The European Commission has granted an approval to lenalidomide in combination with bortezomib and dexamethasone for the treatment of adult patients with previously untreated multiple myeloma who are ineligible for stem cell transplant, as well as pomalidomide in combination with bortezomib and dexamethasone for the treatment of adult patients with myeloma who have received ≥1 prior treatment regimen that included lenalidomide.
The European Commission (EC) has granted an approval to 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, as well as pomalidomide (Pomalyst, US; Imnovid, EU) in combination with bortezomib and dexamethasone (PVd) for the treatment of adult patients with myeloma who have received ≥1 prior treatment regimen that included lenalidomide.1
"The approval of these combination therapies marks a significant milestone for patients with multiple myeloma in Europe," said Nadim Ahmed, president of hematology/oncology for Celgene, the developer of both pomalidomide and lenalidomide. "With these new triplet regimens we hope to improve outcomes for both newly diagnosed patients as well as those who have relapsed or become refractory to first-line therapy. [Immunomodulatory] agents have brought significant benefit to multiple myeloma patients and we are committed to advancing our pipeline of novel myeloma treatments in order to ensure physicians and patients continue to have new treatment options available to fight this disease."
The approval for the lenalidomide triplet is based on results from the phase III SWOG S0777 trial, in which the regimen demonstrated a 12-month improvement in progression-free survival (PFS) and overall survival (OS) versus lenalidomide/dexamethasone alone as a frontline therapy for patients with myeloma without an immediate intent to undergo autologous stem cell transplant (ASCT).2
For the pomalidomide-based regimen, the approval was based on results of the phase III OPTIMISMM trial, in which the pomalidomide-based regimen led to a significant improvement in PFS compared with bortezomib and dexamethasone alone.3
In SWOG S0777, an open-label, multicenter, phase III 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). The median OS was also significantly improved with RVd versus Rd at 89 months and 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. The tolerability of 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.
"Determining first-line therapy is an important consideration in the overall treatment plan for patients with multiple myeloma," said Thierry Facon, MD, professor of haematology, Department of Haematology, Lille University Hospital, France. "Since Revlimid in combination with dexamethasone is already a standard of care in multiple myeloma, we're excited by the prospect of a new Revlimid-based triplet option for previously untreated patients who are not eligible for transplant."
In the international, multicenter, open-label, phase III OPTIMISMM study, 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.
At a median follow-up of 16 months, data showed that the median PFS with PVd was 11.2 months compared with 7.1 months in the Vd arm, which led to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.49-0.77; P <.001).
In an exploratory subgroup analysis of those who had 1 prior line of therapy, the median PFS with PVd was 20.7 months compared with 11.6 months with Vd (HR, 0.54; 95% CI, 7.52-15.74; P = .0027). In these patients, the benefit of PVd was independent of whether they were refractory or non-refractory to prior lenalidomide. Regarding safety, PVd was consistent with the well-established safety profiles of each drug alone.
The most frequently reported grade 3/4 adverse events (AEs) with PVd versus bortezomib/dexamethasone were neutropenia (42% vs 9%), infections (31% vs 18%), and thrombocytopenia (27% vs 29%). Grade 3/4 deep vein thrombosis (0.7%) and pulmonary embolism (4.0%) with PVd were low and no AEs were fatal. A total 3.2% of patients treated with PVd and 1.5% of those on the Vd arm had second primary malignancies.
Patients most commonly discontinued treatment due to progressive disease. Those who discontinued therapy due to AEs were 10.7% of patients on PVd and 17.6% for Vd.
"Today's approval for use of the Imnovid-containing triplet, PVd, as early as first relapse, underscores the potential clinical benefit this regimen can provide to patients following a prior treatment including Revlimid," said Meletios Dimopoulos, MD, professor and chairman, Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. "Revlimid-based regimens are often used as a standard of care in newly diagnosed multiple myeloma patients, and there is a growing patient population who become refractory to Revlimid and need proven treatment options."