(PA-433) Frontline Anti-CD38 Monoclonal Antibodies in Patients with High-Risk, Newly Diagnosed Multiple Myeloma: A Meta Analysis

The anti-CD38 monoclonal antibodies daratumumab and isatuximab are both approved for use in patients with newly diagnosed multiple myeloma (NDMM) in both the transplant-eligible and transplant-ineligible settings. However, the degree to which high risk patients in particular benefit from the addition of an anti-CD38 monoclonal antibody to NDMM regimens is not clear. We conducted a meta-analysis to evaluate the effect of anti-CD38 monoclonal antibodies on progression free survival (PFS) across the NDMM space.

Methods:   

Criteria for inclusion of a study were defined as any randomized, controlled trial (RCT) in NDMM examining standard of care myeloma therapy with or without daratumumab or isatuximab. The primary endpoint was PFS. Only studies stratifying PFS data by cytogenetic risk were included. Notably, classification of cytogenetic risk status was not equivalent across trials (for example, with respect to whether 1q gains are considered high risk), but for the purposes of this analysis all high risk subgroups were combined into one category.   The pooled effect of frontline anti-CD38 monoclonal antibodies across studies was quantified using a PFS hazard ratio, separately in standard-risk and high-risk subgroups, with 95% confidence intervals calculated using theDerSimonian-Laird random effects model. For analysis, trials were divided into transplant trials and nontransplant trials. Hazard ratios and confidence intervals were derived from reported trial data.  The “Meta” package (version 6.5-0), R version 4.3, was used.

Results:   

A total of 9 trials (MAIA, ALCYONE, CEPHEUS, IMROZ, OCTANS, CASSIOPEIA, GRIFFIN, PERSEUS, and GMMG-HD7) were identified and included in the analysis. Frontline receipt of an anti-CD38 monoclonal antibody was associated with improved PFS both in patients with standard-risk NDMM (HR 0.51; 95% CI 0.46-0.58, p(heterogeneity) 0.44) and high-risk NDMM (HR 0.64, 95% CI 0.49-0.84, p(heterogeneity) 0.13). Subgroups of patients with standard risk disease derived similar benefit from frontline anti-CD38 monoclonal antibody receipt whether on a nontransplant study (HR 0.49, 95% CI 0.43-0.57, p(heterogeneity) 0.52) or a transplant study (HR 0.52, 95% CI 0.40-0.67 p(heterogeneity) 0.26). Subgroups of patients with high-risk disease also benefitted, both if treated on transplant studies (HR 0.57, 95% CI 0.35-0.94, p(heterogeneity) 0.56) and on nontransplant studies (HR 0.71, 95% CI 0.53-0.97, p(heterogeneity) 0.04).

Conclusions:   

Patients with high-risk NDMM and standard-risk NDMM treated on frontline myeloma trials experienced improved PFS with anti-CD38 monoclonal antibody-based regimens, although the effect was less pronounced in high-risk patients treated on nontransplant studies. The myeloma community continues to refine clinical risk classification systems. Further comparison of NDMM therapeutic strategies in more refined cytogenetic subgroups should be a focus of future work.