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Minimal residual disease negativity and lenalidomide maintenance therapy are associated with superior survival outcomes in multiple myeloma
Patel, D. A., Gopalakrishnan, R., Engelhardt, B. G., McArthur, E., Sengsayadeth, S., Culos, K. A., Byrne, M., Goodman, S., Savani, B. N., Chinratanalab, W., et al
Bone marrow transplantation. 2020
Abstract
Modern combinations of therapies for multiple myeloma have led to improvement in survival outcomes with near 100% overall response rate and 25% complete response rates, particularly with autologous hematopoietic cell transplant (AHCT). Minimal residual disease (MRD) assessment with multiparameter flow cytometry is a valid prognostic biomarker for progression-free survival (PFS) and overall survival (OS). However, few data exist regarding whether MRD positivity or negativity will meaningfully influence treatment decisions. We evaluated 433 patients who received induction therapy, followed by AHCT. Participants had MRD assessment by multiparameter flow cytometry before and at days +100 and +365 following AHCT. They also received either lenalidomide, bortezomib, or no maintenance therapy following AHCT. Maintenance treatment with lenalidomide improved MRD negativity at day +365 compared to bortezomib (92.9% vs 41.6%, p = 0.01), or no maintenance therapy (92.9% vs 24.4%, p = 0.012). The median PFS for patients who were MRD negative at day + 365 was 42 vs 17.5 months (p < 0.001) and median OS was 80.6 vs 59 months (p = 0.02). Maintenance therapy following AHCT for multiple myeloma improves the depth of response as assessed by MRD.
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Revised-International Staging System (R-ISS) is Predictive and Prognostic for Early Relapse (<24 months) after Autologous Transplantation for Newly Diagnosed Multiple Myeloma (MM)
Gopalakrishnan, S., D'Souza, A., Scott, E., Fraser, R., Davila, O., Shah, N., Gale, R. P., Kamble, R., Diaz, M. A., Lazarus, H. M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
The Revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase, and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on post-relapse survival after an early relapse. Using the Center for International Blood and Marrow Transplant Research database, we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n= 628). Relative risks of relapse/progression, progression-free survival (PFS) and OS were calculated with R-ISS group as a predictor in multivariate analysis. Among early relapsers, post-relapse survival was tested to identify factors affecting post-relapse OS. The cumulative incidence of early relapse was 23%, 39% and 50% for R-ISS I, R-ISS II and R-ISS III, respectively (p <0.001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior post-relapse OS among early relapsers, as was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects post-relapse survival among early relapsers.
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Lenalidomide vs bortezomib maintenance choice post-autologous hematopoietic cell transplantation for multiple myeloma
Huang, J., Phillips, S., Byrne, M., Chinratanalab, W., Engelhardt, B. G., Goodman, S. A., Harrell, S. L., Jagasia, M., Kassim, A., Rawling, K. T., et al
Bone marrow transplantation. 2018;53(6):701-707
Abstract
Maintenance therapy post-autologous hematopoietic cell transplantation (AHCT) with either lenalidomide or bortezomib for multiple myeloma (MM) have separately been shown to improve progression-free survival (PFS), but have never been directly compared. We performed a retrospective study to investigate progression-free and overall survival outcomes and toxicities of lenalidomide maintenance therapy compared with bortezomib maintenance in MM patients post-AHCT. This study included 156 patients who received post-AHCT lenalidomide or bortezomib maintenance therapy for MM. The primary outcome was PFS. Ninety-two patients received lenalidomide maintenance and 64 received bortezomib maintenance post-AHCT. By multivariable analysis, maintenance therapy choice and cytogenetics risk did not impact PFS or OS. Staging by International Staging System and pre-maintenance disease response were the greatest predictors for PFS. Treatment-related toxicities were as anticipated with 5.4% of patients receiving maintenance lenalidomide experiencing secondary primary malignancies (SPMs) compared with 3% for bortezomib. These findings suggest there were no differences in PFS or OS between lenalidomide and bortezomib maintenance therapy options for post-transplantation MM patients. These data should be validated in a larger, prospective cohort to determine if maintenance choice should be guided by side effect profile and patient anticipated tolerance rather than by disease biology alone.
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Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis
Mahindra, A., Hari, P., Fraser, R., Fei, M., Huang, J., Berdeja, J., Callander, N., Costa, L., Diaz, M. A., Freytes, C., et al
Bone Marrow Transplantation. 2017;52(12):1616-1622
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Abstract
Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (60mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.
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Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis
Scott, E. C., Hari, P., Sharma, M., Le-Rademacher, J., Huang, J., Vogl, D., Abidi, M., Beitinjaneh, A., Fung, H., Ganguly, S., et al
Biology of Blood & Marrow Transplantation. 2016;22(10):1893-9
Abstract
Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P<.001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P=.6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P=.004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P<.001) and 72% versus 85% (P<.001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.