There is an unmet need for relapsed/refractory multiple myeloma (MM) patients who have failed treatment with newer agents (e.g., lenalidomide and bortezomib), as overall survival (OS) is decreased in this population. In the pivotal phase II MM-002 and phase III MM-003 clinical trials, the combination of pomalidomide and low-dose dexamethasone was shown to improve response and survival rates compared with pomalidomide alone and with high-dose dexamethasone, respectively, among patients with relapsed/refractory MM.
To further assess the safety and efficacy of pomalidomide plus low-dose dexamethasone, Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece, and investigators conducted the open-label, single-arm, phase IIIb STRATUS MM-010 trial. According to results published in Blood, Dr. Dimopoulos and co-authors confirmed the benefit of pomalidomide plus low-dose dexamethasone, with an overall response rate (ORR; the study's primary endpoint) of 32.6 percent (95% CI 29-36.2) and a median duration of response (DOR; one of the study's secondary endpoints) of 7.4 months (95% CI 4.2-5.6).
MM-010 STRATUS included 682 patients with relapsed/refractory MM enrolled at 91 centers in 19 European countries between November 2012 and December 2014.
Adult patients were considered for inclusion if they:
- had received â‰¥2 previous lines of treatment, including â‰¥2 cycles of lenalidomide and bortezomib (alone or in combination) and adequate prior alkylator therapy (â‰¥4 cycles or progressive disease [PD] after â‰¥2 cycles or received alkylator treatment as a part of a stem cell transplant)
- had failed treatment with both bortezomib and lenalidomide (defined as PD on or within 60 days of treatment, PD â‰¤6 months after achieving a partial response, or intolerance to bortezomib)
Patients were excluded if they had received a hematopoietic cell transplant or if they were planning for or eligible for transplant.
The median patient age was 66 years, and median time since initial diagnosis was 5.3 years. Patients had been treated with a median of five prior anti-myeloma treatment regimens (range = 2-18 treatments).
Patients received pomalidomide 4 mg on days one through 21 of a 28-day cycle and low-dose dexamethasone 40 mg (if â‰¤75 years) or 20 mg (if >75 years) on days one, eight, 15, and 22 of a 28-day cycle. Patients who discontinued treatment were followed every three months for up to five years after enrollment to monitor subsequent treatments, dates of progression, survival, and second primary malignancies (SPMs).
The study's primary safety endpoint was the incidence of adverse events (AEs; type, frequency, severity, and relationship to drug), including SPMs. Secondary endpoints included pomalidomide exposure, ORR, DOR, progression-free survival (PFS), overall OS, time to response, and time to progression.
After a median follow-up of 16.8 months, 15.2 percent of patients (n=104) remained on treatment and 83.9 percent had discontinued treatment (n=572). Discontinuations were due to PD (62.2%), death (7.9%), and AEs (5.9%).
The median treatment duration was 4.9 months, with a median relative dose intensity (measured by comparing actual dose intensity with planned dose intensity) of 0.901, which the researchers noted "[indicates] that treatment was generally well tolerated with a low dose reduction/interruption rate and high treatment compliance."
Of the 676 patients evaluable for safety endpoints, the most frequently reported grade 3/4 hematologic AEs included neutropenia (49.7%), anemia (33%), and thrombocytopenia (24.1%). Pneumonia of any grade occurred in 111 patients (16.4%), and all but 0.1 percent of those cases were infectious. Serious AEs were observed in 62.9 percent of patients (n=425), with SPMs reported in 15 patients (5 with solid tumors and 10 with non-invasive skin cancers).
Hematologic and non-hematologic AEs tended to occur mostly in early treatment cycles with a diminished frequency afterward, they added. At the time of analysis, 57.7 percent of patients in the safety population had died, the majority (68.5%) after treatment discontinuation.
"The safety profile was consistent with the profile observed in the pivotal studies of pomalidomide plus low-dose dexamethasone, and no new safety signals were identified in this large patient population," Dr. Dimopoulos and authors noted. "Similar to the MM-002 and MM-003 studies, the most frequent grade 3/4 AEs were hematologic with a low incidence of febrile neutropenia and discontinuations due to AEs were infrequent [6%]."
The efficacy results with pomalidomide plus low-dose dexamethasone observed in STRATUS MM-010 were also consistent with those seen in the MM-002 and MM-003 trials. The ORR in MM-010 was 32.6 percent (7.6% of patients achieving very good partial response or better), and 32.7 percent and 31.4 percent in MM-002 and MM-003, respectively.
The median PFS was 4.6 months (95% CI 3.9-4.9), and the median OS was 11.9 months (95% CI 10.6-13.4). In addition, ORR, PFS, and OS were similar to previous trials regardless of prior treatments, number of prior therapies, and presence or absence of moderate renal impairment.
"The greater-than seven-month difference between PFS and OS may be reflective of early identification of biochemical relapse (which precedes clinical manifestations of relapse) and subsequent salvage regimens," the authors explained. "Thus, despite being a heavily pretreated population, patients who progress following treatment in this study may be medically fit enough to tolerate subsequent treatments that might not otherwise have been an option."
The open-label design and the high rate of treatment discontinuation were limitations to the study, but Dr. Dimopoulos and authors concluded that, "taken together, these data support pomalidomide plus low-dose dexamethasone as a standard of care for patients with relapsed/refractory MM who have poor prognosis and high need for effective treatments."
Dimopoulos MA, Palumbo A, Corradini P, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUSâ„¢ (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 May 25. [Epub ahead of print]