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Maintenance therapies in Multiple Myeloma

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Feasibility of Lenalidomide Maintenance After ASCT in Patients With Multiple Myeloma Slide set on: McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781 This program is supported by educational grants from

Background Autologous hematopoietic stem cell transplantation (ASCT) after induction chemotherapy for MM improves responses and consolidates CR[1] Maintenance therapy given to prevent relapse, prolong CR Thalidomide maintenance after ASCT improves PFS, OS, but limited by toxicity[2] Lenalidomide: oral immune-modulating agent active against MM Favorable toxicity profile ASCT, autologous hematopoietic stem cell transplantation; CR, complete response; OS, overall survival; PFS, progression-free survival; MM, multiple myeloma 1. Palumbo A., et al. N Engl J Med. 2011;364:1046-1060. 2. Morgan GJ, et al. Blood. 2012;119:7-15

Lenalidomide Maintenance After ASCT Stratified by β2-microglobulin level at registration, type of induction therapy Induction of melphalan maintenance therapy between Days 100-110 Lenalidomide 10 mg/d (n = 135) Restage on Days 90-100, then randomize Patients symptomatic, stage I-III MM with ≥SD following ≤2 cycles of induction and adequate stem cells (N = 568) Single ASCT CR, PR, SD Placebo (n = 229) ASCT, autologous stem cell transplantation; CR, complete response; OS, overall survival; PR, partial response; SD, stable disease; TTP, time to progression Primary endpoint: TTP following ASCT Secondary endpoints: OS, overall response, safety McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781

TTP, EFS, and OS With Lenalidomide Maintenance Outcome Lenalidomide (n = 231) Placebo (n = 229) Median EFS (mo.) 43 27 Median TTP (mo.) 46 Combined PD, death, and SPM 40% 58% Deaths 15% 23% Response after ASCT 60 Lenalidomide 50 Placebo 40 Patients (%) Improved OS at 3 years in lenalidomide arm (P = .03) EFS = PD + death + SPM Post-hoc endpoint to assess influence of SPM on outcomes Lenalidomide reduced risk of event 47% (HR = 0.53 (95% CI, 0.41-0.69) 30 ASCT, autologous stem cell transplantation; CR, complete response; EFS, event-free survival; MR, minimal response; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; SPM, second primary malignancy; TTP, time to progression 20 10 CR PR MR SD PD McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781

Lenalidomide Maintenance After ASCT: Risk Stratification and Outcomes Reduction in risk of death or PD Fewer events in lenalidomide (37%) vs placebo (58%) Fewer deaths in lenalidomide (15%) vs placebo (23%) TTP by stratification factors Trend to superiority of lenalidomide induction vs no lenalidomide induction (P value for interaction = .06) No significant difference in TTP for thalidomide induction vs no thalidomide induction OS by stratification factors Lenalidomide induction superior to no lenalidomide (P = .03) Thalidomide induction inferior to no thalidomide (P = .05) CR, complete response; OS, overall survival; PD, progressive disease; OS, overall survival; TTP, time to progression McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781

Adverse Events Associated with Lenalidomide Maintenance After ASCT Grade 3/4 Hematologic AEs (%) Lenalidomide (n = 231) Placebo (n = 229) P Value Any event 48 17 < .001 Neutropenia 45 15 Thrombocytopenia 14 4 0.001 Lymphopenia 6 1 0.01 Anemia 5 0.006 Leukocytopenia 11 3 AE, adverse event; ASCT, autologous stem cell transplantation McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781

Lenalidomide Maintenance After ASCT: Second Primary Malignancies Outcome Lenalidomide (n = 231) Placebo (n = 229) Second primary cancer, % 8 3 Second primary hematologic cancers, n 1 AML, ALL, MDS, Hodgkin lymphoma non-Hodgkin lymphoma Second primary solid tumors, n 10 5 breast, gastrointestinal, malignant melanoma, gynecologic, central nervous system, thyroid, prostate gastrointestinal, malignant melanoma, gynecologic, carcinoid Risk of SPM higher with lenalidomide (P = .008) Risk of PD higher in placebo group (P < .001) Risk of death higher in placebo group (P = .002) 47% reduction in risk of EFS event (death, SPM, or PD) (HR = 0.53, 95% CI, 0.41-0.69) in lenalidomide arm ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; EFS, event-free survival; MDS, myelodysplastic syndrome; PD, progressive disease; SPM, second primary malignancy McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781

Lenalidomide Maintenance After ASCT: Summary of Results Lenalidomide maintenance therapy feasible for long-term administration after ASCT in patients with multiple myeloma Significantly improved OS and TTP Significantly more grade 3/4 hematologic adverse events with lenalidomide vs placebo In post hoc analysis, lenalidomide maintenance still superior in EFS despite increased incidence of SPM in lenalidomide arm Patients should be carefully monitored when using this approach Further study needed to determine if additional agents combined with lenalidomide may provide further survival benefit ASCT, autologous stem cell transplantation; OS, overall survival; TTP, time to progression McCarthy PL, et al., N Engl J Med. 2012;366:1770-1781