Daratumumab Combo Safe, Durable in Relapsed/Refractory Myeloma

Patients with relapsed or refractory multiple myeloma enrolled in a phase II study of the anti-CD38 monoclonal antibody daratumumab plus lenalidomide/dexamethasone continued to have deep and durable responses to the drug combination, according to updated results of the GEN503 study (Abstract 507) presented at the 57th Annual American Society of Hematology (ASH) Meeting and Exposition, held December 5–8 in Orlando, Florida.

“Daratumumab plus lenalidomide/dexamethasone induces rapid, deep, and durable responses,” said Torben Plesner, MD, of Vejle Hospital in Vejle, Denmark, during a press conference at the meeting.

The US Food and Drug Administration (FDA) approved daratumumab in November for the treatment of patients with multiple myeloma with three or more prior lines of therapy. It was the first monoclonal antibody approved for multiple myeloma.

According to Plesner, CD38, the target of daratumumab, is highly expressed in myeloma cells. With three mechanisms of action, daratumumab is very active against myeloma. First, daratumumab can cause tumor cell death indirectly with immune-meditated activity. Second, it has a direct antitumor effect, binding directly to myeloma cells and killing them. Finally, it has been recently shown that there is also an important immunomodulatory function of daratumumab.

Prior studies have explored the use of daratumumab monotherapy in heavily pretreated/refractory myeloma. In this study, Plesner and colleagues examined daratumumab in combination with lenalidomide/dexamethasone, a commonly used treatment in multiple myeloma.

Phase I of the study was a dose-escalation study with patients assigned to daratumumab from 2 mg/kg to 16 mg/kg plus lenalidomide/dexamethasone. Phase II of the study was a cohort expansion study using the phase II recommended dose of daratumumab. Patients were given daratumumab 16 mg/kg weekly during the first two 28-day cycles, every other week during cycles 3 to 6, and monthly in cycle 7 and beyond. The primary endpoint of the trial was safety.

According to the results, there were no new safety signals identified when daratumumab was given in combination with lenalidomide/dexamethasone. Only three of 32 patients had to discontinue treatment due to adverse events.

The most common adverse events were neutropenia (84%), cough (50%), diarrhea (44%), and muscle spasms (44%). Although half of the patients experienced a serious adverse event, only neutropenia, gastroenteritis, and pyrexia occurred in more than one patient.

“Infusion-related reactions occurred in 56% of patients,” Plesner said. “This was usually at the first infusion, very low grade and was easily managed with premedication or slowing of the infusion rate.”

Plesner also discussed efficacy results during his presentation. The overall response rate for patients assigned this combination was 81%; 63% of patients had a very good partial response or better and 34% had a complete response or better.

In addition, he noted that responses to daratumumab were durable and occurred rapidly. The median time to first response was 1 month and the median time to best response was 5.1 months. The median duration of response has not yet been reached, with 91% of patients free from progression at 12 months.

Plesner also called the progression-free survival rate impressive, with an 18-month rate of 72% (95% confidence interval [CI], 51.7–85.0). The 18-month overall survival was 90% (95% CI, 73.1–96.8).

“Randomized phase III studies of daratumumab and lenalidomide/dexamethasone are ongoing both in the relapsed/refractory setting and in newly diagnosed myeloma patients,” Plesner said.