The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has granted positive opinions to 2 triplet regimens with immunomodulatory agents (IMiDs) for patients with multiple myeloma.
The first 3-drug treatment is lenalidomide (Revlimid) in combination with bortezomib (Velcade) and dexamethasone (RVd) for the treatment of adult patients with previously untreated multiple myeloma who are ineligible for stem cell transplant. The CHMP also recommended approval of pomalidomide (Pomalyst, US; Imnovid, EU) in combination with bortezomib and dexamethasone (PVd) for the treatment of adult patients with multiple myeloma who have received at least 1 prior treatment regimen that included lenalidomide.
The opinion for the lenalidomide triplet is based on findings from the phase III SWOG S0777 trial, in which the regimen demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) compared with lenalidomide/dexamethasone alone as a first-line treatment for patients with myeloma without an immediate intent to undergo autologous stem cell transplant (ASCT).
For the pomalidomide-based regimen, the EU panel based its recommendation on results of the phase III OPTIMISMM study, in which the pomalidomide-based regimen led to a significant improvement in PFS compared with bortezomib and dexamethasone alone.
“The CHMP positive opinions for our IMiD combinations, RVd and PVd represent very good news for patients with multiple myeloma in Europe,” Nadim Ahmed, president, Hematology/Oncology of Celgene, the manufacturer of both lenalidomide and pomalidomide, said in a press release. “We look forward to potential European Medicines Agency approvals, which would make these new triplet regimens available to patients, as we aim to improve patient outcomes across multiple stages of their disease.”
The European Commission is expected to make a decision on the approvals in approximately 2 months.
In the open-label, multicenter, phase III SWOG S0777 trial, investigators evaluated the efficacy and safety of RVd compared with Rd in 525 patients with previously untreated multiple myeloma without an intent for immediate ASCT. Patients were ≥18 years old, had symptomatic and measurable newly diagnosed disease, and were randomized 1:1 to receive the triplet therapy or Rd alone; randomization stratified based on International Staging System stage and intent to transplant.
RVd was administered in 8 21-day cycles; bortezomib was given at 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1 to 14, plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. In the Rd arm, patients received the regimen as 6 28-day cycles with 25 mg oral lenalidomide once daily for days 1 to 21 plus 40 mg oral dexamethasone once daily on days 1, 8, 15, and 22.
Results showed that the median PFS was 42 months with RVd versus 30 months with Rd alone (HR, 0.76; 95% CI, 0.62-0.94; P
= .01). Additionally, median OS also significantly favored RVd over Rd at 89 months versus 67 months, respectively (HR, 0.72; 95% CI, 0.56-0.94; P
= .013). The overall response rate was 82% with the triplet regimen compared with 72% with lenalidomide/dexamethasone; this included complete response rates of 16% and 8%, respectively. Regarding safety, RVd was consistent with the safety profiles of each drug alone.
Moreover, following completion of induction therapy, all patients were treated with ongoing maintenance with 25 mg oral lenalidomide once daily for 21 days, along with 40 mg oral dexamethasone once daily for days 1, 8, 15, and 22 of each 28-day cycle.
In the international, multicenter, open-label, phase III OPTIMISMM trial, 559 patients with relapsed/refractory myeloma who received 1 to 3 prior lines of therapy, including prior exposure to lenalidomide, were randomized to receive PVd or bortezomib/dexamethasone alone. Patients were stratified based on age, number of prior anti-myeloma regimens, and β2-microglobulin levels.
Patients on the PVd arm received pomalidomide at 4 mg daily on days 1 to 14; bortezomib at 1.3 mg/m2
on days 1, 4, 8, and 11 of cycles 1 to 8 and on days 1 and 8 of cycles 9 and thereafter; and dexamethasone at 20 mg daily on the days of and following bortezomib, all in 21-day cycles. Dexamethasone was given at 10 mg if patients were >75 years.
The baseline characteristics were well balanced between the 2 arms. The median number of prior lines of therapy was 2, though more than one-third of patients had one prior line of treatment. All patients had prior lenalidomide, with the majority being lenalidomide-refractory (71% in the PVd arm vs 69% in the Vd arm). Seventy percent and 66% of patients in the PVd and Vd arms, respectively, were refractory to their most recent treatment.