P07 bortezomib-melphalan-prednisone (vmp) vs. lenalidomide-dexamethasone (rd) in real-life multiple myeloma patients ineligible for transplant: updated analysis of the randomized phase iv real mm trial

Background: Until the recent introduction of daratumumab (Dara), bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have been standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) in the frontline setting. Nonetheless, no prospective randomized trial has directly compared VMP with Rd, and only few data on real-life experiences in older NTE pts are available. Methods: In this multicenter randomized phase IV trial (NCT03829371; funded by the Italian Medicines Agency AIFA - Independent Research), real-life NDMM pts ineligible for transplant due to comorbidities or age ≥65 years were randomized 1:1 to VMP (nine 42-day [dd] cycles [cc], V: 1.3 mg/m2 dd 1,4,8,11,22,25,29,32 cc 1-4 and dd 1,8,22,29 cc 5-9; M: 9 mg/m2 dd 1-4; P: 60 mg/m2 dd 1-4) vs continuous Rd (28-day cc, R: 25 mg dd 1-21; d: 40 mg dd 1,8,15,22), according to standard practice. Upon written informed consent, pts were enrolled regardless of comorbidities, performance status, baseline laboratory values, or renal function. Stratification was performed according to the International Myeloma Working Group frailty score and to cytogenetic risk by fluorescence in situ hybridization [high risk with del(17p), t(14;16), or t(4;14)]. Progression-free survival (PFS) in the intention-to-treat (ITT) population was the primary endpoint. Overall survival (OS), response rates, and safety were key secondary endpoints. Results: The data cut-off was July 4, 2022: 231 pts were randomly assigned to VMP (n=114) or Rd (n=117). Baseline characteristics were balanced in VMP vs Rd: median age 77 (IQR 73-80) and 76 years (IQR 73-79); frail pts 49% vs 50%; pts with high-risk cytogenetics 17% vs 19%. After a median follow-up of 19 months, median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Fig. 1A). HR was 0.21 (95% CI 0.04-0.99) in pts with high-risk cytogenetics vs 1.24 (95% CI 0.70-2.18) in standard-risk pts (interaction P=0.036). No differences in terms of age or frailty status were observed. In the ITT population, 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Fig. 1B). No safety concerns were reported. Thrombocytopenia (15%) and neuropathy (7%) were the most frequent grade 3-4 adverse events with VMP; neutropenia (23%), infections (12%), and dermatologic toxicities (9%) with Rd. At least 1 dose reduction (any drug) was reported in 66% of pts in the VMP and 59% in the Rd arms, including 35% of pts in the VMP arm switching to once-weekly V before cc 5. Conclusion: Overall, the advantage of Rd over VMP was lower than anticipated in this older real-life NTE NDMM population with 50% of frail patients. However, a strong effect modification by cytogenetic risk was found, with high-risk pts benefiting more from VMP vs Rd in terms of PFS (HR 0.21). Safety data were consistent with those previously reported. Of note, only 1/3 of real-life pts were able to receive full-dose VMP or Rd. Despite the limited follow-up, the poor outcomes in pts failing R-based treatment could explain the different OS rates in the two arms. As of July 2022, pts have been randomized to Dara-VMP vs Dara-Rd. With longer follow-up, an analysis of the addition of Dara will further improve decision-making.