Usmani, S.Z. (Saad Z.)
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- Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project(Springer Nature, 2018) Durie, B. (B.); Attal, M. (Michele); Moreau, P. (Philippe); Lee, J.H. (Jae Hoon); Turesson, I. (Ingemar); Cavo, M. (Michele); Barlogie, B. (Bart); Usmani, S.Z. (Saad Z.); Hajek, R. (R.); Kumar, S. (Shaji); Lenhof, S. (Stig); Morgan, G.J. (Gareth J.); Lahuerta, J.J. (Juan José); Goldschimdt, H. (Hartmut); Hoering, A. (Antje); Rajkumar, S.V. (S. Vincent); San-Miguel, J.F. (Jesús F.)Purpose: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. Patients & Methods: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan–Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. Results: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/μL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. Conclusions: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.
- Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX(2020) Moreau, P. (Philippe); Cochrane, T. (Tara); Ukropec, J. (Jon); Kaufman, J.L. (Jonathan L.); Usmani, S.Z. (Saad Z.); Kim, K. (Kihyun); Morton, J. (James); Sutherland, H.J. (Heather J.); Magen, H. (Hila); Krevvata, M. (Maria); Iida, S. (Shinsuke); Kim, J.S. (Jin Sheok); Benboubker, L. (Lotfi); Takezako, N. (Naoki); Casneuf, T. (Tineke); White, D.J. (Darrell J.); Dimopoulos, M.A. (Meletios A.); Trivedi, S. (Sonali); Prince, H.M. (H. Miles); Avet-Loiseau, H. (Herve); Oriol, A. (Albert); Leiba, M. (Merav); San-Miguel, J.F. (Jesús F.); Cook, G. (Gordon); Kobos, R. (Rachel); O’Rourke, L. (Lisa)High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
- Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial(2023) Moreau, P. (Philippe); Carey, J. (Jodi); Ahmadi, T. (Tahamtan); Yoon, S.S. (Sung-Soo); Gai, X. (Xue); Usmani, S.Z. (Saad Z.); Ben-Yehuda, D. (Dina); Bahlis, N.J. (Nizar J.); Reece, D. (Donna); Nahi, H. (Hareth); Suzuki, K. (Kenshi); Rabin, N. (Neil); Goldschmidt, H. (Hartmut); Dimopoulos, M.A. (Meletios A.); Richardson, P.G. (Paul G.); Oriol, A. (Albert); Orlowski, R.Z. (Robert Z.); Garvin-Mayo, W. (Wendy); Carson, R. (Robin); Qin, X. (Xiang); Plesner, T. (Torben); San-Miguel, J.F. (Jesús F.)Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS). Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ¿ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression. Results: Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ¿ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (¿ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%). Conclusion: D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).
- International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)(2020) Gonzalez-Calle, V. (Veronica); Durie, B. (B.); Hansson, M. (Markus); Ukropec, J. (Jon); Usmani, S.Z. (Saad Z.); Merlini, G. (G.); Zamagni, E. (Elena); Min, C.K. (Chang-Ki); Qi, M. (Ming); Ludwig, H. (Heinz); Hajek, R. (R.); Mateos, M.V. (María Victoria); De-Larrea, C.F. (Carlos Fernández); Esteves, G. (Graça); Kumar, S. (Shaji); Gozzetti, A. (A.); Morgan, G.J. (Gareth J.); Geraldes, C. (Catarina); Kyriakou, C. (Charalampia); Goldschmidt, H. (Hartmut); Kim, B.S. (Byung-Su); Dimopoulos, M.A. (Meletios A.); Kastritis, E. (Efstathios); Weiss, B.M. (Brendan M.); Fantl, D. (Dorotea); Rajkumar, S.V. (S. Vincent); San-Miguel, J.F. (Jesús F.); Leleu, X. (Xavier); Garderet, L. (Laurent)Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
- BMT CTN myeloma intergroup workshop on minimal residual disease and immune profiling: summary and recommendations from the organizing committee(Elsevier BV, 2018) Tario-Jr, J.D. (Joseph D.); Weisel, K. (Katja); Usmani, S.Z. (Saad Z.); McCarthy, P.L. (Philip L.); Pasquini, M.C. (Marcelo C.); Hahn, T. (Theresa); Ho, C.M. (Christine M.); Munshi, N.C. (Nikhil C.); Paiva, B. (Bruno); Avet-Loiseau, H. (Herve); Holstein, S.A. (Sarah A.); Lohr, J.G. (Jens G.); Wallace, P.K. (Paul K.)The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 1, 2016 at the American Society of Hematology meeting to discuss the emerging data and technologies for minimal residual disease assessment and immune profiling in myeloma. Particular emphasis was placed on developing strategies to incorporate these techniques into clinical trial design. This document reviews the literature, summarizes the topics discussed in the workshop, and provides recommendations for integration of these techniques into future clinical trial design.