Further Research on Anti-CD38 mAbs Warranted in Multiple Myeloma

A systematic review of 8 randomized trials showed that anti-CD38 monoclonal antibodies did not improve overall survival in high-risk subgroups.

The absence of an overall survival (OS) benefit with anti-CD38 monoclonal antibodies in high-risk subgroups of patients with multiple myeloma warrants attention despite the overall enhancement of treatment efficacy and manageable toxicity, according to findings from an updated systematic review and meta-analysis (CRD42024599221) shared in Leukemia and Lymphoma.

In the pooled analysis, the addition of anti-CD38 monoclonal antibodies significantly improved progression-free survival (PFS; HR, 0.50; 95% CI, 0.42-0.59; P <.00001); significant heterogeneity was detected on the chi-squared Q-test (P = .02) with an I2 statistic of 65%. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment showed a moderate certainty of evidence. A benefit was also observed for OS (HR, 0.63; 95% CI, 0.55-0.71; P <.00001), with low heterogeneity (P = .82; I2 = 0%).

Therapy with anti-CD38 monoclonal antibodies significantly increased the minimal residual disease (MRD)–negative rate (risk ratio, 1.85; 95% CI, 1.43-2.39; P <.00001); significant heterogeneity was identified (P <.00001; I2 = 90%).

Subgroup analyses of PFS showed that anti-CD38 monoclonal antibody-based therapy was favorable regardless of transplant eligibility (transplant-eligible: HR, 0.52; 95% CI, 0.36-0.75; P = .0004; transplant-ineligible: HR, 0.48; 95% CI, 0.39-0.59; P <.00001); the benefit was consistent across all subgroups, such as sex, International Staging System (ISS) stage, and ECOG performance status, among others. Stratification based on median follow-up duration revealed a marked reduction in I2.

The MRD-negative rate was improved with anti-CD38 monoclonal antibodies in all subgroups, except for those with non-IgG type status. OS data showed consistent survival benefits in most subgroups, although no significant improvement was identified in those with high-risk cytogenetics, ISS stage I disease, and baseline hepatic impairment.

An analysis based on anti-CD38 monoclonal antibody-based therapy types revealed significantly reduced heterogeneity in the isatuximab-irfc (Sarclisa) subgroup, although it was higher in the daratumumab (Darzalex) subgroup (risk ratio, 1.99; 95% CI, 1.36-2.91).

“In conclusion, this study confirms that anti-CD38 [monoclonal antibodies] significantly improve PFS, MRD negativity, and OS in [patients with newly diagnosed multiple myeloma], highlighting their clinical value. However, high-risk subgroups showed no OS benefit,” wrote lead study author Zujie Lin, of the Department of Hematology at The Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, Shaanxi, China, and coauthors, in the paper.

Data from a total of 8 trials were included in this analysis; the included randomized, controlled trials had an overall total of 2509 patients in the anti-CD38 monoclonal antibody-based treatment regimen group and 2356 patients in the group without anti-CD38 monoclonal antibodies. Four of the trials included patients who were eligible for transplantation, and 4 did not; 3 used isatuximab as the anti-CD38 monoclonal antibody, and 5 used daratumumab.

Eligible studies were required to have enrolled patients with newly diagnosed multiple myeloma per International Myeloma Working Group criteria, regardless of transplant eligibility; compare therapy with anti-CD38 monoclonal antibody-based therapy with a therapy without; report on treatment response, survival, outcomes, or adverse events (AEs); and be a randomized, controlled phase 3 trial.

Reasons for trial exclusion included intervention utilizing other types of monoclonal antibodies or cell therapies and treatment of a population who had relapsed/refractory multiple myeloma.

The primary trial end point was PFS; secondary end points were the MRD-negative rate, OS, infection-related AEs, and second primary malignancies.

Therapy with anti-CD38 monoclonal antibodies led to enhanced risk for infection-related AEs, such as any-grade and grade 3 or 4 pneumonia (any-grade: risk ratio, 1.86; 95% CI, 1.45-2.38; P <.00001; grade 3/4: risk ratio, 1.93; 95% CI, 1.50-2.49; P <.00001), and any-grade and grade 3 or 4 overall infections (any-grade: risk ratio, 1.16; 95% CI, 1.09-1.25; P <.0001; grade 3/4: risk ratio, 1.36; 95% CI, 1.18-1.56; P <.0001). Bronchitis risk was amplified (any-grade: risk ratio, 1.68; 95% CI, 1.12-2.52, P = .01; grade 3/4: risk ratio, 2.19; 95% CI, 1.12-4.28, P = .02), any-grade upper respiratory tract infections showed differential risk patterns (risk ratio, 1.55; 95% CI 1.15-2.10; P = .004), and pneumonia-related serious AEs showed a 1.90-fold increase in risk (risk ratio, 1.90; 95% CI, 1.53-2.36, P <.00001) with anti-CD38 monoclonal antibodies.

Notably, anti-CD38 monoclonal antibodies demonstrated a 44% increased risk of a second primary malignancy (risk ratio, 1.44; 95% CI, 1.14-1.81; P = .002).

Reference

Lin Z, Dong R, Zhang W, Liu R, Fu B, He A. Efficacy and safety of anti-CD38 monoclonal antibodies in patients with newly diagnosed multiple myeloma: an updated systematic review and meta-analysis based on randomized controlled trials. Leuk Lymphoma. Published online June 12, 2025. doi:10.1080/10428194.2025.2512031