Comparison of Standard of Care with or without a PD-1/Pdl-1 Inhibitor for the Treatment of Multiple Myeloma: A Meta-Analysis of Phase II and III Randomized Controlled Trials
Authors: Alsaddi Zain , Khasawneh Ghena , Shatnawi Yara , Ahmed Nausheen , Mahmoudjafari Zahra , Mushtaq Muhammad Umair , Abdallah Al-Ola , Paul Barry , Atrash Shebli 
Published: December 2024

Background: Although recent advances in Multiple Myeloma (MM) therapy, combined with enhanced supportive care have led to improved outcomes, MM remains incurable. In recent years, agents targeting the programmed death-1 (PD-1) axis have become essential treatments both as single agents and in combination with other backbones in numerous malignancies. While treatment of myeloma patients with monotherapies targeting PD-1/PD-L1 has been shown to be safe, efficacy has been disappointing. The data for combination therapies including a PD1/PD-L1 inhibitor (PD-1i) in MM has proven to be less conclusive. To address this challenge, we conducted a metanalysis to evaluate safety and efficacy of PD-1/PD-L1 inhibitors in combination to standard of care backbones (SOC) in MM.

Methods: We conducted a systematic search to identify phase II, or III randomized clinical trials in patients with MM treated with a PD-1i. The terms used for the search included “Relapsed Multiple Myeloma”, “PD-1 inhibitors”, “PDL-1 inhibitors”, “PD-1”, “PDL-1” and “programmed death ligand 1 inhibitors” which were combined through Boolean operators “AND” “NOT,” and “OR.” The search was limited to trials published after 2016 in English. The search was conducted in August 2023, in the National Library of Medicine medical literature database via the PubMed gateway as well as the CINAHL, and Cochrane databases. The data were analyzed with Rstudio v 2023.09.0+463. Individual patient data on survival were reconstructed from published data when available. Using R Core Team (2024) software, a descriptive analysis was performed. Continuous variables were summarized and reported the mean (min, max) and median (IQR). Dichotomized factors were summarized by total numbers and frequency. Fisher's exact was used to analyze contingency tables. Wilcoxon rank-sum test is used to compare two independent samples. Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) calculations. A univariate/multivariate Cox proportional hazards analysis assessed the relationship between variables and a time-to-event outcome. The analysis calculates hazard ratios (HRs) and their associated confidence intervals (CIs) for each predictor variable, adjusting for censoring in survival data.

Results: Our search yielded a total of 19 trials, of which 5 met the inclusion criteria and were included in the study. These trials included 889 patients and contained both newly diagnosed and relapsed and/or refractory MM patients. A total of 488 patients were treated with a PD + SOC and 401 patients were treated with SOC alone. The median progression-free survival (PFS) with PD-1i+ SOC was 6.26 months vs. 7.34 months with SOC alone, (HR 1.2; 95%CI: 0.95-1.41, p=0.14,). Median overall survival (OS) with PD-1i+ SOC vs SOC was 22.49 months vs 24.38 months (HR 1.11;95% CI: 0.87, 1.42, p=0.038). The addition of a PD-1i to SOC resulted in a minimal change in overall response rates and depth of response per IMWG criteria. The PD-1i group exhibited a higher incidence of all immune-mediated adverse events (irAEs), including diarrhea, rash, pneumonitis, and endocrine adverse events (RR 12.5, 95% CI 1.22-127.56, p &lt; 0.05) as well as ≥ 3 grade irAEs (RR 12.11; 95% CI 2.24-65.50, p &lt; 0.05). The presence of ≥ 3 grade pneumonia did not show statistical significance with the addition of PD-1i (RR 1.12, 95% CI 0.83-1.52, p&gt;0.05), and there was no statistically significant increase in ≥ 3 grade neutropenia (RR 1.27, 95% CI 0.99-1.6, p&gt;0.05).

Conclusion: Our analysis underscores the limited efficacy and additional toxicity of PD-1i when added to SOC regimens for myeloma patients. However, additional research is warranted during this era of novel therapies to determine whether targeting the PD-1/PD-L1 axis can safely enhance efficacy in patients undergoing immunotherapies.