Multivariable Analyses of Prognostic Factors for Progression-Free Survival (PFS) and Complete Response (CR) with Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (ASCT) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Determination Phase 3 Trial

Introduction The recently reported DETERMINATION trial of RVd-alone vs RVd+ASCT and lenalidomide (R) maintenance to progression in pts with NDMM demonstrated a highly significant benefit in the primary endpoint of PFS (median 46.2 vs 67.5 months; hazard ratio [HR] 1.53, 95% CI 1.23–1.91) for RVd+ASCT, but no overall survival benefit after median follow-up of 76 months and despite only 28% of RVd-alone pts receiving subsequent ASCT to date (Richardson PG, et al. NEJM 2022). The trial was not specifically powered for subgroup comparisons, and in this context no statistically significant interactions (p<0.05) were seen. However, PFS HRs were clinically noteworthy and ranged from 0.96 to 3.40 in subgroups defined by race, body mass index (BMI), International Staging System (ISS) disease stage, and cytogenetics. Here we report univariate and multivariable analyses conducted to identify prognostic factors mediating differential outcomes with RVd-alone and RVd+ASCT.

Methods Pts aged 18–65 years received 3 21-day cycles of RVd triplet combination therapy, stem cell mobilization, and then either 5 more cycles of RVd (RVd-alone: n=357) or melphalan 200 mg/m² + ASCT and 2 more cycles of RVd (RVd+ASCT: n=365), plus R maintenance until progression or intolerance (RVd-alone: n=291; RVd+ASCT: n=289; median duration 36.4 vs 41.5 months). We evaluated select pt and disease characteristics by race (white/Caucasian, black/African-American, other), BMI (<25, 25–<30, ≥30), and ISS stage (I, II, III) to identify factors with imbalances among subgroups. Univariate analysis was then conducted for PFS on all pts (N=722), using Cox proportional hazards regression. Factors with imbalances among subgroups and/or with univariate PFS association (p<0.20) were included in a multivariable model. These same factors were used in independent univariate and multivariable analyses of pts within each arm.

Results Analyses of baseline characteristics in subgroups defined by race showed notable imbalances, with black pts more likely to be female (p=0.001) and aged <60 years (p=0.024), and to have BMI ≥25 (p=0.024), ECOG performance status (PS) >0 (p=0.066), elevated lactate dehydrogenase (LDH) (p=0.042), hemogloblin ≤10 g/dL (p<0.001), and high-risk cytogenetics [t(4;14), t(14;16), del17p] (p=0.12). In BMI subgroups, pts with higher BMI were more likely to be male (p<0.001) and black (p=0.024). In ISS stage subgroups, pts with higher-stage disease were more likely to be aged ≥60 years (p=0.003) and to have ECOG PS >0 (p=0.018), elevated LDH (p<0.001), elevated calcium (p=0.009), and hemogloblin ≤10 g/dL (p<0.001).

From univariate analyses, the variables associated with poorer PFS among all 722 pts were ECOG PS >0, ISS stage II or III MM, high-risk cytogenetics, elevated LDH, and hemoglobin ≤10 g/dL. All except hemoglobin were independently associated with poorer PFS on multivariable analysis (Table). When multivariable models were evaluated by arm, white race, ECOG PS >0, high-risk cytogenetics, and LDH >ULN were all independent prognostic factors for poorer PFS with RVd-alone but not RVd+ASCT, suggesting that ASCT abrogates the poor prognosis associated with these factors. ISS stage II-III disease was associated with poorer PFS with RVd+ASCT but not RVd-alone, with ASCT offering greater PFS benefit in pts with stage I MM. Univariate/multivariable analyses for achievement of ≥CR also identified discrepancies in prognostic impact of pt and disease characteristics between treatment arms. Analyses of additional factors (e.g. revised ISS stage) and outcomes are ongoing, including correlative studies of minimal residual disease and whole-genome sequencing. Additional and updated data will be presented at the meeting.

Conclusions These data show a differential impact of prognostic factors between treatment approaches and may also reveal differences in MM pathobiology between subgroups. Further consideration of the significant associations among baseline clinicopathologic characteristics is warranted, as well as estimation of the differential impact of various risk factors. Pending validation, such models may help identify subgroups of NDMM pts for whom upfront ASCT could be more or less valuable. This will be especially important in the context of monoclonal antibody-based quadruplet induction therapies, which are showing increasingly high quality and durable responses with or without ASCT.