving and not receiving novel agent induction therapy was not reached vs 46 months (P<0.001). The median OS for patients with CrCl ⩾40 ml/min at diagnosis, CrCl <40 ml/min at diagnosis but improved to ⩾40 ml/min and CrCl <40 ml/min at diagnosis and remained <40 ml/min, were 112, 56 and 33 months, respectively (P<0.001). The complete renal response rate for patients with RI at diagnosis receiving novel agent induction therapy compared to the rest was 40 vs 16% (P<0.001). In conclusion, patients with reversal of RI have improved outcomes, but it remains inferior to patients with normal renal function at diagnosis. These results have implications for identifying early treatment strategies for patients at risk of developing renal insufficiency.
- Published
- 2015
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28. Phase I/II study of melphalan, prednisone and lenalidomide combination for patients with newly diagnosed multiple myeloma who are not candidates for stem cell transplantation.
- Author
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Roy V, Stewart AK, Bergsagel PL, Dispenzieri A, Laumann K, Allred J, Lacy MQ, Fonseca R, Reeder CB, Kumar S, Rivera CE, Gertz MA, Buadi FK, Hayman SR, and Rajkumar SV
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Lenalidomide, Male, Melphalan adverse effects, Middle Aged, Multiple Myeloma pathology, Prednisone adverse effects, Stem Cell Transplantation, Thalidomide administration & dosage, Thalidomide adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Melphalan administration & dosage, Multiple Myeloma drug therapy, Prednisone administration & dosage, Thalidomide analogs & derivatives
- Published
- 2015
- Full Text
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29. Racial differences in primary cytogenetic abnormalities in multiple myeloma: a multi-center study.
- Author
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Greenberg AJ, Philip S, Paner A, Velinova S, Badros A, Catchatourian R, Ketterling R, Kyle RA, Kumar S, Vachon CM, and Rajkumar SV
- Subjects
- Adult, Aged, Aged, 80 and over, Black People, Chromosomes, Human, Pair 13 genetics, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 17 genetics, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Middle Aged, Multiple Myeloma epidemiology, Multiple Myeloma pathology, White People genetics, Chromosome Aberrations, Multiple Myeloma genetics, Prognosis, Translocation, Genetic
- Abstract
We examined four clinically assessed cytogenetic subtypes (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p in 292 black patients with newly diagnosed multiple myeloma (MM) from four medical centers, who had fluorescent in situ hybridization testing results available in their medical records. We then compared the prevalence of these abnormalities with a previously characterized Mayo Clinic cohort of 471 patients with MM. We found a significant difference in the prevalence of the t(11;14) immunoglobulin heavy chain (IgH) translocation between blacks and whites, 6.5% versus 17.6%, respectively, P<0.0001. Blacks also had lower rates of the t(4;14) IgH translocation, (5.5% versus 10%); monosomy 13/del13q (29.1 versus 49.3%); and monosomy 17/del17p (7.9% versus 13%). Consequently, 63.4% of blacks versus 34.6% of whites did not have any of the four abnormalities that we studied, P<0.001. As almost all MM is associated with either an IgH translocation or trisomies, we hypothesize that MM in blacks is associated with either excess prevalence of either the trisomic (hyperdiploid) form of MM or an IgH translocation besides t(11;14) or t(4;14). We conclude that there are significant differences in the cytogenetic subtypes of MM that occur in blacks and whites.
- Published
- 2015
- Full Text
- View/download PDF
30. Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma.
