Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial
Authors: Manier Salmon , Dimopoulos Meletios A. , Hulin Cyrille , Leleu Xavier , Delforge Michel , Weisel Katja C. , Jiang Ruiyun , Srinivasan Shankar , Costa Bruno , Robinson Suzanne , Facon Thierry 
Published: November 2019

BACKGROUND: Rd continuous is now a standard treatment option in patients (pts) with transplant-ineligible NDMM based on the results of the large phase 3 registrational FIRST trial showing significant PFS and OS benefits of lenalidomide (LEN) + low-dose dexamethasone until disease progression (Rd continuous) vs melphalan + prednisone + thalidomide (MPT). However, pts who relapse on frontline LEN represent a growing population for whom there is limited clinical evidence on subsequent treatment. Factors associated with relapse within 12 mos in Rd- and MPT-treated pts (LDH ≥ 200 U/L, ISS stage III, high-risk cytogenetics, ECOG PS ≥ 2, and baseline platelet count ≤ 150 × 109/L) indicate that the individual risk of progression may involve a combination of disease biology, genetics, and pt-specific factors (Facon, EHA 2019). Physicians may consider these early relapse factors when making treatment decisions. To characterize pts relapsing while receiving frontline LEN, this analysis evaluated Rd-treated pts from the FIRST trial who progressed while receiving LEN based on their time of relapse, type of relapse (CRAB [symptomatic] vs non-CRAB [nonsymptomatic]), and second-line treatment.
METHODS: Pts randomized to Rd continuous (n = 535) or Rd for 18 cycles (n = 541) arms and who progressed while receiving LEN or within 60 days of treatment end (per IMWG criteria) were pooled and grouped according to their time of relapse after randomization (< 12 mos = early< 12; 12-18 mos = early12-18, and > 18 mos = late relapse). The data cutoff was January 2016.
RESULTS: Of the 389 pts who relapsed, 203 had early< 12 relapse, 69 had early12-18 relapse, and 117 had late relapse. Pts who relapsed within the first 12 mos or between 12 and 18 mos had higher rates of elevated LDH, ISS Stage III disease, and ECOG PS 2 compared with those who relapsed beyond 18 mos (Table). Early< 12 and early12-18 relapses were also associated with poor PFS and OS outcomes. Median PFS in pts with early< 12, early12-18, and late relapse was 6.5, 15.9, and 26.4 mos, and median OS was 26.8, 41.6, and 78.0 mos, respectively (Figure). Pts with late relapse had more dose reductions prior to PD vs those with early relapse and were more likely to experience nonsymptomatic progression. Across the 3 groups, in pts experiencing a nonsymptomatic progression who started second-line treatment, 88% started second-line treatment prior to experiencing CRAB symptoms. The median time from PD to second-line treatment was shorter in those with CRAB relapse (1.4-2.5 mos) vs non-CRAB relapse (2.5-5.9 mos).
Second-line treatment was reported in 170 (83.7%), 62 (89.9%), and 99 (84.6%) pts with early< 12, early12-18, and late relapse, respectively. The majority of these pts received bortezomib-based regimens (65.6% overall), most commonly bortezomib + dexamethasone, bortezomib + melphalan + prednisone, or bortezomib + alkylator (cyclophosphamide or bendamustine). Second PFS was similar regardless of time of relapse.
CONCLUSIONS: This analysis focused on an emerging and clinically relevant population of transplant-ineligible pts relapsing on frontline LEN. Pts with late relapse on LEN more commonly had nonsymptomatic progression vs pts relapsing early. This raises the question on the possible impact of the immune stimulatory effects of LEN in pts able to remain on therapy and achieve a longer OS and warrants further investigation of the biological impact of IMiD agent-based therapies on long-term disease control. The increase in dose reductions in the late- vs early-relapse groups is also an important consideration for continuous treatment.
Consistent with the prior analysis of the FIRST study exploring Rd and MPT-treated pts with early< 12 relapse (Facon, EHA), pts relapsing on LEN within 12 mos and between 12-18 mos both appeared to have functionally high-risk disease and represent a population with an unmet need that should be considered for inclusion in clinical trials investigating new therapeutic strategies. Due to the timing of the FIRST trial, limited novel-novel agent combination treatments were available at relapse, and the majority of pts received bortezomib-based second-line regimens. These results highlight the need for effective therapies for pts with early relapse. Further characterization of first- and second-line outcomes according to type of relapse are ongoing and will be reported at the meeting.

Disclosures
Dimopoulos: Sanofi Oncology: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Merck: Honoraria. Delforge:Amgen, Celgene, Janssen , Takeda: Honoraria. Weisel:Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Costa:Celgene: Employment, Equity Ownership. Robinson:Celgene: Employment, Equity Ownership. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.