Daratumumab-Related Hematological Toxicities in Patients with Multiple Myeloma: A Combined Analysis of Five Phase III Randomized Controlled Trials

Introduction:

Multiple myeloma is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Daratumumab is a humanized IgGκ monoclonal antibody that targets CD38 with direct antitumor effects along with immunomodulatory activity, resulting in depletion of immunosuppressive cells and clonal expansion of cytotoxic T cells. Addition of daratumumab to standard multiple myeloma regimens has recently shown to improve survival in patients with multiple myeloma with considerable safety profile. We undertook a meta- analysis of randomized controlled trials (RCT) to determine the risk of hematological toxicities 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 hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) 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 0, suggesting homogeneity among RCT. The RR of all-grade side effects were as follows: anemia, 0.85 (95% CI: 0.76 - 0.95; p = 0.005); neutropenia, 1.38 (95% CI: 1.09 - 1.74; p = 0.008); thrombocytopenia, 1.15 (95% CI: 0.90 - 1.47; p = 0.27); and leukopenia, 1.60 (95% CI: 1.16 - 2.20; p = 0.004). The RR of high-grade adverse effects were as follows: anemia, 0.72 (95% CI: 0.60 - 0.86; p = 0.0004); neutropenia, 1.48 (95% CI: 1.17 - 1.88; p = 0.001); thrombocytopenia, 1.15 (95% CI: 0.88 - 1.49; p = 0.31); and leukopenia, 1.72 (95% CI: 1.28 - 2.30; p = 0.0003).

Conclusions:

Our study demonstrated that patients on daratumumab combination regimens experienced higher risk of all grades of neutropenia and leukopenia, with RR of 1.48 and 1.72 for high-grade neutropenia and leukopenia. However, there was lower incidence of all grades of anemia in daratumumab containing group compared to control arm, favoring daratumumab-based regimens.