- Author
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Gonsalves WI, Rajkumar SV, Gupta V, Morice WG, Timm MM, Singh PP, Dispenzieri A, Buadi FK, Lacy MQ, Kapoor P, Gertz MA, and Kumar SK
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Proliferation, Cytogenetics, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Plasma Cells cytology, Prognosis, ROC Curve, Retrospective Studies, Risk, Treatment Outcome, Flow Cytometry methods, Multiple Myeloma blood, Multiple Myeloma diagnosis
- Abstract
The presence of clonal circulating plasma cells (cPCs) is a marker of high-risk disease in all stages of monoclonal gammopathies. However, the prognostic utility of quantitating cPCs using multiparametric flow cytometry in multiple myeloma (MM) patients with current treatments is unknown. There were 157 consecutive patients with newly diagnosed MM seen at the Mayo Clinic, Rochester from 2009 to 2011 that had their peripheral blood evaluated for cPCs by multiparameter flow cytometry. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log-rank test. Using a receiver operating characteristics (ROC) analysis, ⩾400 cPCs were considered as the optimal cutoff for defining high-risk disease. The presence of ⩾400 cPCs was associated with higher plasma cell (PC) proliferation and adverse cytogenetics. The median time-to-next-treatment and overall survival (OS) in patients with ⩾400 cPCs (N=37, 24%) was 14 months and 32 months compared with 26 months and not reached for the rest (P<0.001). In a multivariable model, the presence of ⩾400 cPCs and older age adversely affected OS. Flow cytometry to quantify cPCs is a valuable test for risk stratifying newly diagnosed MM patients in the era of novel agents. Future studies are needed to determine its role in developing a risk-adapted treatment approach.
- Published
- 2014
- Full Text
- View/download PDF
31. Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma.
- Author
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Ramakrishnan V, Painuly U, Kimlinger T, Haug J, Rajkumar SV, and Kumar S
- Subjects
- Antineoplastic Agents pharmacology, Antineoplastic Agents toxicity, Apoptosis drug effects, Apoptosis Regulatory Proteins antagonists & inhibitors, Caspases metabolism, Cell Death, Cell Line, Tumor, Cell Proliferation, Enzyme Activation drug effects, Fas Ligand Protein pharmacology, Humans, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Molecular Targeted Therapy, Multiple Myeloma drug therapy, NF-kappa B metabolism, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, TNF-Related Apoptosis-Inducing Ligand pharmacology, Thiazoles pharmacology, Thiazoles toxicity, Tumor Microenvironment drug effects, Apoptosis Regulatory Proteins metabolism, Multiple Myeloma metabolism
- Abstract
The inhibitor of apoptosis (IAP) proteins have a critical role in the control of apoptotic machinery, and has been explored as a therapeutic target. Here, we have examined the functional importance of IAPs in multiple myeloma (MM) by using a Smac (second mitochondria-derived activator of caspases)-mimetic LCL161. We observed that LCL161 was able to potently induce apoptosis in some MM cell lines but not in others. Examining the levels of X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2) post LCL161 treatment indicated clear downregulation of both XIAP activity and cIAP1 levels in both the sensitive and less sensitive (resistant) cell lines. cIAP2, however, was not downregulated in the cell line resistant to the drug. Small interfering RNA-mediated silencing of cIAP2 significantly enhanced the effect of LCL161, indicating the importance of downregulation of all IAPs simultaneously for induction of apoptosis in MM cells. LCL161 induced marked up regulation of the Jak2/Stat3 pathway in the resistant MM cell lines. Combining LCL161 with a Jak2-specific inhibitor resulted in synergistic cell death in MM cell lines and patient cells. In addition, combining LCL161 with death-inducing ligands clearly showed that LCL161 sensitized MM cells to both Fas-ligand and TRAIL.
- Published
- 2014
- Full Text
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32. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients.
- Author
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Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, Kapoor P, Dingli D, Hayman SR, Leung N, Lust J, McCurdy A, Russell SJ, Zeldenrust SR, Kyle RA, and Rajkumar SV
- Subjects
- Aged, Cohort Studies, Female, Humans, Male, Multiple Myeloma mortality, Multiple Myeloma surgery, Prognosis, Stem Cell Transplantation, Treatment Outcome, Multiple Myeloma pathology, Survival Rate
- Abstract
Therapy for multiple myeloma (MM) has markedly changed in the past decade with the introduction of new drugs, but it is not clear whether the improvements have been sustained. We studied 1038 patients diagnosed between 2001 and 2010, grouping patients into two 5-year periods by diagnosis, 2001-2005 and 2006-2010. The median estimated follow-up for the cohort was 5.9 years with 47% alive at the last follow-up. The median overall survival (OS) for the entire cohort was 5.2 years: 4.6 years for patients in the 2001-2005 group compared with 6.1 years for the 2006-2010 cohort (P=0.002). The improvement was primarily seen among patients over 65 years, the 6-year OS improving from 31 to 56%, P<0.001. Only 10% of patients died during the first year in the latter group, compared with 16% in the earlier cohort (P<0.01), suggesting improvement in early mortality. The improved outcomes were linked closely to the use of one or more new agents in initial therapy. The current results confirm continued survival improvement in MM and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival is benefitting older patients and that early mortality in this disease has reduced considerably.
