Systematic Review of Phase III Trials of Daratumumab Based Regimens in Relapsed Refractory Multiple Myeloma

Introduction:

Multiple myeloma (MM) is a hematologic malignancy in which clonal plasma cell proliferation leads to complications and death. Daratumumab (Dara) is a humanized IgGk monoclonal antibody that targets CD38- a glycoprotein expressed on plasma cells and malignant cells. Dara has direct anti-tumor effects along with immunomodulatory activities, resulting in clonal expansion of cytotoxic T cells and diminution of immunosuppressive cells. This review highlights the efficacy and safety of Dara addition to the standard of care regimen, tested in Phase III trials, in patients with relapsed refractory MM (RRMM).

Methods:

We conducted a systematic literature search in four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov) using MeSH terms and keywords for multiple myeloma and Dara including trade names and generic names from date of inception to April 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, we included three phase III trials reporting daratumumab addition to the standard of care regimens for RRMM patients.

Results:

A total of 1521 patients out of 1533 enrolled patients were evaluated in three phase III randomized controlled trials. A total of 849 patients were evaluated in the Dara group and 684 patients were evaluated in the control group. Catja. C et al. (2019) studied the role of Dara + bortezomib (V) + dexamethasone (d) in RRMM pts (n=498) in phase III trial (CASTOR). Saad Z.U et al. (2019) underlined the efficacy of Dara + carfilzomib (K) and (d) in RRMM pts (n=466) in phase III trial (CANDOR), and Nizar J. Bahlis et al. (2020) studied Dara + lenolidamide (R) + d in RRMM pts (n=569) in phase III trial (POLLUX).

The addition of Dara to Vd, Rd, and Kd group was significant in term of overall response rate (ORR): 85% vs 63% (P <0.0001), 93% vs 76% (P < 0.0001), and 84.3% vs 74.7% (p=0.004), and minimal residual disease (MRD) negative status ((10^-⁵ sensitivity threshold, assessed by multipara metric flow cytometry) in bone marrow: 11.6% vs 2.4% (P=0.000034), 30.4% vs 5.3% (P<0.0001), and 12.5% vs 1.3% (p<0.0001) group, respectively. Moreover, addition of Dara to Vd, and Rd group also showed marked improvement in progression free survival (PFS): 48% vs 7.9% (HR, 0.31; 95% CI, 0.25-0.39, P <0.0001) at 18 months, 44.5% vs 17.5% at 44 months (HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001), and OS: 61% vs 51% at three years, and 65% vs 57% at 42 months, respectively. However, PFS and OS in Dara-Kd group was not reached vs control group: Kd group (HR= 0.63, 95% CI, 0.46-0.85, p=0.0014). Significant toxicities mainly included neutropenia, anemia, and thrombocytopenia (table 2).

Addition of Dara to standard care regimen (Vd and Rd) achieved superior outcomes in terms of ORR, PFS and OS, except Kd group, in which only ORR was improved as compared to control group. Combination of Dara plus standard care regimen improved MRD negative status in RRMM patients as compared to standard regimen.

Conclusion:

Treatment of RRMM with Dara plus standard care therapy (Vd, Rd, and Kd) has shown promising outcomes with improved efficacy and higher negative MRD status, providing a new benchmark for future studies.

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