Three-Drug Regimen with Daratumumab a New Standard of Care for Relapsed or Refractory Multiple Myeloma

Adding the recently approved daratumumab (Darzalex), a human, CD38-direct monoclonal antibody, to a standard regimen of bortezomib (Velcade) and dexamethasone improved progression-free survival (PFS) by >60% compared with the standard regimen in patients with relapsed or refractory multiple myeloma, according to Antonio Palumbo, MD, Chief of the Multiple Myeloma Unit, University of Torino, Italy. Dr Palumbo presented new data at the 2016 American Society of Clinical Oncology (ASCO) annual meeting.

The 61% improvement in PFS is “unprecedented in randomized studies that compare novel treatments for relapsed or refractory multiple myeloma,” he emphasized, saying that based on these data, the 3-drug regimen should be considered a new standard of care for this patient population. Daratumumab received accelerated approval by the FDA in November 2015 based on results from a nonrandomized, phase 2 clinical trial.

Phase 3 CASTOR Study

Dr Palumbo presented data from an interim analysis of the ongoing, randomized, controlled, phase 3 CASTOR clinical trial after approximately 177 PFS events. At the time of the last follow-up, he said, the median PFS had not yet been reached in patients who received daratumumab.

Overall, 498 patients in the phase 3 study received ≥1 previous lines of therapy; the patients were randomized to standard therapy with bortez­omib and dexamethasone or to the 3-drug regimen of bortezomib, dexamethasone, and daratumumab 16 mg/kg intravenously weekly during cycles 1 to 3, then every 3 weeks during cycles 4 to 8. After completing 8 cycles in the experimental arm, daratumumab was given monthly until disease progression.

The daratumumab arm had a 61% improvement in PFS, and was not yet reached in the 3-drug arm compared with PFS of 7.2 months in the 2-drug arm.

Randomization to daratumumab doubled the very good partial response rate, from 29% to 59% (P <.001) and the complete response rate from 9% to 19% (P = .001).

The safety profile of the 3-drug regimen was consistent with the safety profile of these drugs. “Daratumumab did not significantly increase any toxicity that was already present in the combination bortezomib and dexamethasone [arm],” Dr Palumbo said.

The rates of thrombocytopenia and peripheral neuropathy were higher with the 3-drug regimen (59% and 47%, respectively) versus the 2-drug regimen (44% and 38%, respectively); this was attributed to the longer exposure to bortezomib in the 3-drug arm.

Although the study examined the 3-drug regimen after ≥1 lines of previous therapy, exploring combination regimens in the early phases of disease is important, Dr Palumbo said.

In multiple myeloma, daratumu­mab “is likely to score high” on the Abacus value framework, said Deborah Schrag, MD, MPH, Chief, Division of Population Sciences, Dana-Farber Cancer Institute, Boston. “It has high efficacy and a novel mechanism of action.”

To recommend a fair launch price, Abacus incorporates drug efficacy, cost, toxicity, the novelty of the mechanism of action, the costs of developing the drug, the rarity of the disease, and the burden of the disease.

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