Pomalidomide in combination with bortezomib and low-dose dexamethasone demonstrated an improved median progression-free survival compared with bortezomib and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have previously received lenalidomide, according to results from the OPTIMISMM trial.
Paul Richardson, MD
According to findings from the phase III OPTIMISMM trial, pomalidomide (Pomalyst) in combination with bortezomib (Velcade) and low-dose dexamethasone (PVd) demonstrated a median progression-free survival (PFS) of 11.20 months after a median follow-up of 16 months compared with 7.10 months with bortezomib and low-dose dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma who have previously received lenalidomide (Revlimid).
The addition of pomalidomide led to a reduction in the risk of disease progression or death by 39% (HR, 0.61; 95% CI, 0.49-0.77;P<.0001). In subgroup analyses, the PFS benefit with pomalidomide was observed regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy.
“This study investigated a clinically relevant and growing patient population who received upfront lenalidomide but for whom lenalidomide is no longer a treatment option,” said lead investigator Paul Richardson, MD, during a presentation at the 2018 ASCO Annual Meeting.
“The results support the use of PVd in first relapse patients with relapsed/refractory multiple myeloma and prior exposure to lenalidomide,” added Richardson, who is clinical program leader and director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School.
The international, open-label phase III OPTIMISMM study randomized 559 patients with relapsed/refractory multiple myeloma in a 1:1 ratio to PVd (n = 281) or Vd (n = 278). The median patient age was 67 years in the PVd arm and 68 years in the Vd arm. The percent of patients with high-risk cytogenetics (deletion 17p, t[4;14], and or t[14;16]) was similar between the treatment arms, at 22% in the PVd arm and 18% in the Vd arm. The median time since diagnosis was 4.0 versus 4.3 years, respectively.
Patients were required to have received a minimum of 1 but not more than 3 prior treatments for myeloma, including a lenalidomide containing regimen for at least 2 consecutive cycles. The median number of prior treatment lines was 2. In the PVd arm, 40% of patients had 1 prior line of therapy compared with 41% in the Vd group.
In the PVd group, 71% of patients were lenalidomide refractory versus 69% in the Vd group. Seventy-two percent of patients in the pomalidomide group had prior bortezomib versus 73% in the control arm. Nine percent of patients in the experimental arm were bortezomib refractory versus 12% of patients in the control arm. Seventy percent and 66% of patients in the PVd and Vd arms, respectively, were refractory to their last treatment.
In 21-day cycles, all patients received bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1 through 8, and on days 1 and 8 of cycle 9 and beyond. Dexamethasone was given to all patients at 20 mg/day (10 mg/day if aged >75 years) on the days of and following bortezomib treatment. In the experimental arm, patients received 4 mg/day of pomalidomide on days 1 to 14 of each cycle. The primary endpoint was PFS, with secondary endpoints including overall survival (OS), overall response rate (ORR), duration of response, and safety.
The median duration of treatment was 8.8 months with PVd versus 4.9 months with Vd. The ORR was 82.2% versus 50.0%, respectively. In the overall population, 52.7% of patients achieved at least a very good partial response (VGPR) with PVd versus 18.3% with Vd. The OS data are not yet mature.
Among patients who received 1 prior treatment line (111 in PVd arm vs 115 in the Vd arm), the addition of pomalidomide reduced the risk of disease progression or death by 46% versus Vd alone. The median PFS was 20.73 months versus 11.63 months with PVd versus Vd, respectively (HR, 0.54; 95% CI, 0.36-0.82;P= .0027). The ORRs were 90.1% versus 54.8%, respectively, and the VGPRs were 61.3% versus 22.6%, respectively.
Notably, PFS was improved, regardless of lenalidomide refractory status, with an HR of 0.65 favoring PVd among refractory patients and an HR of 0.48 among those who were not refractory. The time to next treatment was 22.24 months with PVd versus 8.51 months with Vd (HR, 0.42; 95% CI, 0.33-0.54;P<.001).
The most common reason for treatment discontinuation was progression disease, which led to treatment being stopped for 39.1% of the pomalidomide arm versus 47.1% of the control arm.
The most frequent grade 3/4 treatment-emergent adverse events were neutropenia (42% with PVd vs 9% with Vd), infections (31% vs 18%, respectively), and thrombocytopenia (27% vs 29%, respectively). Of note, the rates of febrile neutropenia were low, at 3.2% with PVd versus 0% with Vd, as were the rates of secondary malignancies, at 3.2% versus 1.5%, respectively.
Pomalidomide is approved by the FDA for use in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and have had disease progression on or within 60 days of completing their last therapy.
Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial.J Clin Oncol. 2018;36 (suppl; abstr 8001).