Darzalex Continues to Advance in Multiple Myeloma

Two phase 3 trials led to Darzalex being granted a breakthrough therapy designation by the FDA. 
BY JASON M. BRODERICK @jasoncology
Darzalex (daratumumab) was granted a breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for use in combination with Revlimid /dexamethasone or Velcade /dexamethasone for patients with multiple myeloma who have had at least one prior therapy, according to the developers of the CD38-targeted antibody, Janssen and Genmab.

The designation, which will expedite the development and review of the Darzalex regimens, is based on two phase 3 trials. The phase 3 POLLUX trial demonstrated that combining Darzalex with Revlimid (lenalidomide) and dexamethasone reduced the risk of disease progression by 63 percent versus Revlimid and dexamethasone alone in patients with relapsed/refractory multiple myeloma. In the phase 3 CASTOR trial, adding Darzalex to Velcade (bortezomib) and dexamethasone reduced the risk of progression or death by 61 percent in patients with recurrent or refractory multiple myeloma.

“Despite tremendous progress in the past 15 years, multiple myeloma remains a highly complex and difficult disease to treat, with most patients relapsing or becoming resistant to therapy,” POLLUX lead author Meletios A. Dimopoulos, department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, said in a statement. “Daratumumab has already shown pronounced activity as a monotherapy in heavily pretreated patients. This designation underscores the potential of daratumumab in combination with either a proteasome inhibitor or an immunomodulatory agent to provide much-needed benefit to patients with at least one prior therapy.”

The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to Darzalex combined with Revlimid dexamethasone (286 patients) or Revlimid plus dexamethasone alone (283 patients). Darzalex was dosed at 16 mg/kg IV once weekly during cycles one and two, every two weeks during cycles three to six, and once only (on day one) of cycles seven onward. Oral Revlimid was administered at 25 mg daily for the first three weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI less than 8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.

The median patient age was 65 years. The median number of of prior treatment lines was one, with 19 percent of patients having received three or more lines of therapy. Eighty-six percent of patients had received a proteasome inhibitor; 55 percent had been treated with an immunomodulatory agent (IMiD), including 18 percent with Revlimid; and 44 percent had previously receiving both a proteasome inhibitor and an IMiD. Across the study population, 27 percent of patients were refractory to their most recent treatment and 18 percent were refractory to a proteasome inhibitor; however, no patients were refractory to Revlimid.

The primary endpoint of the study was progression-free survival (PFS), with secondary outcome measures including time to progression, overall response rate (ORR), overall survival and very good partial response (VGPR). At a preplanned interim analysis in May 2016, the study was unblinded after an independent panel determined the trial met its primary endpoint of improved PFS. Patients in the control arm were allowed to receive Darzalex at progression.

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