Lenalidomide Maintenance Therapy in Multiple Myeloma: A Meta-Analysis of Randomized Trials Singh PP et al. Proc ASH 2013;Abstract 407.

Slides:

Advertisements

Similar presentations

Palumbo A et al. Proc ASH 2013;Abstract 536.

Advertisements

Paz-Ares LG et al. Proc ASCO 2011;Abstract CRA7510.

Facon T et al. Proc ASH 2013;Abstract 2.

Efficacy and Safety of Three Bortezomib-Based Combinations in Elderly, Newly Diagnosed Multiple Myeloma Patients: Results from All Randomized Patients.

1. 2 Lenalidomide in Newly Diagnosed Multiple Myeloma Clinical Update EHA 2010 DR. OUSSAMA JRADI.

Palumbo A et al. Proc ASH 2012;Abstract 446.

LaCasce A et al. Proc ASH 2014;Abstract 293.

Final Study Results of the Phase III Dasatinib versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA )1.

A Meta Analysis of Risk of Cardiovascular Events in Patients with Metastatic Breast Cancer (MBC) Treated with Anti Vascular Endothelial Growth Factor (VEGF)

Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone.

Treatment with Bendamustine- Bortezomib-Dexamethasone in Relapsed/Refractory Multiple Myeloma Shows Significant Activity and Is Well Tolerated Ludwig H.

Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients: Initial Results of a Multicenter, Open Label.

ENESTnd Update: Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and the Impact.

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Updated.

NHL13: A Multicenter, Randomized Phase III Study of Rituximab as Maintenance Treatment versus Observation Alone in Patients with Aggressive B ‐ Cell Lymphoma.

1Bachelot T et al. Proc SABCS 2010;Abstract S1-6.

Alternating Courses of CHOP and DHAP Plus Rituximab (R) Followed by a High-Dose Cytarabine Regimen and ASCT is Superior to Six Courses of CHOP Plus R Followed.

A Randomized Trial of Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism Schulman S et al. Proc ASH 2011;Abstract 205.

Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide: Analysis of Pooled Data in 2459 Patients Palumbo A.

A Phase II Study with Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma Bringhen S et al. Proc ASH 2013;Abstract.

Maintenance Therapy in Myeloma Myeloma Canada National Conference Donna E. Reece, M.D. Princess Margaret Hospital 24 September 2011.

Bortezomib Induction and Maintenance Treatment Improves Survival in Patients with Newly Diagnosed Multiple Myeloma: Extended Follow-Up of the HOVON-65/GMMG-HD4.

Final Analysis of Overall Survival for the Phase III CONFIRM Trial: Fulvestrant 500 mg versus 250 mg Di Leo A et al. Proc SABCS 2012;Abstract S1-4.

Epic: A Phase 3 Trial of Ponatinib Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CP-CML) Lipton JH.

Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin plus Cytarabine versus Placebo plus.

Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLC Spigel DR.

Head-to-Head Comparison of Obinutuzumab (GA101) plus Chlorambucil (Clb) versus Rituximab plus Clb in Patients with Chronic Lymphocytic Leukemia (CLL) and.

Rituximab Maintenance versus Wait and Watch After Four Courses of R-DHAP Followed by Autologous Stem Cell Transplantation in Previously Untreated Young.

A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance.

Rituximab plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in.

OCEANS: A Randomized, Double- Blinded, Placebo-Controlled Phase III Trial of Chemotherapy with or without Bevacizumab (BEV) in Patients with Platinum-

Long Term Follow-up on the Treatment of High Risk Smoldering Myeloma with Lenalidomide plus Low Dose Dex (Rd) (Phase III Spanish Trial): Persistent Benefit.

Results of a Randomized Phase 2 Study of PD , a Cyclin ‐ Dependent Kinase (CDK) 4/6 Inhibitor, in Combination with Letrozole vs Letrozole Alone.

Maintenance Therapy with Bortezomib plus Thalidomide (VT) or Bortezomib plus Prednisone (VP) in Elderly Myeloma Patients Included in the GEM2005MAS65 Spanish.

Frontline Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Shows Superior Efficacy in Comparison to Bendamustine.

Kang Y et al. Proc ASCO 2010;Abstract LBA4007.

ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Mark TM et al. Proc ASH 2012;Abstract 77.

Four vs 6 Cycles of Doxorubicin and Cyclophosphamide (AC) or Paclitaxel (T) as Adjuvant Therapy for Breast Cancer in Women with 0-3 Positive Axillary Nodes:

Continued Overall Survival Benefit After 5 Years’ Follow-Up with Bortezomib-Melphalan-Prednisone (VMP) versus Melphalan-Prednisone (MP) in Patients with.

Impact of Bevacizumab (Bev) on Efficacy of Second-Line Chemotherapy (CT) for Triple- Negative Breast Cancer: Analysis of RIBBON-2 Brufsky A et al. Proc.

An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab,

Second Interim Analysis of a Phase 3 Study of Idelalisib Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient.

Lenalidomide Maintenance After Stem-Cell Transplantation for Multiple Myeloma: Follow-Up Analysis of the IFM Trial Attal M et al. Proc ASH 2013;Abstract.

Moskowitz CH et al. Proc ASH 2014;Abstract 673.

Chemoimmunotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) versus Bendamustine and Rituximab (BR) in Previously Untreated and.

Results from a Randomized Phase III Trial of Decitabine versus Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed.

Phase II Multicenter Study of Single-Agent Lenalidomide in Subjects with Mantle Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib:

Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma: Final Results of the Phase Ib/II Ro-CHOP Study Dupuis J et al. Proc ASH.

Vose JM et al. Proc ASH 2011;Abstract 661.

1 Stone RM et al. Proc ASH 2015;Abstract 6.

Palumbo A et al. Proc ASH 2012;Abstract 200.

Attal M et al. Proc ASH 2010;Abstract 310.

Korde N et al. Proc ASH 2012;Abstract 732.

Platzbecker U et al. Proc ASH 2014;Abstract 12.

IFM/DFCI 2009 Trial: Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM) in the Era of New Drugs Phase III study of lenalidomide/bortezomib/dexamethasone.

Randomized, Open-Label Phase 1/2 Study of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple.

Slide set on: McCarthy PL, Owzar K, Hofmeister CC, et al

Mateos MV et al. Proc ASH 2013;Abstract 403.

Goede V et al. Proc ASH 2014;Abstract 3327.

Kahl BS et al. Proc ASH 2011;Abstract LBA-6.

Dimopoulos MA et al. Proc ASH 2012;Abstract LBA-6.

Attal M et al. Proc ASCO 2010;Abstract 8018.

Palumbo A et al. Proc ASCO 2011;Abstract 8007.

Coiffier B et al. Proc ASH 2010;Abstract 857.

Faderl S et al. Proc ASCO 2011;Abstract 6503.

Martin M et al. Proc SABCS 2012;Abstract S1-7.

1 Verstovsek S et al. Proc ASH 2012;Abstract Cervantes F et al.

Advani RH et al. Proc ASH 2011;Abstract 443.

Boccadoro M et al. Proc ASCO 2011;Abstract 8020.

Coiffier B et al. Proc ASH 2011;Abstract 265.

Presentation transcript:

Lenalidomide Maintenance Therapy in Multiple Myeloma: A Meta-Analysis of Randomized Trials Singh PP et al. Proc ASH 2013;Abstract 407.

Background Conflicting results have emerged with respect to the impact on overall survival (OS) from trials evaluating lenalidomide maintenance (LM) therapy after induction therapy alone or after autologous stem cell transplant (ASCT) in multiple myeloma (MM). The CALGB trial reported that LM after ASCT significantly improved OS but was associated with more toxicity (N Engl J Med 2012;366(19):1770). The IFM study showed a significant improvement in progression-free survival (PFS) but no difference in OS with LM after transplantation (N Engl J Med 2012;366(19):1782). Study objective: To perform a systematic review and meta- analysis of existing outcome data from LM trials to evaluate the role of lenalidomide as a maintenance strategy in MM. Singh PP et al. Proc ASH 2013;Abstract 407.

