SAN FRANCISCO – Combining anti-CD38 monoclonal antibodies with standard antimyeloma therapies proved highly active without excessive toxicity in newly diagnosed as well as relapsed or refractory multiple myeloma in a pair of phase Ib studies.
“These anti-CD38 antibodies are the next blockbuster class of agents,” Dr. Thomas Martin III, lead author of one of the studies, said during a press briefing at the annual meeting of the American Society of Hematology. “These are the next agents that are really going to show some benefit for myeloma patients. And the next 5 years are going to be really fun moving them from the refractory setting to the less refractory setting to the frontline setting.”
Patrice Wendling/Frontline Medical News
Dr. Thomas Martin
Three agents are in development that target CD38, a cell surface glycoprotein that is strongly expressed in multiple myeloma. All three – daratumumab, SAR650984, and MOR202 – bind to a different part of the anti-CD39 receptor, but “whether that makes any clinical difference, we certainly don’t know at this point in time,” said Dr. Martin of the University of California, San Francisco.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are the current blockbuster agents in myeloma and have advanced overall survival from about 3 years to 7-10 years. But all patients still relapse after IMiD and PI failure, and survival outcomes remain poor at a median of about 9 months for those with advanced relapsed/refractory disease. Further, myeloma has failed to respond like the B-cell lymphomas to anti-CD20 antibodies such as rituximab (Rituxan).
Dr. Martin and his associates launched a phase Ib dose-escalation trial to evaluate SAR650984 in combination with standard doses of lenalidomide (Revlimid) and dexamethasone in adults with relapsed or refractory multiple myeloma failing at least two prior therapies.
SAR650984 was given intravenously on days 1 and 15 of a 28-day cycle at 3 mg/kg to 4 patients (cohort 1), 5 mg/kg to 3 patients (cohort 2), and 10 mg/kg to 6 patients (cohort 3) plus an additional 18 patients in an expansion cohort.
All 31 patients were heavily pretreated, with 94% previously treated with lenalidomide or bortezomib (Velcade), 29% with pomalidomide (Pomalyst), and 48% with carfilzomib (Kyprolis). Many (84%) were considered double refractory, or relapsed and refractory, to their last IMiD therapy, Dr. Martin reported.
Despite this, nearly two-thirds (58%) had a response, including two stringent complete responses, seven very good partial responses, and nine partial responses. The overall response rate (ORR) was 25% in cohort 1, 67% in cohort 2, and 63% at the 10-mg dose level or double what was seen as a single agent, he said. The clinical benefit rates were 50%, 67%, and 67%.
In addition, the ORR was 50% in patients who were IMiD relapsed and refractory and 33% in patients pomalidomide relapsed and refractory, he reported.
At 9 months’ follow-up, median progression-free survival was 6.2 months and had not been reached in patients who received fewer than three lines of prior therapy.
The most common treatment-related adverse events were infusion reactions, fatigue, nausea, upper respiratory tract infection, and diarrhea. Infusion reactions occurred about a third of the time, typically in the first or second cycle, and were mostly mild (grade 1 or 2), Dr. Martin said. Only two patients discontinued treatment because of infusion reactions, one for a serious grade 3 anaphylactic reaction in cycle 1 and the other for a nonserious grade 3 maculopapular rash in cycle 2.
Daratumumab
The second highlighted study looked at the benefit and safety of adding daratumumab to commonly used backbone regimens in patients with newly diagnosed, relapsed, or treatment-resistant myeloma.
Single-agent daratumumab has shown activity in prior studies and received breakthrough therapy designation in May 2013 for patients with multiple myeloma after at least three prior lines of therapy including a proteasome inhibitor and an IMiD or those double refractory to a PI and IMiD.
In the four-arm, open-label study, daratumumab was given at a starting dose of 16 mg/kg in combination with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Treatment was for 18 three-week cycles or until transplantation in the VD and VTD arms, for 9 six-week cycles in the VMP arm, and was given in four-week cycles until disease progression in the POM-D arm.
Newly diagnosed patients were included in the VD and VTD arms irrespective of transplant eligibility, while patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were relapsed/refractory to two or more lines of therapy including two consecutive cycles of lenalidomide and bortezomib. In all, 24 patients were evaluable for efficacy.