A three-drug regimen that includes the novel agent daratumumab (Darzalex, Janssen Biotech) was declared a new standard of care in relapsed multiple myeloma after a presentation during the plenary session here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

This is “one of the most exciting presentations of the entire meeting,” said Richard Schilsky, MD, ASCO chief medical officer and former chief of the section of hematology–oncology at the University of Chicago.

Data from this trial were released early after the primary end point of progression-free survival was met at the interim analysis (median follow-up, 7.4 months).

The median progression-free survival was not reached in the three-drug daratumumab group, although it was in the two-drug group (not reached vs 7.16 months; hazard ratio [HR], 0.39; P < .001).

Dr Antonio Palumbo

This hazard ratio of 0.39 is “unprecedented in randomized studies that compare novel treatments in refractory multiple myeloma,” said lead study author Antonio Palumbo, MD, chief of the myeloma unit at the Department of Oncology, University of Torino, in Italy.

“This translated to a 61% reduction in the risk of progression or death,” he reported.

In addition, response rates doubled with the addition of daratumumab. For very good partial response, the rate in the three-drug group was 59% and in the two-drug group was 29%. For complete response, rates were 19% and 9%, respectively.

“Daratumumab plus bortezomib and dexamethasone should be considered a new standard of care for relapsed or refractory multiple myeloma patients currently receiving bortezomib/dexamethasone alone,” Dr Palumbo said.

“The three-drug regimen with daratumumab significantly improved progression-free survival and the overall response rate, and this benefit was maintained across clinically relevant subgroups,” he noted.

This will become the new standard of care, said Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, in Boston.

“It will become a new standard of care once approvals are through, and both CASTOR and the POLLUX study are game changers in my view,” he told Medscape Medical News.

However, another expert is a little more cautious.

“The results were very impressive when comparing daratumumab, bortezomib, dexamethasone with bortezomib and dexamethasone for relapsed/refractory multiple myeloma,” said Philip McCarthy, MD, professor of oncology and director of the Blood and Marrow Transplant Center, Roswell Park Cancer Institute, in Buffalo, New York.

“However, the daratumumab was continued, whereas the bortezomib dexamethasone arm did not continue any therapy,” he told Medscape Medical News. “We would expect the daratumumab to have continued activity versus no therapy.”

Although these findings are impressive, it would have been better to have some form of continued therapy for the control group. “We look forward to the upfront studies with this drug in combination with an immunomodulatory drug and a proteasome inhibitor,” Dr McCarthy added.

Toxicities were consistent with those previously reported with daratumumab monotherapy and with bortezomib plus dexamethasone.

Adverse events that affected more than 25% of the three- and two-drug groups were thrombocytopenia (59% vs 44%), peripheral sensory neuropathy (47% vs 38%), diarrhea (32% vs 22%), and anemia (26% vs 31%).

Grade 3/4 events that affected more than 10% the of the three- and two-drug groups were thrombocytopenia (45% vs 33%), anemia (14% vs 16%), and neutropenia (13% vs 4%). Discontinuation related to treatment was similar in the three- and two-drug groups (7% vs 9%).

First Antibody for Myeloma

Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through apoptosis, as well as through other multiple immune-mediated mechanisms.

It is the first monoclonal antibody to be approved for multiple myeloma by the US Food and Drug Administration). The current indication is for use as a monotherapy in heavily pretreated patients with multiple myeloma.

The CASTOR study shows that daratumumab can be combined with bortezomib and dexamethasone. A similar study, known as POLLUX, has shown that it can be combined with lenalidomide and dexamethasone.

The POLLUX study was unblinded last month and, at the preplanned interim analysis, the primary end point of improved progression-free survival was met. The POLLUX data will be presented during the Presidential Symposium at the annual meeting of the European Hematology Association, to be held in Copenhagen on June 12 (Abstract LB2238), and will be reported at that time by Medscape Medical News.

A number of other drugs have been approved recently for myeloma, including panobinostat (Farydak, Novartis Pharmaceuticals Corporation), ixazomib (Ninlaro, Takeda Pharmaceutical Company, Ltd.), and elotuzumab (Empliciti, Bristol-Myers Squibb Company).

Replacing Transplants?

Currently, high-dose chemotherapy and autologous stem cell transplantation (ASCT) is still the standard of care for younger, fit patients with multiple myeloma, but this is being called into question as the newer drugs push responses ever higher, Dr Schilsky told Medscape Medical News.

For the time being, however, ASCT remains the standard of care. Another study presented at the meeting showed that up-front transplantation significantly reduced the risk for progression, compared with a bortezomib-based drug regimen.

However, Dr Schilsky said he believes that it is unlikely that those results will settle the wider debate of whether ASCT is needed in the era of novel targeted agents.

“This won’t settle the issue, mostly because there is a whole slew of newer agents that have been introduced since bortezomib that are even more effective. How those drugs compare with a transplant-based regimen remains to be seen,” he said.

Another expert agreed that the field of myeloma treatment is in flux.

In the CASTOR study, it wasn’t “surprising that the three-drug regimen did better, but we will have to wait and see what the progression-free survival is,” said Noopur Raje, MD, associate professor of medicine at Harvard Medical School and director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center in Boston.

“The P value is quite significant,” Dr Raje said told Medscape Medical News. “We are going to see a difference in progression-free survival, compared with bortezomib. It’s not surprising, as we’ve seen this result with all of the new drug approvals from last year.”

For now, ASCT is here to stay for younger patients who want to go that route. “Younger patients should have that option,” she said. “But this is going to be evolving with new drugs.”