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Daratumumab exhibits efficacy, safety in heavily pretreated, refractory myeloma
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Single-agent therapy with daratumumab conferred encouraging efficacy and favorable safety in patients with heavily pretreated, refractory multiple myeloma, according to the results of a phase 2 study.
Sagar Lonial, MD, FACP, chief medical officer of Winship Cancer Institute, professor and executive vice chair of hematology and oncology at Emory University, and a HemOnc Today Editorial Board member, and colleagues sought to study the safety and efficacy of daratumumab (Darzalex, Janssen) — a novel CD38-targeted monoclonal antibody — in patients with multiple myeloma refractory to proteasome inhibitors and immunomodulatory drugs.
Sagar Lonial, MD, FACP
Thus, they initiated the open-label, randomized, phase 2 SIRIUS study of adult patients with multiple myeloma. All patients had undergone at least three prior lines of therapy or were refractory to both proteasome inhibitors and immunomodulatory drugs.
The researchers randomly assigned patients to IV daratumumab at 8-mg/kg (every 4 weeks) or 16-mg/kg (weekly for 8 weeks, every 2 weeks for 16 weeks, then every 4 weeks thereafter) doses in part 1, stage 1 of the study. Researchers used data from this stage of the study to determine the dose in part 2.
In the part 1, stage 2 of the study — as well as part 2 — patients received 16 mg/kg daratumumab as dosed in the part 1, stage 1.
Overall response rate (ORR) — including partial response, very good partial response, complete response and stringent complete response — served as the primary endpoint.
The study remains ongoing, according to Lonial.
In the current analysis, researchers reported data from 106 patients (median age, 63.5 years; 49% men; median prior therapy lines, n = 5) assigned to 16-mg/kg daratumumab in parts 1 and 2 of the study.
Eighty percent of patients (n = 85) previously underwent autologous hematopoietic stem cell transplantation. Nearly all patients were refractory to the most recent proteasome inhibitors and immunomodulatory drugs (95%; n = 101), and to their most recent line of therapy (97%; n = 103).
Median follow-up was 9.3 months (range, 0.5-14.4).
The researchers reported an ORR of 29.2% (n = 31; 95% CI, 20.8-38.9). Three patients achieved a stringent complete response (2.8%; 95% CI, 0.6-8), 10 patients achieved a very good partial response (9.4%; 95% CI, 4.6-16.7) and 18 patients achieved a partial response (17%; 95% CI, 10.4-25.5).
The median time to first response was 1 month (95% CI, 0.9-5.6) and the median duration of response was 7.4 months (95% CI, 5.5-not reached).
Median PFS was 3.7 months (95% CI, 2.8-4.6), with 64.8% (95% CI, 51.2-75.5) of patients remaining alive at 12 months.
At a subsequent cutoff, median OS was 17.5 months (95% CI, 13.7-not reached).
No patients discontinued treatment due to drug-related adverse events. The researchers reported that the drug appeared well tolerated.
Commonly reported adverse events included fatigue (40%; n = 42), anemia (33%; n = 35), thrombocytopenia (25%; n = 27) and neutropenia (23%; n = 24).
“The tolerability of daratumumab in combination with other backbone agents is being
assessed in early phase studies,” Lonial and colleagues wrote. “Patients with early to late stages of multiple myeloma are being enrolled in randomized phase 3 studies of daratumumab in combination with bortezomib [Velcade; Millennium, Takeda Oncology], or lenalidomide [Revlimid, Celgene] and dexamethasone, and other combinations, for the assessment of efficacy and safety, including patient-reported outcomes.”
In an accompanying editorial, S. Vincent Rajkumar, MD, professor of medicine at Mayo Clinic in Rochester, Minn., wrote that excitement over daratumumab should not give way to improper prescription of the agent.
“We need abundant caution to prevent unnecessary, perfunctory use of the drug,” Rajkumar wrote. “First, we need to develop validated surrogate endpoints of clinical benefit in myeloma. … Second, multiple myeloma is a heterogeneous malignant disease with several cytogenetically distinct subtypes. The data in Lonial and colleagues’ trial were insufficient to determine the cytogenetic subtypes that respond best to daratumumab.”
However, Rajkumar acknowledged that daratumumab represents one of many strong advances in the treatment of multiple myeloma.
“Multiple myeloma has witnessed 15 years of remarkable progress,” Rajkumar wrote. “Daratumumab is the first monoclonal antibody approved for treating the disease, ending a decades-long wait for a targeted approach. … The progress in this disease is astonishing; there is no hype here.” – by Cameron Kelsall
Disclosure: Janssen Research & Development funded this study. Lonial reports research funding from and a consultant role with Janssen, as well as consultant roles with Bristol-Myers Squibb, Celgene, Millennium, Novartis and Onyx. Please see the full study for a list of all other researchers’ relevant financial disclosures. Rajkumar reports no relevant financial disclosures.
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