Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation announced that the European Commission (EC) has approved REVLIMID® (lenalidomide) as monotherapy for the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation (ASCT). REVLIMID® is the first and only licensed maintenance treatment available to these patients.

The REVLIMID® Marketing Authorization has been updated to include this new indication, which expands on the existing multiple myeloma indications as combination therapy for the treatment of those not eligible for transplant who are newly diagnosed, or have received at least one prior therapy.

Multiple myeloma is an incurable and life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system. It is a rare but deadly disease: around 39,000 people are diagnosed with multiple myeloma in Europe, and around 24,000 people die from the disease each year. The median age at diagnosis in Europe is between 65 and 70 years. In Europe, patients who are fit and in good clinical condition are typically considered eligible for ASCT.

For patients who are newly diagnosed with multiple myeloma and eligible for ASCT, key treatment goals are to delay disease progression and ultimately achieve long-term control over multiple myeloma. These patients typically receive induction therapy and high-dose chemotherapy with melphalan followed by ASCT. This treatment approach has been an established standard of care for over 20 years. Considering that over half of those patients who relapse do so within 2 to 3 years of ASCT, the approval of a maintenance therapy for use after ASCT that may delay disease progression represents a major advance for these patients.

"After ASCT, most patients will still see their disease recur or progress. We now have an opportunity to enhance immune function and delay disease progression by controlling residual malignant cells and slowing tumor growth. REVLIMID® has been shown to increase progression-free survival after ASCT in clinical trials. Having a licensed therapy for use in this very important setting means we now have the opportunity to delay disease progression by sustaining the response," says Professor Michel Attal, Executive Director of the Institut Universitaire du Cancer Toulouse Oncopole and Institut Claudius Regaud, France.

The EC decision to approve REVLIMID® as monotherapy for multiple myeloma in the post-ASCT setting was based on the results of two cooperative group-led studies, CALGB 100104 and IFM 2005-02.

CALGB 100104 was a phase III, controlled, double-blind, multi-center study of 460 patients with newly diagnosed multiple myeloma undergoing ASCT who were randomized to receive continuous daily treatment with REVLIMID® or placebo until relapse or intolerance.

IFM 2005-02 was an international, phase III, controlled, double-blind, multi-center study of 614 patients newly diagnosed with multiple myeloma who were randomized to receive a 2-month consolidation regimen post-ASCT of REVLIMID®monotherapy, followed by continuous daily treatment with either REVLIMID® or placebo until relapse or intolerance.

In both studies, the primary efficacy endpoint in the study was progression-free survival (PFS) from transplant to the date of disease progression or death, whichever occurred first. REVLIMID® monotherapy as maintenance treatment post-ASCT significantly reduced the risk of disease progression or death in patients with multiple myeloma, leading to the studies being unblinded based on passing their pre-specified boundary for superiority at interim analysis. The updated PFS, using a cut-off of 1 February 2016 continues to show a PFS advantage:

CALGB 100104: after 81.6 months of follow up, median PFS was 56.9 months (95% CI 41.9, 71.7) in the REVLIMID® arm versus 29.4 months (95% CI 20.7, 35.5) in the placebo arm (HR=0.61; 95% CI 0.48, 0.76; p<0.001).

IFM 2005-02: after 96.7 months of follow up, median PFS was 44.4 months (95% CI 39.6, 52.0) in the REVLIMID® arm versus 23.8 months (95% CI 21.2, 27.3) in the placebo arm (HR=0.57; 95% CI 0.47, 0.68; p<0.001).

Individual studies were not powered for an overall survival (OS) endpoint. Using a cut-off of 1 February 2016, a descriptive analysis showed that the median overall survival in the CALGB 100104 was 111.0 months (95% CI, 101.8, not estimable) for patients who received REVLIMID versus 84.2 (95% CI 71.0, 102.7) in the placebo arm (HR=0.61; 95% CI 0.46, 0.81; p<0.001). In the IFM 2005-02 study, median overall survival was 105.9 months (95% CI, 88.8, not estimable) for patients who received REVLIMID versus 88.1 (95% CI 80.7, 108.4) in the placebo arm (HR=0.90; 95% CI 0.72, 1.13; p=0.355, not significant).

In both of these phase III studies, the safety profile was in line with other clinical data in newly diagnosed non-stem cell transplant and a post-approval safety study in relapsed/refractory multiple myeloma. The most commonly reported adverse events in these two studies were hematological, and included neutropenia and thrombocytopenia. The most commonly reported non-hematological adverse events were infections. An increased incidence rate of hematological second primary malignancies (SPMs) was also observed in the REVLIMID® group compared with the placebo group in both studies. However, the EC decision confirms that the benefit-risk ratio for REVLIMID® is positive in this expanded indication.

Tuomo Pätsi, President of Celgene European and International Operations, said, "We are glad to provide a treatment option for these patients with multiple myeloma, who have previously had no licensed medicine available to them for maintenance treatment following ASCT. This latest approval underlines the important role of REVLIMID® in the treatment of multiple myeloma, extending its use across the disease spectrum, and demonstrating our commitment to multiple myeloma patients. We continue to invest in research and development as we strive to turn multiple myeloma – and other currently incurable diseases – into manageable conditions."

The EC decision for the use of REVLIMID® as monotherapy for the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone ASCT follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) in January 2017.

Celgene announced on 22 February 2017 that the U.S. Food and Drug Administration (FDA) has expanded the existing indication for REVLIMID® to include use for patients with multiple myeloma as maintenance therapy following autologous hematopoietic stem cell transplant in the U.S.