(OA-53) Functional High-Risk (FHR) Phenotype Predicts Poor Survival in Multiple Myeloma (MM) Independent of Frontline Treatment: A Secondary CIBMTR Analysis

FHRMM following autologous stem cell transplantation (ASCT) is generally defined as early progression within 12-24 months of ASCT. For patients (pts) with early progression after suboptimal 1L therapies, it is challenging to assign the disease progression to a true FHR phenotype vs less effective 1L therapy. While the impact of FHRMM on overall survival (OS) in pts with MM is well established, it is unclear how the 1L treatment path leading to FHRMM impacts subsequent OS.

Methods:

We screened all CIBMTR MM studies with publicly available data (N=11) and included 3 studies that reported induction therapy prior to 1L ASCT (MM18-02, MM19-01, and MM20-03). We included pts with FHRMM who received 1L ASCT from 2013-2018, and had progression < 12 (FHR12), < 18 (FHR18), or < 24 months (FHR24) after ASCT. To avoid duplication across studies, we created a unique patient ID using age, sex, race, and ISS stage. We classified induction therapy as standard lenalidomide-containing triplets (VRD/KRD) vs other (VTD/VCD/VD/RD). We studied the impact of 1L therapy on OS, measured from first relapse (establishment of FHR status) until death from any cause using the Kaplan-Meier method. We assessed the impact of 1L therapy, age, sex, race, Karnofsky performance status, ISS stage, cytogenetic risk, renal impairment, pre-ASCT response, and year of ASCT on OS using univariable analyses, and included variables with p< 0.05 in the multivariable Cox model.

Results:

A total of 465 pts with FHR12 were included; 32% had ISS stage III disease, and 43% had high-risk cytogenetics [t(4;14), t(14;16), t(14;20), del(13q), del(17p), gain(1q), or del(1p)] at diagnosis. Overall, 51% had achieved ≥VGPR before ASCT and 93% received melphalan 200 mg/m2.

The median (m) follow-up was 48 months (95% CI: 37-53), and mOS was 20 months (95% CI: 14-21). The mOS in the VRD/KRD cohort (n=238) was 21 months (95% CI: 14-31) vs 17 months (95% CI: 12-25) with the other 1L regimen cohort [n=227, hazard ratio (HR) 1.2 [95% CI: 0.6-1.06], p=0.16). In the multivariable model adjusting for age, race, cytogenetic risk, and ISS; the HR for OS was 0.94 (95% CI: 0.7-1.3, p=0.69) for VRD/KRD vs other regimens. There was no significant interaction between type of 1L therapy and time from 1L ASCT to first relapse in predicting OS (HR for interaction term 1.02 [0.9-1.09], p=0.56).

Analyses for FHR18 (n=672) and FHR24 (n=853) demonstrated a statistically non-significant difference in the adjusted HRs for OS with VRD/KRD vs other regimens (FHR18 HR 0.8 [0.6-1.04], p=0.1; FHR24 HR 0.86 [0.7-1.08], p=0.2). Likewise, there were no significant interactions between type of 1L therapy and time from ASCT to relapse in both these cohorts.

Conclusions:

Among pts with MM undergoing ASCT, the 1L treatment path leading to FHR status did not impact subsequent OS. Early relapse remains a negative prognostic factor irrespective of 1L therapy and warrants consideration of novel immunotherapies as the next line of treatment.