- Published
- 2014
- Full Text
- View/download PDF
33. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG).
- Author
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Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, Kumar S, Usmani S, Roodman D, Niesvizky R, Einsele H, Anderson KC, Dimopoulos MA, Avet-Loiseau H, Mellqvist UH, Turesson I, Merlini G, Schots R, McCarthy P, Bergsagel L, Chim CS, Lahuerta JJ, Shah J, Reiman A, Mikhael J, Zweegman S, Lonial S, Comenzo R, Chng WJ, Moreau P, Sonneveld P, Ludwig H, Durie BG, and Miguel JF
- Subjects
- Humans, Antineoplastic Agents therapeutic use, Multiple Myeloma drug therapy
- Abstract
Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
- Published
- 2014
- Full Text
- View/download PDF
34. Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma.
- Author
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Greenberg AJ, Rajkumar SV, Therneau TM, Singh PP, Dispenzieri A, and Kumar SK
- Subjects
- Chromosome Aberrations, Cytogenetic Analysis methods, Humans, Immunoglobulin Heavy Chains genetics, Multiple Myeloma complications, Multiple Myeloma mortality, Prognosis, Multiple Myeloma diagnosis, Multiple Myeloma genetics
- Abstract
Multiple myeloma (MM) consists of several distinct cytogenetic subtypes, and we hypothesized that each subtype may have a unique mode of initial presentation and end-organ damage. We studied 484 patients with newly diagnosed MM to determine the relationship between specific myeloma-defining event (MDE) and the cytogenetic subtype. Patients were divided into four non-overlapping groups based on the MDE at diagnosis: isolated renal failure, isolated anemia, isolated lytic bone disease or a combination (mixed). MM with translocations without trisomies accounted for 30% of all patients, but accounted for 50% of patients with renal failure. Specifically, the t(14;16) translocation accounted for only 5% of all MM patients, but was present in 13.5% of patients with renal failure as MDE. Among patients with t(14;16), 25% presented with renal failure only as MDE. Patients with isolated renal failure as MDE had significantly poorer survival compared with all other groups, whereas patients with bone disease as MDE had the best outcome (P<0.001). Our findings support the hypothesis that in addition to prognostic differences, there is significant heterogeneity in clinical presentation associated with the cytogenetic subtype, suggesting that MM encompasses a group of cytogenetically and phenotypically distinct disorders rather than a single entity.
- Published
- 2014
- Full Text
- View/download PDF
35. The current status of minimal residual disease assessment in myeloma.
- Author
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Kumar SK and Rajkumar SV
- Subjects
- Humans, Alleles, Multiple Myeloma genetics, Multiple Myeloma pathology, Neoplasm, Residual genetics
- Published
- 2014
- Full Text
- View/download PDF
36. Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma.
