SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID® (Lenalidomide), and has been shown to be active in REVLIMID® and VELCADE® (Bortezomib) refractory patients. POMALYST® 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 REVLIMID® and a Proteasome Inhibitor, and have had disease progression on or within 60 days of completing their last therapy.
POMALYST® has demonstrated synergistic anti-myeloma activity with Dexamethasone and Proteasome Inhibitors. It has been shown to inhibit proliferation of REVLIMID® resistant cells in preclinical studies. With the increasing use of REVLIMID® as first line treatment for patients with Multiple Myeloma, there is a clinically relevant unmet medical need for patients who have progressed on REVLIMID®. The authors herein report the outcomes of a first phase III trial, comparing a combination of POMALYST®, VELCADE® and low dose Dexamethasone (PVd) with VELCADE® and Dexamethasone (Vd), in an entirely post-REVLIMID® treated population.
OPTIMISMM is an international, open label phase III study in which 559 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive POMALYST® in combination with VELCADE® and low dose Dexamethasone (PVd – N=281) or VELCADE® and Dexamethasone (Vd – N=278). Patients in both treatment groups received VELCADE® 1.3 mg/m² SC, on days 1, 4, 8, and 11 of cycles 1 thru 8, and on days 1 and 8 of cycle 9 and beyond, of each 21 day cycle. Dexamethasone was given to all patients at 20 mg orally daily (10 mg/day if more than 75 years of age) on the days of and after VELCADE® treatment. In the experimental arm, patients received POMALYST® 4 mg orally daily on days 1 thru 14, of each 21 day cycle. The median age was 67.5 years and both treatment groups were well balanced. All patients had prior treatment with REVLIMID® and 70% were refractory to this agent, whereas 72% of the patients had prior treatment with VELCADE® and 68% were refractory to the last treatment. The median number of prior treatment lines was 2 and approximately 40% of the patients in both treatment groups had one prior line of therapy. The percentage of patients with high-risk cytogenetics such as del(17p), t(4;14), and or t(14;16]), was similar in both treatment groups. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Safety.
At a median follow up of 16 months, the median PFS was 11.2 months with PVd compared with 7.1 months with Vd alone (HR=0.61; P<0.0001). This meant a 39% reduction in the risk of progression or death with POMALYST®, VELCADE® and low dose Dexamethasone combination, compared with VELCADE® and low dose Dexamethasone alone. This PFS benefit was noted regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy. The OS data are not mature. The most common side effects of the drug combinations were neutropenia, infections, and thrombocytopenia, which were manageable.
It was concluded that in the treatment of Multiple Myeloma, there remains an unmet medical need for those patients who have received REVLIMID® based therapies and are in early relapse. OPTIMISMM is the only phase III study to date in early Relapsed/Refractory Multiple Myeloma, that has demonstrated a significant and clinically meaningful PFS improvement in patients who have previously received REVLIMID® and especially those who are refractory to REVLIMID®, suggesting that the combination of POMALYST®, VELCADE® and low dose Dexamethasone may be a new standard of care in patients with Relapsed/Refractory Multiple Myeloma, with prior exposure to REVLIMID®. Pomalidomide (POM), bortezomib, and lowâ€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. Richardson PG, Rocafiguera AO, Beksac M, et al. J Clin Oncol 36, 2018 (suppl; abstr 8001)
