Reassessing ASCT in patients aged 65–75 with multiple myeloma in the era of anti-CD38 therapies

Abstract Introduction: The role of autologous stem cell transplantation (ASCT) in older patients (pts) with multiple myeloma (MM) is being re-evaluated in light of effective anti-CD38-based regimens now available for non-transplant eligible (NTE) pts. In this context, we retrospectively compared outcomes of transplant-eligible (TE) elderly pts receiving ASCT after Dara-VTD induction versus NTE pts treated with anti-CD38-based regimens, evaluating the impact of frailty status on outcomes. Patients and Methods We analyzed 122 unselected pts aged 65–75 years (median age 72) with newly diagnosed MM at our institution between April 2016 and December 2024. ASCT eligibility was based on clinical judgment. TE pts received Dara-VTD induction, ASCT, Dara-VTD consolidation and lenalidomide maintenance (ASCT cohort), while NTE pts received anti-CD38-based regimens (no-ASCT cohort). Response rate, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity were assessed. The IMWG frailty score was retrospectively applied to evaluate outcomes according to frailty status. Results: Out of 122 pts recorded, 22 (18%) were ISS stage 3 and 40 (32%) had high risk (HR) cytogenetics. Median age was 68 vs 73 years in ASCT vs no-ASCT cohorts (p0.0001), while HR cytogenetics and ISS-3 distribution were well balanced between cohorts. Thirty-six (29%) were assigned to the ASCT cohort (5 receiving double ASCT); 86 (71%) constituted the no-ASCT cohort: DRd 54%, D-VMP 16%, Isa-VRd 1%. According to the IMWG frailty score, 27 pts (22%) were classified as fit, 91 (75%) as intermediate-fit (unfit), and 4 (3%) as frail. In the ASCT cohort, 47% were fit and 53% were intermediate-fit. In the no-ASCT cohort, 11% were fit, 84% intermediate-fit, and 5% frail. ORR was 94% in the ASCT cohort vs 91% in the no-ASCT cohort (p=0.7), and ≥VGPR rates were 75% vs 62%, respectively (p=0.5). sCR+CR rates were higher in the ASCT cohort (53% vs 24%, p=0.032). MRD assessed by multiparametric flow cytometry (sensitivity 10⁻⁵) was available in 17 ASCT pts before maintenance, of which 13 (76%) were negative. After a median follow-up of 24 months, PFS was similar between ASCT and no-ASCT (median NR vs 75.5 months; 3-year PFS 83% vs 76%, p=0.55), as was OS (median NR in both cohorts; 3-year OS 93% vs 86%; p=0.41). In the ASCT cohort, PFS was longer in fit pts compared to unfit, although not statistically significant (3-year PFS 94% vs 73%; median NR in both groups; p=0.191). OS showed a similar trend (3-year OS 100% vs 87%; median NR; p=0.208). Among ASCT pts, the subgroup aged 70 years (n=4) showed outcomes comparable to those aged 65–70, with no PFS and OS events reported at the time of analysis. In the no-ASCT cohort, PFS differed significantly according to frailty status (p=0.04): 3-year PFS was 100% in fit pts, 70% in unfit, and 50% in frail; median PFS was 80, 75, and 29 months, respectively. OS was not significantly different between groups (p=0.3), with 3-year OS of 100%, 83%, and 100%, and median OS NR, NR, and 45 months, respectively. No significant differences in PFS or OS were observed when comparing pts aged 65–70 and 71–75 years within each treatment cohort. Notably, PFS in unfit pts receiving ASCT was comparable to that observed in the no-ASCT cohort (3-year PFS 73% vs 70%; p=0.891). Grade ≥3 hematologic toxicities were significantly more frequent in the ASCT cohort, with neutropenia in 92% vs 51% (p0.0001) and thrombocytopenia in 89% vs 16% (p0.0001). Infections of any grade occurred in 92% of ASCT pts vs 67% in the no-ASCT cohort (p=0.0017), with grade ≥3 infections reported in 64% vs 34% (p=0.0027), respectively. Temporary treatment discontinuation was comparable between groups. However, when considering the temporary discontinuation of at least one drug within the treatment regimen, the rate was significantly higher in the ASCT cohort (67% vs 43%; p=0.028), mainly due to thalidomide-related complications. Conclusion: These findings support the feasibility and effectiveness of ASCT in carefully selected pts aged 70 years. However, modern anti-CD38-based regimens represent a valid alternative in the 65–75 age group, offering comparable outcomes with a more favorable safety profile. The IMWG frailty score emerges as a valuable tool to guide therapeutic decisions regarding treatment intensity and transplant eligibility, particularly in unfit pts, whose outcomes were comparable to those treated with non-intensive regimens.