Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and examethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone.

— Antonio Palumbo, MD, and colleagues

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In the phase III CASTOR trial reported in The New England Journal of Medicine, Antonio Palumbo, MD, of the University of Turin, and colleagues found that adding the anti-CD38 antibody daratumumab (Darzalex) to bortezomib (Velcade) and dexamethasone markedly improved progression-free survival among patients with relapsed or relapsed and refractory multiple myeloma.¹ The data were first disclosed by Dr. Palumbo during the Plenary Session of the ASCO Annual Meeting in June 2016.²

Study Details

In the open-label trial, 498 patients from 115 sites in 16 countries in Europe, North America, South America, and the Asia-Pacific region were randomly assigned between September 2014 and September 2015 to receive bortezomib at 1.3 mg/m² and dexamethasone at 20 mg alone (n = 247) or with daratumumab at 16 mg/kg (n = 251). Bortezomib was given subcutaneously on days 1, 4, 8, and 11 of 21-day cycles in cycles 1 to 8. Dexamethasone was given orally or intravenously on cycle days 1, 2, 4, 5, 8, 9, 11, and 12. Daratumumab was given intravenously on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 during cycles 4 to 8, and once every 4 weeks thereafter until withdrawal of consent, disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival.

Treatment groups were well matched for baseline demographics and disease characteristics.

Among all patients, median age was 64 years (range = 30–88 years), and median time from initial diagnosis was 3.8 years. The median number of previous lines of therapy was 2 (range = 1–10; ≥ 3 in 24%), with 61% having undergone autologous stem cell transplantation, 66% having received previous bortezomib, 76% having received immunomodulatory drugs, and 48% having received both proteasome inhibitors and immunomodulatory drugs. Overall, 32% had disease refractory to their last line of therapy, and 33% had disease refractory to immunomodulatory drugs.

Efficacy

At a prespecified interim analysis after a median follow-up of 7.4 months, a total of 189 events of disease progression or death had occurred (64% of 295 planned events for the final analysis), with 67 occurring in the daratumumab group and 122 occurring in the control group. Estimated progression-free survival at 12 months was 60.7% (95% confidence interval [CI] = 51.2%–69.0%) in the daratumumab group vs 26.9% (95% CI = 17.1%–37.5%) in the control group.

Median progression-free survival was not reached (95% CI = 12.3 months to not estimable) vs 7.2 months (95% CI = 6.2–7.9 months); the hazard ratio (HR) was 0.39 (95% CI = 0.28–0.53, P < .001), crossing the prespecified interim analysis stopping boundary. On the basis of these results, the independent data and safety monitoring committee recommended that the trial be unblinded early and that daratumumab be offered to patients in the control group with disease progression.

Subgroup analyses showed a consistent progression-free survival benefit with daratumumab in all subgroups, including patients who had received prior bortezomib treatment (HR = 0.46, 95% CI = 0.32–0.66) and patients with disease refractory to their last line of previous therapy (HR = 0.42, 95% CI = 0.25–0.70), as well as in subgroups according to age < 65 and ≥ 65 years, International Staging System stage, number of lines of previous therapy, and prior autologous stem cell transplantation.

Overall response rates were 82.9% in the daratumumab group vs 63.2% in the control group (P < .001), with very good partial response or better in 59.2% vs 29.1% (P < .001) and complete response or better in 19.2% vs 9.0% (P = .001). Due to the short follow-up, median progression-free survival during the next line of therapy and median overall survival were not reached in either treatment group.

Overall, progression-free survival events during the next line of therapy occurred in 31 patients in the daratumumab group and 49 patients in the control group (HR = 0.57, 95% CI = 0.37–0.90), and death occurred during the study in 29 and 36 patients (HR = 0.77, 95% CI = 0.47–1.26). Long-term follow-up is continuing in the study population.

Adverse Events

The most common adverse events of any grade in the daratumumab group were thrombocytopenia (58.8% vs 43.9%), peripheral sensory neuropathy (47.3 % vs 37.6%), and diarrhea (31.7% vs 22.4%). The most common grade 3 or 4 adverse events were thrombocytopenia (45.3% vs 32.9%), anemia (14.4% vs 16.0%), and neutropenia (12.8% vs 4.2%) among hematologic events and pneumonia (8.2% vs 9.7%), hypertension (6.6% vs 0.8%), peripheral sensory neuropathy (4.5% vs 6.8%), and fatigue (4.5% vs 3.4%) among nonhematologic events.

Bleeding events of any grade occurred in 7.0% vs 3.8% of patients. Secondary primary cancers occurred in 2.5% vs 0.4%. Infusion-related reactions occurred in 45.3% of patients in the daratumumab group (grade 3 in 8.6%; no grade 4); among patients with such reactions, 98.2% had them during the first infusion.

Treatment was discontinued due to adverse events in 7.4% vs 9.3% of patients, including due to peripheral sensory neuropathy (0.4% vs 2.5%) and pneumonia (1.2% vs 0.4%). Adverse events led to death in 5.3% vs 5.9%.

The investigators concluded: “Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone.” ■

Disclosure: The study was funded by Janssen Research and Development. For full disclosures of the study authors, visit www.nejm.org.

References

1. Palumbo A, Chanan-Khan A, Weisel K, et al: Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754-766, 2016.

2. Palumbo A, Chanan-Khan AA, Weisel K, et al: Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma: CASTOR study. 2016 ASCO Annual Meeting. Abstract LBA4.