- Author
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Srivastava G, Rana V, Lacy MQ, Buadi FK, Hayman SR, Dispenzieri A, Gertz MA, Dingli D, Zeldenrust S, Russell S, McCurdy A, Kapoor P, Kyle R, Rajkumar SV, and Kumar S
- Subjects
- Adult, Aged, Aged, 80 and over, Dexamethasone administration & dosage, Female, Follow-Up Studies, Humans, Lenalidomide, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Neoplasm Staging, Prognosis, Retrospective Studies, Survival Rate, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Abstract
The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma (MM). Although the initial response rates and toxicity are well known, long-term outcome is not well described. We studied 286 consecutive patients with newly diagnosed MM initially treated with Len-Dex. The median (range) age at diagnosis was 63 (28-92) years, 166 (58%) patients ≤ 65 years and 175 (61%) male. The median estimated duration on Len-Dex was 5.3 months with overall response (≥ partial response) of 72%, including 26% with very good partial response or better. The median overall survival (OS) from the diagnosis was not reached (NR) and the estimated 5-year survival was 71%. The median time to first disease progression, irrespective of transplant status, was 30.2 months. Overall, 143 (50%) patients underwent stem cell transplant. The median OS was NR for patients ≤ 70 years and 5.8 years for the older patients (P=0.01). The 5-year OS estimate for patients in International Staging System stage 1, 2 and 3 were 82, 65, and 44% respectively. There were 21 new second malignancies after MM diagnosis (6.6%). The median survival exceeding 7 years reflects the efficacy of novel agents. The risk of second malignancies doesn't appear to be excessive in this population.
- Published
- 2013
- Full Text
- View/download PDF
37. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma.
- Author
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Rajkumar SV, Gupta V, Fonseca R, Dispenzieri A, Gonsalves WI, Larson D, Ketterling RP, Lust JA, Kyle RA, and Kumar SK
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Immunoglobulin Heavy Chains genetics, Male, Middle Aged, Multiple Myeloma mortality, Risk, Translocation, Genetic, Chromosome Aberrations, Multiple Myeloma diagnosis, Multiple Myeloma genetics
- Abstract
We studied 351 patients with smoldering multiple myeloma (SMM) in whom the underlying primary molecular cytogenetic subtype could be determined based on cytoplasmic immunoglobulin fluorescent in situ hybridization studies. Hundred and fifty-four patients (43.9%) had trisomies, 127 (36.2%) had immunoglobulin heavy chain (IgH) translocations, 14 (4%) both trisomies and IgH translocations, 53 (15.1%) no abnormalities detected and 3 (0.9%) had monosomy13/del(13q) in the absence of any other abnormality. Among 127 patients with IgH translocations, 57 were t(11;14), 36 t(4;14), 11 musculoaponeurotic fibrosarcoma (MAF) translocations, and 23 other or unknown IgH translocation partner. Time to progression (TTP) to symptomatic multiple myeloma was significantly shorter in patients with the t(4;14) compared with patients with t(11;14), median 28 versus 55 months, respectively, P=0.025. The median TTP was 28 months with t(4;14) (high-risk), 34 months with trisomies alone (intermediate-risk), 55 months with t(11;14), MAF translocations, other/unknown IgH translocations, monosomy13/del(13q) without other abnormalities, and those with both trisomies and IgH translocations (standard-risk), and not reached in patients with no detectable abnormalities (low-risk), P=0.001. There was a trend to shorter TTP with deletion 17p (median TTP, 24 months). Overall survival from diagnosis of SMM was significantly inferior with t(4;14) compared with t(11;14), median 105 versus 147 months, respectively, P=0.036.
- Published
- 2013
- Full Text
- View/download PDF
38. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.
- Author
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Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, and Rajkumar SV
- Subjects
- Female, Humans, Male, Middle Aged, Multiple Myeloma diagnosis, ROC Curve, Sensitivity and Specificity, Biomarkers, Tumor blood, Immunoglobulin Light Chains blood, Multiple Myeloma blood
- Abstract
A markedly elevated serum free light chain (FLC) ratio may serve as a biomarker for malignant transformation in high-risk smoldering multiple myeloma (SMM) and identify patients who are at imminent risk of progression. We retrospectively studied the predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥ 100 was used to define high-risk SMM, which included 15% (n=90) of the total cohort. Receiver operating characteristics analysis determined the optimal FLC ratio cut-point to predict progression to symptomatic multiple myeloma (MM) within 2 years of diagnosis, which resulted in a specificity of 97% and sensitivity of 16%. Fifty-six percent of patients developed progressive disease during median follow-up of 52 months, but this increased to 98% in the subgroup of patients with FLC ratio ≥ 100. The median time to progression in the FLC ratio ≥ 100 group was 15 months versus 55 months in the FLC <100 group (P<0.0001). The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥ 100 was 72%; the risk of progression to MM or light chain amyloidosis in 2 years was 79%. We conclude that a high FLC ratio ≥ 100 is a predictor of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention.
