Daratumumab Data Impresses in Myeloma, FDA Submission Expected

Saad Zafar Usmani, MD

The anti-CD38 monoclonal antibody daratumumab demonstrated a 65% one-year overall survival (OS) rate and a 29.2% objective response rate (ORR) in patients with double refractory heavily pretreated multiple myeloma, according to findings from the ongoing phase II MMY2002 study presented at the 2015 ASCO Annual Meeting.

“This is the first monoclonal antibody in myeloma that has shown single-agent activity. One in three patients in this study benefited from getting the drug, and that truly is unprecedented,” study author Saad Zafar Usmani, MD, a hematologist at Levine Cancer Institute/Carolinas Healthcare System, said during a press briefing. “These results highlight the potential of daratumumab as a novel, well-tolerated, single-agent therapy in various stages of myeloma treatment.”

In May 2013, single-agent daratumumab received a breakthrough therapy designation from the FDA as a treatment for patients with double refractory multiple myeloma following three lines of therapy, based on a phase I study. Data from the phase II analysis will be submitted to the FDA and European Medicines Agency for potential approval in double refractory multiple myeloma, according to the drug’s developer, Janssen.

In the pivotal phase II study, the first 34 patients enrolled received daratumumab at 16 mg/kg (n = 16) or 8 mg/kg (n = 18). After a response evaluation, the 16 mg/kg dose was selected for future study, with an additional 90 patients enrolled at this dose (N = 106).

Patients in the trial had received a median of five prior therapies over a median of 4.8 years following diagnosis. Ninety-six percent of patients were refractory to their last treatment, including proteasome inhibitors and immunomodulatory agents (95%).

Responses to daratumumab consisted of stringent complete responses (n = 3; 2.8%), very good partial responses (n = 10; 9.4%), and partial responses (n = 18; 17%). The median duration of response was 7.4 months, with a median time to progression of 3.7 months.

After a median follow-up of 9.4 months, the median OS had not been reached. At this analysis, 45.2% of patients remained on therapy.

Infusion-related reactions (IRR) predominately occurred during the first infusion and were mostly grade 1/2 (all-grade 42.5%). Grade 3 IRRs were seen in 4.7% of patients; however, no grade 4 events were experienced. No patients discontinued daratumumab as a result of an IRR.

The most common all-grade adverse events were fatigue (39.6%), anemia (33%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), and cough (20.8%). Overall, 4.7% of patients discontinued treatment due to adverse events. These side effects were not deemed to be associated with daratumumab.

“It is particularly noteworthy to see this level of response with a single-agent in this heavily pretreated population,” lead investigator Sagar Lonial, MD, chief medical officer, Winship Cancer Institute of Emory University, said in a statement. “These findings speak to the potential of daratumumab as an effective and tolerable option for people with multiple myeloma who have exhausted other available treatment options.”

Daratumumab is a fully human monoclonal antibody that binds to glycoprotein CD38. Once bound, the antibody interacts with natural killer cells by mimicking the normal interaction between CD38 and CD31. This interaction elicits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity resulting in antitumor activity.

“CD38 is highly expressed on multiple myeloma cells and is a promising therapeutic target,” Usmani noted.

In addition to single-agent activity, daratumumab is also being explored in a number of combination studies. At this time, several phase III clinical trials are looking at the antibody in various treatment settings.

“Currently there are five big phase III studies that are evaluating daratumumab in combination with existing therapies. Three of the five are in the frontline setting,” explained Usmani.

In a preceding early-phase study assessing daratumumab with lenalidomide and dexamethasone in pretreated patients, the ORR was 75%. In an expansion cohort of patients who received daratumumab at 16 mg/kg (n = 13), the ORR was 92.3%.

In the frontline setting, the combination of daratumumab with the proteasome inhibitor bortezomib and other therapies demonstrated an ORR of 100%. In these analyses, the only side effects of concern were IRRs.

“Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone phase III study in the frontline setting has already accrued its 500 patients,” said Usmani. “We’ll probably see some data in the next couple years on that particular study.”

Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33 (suppl; abstr LBA8512).

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