A Three-Drug Combo for Multiple Myeloma

Interim results from CASTOR, a randomized phase III trial, suggest that daratumumab (Darzalex; Janssen) increases the effectiveness of bortezomib (Velcade; Takeda) and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

Daratumumab, which targets CD38 on myeloma cells, “is one of the most exciting drugs for myeloma in quite a while,” says Shaji Kumar, MD, of the Mayo Clinic in Rochester, MN, who wasn't connected to the study. It was the first monoclonal antibody approved for multiple myeloma, although so far only as monotherapy for patients whose disease has progressed on three or more prior therapies, including the proteasome inhibitor bortezomib, a standard therapy.

However, because almost all patients will have a relapse, researchers have been gauging how well daratumumab works in combination with other drugs to extend response times. Last year, a phase I trial suggested that daratumumab, bortezomib, and the steroid dexamethasone might be effective.

CASTOR enrolled 498 patients with relapsed or relapsed and refractory multiple myeloma to further test this possibility. They were randomized to receive all three drugs or just bortezomib and dexamethasone. After a median follow-up of 7.4 months, patients who received the three-drug combination had an overall response rate of 82.9% and a 12-month progression-free survival (PFS) rate of 60.7% versus 63.2% and 26.9%, respectively, in the control arm. The median PFS has not been reached in the patients who received all three drugs, whereas it was 7.2 months for the controls.

Subgroup analyses indicated that daratumumab was effective even when patients had been previously treated with bortezomib or had already received two or three previous lines of therapy.

Hematologic side effects were more common in patients who received daratumumab, particularly thrombocytopenia and neutropenia. Daratumumab “is by far the best treatment so far” for multiple myeloma, says co-author Pieter Sonneveld, MD, of Erasmus MC in Rotterdam, the Netherlands. “It should be used in the relapsed and refractory setting and, [perhaps] eventually, in newly diagnosed patients,” in whom it's now being tested, he says.

“Even though the follow-up is short, we can see that the difference [between CASTOR's two groups] is quite large,” Kumar says, adding that he thinks this drug combination will be approved by the FDA.

Suzanne Lentzsch, MD, PhD, of Columbia University Medical Center in New York, NY, agrees that the findings are impressive. “The combination is potent and is well tolerated,” she says, and the results suggest “we have an additional option for relapsed or relapsed and refractory myeloma.”

The puzzle for researchers may be determining the optimal drugs to combine with daratumumab. Earlier this year, another randomized phase III trial, POLLUX, reported durable responses among previously treated patients with multiple myeloma who received the combination of daratumumab, dexamethasone, and the immune-modulating agent lenalidomide (Revlimid; Celgene). –Mitch Leslie