New Class of Antibodies Highly Effective in Multiple Myeloma

Anti-CD38 monoclonal antibodies continue to demonstrate promise across a variety of settings, generating excitement that a new treatment paradigm could be on the horizon for patients with multiple myeloma.

Two studies spotlighted at the 2014 annual meeting of the American Society of Hematology, the leading organization devoted to research and treatment of blood disorders, characterized the efficacy of these agents in the frontline setting and for patients with refractory disease.

Daratumumab

In a phase 1b trial, the antibody daratumumab combined with standard frontline therapies induced a dramatic improvement in outcomes without additional toxicity for patients with multiple myeloma. Additionally, in a separate phase 1b study, nearly two-thirds of patients with heavily pretreated relapsed/refractory multiple myeloma responded to treatment with the monoclonal antibody SAR650984 in combination with Revlimid (lenalidomide) and the steroid dexamethasone.

“These therapies are going to be tested in the frontline, in the early relapsed patients, and in the multiple relapsed patients. These are some of the most exciting agents in multiple myeloma,” said the lead researcher of the SAR650984 trial, Thomas Martin, of the University of California, San Francisco. “These CD38 therapies are blockbuster drugs.”

In May 2013, single-agent daratumumab received a breakthrough therapy designation from the Food and Drug Administration as a treatment for patients with multiple myeloma following two lines of therapy. In combination with Revlimid and dexamethasone, daratumumab demonstrated an overall response rate (ORR) of 75 percent across the entire study, which included a dose-escalation portion. In an expansion cohort of patients who received daratumumab at the maximum-tolerated dose of 16, the ORR was 92 percent.

In the frontline setting, the four-arm phase 1b study combined daratumumab with Velcade (bortezomib) and dexamethasone (VD); Velcade, thalidomide and dexamethasone (VTD); Velcade, melphalan and prednisone (VMP); or Pomalyst (pomalidomide) and dexamethasone (POM-D).

Patients in the VD and VTD arms were untreated and transplant eligible, patients in the VMP arm were untreated but not candidates for transplant, and those in the POM-D arm were relapsed/refractory to at least two lines of therapy.

At the time of the analysis, 24 patients received treatment with daratumumab plus the backbone therapy at a standard dose. In the VD and VTD arms, patients were treated for 18 three-week cycles or until transplantation. In the VMP arm, treatment continued for nine six-week cycles. In the POM-D arm, patients received treatment in four-week cycles until progression.

The ORR was 100 percent with VD, VTD and VMP, and 50 percent with POM-D. Responses comprised very good partial responses and partial responses; no patients in the frontline arms achieved a complete response (CR). In the POM-D arm, one patient had a CR. Most patients responded within 30 days of receiving treatment.

“We consider that the addition of 16 mg/kg [of] daratumumab to the various backbones was well tolerated in all evaluable patients and did not result in significant additional toxicity,” study author María-Victoria Mateos, from Hospital Universitario Salamanca, Spain, said during a press briefing. “Daratumumab was associated with high rates of response in combination with the different backbones.”

Infusion-related reactions were the only added toxicity seen with daratumumab when combined with a Velcade-containing regimen. All infusion reactions were mild and resolved with supportive care. Most other side effects reported in the study could be attributed to the backbone therapy, the authors of the study wrote.

“This is a very new and exciting concept in multiple myeloma, as we are seeing that combining this precision approach with the standard of care is leading to more effective treatment without increased toxicity,” lead study author Philippe Moreau, University Hospital of Nantes in France, said in a statement. “By targeting a simple molecule expressed by the cancer cells, this therapy has the potential to become a potent addition to conventional treatment.”

SAR650984

In addition to daratumumab, findings for SAR650984 also support the dramatic efficacy of targeting CD38 in patients with multiple myeloma. In the phase 1b study, three separate dosages of SAR650984 were administered every two weeks in combination with Revlimid and dexamethasone.

Patients in the study had received a median of six prior therapies over the course of a median of 4.5 years following diagnosis. These treatments included prior immunomodulatory therapy with Revlimid Pomalyst, Velcade and Kyprolis (carfilzomib). Eighty-four percent of patients were relapsed and refractory to a least one prior immunomodulatory agent. After a median follow-up of nine months, the ORR across the entire population was 58 percent, with a clinical benefit rate of 65 percent, including a 6 percent complete response rate.

After a nine-month follow-up, the median progression-free survival (PFS) was 6.2 months. The median PFS was not yet reached in patients who received fewer than three prior regimens before entering the study. In patients who were relapsed and refractory to immunomodulatory therapy, the ORR was 50 percent. In patients refractory to Kyprolis, the ORR was 40 percent, and in those relapsed and refractory to Pomalyst, the ORR was 33 percent.

“This combination was well tolerated, there were no unexpected toxicities, and in my mind had a fairly dramatic response, with two-thirds of patients having a response even though they were refractory to other agents,” said Martin. “I do think these anti-CD38 antibodies are the next blockbuster class of agents. These are the next agents that are really going to start showing some benefits for our myeloma patients.”

The most common treatment-related adverse events were fatigue, nausea, upper respiratory tract infection and diarrhea. Two patients experienced grade 3 infusion-associated reactions, resulting in treatment discontinuation.

“These antibodies tend to be very well tolerated drugs, there tends to be some incidence of infusion reaction, which occurs about a third of the time,” Martin explained. “These are mostly mild, grade 1 and 2. We only had to stop the infusion in 3% of overall infusions. After the second cycle, there are no infusion reactions.”

Press briefing moderator, Brad S. Kahl, MD, from the University of Wisconsin School of Medicine, provided further insight into the CD38 antibodies, calling their development very exciting.

“Obviously it’s very early, probably too early to plant the victory flag in the ground. Having said that, the early data is very promising and totally justifies moving these therapies forward to the frontline,” explained Kahl.