While it has become a standard to include lenalidomide in the frontline treatment of patients with multiple myeloma (MM), most patients have disease that will become refractory to lenalidomide-based regimens.
According to results from a phase I/II trial published in Blood, secondline treatment that includes pomalidomide could lead to high response rates. "[Pomalidomide, bortezomib, and dexamethasone (PVD)] is an appealing secondline option in many patients given the well accepted use of lenalidomide-containing regimens in the frontline setting and lenalidomide-maintenance therapy after [hematopoietic cell transplantation (HCT)]," wrote the authors, led by Jonas Paludo, MD, from the Mayo Clinic College of Medicine in Rochester, Minnesota. The combination also incorporated a reduced dosing frequency of bortezomib, for "a simpler, more convenient, and potentially better tolerated schedule."
The prospective, non-randomized, open-label trial included patients with MM that was refractory to lenalidomide. Patients were excluded if they had an uncontrolled infection, another active malignancy, deep vein thrombosis, an Eastern Cooperative Oncology Group performance status score of â‰¥3, or grade >2 peripheral neuropathy.
The researchers enrolled 50 patients (median age = 65.5 years; range = 45-83 years) between March 2012 and July 2014. Patients had received a median of two prior regimens (range = 1-5 regimens). Most (72%) had undergone HCT and 58 percent had received bortezomib previously.
The median time from diagnosis to enrollment was 50 months (range = 1.5-142 months). Patients had standard (n=29; 58%), intermediate (n=9; 18%), and high-risk (n=12; 24%) disease, according to the Mayo Clinic's mSMART guidelines, a tool for stratifying newly
diagnosed and relapsed patients.
In the phase I trial, nine patients received pomalidomide and dexamethasone with either bortezomib 1.0 mg/m2 (n=3) or 1.3 mg/m2 (n=6) intravenously on days one, eight, 15, and 22 of each 28-day cycle to determine the maximum tolerated dose (MTD; primary endpoint of phase I). No dose-limiting toxicities (DLTs) were reported at the 1.0 mg/m2 dose, and one DLT (hospitalization for pancytopenia and infection) was reported at the 1.3 mg/m2 dose, so the researchers selected 1.3 mg/m2 as the MTD for the phase II trial.
After a median follow-up of 42 months (range = 13-59 months), the objective response rate (ORR; primary endpoint of phase II) was 86 percent (95% CI 73-94), including:
- stringent complete response (CR): 12% (n=6)
- CR: 10% (n=5)
- very good partial response (PR): 28% (n=14)
- PR: 36% (n=18)
One patient experienced a molecular response (2%) and six had stable disease (12%). At the time of analysis (date not reported), 40 patients had progressive disease (80%) and 17 had died (34%).
The median progression-free survival (PFS) was 13.7 months (95% CI 9.7-17.7), and the median overall survival (OS) had not been reached. PVD appeared to be effective even in high-risk disease with PFS of:
- 12.3 months in high-risk disease (95% CI 5.2-24.6)
- 9 months in intermediate-risk disease (95% CI 3.2-22.9)
- 15.4 months in standard-risk disease (95% CI 9.5-19.1; p=0.5 for all comparisons)
"The noteworthy difference in OS and PFS suggests that patients can easily be rescued with subsequent treatment regimens after progressing on PVD," the authors added.
The most common grade â‰¥3 hematologic AEs were neutropenia (70%), leukopenia (36%), and lymphopenia (20%), and the most common non-hematologic AE was fatigue (72%).
Forty-two percent of patients required dose adjustments of pomalidomide (n=21) after a median of five cycles (range = 2-32 cycles), most of which were related to neutropenia. In addition, dose adjustments of bortezomib and dexamethasone were required in 16 percent and 28 percent of patients, respectively.
"Even though the use of thromboprophylaxis was mandatory in our study, the rate of venous thromboembolism events was higher than in previously reported clinical trials of pomalidomide and low-dose dexamethasone (10% vs. 4%)," the authors wrote.
The authors attributed the regimen's tolerability to the once-weekly administration of bortezomib, which was associated with similar efficacy rates and lower incidence of grade â‰¥3 non-hematologic AEs compared with previous reports of twice-weekly dosing.
The study is limited by its small patient population, non-randomized design, and lack of a comparator arm.
Contributing authors report financial relationships with Celgene, Takeda Oncology, and Millennium Pharmaceuticals.
Paludo J, Mikhael JR, LaPlant BR, et al. Pomalidomide, bortezomib and dexamethasone (PVD) for patients with relapsed, lenalidomide refractory multiple myeloma. Blood. 2017 July 6. [Epub ahead of print]