Over the past few years, approaches to treating multiple myeloma (MM) have changed significantly. In particular, pomalidomide, a third-generation immunomodulatory drug, has emerged as a potent potential component of combination therapies. Pomalidomide is currently approved for use in combination with low-dose dexamethasone in patients with MM who experienced relapse after receiving at least 2 prior lines of therapy including both lenalidomide and bortezomib.1 However, studies suggest that pomalidomide may represent a significant improvement over the current standard of care in select patients after relapse due to its mechanism of action.
Celgene Corporation announced in March 2019 that the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) had adopted positive opinions for 2 triplet regimens based on Celgene’s proprietary medications, Revlimid (lenalidomide)[SG1] and Imnovid (pomalidomide).2 The committee’s recommendations included approving an expanded indication of lenalidomide in combination with bortezomib and dexamethasone to treat patients with previously untreated MM who are not eligible for transplant as well as approving use of pomalidomide in combination with bortezomib and dexamethasone to treat patients with MM who have received at least 1 prior treatment regimen including lenalidomide.
Positive results for treatment with pomalidomide were also seen in OPTIMISMM (ClinicalTrials.gov Identifier: NCT01734928), the first prospective phase 3 trial to evaluate a pomalidomide-based triplet regimen in patients previously treated with lenalidomide.3 The multicenter, international, open label, randomized trial included 559 patients, 70% of whom became refractory. Patients receiving pomalidomide with bortezomib and dexamethasone achieved significantly longer progression-free survival (PFS) compared with those receiving bortezomib and dexamethasone alone (11.20 vs 7.10 months; P <.0001), reducing the risk of disease progression or death by 39% in the pomalidomide arm. In an exploratory subgroup analysis of patients with 1 prior line of therapy, median PFS was 20.73 months with pomalidomide and 11.63 months in the bortezomib and dexamethasone treatment arm.
“Triplet [therapies] have really emerged as the standard of care for most patients, with the next question being the role of quadruplet [therapies],” said Joshua Richter, MD, assistant professor of medicine at The Tisch Cancer Institute at Mount Sinai Medical System in New York, New York, in an interview with Hematology Advisor. He said there are many therapeutic combinations with or without pomalidomide that may improve outcomes in patients with MM. However, figuring out optimal combinations and sequencing may present an obstacle.
In an editorial published in The Lancet Oncology, Francesca Gay, MD, and Roberto Mina, MD, of the University of Torino in Italy, wrote that combination therapy consisting of pomalidomide, bortezomib, and dexamethasone represents one of the future standards of care in lenalidomide-refractory patients.1 In addition, they predicted that this regimen, as well as other drug combinations with or without pomalidomide, will emerge as alternatives for treating first relapse. However, they suggested there is a need to better define the criteria for failure on lenalidomide. “Without reliable biomarkers predictive of a specific-drug disease sensitivity, a deeper knowledge of the meaning of refractoriness is necessary, which will allow clinicians to tailor treatment not only according to prognostic baseline parameters but also based on dynamic predictive markers of disease sensitivity to a specific drug or class, ultimately improving treatment efficacy,” wrote the authors.
Immunomodulatory drugs and proteasome inhibitors have become the backbone of the treatment for myeloma, but pomalidomide as part of combination therapy appears safe and effective in relapsed and refractory patients, as well as in patients with high-risk cytogenetic features. “The different mechanisms of metabolism allow pomalidomide to be used more easily in patients with renal failure compared with lenalidomide. There are also some early data to suggest that pomalidomide may show improved efficacy in patients with poor-risk cytogenetics, although these results need to be confirmed in larger studies,” said Dr Borrello.