Updated Meta-Analysis of Randomized Controlled Trials to Evaluate the Incidence of Infection and Pneumonia in Patients with Multiple Myeloma Treated with Daratumumab

Abstract

Introduction: Multiple myeloma is a hematologic cancer of plasma cell, a blood cell which normally produce antibodies, and accounts for approximately 13% of all hematologic malignancies. Daratumumab is a human anti CD38 IgGκ monoclonal antibody with a well characterized mechanism of action via direct antitumor effects and an immunomodulatory component and the incorporation of daratumumab to standard multiple myeloma regimen has shown to significantly improve response rates and survival, with notable toxicities. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of infection and pneumonia in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention infection including pneumonia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 35, suggesting some heterogeneity among RCT. The incidence of any-grade infection was 58.01% in study group vs 48.06 % in control group (RR, 1.21; 95% CI: 1.12 - 1.31; P < 0.0001). High-grade infection rate was 5.46% higher in daratumumab group compared to control arm (RR, 1.27; 95% CI: 1.13 - 1.44; P = 0.0001). Any-grade pneumonia was reported in 12.58% in study arm versus 7.72%% in control group with RR of 1.63 (95% CI: 1.08 - 2.45; P = 0.02). High-grade pneumonia was 8.47% in study group versus 5.52% in control arm (RR, 1.51; 95% CI: 0.97 - 2.35; P = 0.07). The RR for high-grade pneumonia was statistically significant at 2.07 (95% CI: 1.50 - 2.85; P < 0.0001) in a subset of newly diagnosed multiple myeloma patients treated with daratumumab (n= 2503). Conclusions: The addition of daratumumab to standard multiple myeloma regimen contributed to higher incidence of all grades of infection and any-grade pneumonia, with RR of 1.27 for high-grade infection and RR of 1.63 for any-grade pneumonia. However, high-grade pneumonia was only found to be significant in a subset of patients with newly diagnosed multiple myeloma treated with daratumumab, with RR of 2.07. Timely intervention with proper supportive care is required. Disclosures No relevant conflicts of interest to declare.

B-cell targeting with anti-CD38 daratumumab: implications for differentiation and memory responses

“…The strength of this study is that we have investigated both TD and TI B-cell responses in the presence of DARA with a strong impact on TD stimulation and—in this respect—a differential outcome of different B-cell subsets, demonstrating the most impact of CD38 targeting on the activation and maturation of memory B cells into PBs and PCs. Although derived from an in vitro system, our findings do suggest a possible mechanism for the additional risk of bacterial and viral infections in MM patients receiving anti-CD38–directed therapies in vivo ( 50 , 51 ). Where normally the barrier of immunological memory would protect patients, reduced recall responses by memory B cells upon TI or TD stimulation leave patients who receive DARA treatment prone to infections with common pathogens ( 16 ).…”

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations

“…A meta-analysis of 3547 patients enrolled in 5 phase III trials showed a higher incidence of all grades of infection when daratumumab was added to other agents (relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.13-1.44, P = 0.0001), with high-grade pneumonia in newly diagnosed patients carrying the highest risk. 50 Potential challenges in interpreting these data include overlapping pulmonary symptoms (eg, cough, dyspnea) secondary to CD38-induced basophil degranulation and leukotriene production following initial infusions; however, early recognition, infectious agent diagnosis, and supportive intervention are critical. Grade 3/4 neutropenia following single-agent daratumumab is 20% and increases to >80% in combination regimens.…”