A three-drug combination showed both tolerability and favorable overall response rates (ORR) for patients with smoldering multiple myeloma in a phase 2 trial.
The triplet of Empliciti (elotuzumab), Revlimid (lenalidomide) and dexamethasone showed an overall response rate (ORR) of more than 80 percent, while also proving to be well-tolerated in a phase 2 trial of patients with high-risk smoldering multiple myeloma (SMM), said Irene Ghobrial, M.D., who presented the data at the 2016 American Society of Hematology (ASH) Annual Meeting.
Patients with SMM are a heterogeneous group who have a risk of progression to MM of about 10 percent per year, “yet we know that some of those patients who are high-risk smoldering myeloma patients are the ones who have a high chance of progression of 50 percent over two years,” said Ghobrial, attending physician, Medical Oncology, Dana-Farber Cancer Institute. In this latter group, the possibility to prevent progression through early therapeutic intervention is intriguing.
The appeal to early therapy is inhibition of clonal evolution, possibly enabling cure. “These patients also have a very good immune system, and therefore immunotherapy…could be very appealing because it could potentially cure those patient in the early stages,” she said.
A significant improvement in progression-free survival (PFS) was realized with the combination of Revlimid and dexamethasone in high-risk SMM compared with observation, and the response rate in the first induction phase (before maintenance) was 79 percent.
She and colleagues therefore sought to determine whether early therapeutic intervention with Empliciti, Revlimid and dexamethasone in patients with high-risk SMM could prevent or delay time to progression to overt MM, given the activity of Revlimid/dexamethasone in patients with high-risk MM and the proven safety and activity profile of the combination of Empliciti and Revlimid in patients with relapsed MM.
The primary objective was to determine the proportion of high-risk SMM patients who are progression-free at two years after receiving the triplet. “The two-year time point was picked because we know that high-risk SMM patients in general have a 50 percent chance of progression at two years,” she said. The trial was originally designed with two arms, with one using high-dose dexamethasone and the other using low-dose dexamethasone. The latter arm was closed after enrolling just 10 patients due to similar activity and toxicity to high-dose dexamethasone based on published data demonstrating that high-dose dexamethasone, given once weekly, does not have a detrimental effect on the immune system in patients with SMM.
The 51 patients enrolled in the phase 2 trial met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al. At the time of the presentation, 47 patients were evaluable. The median age of patients was 63 years, the median bone marrow plasma cells was 20 percent, and the median number of treatment cycles completed was eight, with a range of one to 23 cycles. Thirty-eight percent of these patients had high-risk cytogenetics.
Overall, the combination was well-tolerated, with only two patients experiencing grade 4 toxicity (one with thrombocytopenia and one with neutropenia, both of which were reversible). Only one patient had an infusion reaction. No patient discontinued therapy due to toxicity, and only four dose reductions were required, three of which were in the maintenance phase.
Among the 23 patients who completed at least nine cycles of therapy, the complete response rate was 8.7 percent, the rate of very good partial response was 26.1 percent, and the rate of partial response was 47.8 percent, for an ORR response rate of 82.6 percent. The clinical benefit rate was 100 percent. Most patients achieved a response by the second cycle.
Early data indicate PFS may be better than Revlimid/dexamethasone, but “we need long-term follow-up to determine PFS as well as whether those patients indeed would have delayed end-organ and delayed myeloma events,” said Ghobrial. “We’re looking now at immune profiling and mechanisms of response to see, indeed, who are those patients who have a deep response, and whether that correlates with certain immune profiling in those patients.”