- Published
- 2013
- Full Text
- View/download PDF
39. Will the real myeloma please stand up?
- Author
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Kumar S and Rajkumar SV
- Subjects
- Humans, Multiple Myeloma immunology, Multiple Myeloma pathology, Multiple Myeloma diagnosis
- Published
- 2013
- Full Text
- View/download PDF
40. Treatment patterns and outcomes in elderly patients with multiple myeloma.
- Author
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Bang SM, Kyle RA, Rajkumar SV, and Kumar S
- Subjects
- Aged, Aged, 80 and over, Female, Humans, In Situ Hybridization, Fluorescence, Male, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Published
- 2013
- Full Text
- View/download PDF
41. High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma.
- Author
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Bianchi G, Kyle RA, Larson DR, Witzig TE, Kumar S, Dispenzieri A, Morice WG, and Rajkumar SV
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Disease Progression, Female, Humans, Male, Middle Aged, Multiple Myeloma blood, Multiple Myeloma etiology, Multiple Myeloma mortality, Prognosis, Risk Factors, Survival Rate, Multiple Myeloma diagnosis, Neoplastic Cells, Circulating pathology, Plasma Cells pathology
- Abstract
Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2-3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007, who had testing for circulating PCs using an immunofluorescent assay and adequate follow-up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5 × 10(6)/l and/or >5% PCs per 100 cytoplasmic immunoglobulin (Ig)-positive peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 24%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 34%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2-3 years following diagnosis.
- Published
- 2013
- Full Text
- View/download PDF
42. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project.
- Author
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Avet-Loiseau H, Durie BG, Cavo M, Attal M, Gutierrez N, Haessler J, Goldschmidt H, Hajek R, Lee JH, Sezer O, Barlogie B, Crowley J, Fonseca R, Testoni N, Ross F, Rajkumar SV, Sonneveld P, Lahuerta J, Moreau P, and Morgan G
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, International Agencies, Male, Middle Aged, Multiple Myeloma etiology, Multiple Myeloma mortality, Neoplasm Staging, Prognosis, Retrospective Studies, Risk Assessment, Survival Rate, Young Adult, Chromosome Aberrations, In Situ Hybridization, Fluorescence, Multiple Myeloma pathology
- Abstract
The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.
- Published
- 2013
- Full Text
- View/download PDF
43. Single-nucleotide polymorphism rs1052501 associated with monoclonal gammopathy of undetermined significance and multiple myeloma.
- Author
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Greenberg AJ, Lee AM, Serie DJ, McDonnell SK, Cerhan JR, Liebow M, Larson DR, Colby CL, Norman AD, Kyle RA, Kumar S, Rajkumar SV, Diasio RB, Slager SL, and Vachon CM
- Subjects
- Adult, Aged, Case-Control Studies, DNA genetics, Female, Humans, Male, Middle Aged, Minnesota epidemiology, Monoclonal Gammopathy of Undetermined Significance epidemiology, Multiple Myeloma epidemiology, Polymerase Chain Reaction, Prognosis, Risk Factors, Young Adult, Monoclonal Gammopathy of Undetermined Significance genetics, Multiple Myeloma genetics, Polymorphism, Single Nucleotide genetics, Protein Serine-Threonine Kinases genetics
- Published
- 2013
- Full Text
- View/download PDF
44. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma.
