Keith Stewart, MB ChB
The advent of new agents and new classes of agents for treating relapsed or refractory multiple myeloma (RRMM), a notably complex disease state, has stimulated efforts to identify the optimal way to sequence or combine these therapies. An OncLive®
panel of hematology experts convened to discuss how to manage RRMM, the role of transplant, and the evidence for immunotherapy.
The panelists expressed enthusiasm for the potential of new combinations and sequences to cure a greater percentage of patients, but also recognized the need to temper that optimism pending better data on how to integrate the various therapeutic approaches. Keith Stewart, MB, ChB, who moderated the discussion, noted that the many options available have made it even more important to tailor treatment to the individual patient, especially in the relapse setting.
Relapsed or Refractory Disease After a Lenalidomide-Based Regimen
Several factors must be considered when selecting treatment for RRMM, including timing and aggressiveness of relapse, disease stage at relapse, disease-related comorbidities, eligibility for autologous stem cell transplant (ASCT), prior treatment exposure, and patient age.1,2
At the time of relapsed or refractory disease, many patients with multiple myeloma (MM) have already received lenalidomide (Revlimid), an immunomodulatory drug (IMiD), as part of a first-line regimen that included dexamethasone or as maintenance therapy after ASCT. For transplant-ineligible patients, one option is to repeat primary therapy with lenalidomide, with a possible dose increase.2 Another option is to switch to a regimen that combines an IMiD with a proteasome inhibitor or a monoclonal antibody.3
Thomas G. Martin III, MD, a member of the National Comprehensive Cancer Network MM guidelines panel, said, “If somebody is relapsing on lenalidomide, I don’t think going up to a higher dose of lenalidomide is going to get you a lot of distance.” He said he typically switches to a carfilzomib (Kyprolis)-based therapy or a combination of pomalidomide (Pomalyst) plus a monoclonal antibody. Carfilzomib is a proteasome inhibitor, whereas pomalidomide is an analog of lenalidomide. Saad Z. Usmani, MD, said he also frequently uses pomalidomide, which he believes patients tolerate slightly better than lenalidomide.
“Until you know whether the kidney function has stabilized, I’m a little hesitant to use [lenalidomide] because chronic myelosuppression is really an issue,” said Sagar Lonial, MD. “If the creatinine level is stable, then I’m comfortable using it at the recommended dose.” Stewart noted that carfilzomib can also affect creatinine levels, so it is important to monitor patients.
“You have to personalize the treatment to what the patient can tolerate,” Ivan M. Borrello, MD, said. Combining carfilzomib or bortezomib (Velcade) with dexamethasone is an option for patients unable to tolerate an IMiD. Bortezomib is an older proteasome inhibitor associated with a high risk of peripheral neuropathy. The phase III ENDEAVOR trial compared bortezomib plus dexamethasone with carfilzomib plus dexamethasone in patients with RRMM (n = 929).4
Borrello said outcomes were significantly better in the carfilzomib arm. Median progression-free survival (PFS) observed in ENDEAVOR was almost twice as long in the carfilzomib arm than in the bortezomib arm (18.7 vs 9.4 months, respectively; P <.0001).4
For patients who cannot tolerate an IMiD or bortezomib, Lonial recommended combining carfilzomib with panobinostat (Farydak), a histone deacetylase inhibitor. Although panobinostat is sometimes used with bortezomib, Lonial disagrees with that approach. “I don’t think bortezomib is the right partner…there’s just too much overlapping gastrointestinal toxicity,” he said. According to Lonial, trials show that if you administer panobinostat every other week, “you don’t get as much as of the gastrointestinal toxicity that you get with bortezomib, [and] it has pretty reasonable efficacy, as well.”5