Highlights from

ASCO 2019

American Society of Clinical Oncology annual meeting

Chicago, USA 31 May - 4 June 2019

Daratumumab a promising treatment option for transplant-eligible multiple myeloma

Medical writer: Emily Kuhl, PhD

Primary analyses are complete from the first phase III clinical trial to investigate whether transplant-eligible patients with newly diagnosed multiple myeloma (MM) benefit from the addition of daratumumab (DARA) to standard pretransplant treatment. The findings, presented on June 2 (Abstract 8003), suggest that induction and consolidation treatment with the anti-CD38 monoclonal antibody DARA improves response rates without compromising safety.

“This is the largest phase III trial to look at the path of DARA for MM patients,” said study investigator and presenter Philippe Moreau, MD, of the University Hospital Hôtel-Dieu, France.

Previous trials have supported the efficacy of DARA for significantly reducing risk of disease progression and death and improving complete remission (CR) and minimal residual disease–negative rates in relapsed/refractory MM or transplant-ineligible, newly diagnosed MM. DARA in combination with bortezomib/thalidomide/dexamethasone (VTd) is also an approved approach for patients with newly diagnosed MM who are not candidates for autologous stem cell transplant. But until now, the effects of this combination as an induction and consolidation treatment in those who are suitable candidates have been unclear in terms of possibly conferring an additional benefit on response and survival.

The CASSIOPEIA trial (NCT02541383), conducted in two parts, was designed to assess this question. In Part 1, patients with newly diagnosed MM who were candidates for transplant (1,085 patients) were randomly assigned to receive VTd with or without DARA before and after transplant. The primary endpoint was stringent CR (sCR), assessed post-transplant. Safety endpoints were also examined.

The study found that post consolidation sCR was significantly greater among patients receiving combination DARA/VTd compared with VTd alone (29% vs. 20%, odds ratio 1.6; P = 0.001).

“One could comment that the sCR is not that high,” Dr. Moreau said. “But we used a strict method to define sCR, and all of the [inclusion] data were required. If any [single] data [point] was missing, the patient was downgraded to very good partial response. So, clearly, DARA improved the depth of the response.”

Examination of long-term follow-up outcomes (median 18.8 months from first randomization) again revealed a benefit of the combination treatment over VTd (P < 0.0001), including progression-free survival (93% in the DARA/VTd arm vs. 85% in the VTd arm). This led to a 53% reduction in risk of disease progression or death in the combination arm. Minimal residual disease negativity (64% in the DARA/VTd arm vs. 44% in the VTd arm; P < 0.0001) similarly favoured the combination drug.

“Overall survival was immature, but there is already a trend in favor of the DARA arm of the study,” Dr. Moreau said. “The hazard ratio is more than 0.4, and the 24-month overall survival rate is 97% in the DARA arm of study. These are the best ever reported in the setting of stem cell transplantation.”

In addition to efficacy, investigators looked at safety and tolerability. The most common grade 3/4 treatment-emergent adverse events included neutropenia, lymphopenia, stomatitis, and thrombocytopenia. A little over one-third of patients in the combination arm (35%) experienced infusion-related reactions.

Discussant Faith Davies, MD, MRCP, MRCPath, FRCPath, of New York University Langone Health, noted that, although the presented data “clearly demonstrate that these drugs are effective in the newly diagnosed patient group,” questions about patient-reported outcomes are also clinically meaningful.

“We know that many of the side effects of the data in VTd were related to neurotoxicity,” she said. “And now that we have patients with longer survival, we need to think about how we actively manage these side effects or stop them from happening so that patients can have a really good quality of life.”

Data from Part 2 of the trial, in which patients will receive either DARA monotherapy or observation, are currently unavailable but may shed additional light on the clinical benefits of DARA in the transplant-eligible population.

Top image: @ Science Photo Library: Steve Gschmeissner

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.