- Author
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Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, and Rajkumar SV
- Subjects
- Aged, Aged, 80 and over, Disease Progression, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Myeloma mortality, Multiple Myeloma pathology, Neoplasm Staging, Prognosis, Survival Rate, Zoledronic Acid, Bone Density Conservation Agents therapeutic use, Diphosphonates therapeutic use, Imidazoles therapeutic use, Immunosuppressive Agents therapeutic use, Multiple Myeloma drug therapy, Thalidomide therapeutic use
- Abstract
Patients with asymptomatic (smoldering) multiple myeloma (AMM) have a high risk of transformation to active multiple myeloma (MM). Bisphosphonates such as zoledronic acid (ZLD) reduce skeletal events in MM and the immunomodulatory agent thalidomide (Thal) has proven effectiveness in active MM. We hypothesized that treatment with Thal and ZLD would prolong the time to progression (TTP) to MM over ZLD alone. Eligible patients had asymptomatic MM and all patients received ZLD 4 mg intravenous monthly; the treatment arm also received Thal 200 mg per day. The TTP was superior for Thal/ZLD (n=35) patients compared with ZLD alone (n=33); median TTP of 2.4 years (95% confidence interval (CI): 1.4-3.6) versus 1.2 years (95% CI: 0.7-2.5) (hazard ratio (HR), 2.05; 95% CI: 1.1-3.8; P-value: 0.02). At 1 year, 86% of Thal/ZLD patients were progression free compared with 55% on ZLD alone (P=0.0048). The overall response rate after year 1 was 37% for Thal/ZLD with a median duration of response of 3.3 years (95% CI: 1.1-NA); there were no confirmed responses to ZLD alone (P=0.0004). The addition of Thal to standard ZLD produces anti-tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for further studies in patients with AMM to delay chemotherapy.
- Published
- 2013
- Full Text
- View/download PDF
45. A window into immunoglobulin quantitation and plasma cell disease: antigen epitopes defined by the junction of immunoglobulin heavy and light chains.
- Author
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Katzmann JA and Rajkumar SV
- Subjects
- Female, Humans, Male, Apoptosis, Biomarkers blood, Gene Rearrangement, Immunoglobulin Heavy Chains blood, Immunoglobulin Light Chains blood, Immunoglobulin Variable Region genetics, Immunoglobulin gamma-Chains genetics, Immunoglobulin kappa-Chains blood, Immunoglobulin lambda-Chains blood, Leukemia, Myeloid, Acute genetics, Monoclonal Gammopathy of Undetermined Significance blood, Multiple Myeloma blood, Somatic Hypermutation, Immunoglobulin genetics
- Published
- 2013
- Full Text
- View/download PDF
46. Secondary MGUS after autologous hematopoietic progenitor cell transplantation in plasma cell myeloma: a matter of undetermined significance.
- Author
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Manson GV, Campagnaro E, Balog A, Kaplan D, Sommers SR, Fu P, Rajkumar SV, and Lazarus HM
- Subjects
- Adult, Aged, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Multiple Myeloma blood, Retrospective Studies, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation adverse effects, Monoclonal Gammopathy of Undetermined Significance etiology, Multiple Myeloma surgery
- Abstract
Plasma cell myeloma, characterized by clonally aberrant plasma cells that produce abnormal monoclonal Igs, is the most common indication for autologous hematopoietic progenitor cell transplantation (AHPCT) in North America. We observed appearance of new monoclonal gammopathies different from the original protein in the post-AHPCT setting and termed this condition 'secondary MGUS' (monoclonal gammopathy of undetermined significance). Hence, we performed a retrospective, single institution review of serum protein electrophoresis/immunofixation electrophoresis data in 92 AHPCT recipients from the period 2000-2009. In all, 22 of 92 patients (24%) undergoing AHPCT met criteria for secondary MGUS. Contrary to previous studies, often referred to as 'abnormal protein banding,' we did not observe this condition as a favorable prognostic indicator in affected patients when compared with the control group (P=0.686). However, we did note that a subgroup of the study cohort who developed secondary MGUS after a prolonged latency (>10 months) had an improved median OS compared with the remainder of the study cohort (75 months vs 41 months, P=0.005). As there have been significant advancements in understanding the pathobiology and clinical significance of MGUS, we believe that secondary MGUS merits dedication of resources for investigation to determine its true clinical relevance, prognostic value and pathophysiology.
