Adding the recently approved daratumumab (Darzalex), a human, CD38-directed 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 ASCO 2016.
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.
New Mechanism of Action
CD38 has long been recognized as a treatment target for multiple myeloma, but daratumumab’s impressive efficacy goes beyond its effect on CD38, said Dr Palumbo.
Although its cytotoxic activity results in a sizable reduction in tumor burden, the mechanism “that is probably more relevant is the ability to both increase the T-cell activity and the immune system that is able to control the tumor,” he said.
In addition to depleting CD38 immunosuppressive regulatory cells, daratumumab promotes T-cell expansion and activation. This immune effect sustains the immediate cytotoxic effect of daratumumab.
The Value of Daratumumab
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.
Using the ICER (Institute for Clinical and Economic Review) value framework of cost-effectiveness modeling, daratumumab is projected to land in the “intermediate value” quadrant, exceeding $200,000 per quality-adjusted life-year gained, although the overall survival data are not yet available from the CASTOR study.
Based on the ASCO Value Framework, daratumumab is likely to score a net health benefit of 48, which is considered a high score. The ASCO Value Framework estimates a patient cost of $4680 monthly in the early months of treatment with daratumumab, and falls to $1170 monthly in months 6 to 12. The drug acquisition cost is estimated at $23,400 monthly in the early months, with a reduction to $5850 monthly in months 6 to 12.
The individual value of daratumumab is high, but it will result in financial burden for patients without health insurance coverage, at a cost of >$10,000 per month. Therefore, the value of daratumumab to the health system is moderate-to-high, and high-income countries will adopt it or seek to negotiate a discount, said Dr Schrag, whereas it is likely to be cost-prohibitive for middle-income countries.