Impact of maintenance strategies post-autologous stem cell transplant in patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities

Abstract Introduction Outcomes for patients with newly diagnosed multiple myeloma (NDMM) who have high-risk cytogenetic abnormalities (HRCA) are consistently inferior when compared to patients with standard-risk disease, regardless of modern quadruplet induction, autologous stem cell transplantation (ASCT), and maintenance therapy. While the GMMG-CONCEPT and FORTE trials showed benefit with multi-drug maintenance, the optimal choice and duration of maintenance for patients with HRCA after up-front ASCT is still unknown, as there may be greater impacts on quality of life and late toxicities with prolonged treatment. We explored outcomes and maintenance strategies for patients with transplant-eligible NDMM and HRCA at our center. Methods We conducted a single center retrospective analysis of patients who received ASCT for NDMM between 2014-2024 and had at least one HRCA at diagnosis or otherwise met 2025 IMWG high-risk criteria. HRCA was defined as ≥1 of the following: del17p, t(4;14), t(14;16), t(14;20), del1p, or gain/amp 1q. Survival outcomes were analyzed by the Kaplan-Meier (KM) method. Progression free survival (PFS) was defined as time from diagnosis to disease progression or death after ASCT. Univariate and multivariate analyses were conducted using a Cox regression model to identify predictors of survival, with number of HRCA, use of CD38 antibody-based induction, year of ASCT, depth of response prior to ASCT, and type of maintenance therapy included as covariates. Maintenance regimens were grouped into 3 categories: immunomodulatory drug (IMiD) or proteasome inhibitor (PI) singlet, PI + IMiD doublet, or CD38 antibody-based maintenance (doublets and triplets). Results We identified 147 patients who met study inclusion criteria. 138 did not progress within 3 months of ASCT and were included for further analysis. Median age at the time of ASCT was 65 (range 28-81) and 55.1% were male. 71% identified as White, 9.4% as Asian, and 5.8% as Black. 39.4% of patients had ISS 3 disease and 35.5% had ≥2 HRCA. Patients had the following HRCA distribution: 18.1% del17p (13.8% >20% clonal fraction), 18.8% t(4;14), 11.6% t(14;16), 0.7% t(14;20), 13.0% del1p, and 69.6% gain/amp 1q. 44.2% of patients met 2025 IMWG high-risk criteria. 65 patients (47.1%) received CD38 antibody-based induction. 77.5% had at least a VGPR (44.2% VGPR and 33.3% CR/sCR) prior to ASCT. 74 patients had their measurable residual disease (MRD) status evaluated at 10-6 post-ASCT, of whom 37.8% achieved MRD negativity. 29% received 1 drug maintenance, 42.8% received 2 drugs, and 27.5% received ≥3 drugs. 74 patients (53.6%) received an anti-CD38 antibody as part of their maintenance, of whom 60 also received CD38 antibody-based induction. Those who met 2025 IMWG high-risk criteria were more likely to receive ≥2 maintenance drugs (OR 2.90, p=0.009). The median duration of maintenance therapy by KM was 33 months (range 0-115). Among the 64 patients (46.4%) who stopped maintenance therapy during follow-up, reasons for discontinuation included: progressive disease (65.6%), drug intolerance (20.3%), medical comorbidities (7.8%), and sustained remission (6.3%). At a median follow-up duration of 37 months, 3-year PFS was 77.8% (95% CI 69-84). Median overall survival (OS) was not reached with an estimated 5-year OS of 82%. On multivariate analysis, both lower pre-ASCT disease burden (≥VGPR) (HR 0.43, 95% CI 0.23-0.81, p=0.01) and CD38 antibody-based induction (HR 0.32, 95% CI 0.11-0.88, p=0.03) were associated with greater PFS. After adjusting for induction regimen and number of HRCA, there was no difference in PFS or OS between different maintenance strategies. In patients without progression at 24 months post-ASCT, continuation of maintenance therapy beyond two years was associated with improved PFS (HR 0.34, p=0.005) and OS (HR 0.25, p=0.05). Conclusion Among patients with NDMM and HRCA, CD38 antibody-based induction and depth of response prior to ASCT was associated with improved PFS, suggesting there may be potential utility in intensifying responses before transplant. Doublet and triplet maintenance strategies could not overcome disease characteristics in this cohort of high-risk patients. Although longer duration of maintenance (≥24 months) improved survival, high rates of disease progression highlight a need for novel maintenance strategies. Additional prospective studies are warranted to determine ideal choice and duration of maintenance therapy for high-risk patients.