ATLANTA (IMNG) - Patients with refractory multiple myeloma, including those with heavily pretreated disease, lived significantly longer with the immunomodulatory drug pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone alone in a phase III, head-to-head study.
Patients given pomalidomide (Pomalyst) and low-dose dexamethasone (Decadron) lived a median of 3.2 months without progression, compared with 1.7 months for patients on high-dose dexamethasone (hazard ratio, 0.45; P less than .001).
Moreover, the combination was equally beneficial in patients refractory to both lenalidomide (Revlimid) and bortezomib (Velcade) (3.2 vs. 1.7 months; HR, 0.48; P less than .001), who comprised three-fourths of the study cohort. Such patients are currently without standard treatment options and frequently receive only palliative care, Dr. Meletios Dimopoulos reported in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
An interim survival analysis also showed a statistically significant improvement in overall survival with the combination compared with high-dose dexamethasone (median not reached vs. 7.8 months; HR, 0.53; P less than .001), prompting the data-monitoring committee to recommend that patients in the control arm be allowed to cross over to pomalidomide plus low-dose dexamethasone.
"We believe that pomalidomide and low-dose dexamethasone should be considered as a new treatment option for these patients," said Dr. Dimopoulos of Alexandra Hospital, Athens.
Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York and comoderator of the session, described the MM-003 trial as a large, well-done "definitive" study.
"It's a very active new agent, pomalidomide, a new IMiD, and I think it will emerge as a new standard of care for relapsed and refractory patients - a population for whom, as Dr. Dimopoulous indicated, we don't have very good therapies" he said in an interview.
Pomalidomide, a derivative of thalidomide that acts as an immunomodulator, is expected to be approved in early 2013 in the United States, with a decision by European regulatory authorities in the second half of 2013, according to Celgene.
Dr. Dimopoulos said MM-003 did not address whether pomalidomide is more potent as a rescue therapy than carfilzomib (Kyprolis), a second-generation proteasome inhibitor granted accelerated approval in July 2012, for patients with multiple myeloma progressing after at least 2 prior therapies, including bortezomib and an IMiD. The approval was based on response rate only, with clinical benefit such as improved survival not yet verified.
"It is not possible to compare two different drugs from two different trials; however, as the myeloma community, we are encouraged that we now have carfilzomib and pomalidomide with low-dose dexamethasone that could be used to salvage, to rescue and help some patients with an unmet need in multiple myeloma," he said in an interview.
The MM-003 trial randomly assigned 455 patients with relapsed or refractory multiple myeloma to 4 mg oral pomalidomide on days 1-21 of a 28-day cycle plus oral dexamethasone 40 mg weekly, or to 40 mg high-dose dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle until disease progression. Patients older than 75 years in each arm received 20 mg dexamethasone on the same schedules.
All 302 patients in the experimental arm and 153 patients in the control arm had received prior lenalidomide and bortezomib, with 75% refractory to both. The median number of prior therapies was five in each arm, including dexamethasone, thalidomide, and stem cell transplant. One-third of all patients had renal impairment, defined by a creatinine clearance of less than 60 mL/min. The median age of patients in each arm was 64 and 65, respectively.
The overall response rate, defined as at least a partial response, was significantly higher in the experimental arm than the control arm at 21% vs. 3%, reaching 24% vs. 3% among patients randomized for at least 6 months (P less than .001), Dr. Dimopoulos reported.
Progression-free survival, the study's primary endpoint, was significantly longer in patients on pomalidomide plus low-dose dexamethasone regardless of whether patients' last prior treatment was bortezomib (median 3.6 vs. 1.8 months; HR, 0.47) or lenalidomide (median 3.7 vs. 1.8 months; HR, 0.38), or whether they had renal impairment (median 3.2 vs. 1.6 months; HR, 0.44; P less than .001 for all comparisons).
The combination therapy was generally well tolerated, although roughly one-third of patients experienced grade 3/4 neutropenia, an expected complication of pomalidomide (42% vs. 15% of controls), Dr. Dimopoulos observed.
Rates of any grade venous thromboembolism were low at 3% vs. 2% in controls, as were exacerbations of peripheral neuropathy at 12% vs. 11%. In all, 7% of patients discontinued pomalidomide plus low-dose dexamethasone, compared with 6% on high-dose dexamethasone, he said.
Session comoderator Dr. Agnes Lee of the University of British Columbia and Vancouver Coastal Health said her colleagues who enrolled patients in the trial are thrilled with having a possible new option for relapsed/refractory myeloma and very surprised with the minimal amount of toxicity they've seen. "Right now we're just waiting for the next step - will this drug be available, especially here in Canada ... and whether it will now be investigated in earlier disease, especially when it's so well tolerated."
Dr. Dimopoulos reported honoraria from the study sponsor, Celgene. Several of his coauthors reported commercial relationships with Celgene including employment and equity ownership. Dr. Tallman and Dr. Lee reported no relevant financial conflicts.
Dimopoulos, M.A. et al. Pomalidomide in combination with low-dose dexamethasone: Demonstrates a significant progression-free survival and overall survival advantage in relapsed/refractory MM: A phase 3, multicenter, randomized, open-label study. LBA-6.