Methods Singh PP et al. Proc ASH 2013;Abstract 407. A systematic literature search of PubMed, Embase, Scopus and Web of Science (through June 2013) and major conferences ( ) was performed to identify randomized controlled trials that compared LM to placebo/no maintenance. Pooled hazard ratio (HR) or odds ratio (OR) estimates with 95% confidence intervals were calculated using the random- effects model for PFS, OS, response rate and adverse events (AEs), including second primary malignancies. Between-study heterogeneity was evaluated with the Cochran Q test, and its extent was quantified with the inconsistency index (I 2 ) statistic.

Trials Included in Meta-Analysis Data were extracted from 4 Phase III trials*: 3 publications, 1 abstract (n = 1,935) –IFM and CALGB : Placebo controlled, addressed the role of LM after ASCT –MM-015: Placebo controlled, studied LM therapy in the nontransplant setting –RV-MM-PI209: 2 x 2 design comprising ASCT and nontransplant randomized arms followed by a second randomization to LM versus no maintenance Singh PP et al. Proc ASH 2013;Abstract 407. * MRC MM XI study was excluded from analyses because survival data were not available

LM and PFS Study nameHR p-value IFM <0.001 CALGB <0.001 MM <0.001 RV-MM-PI <0.001 Summary estimate0.491<0.001 Outcome: HR for death or progression; LM vs no maintenance (<1 implies better outcome with LM) Minimal heterogeneity for estimate of PFS: Cochran Q = 1.51 (p = 0.68), I 2 = 0% Singh PP et al. Proc ASH 2013;Abstract 407.

LM and OS Study nameHR p-value IFM CALGB MM RV-MM-PI Summary estimate Outcome: HR for death or progression; LM vs no maintenance (<1 implies better outcome with LM) Significant heterogeneity for estimate of OS: Cochran Q = 8.11 (p = 0.044), I 2 = 63% Singh PP et al. Proc ASH 2013;Abstract 407.

LM and OS: Post-Transplant Group Study nameHR p-value IFM CALGB Summary estimate Outcome: HR for death or progression; LM vs no maintenance (<1 implies better outcome with LM) Significant heterogeneity for estimate of OS: Cochran Q = 5.82 (p = 0.016), I 2 = 82.8% Singh PP et al. Proc ASH 2013;Abstract 407.

Grade 3/4 AEs During LM OR p-value Neutropenia Thrombocytopenia Fatigue Venous thromboembolism < Treatment discontinuation2.9<0.001 Singh PP et al. Proc ASH 2013;Abstract 407.

Secondary Primary Malignancies Study nameHR p-value IFM CALGB MM RV-MM-PI Summary estimate Outcome: Odds of developing secondary primary malignancy; LM vs placebo/no maintenance (>1 implies increased risk of secondary primary malignancy with LM) Minimal heterogeneity for estimate of secondary primary malignancy: Cochran Q = 1.67 (p = 0.644), I 2 = 0% Singh PP et al. Proc ASH 2013;Abstract 407.

Author Conclusions Meta-analysis of randomized controlled trials demonstrates significant improvement in PFS and a trend toward improvement in OS with LM. LM is associated with increased risk of Grade 3/4 AEs and second primary malignancies. Substantial heterogeneity for estimate of OS among protocols is a limitation of this analysis. Lack of uniform access to lenalidomide upon disease progression in the placebo/no maintenance arms of the constituent studies should be taken into account when interpreting aggregate effect estimates for OS in this meta- analysis. The subset of patients benefitting the most from LM is not yet defined, and risks and benefits should be discussed with all patients. Singh PP et al. Proc ASH 2013;Abstract 407.

Investigator Commentary: Meta-Analysis of Randomized Trials of LM Therapy in MM The results of this meta-analysis showed a significant increase in PFS and a moderate improvement in OS with LM. The incidence of side effects was higher in the group that received maintenance. This analysis included both younger and older patients. It included studies of LM in the nontransplant and post-transplant settings. That’s mixing apples and oranges. I believe you need to answer the question of the role of LM after a transplant in that setting. Two points of view exist regarding LM. I am in the camp that advocates maintenance until disease progression. I believe that a survival benefit is evident with maintenance in the CALGB trial. The other view is that maintenance can harm people. I don’t believe that the results of this study are convincing one way or the other. Interview with Sagar Lonial, MD, January 22, 2014