Triplet Combination of Daratumumab, Bortezomib, and Dexamethasone Improves Multiple Myeloma Survival

In the pivotal, randomized, controlled, phase III CASTOR study, adding daratumumab to bortezomib and dexamethasone (DVd) extended progression-free survival (PFS) and time to progression (TTP) compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (MM). Antonio Palumbo, MD, from the University of Torino in Italy, presented the study’s findings during the Plenary Session at the 2016 ASCO Annual Meeting.

“These results are unprecedented in this cancer,” Dr. Palumbo said during his presentation. “It’s clear that we’ll be moving to a three-drug regimen with daratumumab as the standard of care.”

THE CASTOR trial included 498 patients who received ≥1 prior lines of therapy. Patients were randomized 1:1 to receive eight cycles of:

  • Bortezomib 1.3 mg/m2 administered subcutaneously on days 1, 4, 8, and 11 plus dexamethasone 20 mg administered orally on days 1, 2, 4, 5, 8, 9, 11, 12 (Vd; n=247)
  • The Vd regimen plus daratumumab 16 mg/kg administered intravenously once weekly during cycles 1-3, on day 1 of cycles 4-8, then every 4 weeks until progression (DVd; n=251)

Patients received a median of two prior lines of therapy (range = 1-10 therapies), including prior:

  • Bortezomib (66%)
  • Immunomodulatory drug (IMiD; 76%)
  • Protease inhibitor and IMiD (48%)

One-third of patients were IMiD-refractory (33%), and 32 percent were refractory to the last line of prior therapy.

“The accrual [took] one year for 500 patients – very fast,” Dr. Palumbo explained in an interview with ASH Clinical News. “After three months from the last patient enrolled, the Independent Data Monitoring Committee stopped the trial early in a planned analysis because daratumumab improved progression-free survival [over the two-drug combination]. From that point of view, the study results are unprecedented.”

After a median follow-up of 7.4 months, DVd significantly extended the median PFS (the study’s primary endpoint), with a 61 percent reduction in the risk of disease progression: not reached vs. 7.16 months (hazard ratio [HR] = 0.39; 95% CI 0.28-0.53; p<0.0001).

The median TTP was significantly increased for DVd compared with Vd: not reached versus 7.29 months (HR=0.3; 95% CI 0.21-0.43; p<0.0001).

The three-drug regimen also significantly increased the objective response rate compared with the two-drug regimen (83% vs. 63%; p<0.0001), including:

  • Very good partial response or better: 59% vs. 29% (p<0.0001)
  • Complete response or better: 19% vs. 9% (p=0.0012)

Responses in the DVd group were also more durable: the median duration of response was not reached for DVd and 7.9 months for Vd.

Notably, though patients in the daratumumab arm continued receiving therapy until progression, patients in the bortezomib-dexamethasone arm were treated for a finite period of time – limiting the comparison. Future studies should include continued therapy in the control group.

“The monoclonal antibody did not add [to the] cumulative toxicity: the toxicity was identical in the control and the experimental arms,” Dr. Palumbo said. “The only [exception was for] infusion reactions. Forty-five percent of patients had infusion-related reactions, which were mainly grade 1 or 2, as is usually seen with other monoclonal antibodies.”

The most common treatment-related adverse events (AEs; occurring in >25% of patients) for DVd and Vd included thrombocytopenia (59% vs. 44%), peripheral sensory neuropathy (47% vs. 38%), diarrhea (32% vs. 22%), and anemia (26% vs. 31%). The most common grade 3 or 4 AEs (occurring in >10% of patients) were thrombocytopenia (45% vs. 33%), anemia (14% vs. 16%), and neutropenia (13% vs. 4%). Seven percent of patients in the DVd group and nine percent in the Vd group discontinued treatment due to AEs.

In the future, Dr. Palumbo told ASH Clinical News, daratumumab would hopefully be administered as front-line treatment. “In our trial, [daratumumab] doubled patients’ remission duration, which is already four to five years of remission from diagnosis,” he said. “Extending that to eight to 10 years [as was shown in this study], will mean a major change in myeloma.”


Reference

Palumbo A, Chanan-Khan AAA, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. Abstract #LBA4. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 5, 2016.

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