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Daratumumab-based triplet highly effective in relapsed, refractory myeloma
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The addition of daratumumab to bortezomib and dexamethasone significantly improved PFS in patients with relapsed and refractory multiple myeloma, according to phase 3 trial results published in The New England Journal of Medicine.
However, more patients treated with the triplet regimen experienced infusion-related reactions, thrombocytopenia and neutropenia than patients treated with bortezomib (Velcade; Takeda/Millennium) and dexamethasone alone.
The monoclonal antibody daratumumab (Darzalex, Janssen) has exhibited significant single-agent efficacy in patients with heavily pretreated multiple myeloma. Combined daratumumab and bortezomib has shown considerable efficacy in newly diagnosed patients.
Antonio Palumbo, MD, chief of the myeloma unit and associate professor in the department of oncology at University of Turin in Italy, and colleagues randomly assigned 498 patients (median age, 64 years; range, 30-88) with relapsed or refractory myeloma to eight cycles of bortezomib (1.3 mg/m2 of body-surface area) and 20 mg of dexamethasone alone (n = 247) or with 16 mg/kg of daratumumab (n = 251).
Patients assigned daratumumab received the drug once weekly during the first three study cycles, then once every 3 weeks in subsequent cycles. After that, patients continued to receive daratumumab every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal.
PFS served as the study’s primary endpoint. Time to disease progression, overall response rate and safety served as secondary endpoints.
Median follow-up was 7.4 months.
Results — presented in part at the ASCO Annual Meeting in 2016 — showed the 12-month median PFS rate was 60.7% (95% CI, 51.2-69) among patients assigned daratumumab compared with 26.9% (95% CI, 17.1-37.5) among patients assigned bortezomib and dexamethasone alone.
Median PFS had not been reached (95% CI, 12.3-not estimable) for the daratumumab group at the time of reporting and was 7.2 months (95% CI, 6.2-7.9) in the control group.
The researchers calculated a 61.4% lower risk for death or progression in patients assigned daratumumab, which crossed the prespecified stopping boundary (HR = 0.39; 95% CI, 0.28-0.53).
A significantly higher percentage of patients assigned daratumumab remained progression free after 12 months (65.4% vs. 28.8%; HR = 0.3; 95% CI, 0.21-0.43).
Patients in the daratumumab arm demonstrated a higher ORR (82.9% vs. 63.2%; P < .001), as well as higher rates of very good partial response or better (59.2% vs. 29.1%; P < .001) and complete response or better (19.2% vs. 9%; P = .001).
Adverse events occurred in 98.8% of the daratumumab group and 95.4% of the control group. A greater proportion of patients assigned daratumumab experienced grade 3 or higher adverse events (76.1% vs. 62.4%).
The most common serious adverse events included thrombocytopenia (daratumumab vs. control, 45.3% vs. 32.9%), anemia (14.4% vs. 16%) and neutropenia (12.8% vs. 4.2%).
More patients in the daratumumab group experienced any-grade thrombocytopenia (58.8% vs. 43.9%), neutropenia (17.7% vs. 9.3%) and lymphopenia (13.2% vs. 3.8%), as well as any-grade peripheral sensory neuropathy (47.3% vs. 37.6%).
Both groups had similar rates of grade 3 or worse infections and infestations (21.4% vs. 19%).
Thirteen patients assigned daratumumab and 14 patients in the control group died as a result of adverse events.
Infusion-related reactions occurred in 45.3% of patients assigned daratumumab, 98.2% of which occurred during the first infusion.
The majority of infusion-related reactions were grade 1 or grade 2; 21 patients had grade 3 reactions, and no grade 4 reactions occurred. Two patients discontinued treatment due to infusion-related reactions.
“Among patients with relapsed or relapsed and refractory multiple myeloma, the combination of daratumumab, bortezomib and dexamethasone resulted in significantly longer PFS than bortezomib and dexamethasone alone, with a risk of disease progression or death that was 61.4% lower in the daratumumab group than in the control group,” Palumbo and colleagues wrote. “In the daratumumab group, deep, rapid, and durable responses were reported, with the rates of very good partial response or better and complete response or better approximately double those in the control group.” – by Cameron Kelsall
Disclosure: Janssen Research and Development funded this study. Palumbo reports grant support from Janssen during the conduct of this study, as well as personal fees from Genmab, Janssen-Cilag and Takeda outside of this study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Henry C. Fung
In November 2015, the FDA approved daratumumab (Darzalex, Janssen), an anti-CD38 monoclonal antibody, for the treatment of multiple myeloma in patients who have received three or more prior lines of therapy. The approval was based on response rates, albeit impressive, without knowledge on the impact of PFS and OS. No one expects achievement of durable response by using single-agent daratumumab, and we have been anxiously waiting to find the best partner for daratumumab and, more importantly, how the novel combination performs when compared with conventional salvage regimens.
In this issue of The New England Journal of Medicine, daratumumab was partnered with bortezomib (Velcade, Millennium/Takeda) and dexamethasone. It is no surprise that the outcomes of the combination of daratumumab, bortezomib and dexamethasone (DBD) compares favorably to bortezomib and dexamethasone alone. We congratulate the investigators on completing a phase 3 randomized study swiftly — in approximately 1 year.
However, this study failed to show how we should position this new regimen in patients with relapsed/refractory multiple myeloma. We do not know the best salvage regimen for patients with relapsed/recurrent myeloma and, certainly, the combination of DBD will not be able to claim the throne based on the current study.
In this report, patients were excluded if they had disease that was refractory to a proteasome inhibitor, which is an area of unmet need. In the United States, few practicing oncologists use bortezomib and dexamethasone as the salvage of choice as we have many options, and bortezomib and dexamethasone with a third agent is often used during induction. Thus, a regimen which is better than bortezomib and dexamethasone does not mean too much.
National Comprehensive Cancer Network guideline version 03.2016 listed 24 preferred regimens for patients who failed previous treatment(s), of which seven have category 1 designation. I am sure that DBD will soon earn the category 1 designation.
Sadly, we will never find the best salvage regimen, or at least an acceptable standard for comparison, if we continue using a control arm that most of us do not use. We must stop using lenalidomide (Revlimid, Celgene) with dexamethasone, and bortezomib with dexamethasone as the comparative arms.
Having said that, the outcomes with DBD are very promising. For the daratumumab group, the overall response rate was 82.9%, very good response rate was 52.9% and complete response rate was 19.2%. The rate of 1-year PFS among patients in the daratumumab group who had received one previous line of therapy was 77.5% — and the median PFS was not reached — vs. 29.4% in the control arm.
Among patients who had received two or three previous lines of therapy, median PFS was 9.3 months for the daratumumab group vs. 6.5 months for the control group (HR for progression or death = 0.52; 95% CI, 0.33-0.81).
Based on the available data, it appears that adding daratumumab to either a proteasome inhibitor or immunomodulatory agent improves the outcomes of patients with relapsed/refractory multiple myeloma. Still, we do not know:
1) whether an immunomodulatory agent or proteasome inhibitor is a better partner for daratumumab;
2) if DBD or daratumumab, lenalidomide and low-dose dexamethasone is better than the combination of a proteasome inhibitor and immunomodulator;
3) the impact of adding daratumumab to a proteasome inhibitor/immunomodulator–containing regimen; and
4) how daratumumab can alter the natural history of the disease when used as part of frontline treatment.
Disclosure: Fung reports consultant roles with Amgen and Sanofi.
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