Impact of addition of anti-CD38 monoclonal antibody to first line therapy in newly diagnosed multiple myeloma with high risk cytogenetics: A systematic review and meta-analysis of randomized trials

Abstract Introduction: Quadruplet regimen with anti-CD38 monoclonal antibodies (mAb) with a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) have emerged as the new standard of care (SOC) for treatment of newly diagnosed multiple myeloma (NDMM). Daratumumab (DARA) and Isatuximab (ISA) are two FDA approved anti-CD38 mABs currently in use. While studies have shown improvement in outcomes in patients with NDMM with addition of an anti CD38 mAb, to a triplet or doublet, this benefit was not clearly demonstrated in patients with high-risk cytogenetic abnormalities (HRCAs). HRCA is present in approximately 15–20% of NDMM and is associated with inferior outcomes. In this context, we performed a meta-analysis of randomized clinical trials (RCTs) to evaluate the impact of addition of an anti-CD38 mAb to a SOC triplet/ doublet in NDMM patients with HRCA. Methods: A search was conducted on PubMed, EMBASE, Web of Science, Scopus, Cochrane, clinicaltrials.gov, and publications of ASH/ ASCO from inception to June 2025. RCTs comparing efficacy of anti CD38 based therapy in NDMM versus triplet/doublet therapy were included regardless of eligibility for autologous stem cell transplant. HRCA was defined as the presence of one or more of t(4;14), t(14;16), del(17p), or gain/amp(1q). The primary endpoint was progression-free survival (PFS). Secondary endpoints included measurable residual disease (MRD) negativity at 10-5, complete response (CR) rate and stringent complete response (sCR) rate. Trials were further categorized based on the anti-CD38 mAb used: DARA and ISA. Outcomes for RCTs were generated on intention-to-treat analyses. Subgroup analysis was performed based on the type of drug used. Pooled proportion rates for all outcomes were compared using risk ratio (RR), hazard ratios( HR) and 95% confidence intervals (CI) with p-values generated. A p-value of <.05 was considered statistically significant. Results: Eleven RCTs( N= 5,774) were included, with 1,002 patients classified as HRCA (508 treatment arm, 494 control arm). Eight trials evaluated DARA-based regimens: ALCYONE, MAIA, GRIFFIN, OCTANS, PERSEUS, CASSIOPEIA, CEPHEUS and, ADVANCE. Three trials studied ISA-based regimens: ISKIA, IMROZ and, GMMG-HD7. Other than CASSIOPEIA which did not include t(14:16), all other studies selected for analysis defined HRCA as the presence of one/ more of del17p, t(14;16), or t(4;14). ISKIA and IMROZ also included gain/amp(1q) as HRCA. There were 749 patients in DARA trials ( 383 treatment arm, 366 controls arm); 253 in ISA trials (125 treatment arm, 128 control arm). In the HRCA subset, PFS was reported in 8 trials (DARA-6, ISA- 2), MRD negativity in 6 (DARA-4, ISA -2), outcomes on CR rate in 4 and outcomes on sCR rate in 3. Due to data limitations, subgroup analysis by type of anti-CD38 mAb was feasible only for PFS and MRD negativity. In patients with HRCA, addition of an anti-CD38 mAb significantly prolonged PFS (HR: 0.72; 95% CI: 0.58-0.90) compared to SOC. However, we do not notice significantly improvements in MRD negativity (RR, 1.06; 95% CI, 0.84-1.34), CR rate ( CR, RR, 1.07; 95%CI, 0.85-1.33), and sCR rate (sCR, RR 1.39. 95% CI, 0.63-3.06) with addition of anti-CD38 mAb. Subgroup analysis showed that DARA-based regimens significantly prolonged PFS (HR: 0.63; 95% CI: 0.49–0.82). A similar benefit for PFS was not observed with ISA-based regimen for PFS (HR: 1.04; 95% CI: 0.68–1.61). Both DARA and ISA did not show improvement in MRD negativity (DARA: RR, 0.95; 95% CI, 0.67-1.35, ISA: RR, 1.23, 95% CI: 1.00- 1.52). Reporting of adverse events stratified by HRCA status was insufficient to draw conclusions on the safety profile in this population. Additional analysis based on eligibility for autologous stem cell transplant will be performed and presented at the meeting. Conclusions: Our study shows that addition of an anti-CD38 mAb significantly improves PFS in patients with NDMM with HRCA. This benefit seems to be primarily driven by studies utilizing DARA. No statistically significant benefit was observed for response end points such as MRD negativity in this subgroup highlighting the need for research to develop more effective regimens. The results of this study are limited by the underpowered subgroup analyses. Future phase III trials are warranted with higher enrollment of HRCA patients, especially with recent adoption of new criteria to define HRCA by the International Myeloma Society/International Myeloma Working Group.