- Published
- 2012
- Full Text
- View/download PDF
47. Majority of patients receiving initial therapy with lenalidomide-based regimens can be successfully mobilized with appropriate mobilization strategies.
- Author
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Sinha S, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Micallef IN, Hogan WJ, Gastineau DA, Rajkumar SV, and Kumar SK
- Subjects
- Adult, Aged, Cyclophosphamide administration & dosage, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Lenalidomide, Male, Middle Aged, Thalidomide therapeutic use, Antineoplastic Agents therapeutic use, Hematopoietic Stem Cell Mobilization, Multiple Myeloma drug therapy, Thalidomide analogs & derivatives
- Published
- 2012
- Full Text
- View/download PDF
48. Polymorphism of the erythropoietin gene promotor and the development of myelodysplastic syndromes subsequent to multiple myeloma.
- Author
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Landgren O, Ma W, Kyle RA, Rajkumar SV, Korde N, and Albitar M
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genotype, Humans, Male, Middle Aged, Multiple Myeloma complications, Myelodysplastic Syndromes etiology, Erythropoietin genetics, Multiple Myeloma genetics, Myelodysplastic Syndromes genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
- Published
- 2012
- Full Text
- View/download PDF
49. Management of treatment-emergent peripheral neuropathy in multiple myeloma.
- Author
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Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, Terpos E, Munshi N, Palumbo A, Rajkumar SV, Harousseau JL, Moreau P, Avet-Loiseau H, Lee JH, Cavo M, Merlini G, Voorhees P, Chng WJ, Mazumder A, Usmani S, Einsele H, Comenzo R, Orlowski R, Vesole D, Lahuerta JJ, Niesvizky R, Siegel D, Mateos MV, Dimopoulos M, Lonial S, Jagannath S, Bladé J, Miguel JS, Morgan G, Anderson KC, Durie BG, and Sonneveld P
- Subjects
- Boronic Acids adverse effects, Bortezomib, Early Diagnosis, Humans, Immunologic Factors adverse effects, Incidence, Multiple Myeloma complications, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases diagnosis, Peripheral Nervous System Diseases epidemiology, Proteasome Inhibitors, Pyrazines adverse effects, Thalidomide adverse effects, Multiple Myeloma drug therapy, Peripheral Nervous System Diseases drug therapy
- Abstract
Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
- Published
- 2012
- Full Text
- View/download PDF
50. Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites.
- Author
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Greenberg AJ, Vachon CM, and Rajkumar SV
- Subjects
- Black or African American, Black People, Disease Progression, Health Status Disparities, Humans, Immunoglobulin Light Chains blood, Monoclonal Gammopathy of Undetermined Significance etiology, Multiple Myeloma etiology, Multiple Myeloma genetics, Multiple Myeloma mortality, Prevalence, Risk Factors, Socioeconomic Factors, White People, Monoclonal Gammopathy of Undetermined Significance ethnology, Multiple Myeloma ethnology
- Abstract
There is marked racial disparity in the incidence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma, with a two to threefold increased risk in blacks compared with whites. The increased risk has been seen both in Africans and African Americans. Similarly, an increased risk of monoclonal gammopathies in blacks compared with whites has been noted after adjusting for socioeconomic and other risk factors, suggesting a genetic predisposition. The higher risk of multiple myeloma in blacks is likely a result of the higher prevalence of the premalignant MGUS stage; there are no data to suggest that blacks have a higher progression rate of MGUS to myeloma. Studies are emerging that suggest the baseline cytogenetic characteristics, and progression may differ by race. In contrast, to the increased risk noted in blacks, studies suggest that the risk may be lower in certain racial and ethnic groups, notably persons from Japan and Mexico. We review the literature on racial disparity in the prevalence, pathogenesis and progression of MGUS and multiple myeloma between blacks and whites. We also discuss future directions for research that could inform management of these conditions and positively influence patient outcomes.
- Published
- 2012
- Full Text
- View/download PDF
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