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Dr. Dimopoulos- Analysis of Second-Line Lenalidomide Following Initial Relapse in the MM-015 Trial
Meletios Dimopoulos, MD
University of Athens
Athens, Greece
Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma - Therapy, excluding Transplantation: Clinical issues in myeloma and amyloidosis patients: novel agent and novel agent-based combinations
Tuesday, December 11, 2012: 7:45 AM
Thomas Murphy Ballroom 2-3, Level 5, Building B (Georgia World Congress Center)

Meletios A Dimopoulos, MD1,2, Maria Teresa Petrucci, MD3, Robin Foa, MD4, John V. Catalano, MD5, Martin Kropff, MD6, Zhinuan Yu, PhD7*, Lindsay Herbein, BS7*, Christian J. Jacques, MD7 and Antonio Palumbo, MD8*

1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
2Department of Clinical Therapeutics, University of Athens, Athens, Greece
3Hematology, University La Sapienza, rome
4Department of Cellular Biotechnologies and Hematology, Sapienza University, Division of Hematology, Rome, Italy
5Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston, Australia
6University of Muenster, Muenster, Germany
7Celgene Corp, Summit, NJ
8University of Torino, AOU S.Giovanni Battista, Division of Hematology, Torino, Italy

Background: MM-009/010 established lenalidomide (LEN) + dexamethasone (DEX) as a standard of care in the treatment (Tx) of relapsed/refractory multiple myeloma (RRMM; Dimopoulos, NEJM. 2007; Weber, NEJM. 2007). The greatest benefits were observed when LEN + DEX was used at first relapse (Stadtmauer, Eur J Haematol. 2009). MM-015 is a pivotal, double-blind, randomized, placebo-controlled phase 3 trial comparing the efficacy and safety of melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) with fixed-cycle melphalan-prednisone (MP) and melphalan-prednisone-LEN (MPR) in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem-cell transplant. The final analysis demonstrated unprecedented improvement in progression-free survival (PFS) in pts receiving MPR-R vs MP (31 vs 13 months [mos]; P < 0.001) with manageable toxicity (Palumbo, NEJM. 2012). The aim of this post-hoc analysis was to assess post-progression outcomes by second-line Tx and by initial MM-015 Tx arm (MPR-R, MPR, and MP).

Methods: Induction and maintenance Tx has been described (Palumbo, NEJM. 2012). Pts with progressive disease during MM-015 could enroll in an open-label extension phase (OLEP) to receive LEN 25 mg (D1-21) ± DEX 40 mg (D1-4, 9-12, and 17-20) or could receive any other anti-myeloma Tx outside of the protocol. This analysis includes data up to Apr 10, 2012 (median follow-up: 48 mos after initial randomization). Time to progression (TTP) was assessed from randomization to disease progression as assessed by investigator. Time from start of second line to start of third-line Tx was assessed as a surrogate for TTP in second line.  Safety data were assessed only for pts enrolled in the OLEP.

Results: A total of 459 pts were enrolled in MM-015. Consistent with the superior PFS of MPR-R, fewer pts from the MPR-R arm progressed compared with the MPR and MP arms: 54% (81/150) vs 77% (117/152), and 83% (127/153) respectively. Compared with the overall population, pts receiving second-line Tx had shorter median first-line TTP (29 vs 20 mos), particularly for the MPR-R arm. This suggests that the present subset of pts in the MPR-R arm who started second-line therapy represents the early progressors, those with worse prognosis or more aggressive disease (Table). More pts received second-line Tx in the MP (72%) and MPR (58%) arms vs MPR-R arm (30%, Table); second-line Tx type was heterogeneous for MPR-R pts. Median time from second- to third-line Tx was significantly longer for LEN-based Tx vs non-LEN-based Tx across the 3 arms: MPR-R (18 vs 13 mos; P = 0.044), MPR (23 vs 8 mos; P = 0.02), and MP (18 vs 10 mos; P = 0.001). Median time from second- to third-line therapy with bortezomib (BORT)-based regimens was 14, 16, and 12 mos, respectively. This corresponded to higher proportions of pts remaining on second-line LEN at 2 yrs (38%, 44%, and 40%) vs non-LEN (15%, 30%, and 13%) for MPR-R, MPR, and MP, respectively. When evaluating second-line BORT, 22%, 33%, and 17%, respectively, had not progressed from second- to third-line therapy at 2 years. Prior LEN maintenance did not appear to induce resistant relapses as time from second- to third-line Tx was similar for all arms (Table) and all comparisons: MPR-R vs MP (hazard ratio [HR] = 0.924; P = 0.69), MPR-R vs MPR (HR = 1.076; P = 0.71), and MPR vs MP (HR = 0.895; P = 0.53). With limited follow-up, no significant differences in post-relapse OS have been detected. Newly occurring grade 3/4 adverse events (AEs) reported for ≥ 5% of pts entering the OLEP (n = 153) were neutropenia (11%) and anemia (5%). Grade 3/4 deep vein thrombosis and peripheral neuropathy occurred in 3% and 1% of pts, respectively.

Conclusions: LEN-based Tx was active in the second line, with comparable efficacy regardless of first-line therapy (MPR-R, MPR, or MP). Although pt numbers are relatively small, and this is a non-randomized comparison, results with second-line LEN-based therapy compared favorably to outcomes with other Tx. The OLEP tolerability profile was favorable, with limited newly occurring grade 3/4 AEs. Importantly, LEN maintenance does not appear to induce resistant relapses. These results support the known activity of LEN as second-line MM therapy.

Table. Second-Line Tx Received Following Relapse in MM-015

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