‘Very Encouraging’ Early Results for Single-Agent Daratumumab in Multiple Myeloma

In a phase I–II trial, the CD38 inhibitor daratumumab shows acceptable safety and anti-tumour activity in heavily pretreated multiple myeloma patients

medwireNews: Monotherapy with the anti-CD38 monoclonal antibody daratumumab is well tolerated and elicits durable responses in patients with relapsed or refractory multiple myeloma, according to research reported in The New England Journal of Medicine.

Writing in a linked editorial, Noopur Raje, from Harvard Medical School in Boston, Massachusetts, USA, and Dan Longo, deputy editor of the NEJM, note that the single-agent activity of the drug in this patient population is “surprising and very encouraging”. They attribute the findings to the agent’s pleiotropic mechanisms of action against myeloma, including complement-mediated, cell-mediated and direct cytotoxic effects.

The dose-expansion phase of this phase I–II trial included 72 multiple myeloma patients who had received a median of four previous therapies, including proteasome inhibitors and immunomodulatory drugs. Seventy-six percent of study participants had undergone autologous stem-cell transplantation.

A total of 30 participants were given daratumumab at a dose of 8 mg/kg administered in eight once-weekly infusions and then twice monthly for 16 weeks. The remaining 42 patients received daratumumab 16 mg/kg once-weekly for 8 weeks (including a 3-week washout period after the first infusion), followed by twice a month for 14 weeks. All participants were then treated with monthly infusions for up to 2 years.

The most common side effect was infusion-related reactions, experienced by 71% of study participants. The reactions were mainly of grade 1 or 2 severity, except for one patient in the 16 mg/kg group who had a grade 3 reaction. The study authors also note that the reactions mostly occurred during the first infusion and did not lead to any treatment discontinuations.

Adverse episodes of grade 3 or 4 occurred in 53% of patients in the 8 mg/kg cohort and in 26% of those in the 16 mg/kg cohort, with pneumonia and thrombocytopenia the most frequent toxicities.

Three patients who received the study drug at the 8 mg/kg dose achieved a partial response, equating to an overall response rate of 10%. And two complete responses, two very good partial responses and 11 partial responses were recorded in the 16 mg/kg group, giving an overall response rate of 36%.

After a median follow-up of 16.9 and 10.2 months in the 8 mg/kg and 16 mg/kg cohorts, respectively, the median progression-free survival times in the two groups were respectively 2.4 and 5.6 months. The 1-year overall survival rate was identical in both cohorts, at 77%.

In the 16 mg/kg group, 65% of patients who responded to treatment remained progression free at the 1 year timepoint, reports the team led by Henk Lokhorst, from VU University Medical Center in Amsterdam, the Netherlands, suggesting that daratumumab elicited “durable responses that deepened over time”.

The editorialists refer to the addition of monoclonal antibodies into the myeloma armamentarium as “game-changing”, but note that unanswered questions remain, such as whether daratumumab is active in different stages of treatment and whether resistance to the drug can be predicted.

“As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma”, they write.


Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015; Advance online publication 26 August. doi:10.1056/NEJMoa1506348

Raje N, Longo DL. Monoclonal Antibodies in Multiple Myeloma Come of Age. N Engl J Med 2015; Advance online publication 26 August. doi:10.1056/NEJMe1509419

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