Issue: July 10, 2016
June 05, 2016
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Daratumumab combination improves PFS, ORR in relapsed, refractory multiple myeloma

Issue: July 10, 2016
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CHICAGO — The addition of daratumumab to bortezomib and dexamethasone significantly prolonged PFS and time to progression in patients with relapsed or refractory multiple myeloma, according to early results of the CASTOR study presented during the plenary session of the ASCO Annual Meeting.

The combination with daratumumab also doubled the rates of very good partial and complete response and demonstrated a safety profile consistent with the known toxicity profiles of the agents.

Daratumumab (Darzalex, Janssen) became the first human anti–CD38 monoclonal antibody approved for the treatment of multiple myeloma by the FDA in November 2015. It has been shown to induce deep and durable responses in patients with relapsed or refractory disease.

“In the era of immuno-oncology, we hope to have our own R-CHOP, which has been shown to be a major treatment for lymphoma and which is available with different antibodies for multiple myeloma,” Antonio Palumbo, MD, chief of the myeloma unit in the department of oncology at University of Turin, in Italy, said during a press conference. “With daratumumab we have a monoclonal antibody that is eating the most relevant tumor antigen for plasma cells, a very specific target.”

Palumbo and colleagues evaluated the safety and efficacy of the addition of daratumumab to bortezomib (Velcade; Millennium, Takeda) and dexamethasone in 488 patients who had received at least one prior therapy (median, n = 1; range, 1-10).

The researchers randomly assigned patients to eight cycles every 3 weeks of bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12), with (n = 251) or without (n = 247) IV daratumumab (16 mg/kg per week cycles 1-3; on day 1 of cycles 4-8; then every 4 weeks until progression).

Sixty-six percent of patients had previously received bortezomib, and 32% were refractory to their last prior therapy.

PFS served as the study’s primary endpoint. Secondary endpoints included time to response, overall response rate, OS and safety.

Researchers planned to conduct an interim analysis after approximately 177 PFS events had occurred. Median follow-up was 7.4 months.

Median PFS in the daratumumab arm had not been reached at the time of reporting, and was 7.1 months for the bortezomib and dexamethasone arm. This data equated to a 61% reduction in the risk for progression or death with the addition of daratumumab, thus meeting the study’s primary endpoint at the interim analysis (HR = 0.39; 95% CI, 0.28-0.53).

“This is unprecedented in randomized studies that compare novel treatment for relapsed and refractory multiple myeloma,” Palumbo said.

Patients assigned daratumumab also experienced a significantly longer time to progression (median, not reached vs. 7.2 months; HR = 0.3; 95% CI, 0.21-0.43).

The ORR was significantly higher in the daratumumab arm (83% vs. 63%; P < .0001). Daratumumab doubled rates of complete response or better (19% vs. 9%; P = .0012) and very good partial response or better (59% vs. 29%; P < .0001).

Median duration of response has not been reached in patients assigned daratumumab and was 7.9 months among patients assigned bortezomib and dexamethasone alone.

The most common any-grade adverse events included thrombocytopenia (59% vs. 44%), peripheral sensory neuropathy (47% vs. 38%), diarrhea (32% vs. 22%) and anemia (26% vs. 31%). Grade 3 or worse adverse events observed in more than 10% of patients included thrombocytopenia (45% vs. 33%), anemia (14% vs. 16%) and neutropenia (13% vs. 4%).

Forty-five percent of patients in the daratumumab arm experienced infusion-related reactions, the majority of which were low grade (grade 3, 9%; grade 4, 0).

Seven percent of patients assigned the daratumumab combination and 9% assigned bortezomib and dexamethasone alone discontinued treatment due to adverse events.

“The benefit of daratumumab with bortezomib and dexamethasone was maintained across different subgroups: younger patients, older patients, good prognoses, bad prognoses,” Palumbo said. “The final conclusion is that daratumumab in this combination might be considered a new standard of care for relapsed and refractory multiple myeloma.” by Cameron Kelsall

Reference:

Palumbo A, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: Janssen Research & Development provided funding for this study. Palumbo reports institutional research funding from, as well as consultant roles with, Genmab, Janssen–Cilag and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.