Selecting Treatment for Relapsed/Refractory Multiple Myeloma in the Era of Multiple Choices

Keeping up with the many treatment advances in relapsed or refractory multiple myeloma can be a challenge for even the most informed providers, according to Jorge J. Castillo, MD, Clinical Director, Bing Center for Waldenström’s Macroglobulinemia, Dana-­Farber Cancer Institute, Boston, MA.

“In myeloma, a higher variety of medications have been approved in recent years than in any other oncology malignancy,” Dr Castillo said at the NCCN 2019 Hematologic Malignancies meeting. “And that, in itself, is a good thing. But then it also gives us a number of headaches.”

The main headache, he says, is simply deciding which treatment options to use for which patient. The NCCN guidelines for multiple myeloma list 8 preferred regimens alone, in addition to more than 20 recommended regimens. Choice of treatment comes down to personalization, according to Dr Castillo.

Treatment Selection

Disease-related factors. Deciding on a course of treatment for relapsed or refractory multiple myeloma often seems less scientific and more of a “wheel of fortune,” he said. To hone this process, first consider an individual’s disease-related factors, such as the nature of relapse (indolent vs aggressive), risk stratification (high, intermediate, or low), genomic abnormalities, and disease burden.

Patient-related factors should also be carefully weighed, especially patient preferences (intravenous vs oral therapy, distance to treatment center) and clinical considerations, such as renal insufficiency. Almost 50% of all patients with multiple myeloma will have some degree of renal insufficiency; in these patients, providers should favor cyclophosphamide, proteasome inhibitors, and dose-reduced immunomodulatory drugs (IMiDs), because these are more likely to be effective, but with lower toxicity than other drugs.

“In the relapsed and refractory setting, patient preference has become much more important,” Dr Castillo noted.

Previous therapy is also a critical factor that should inform treatment decisions. Consider whether the patient progressed while receiving proteasome inhibitors or IMiDs, and if they progressed on or off maintenance. What was the depth and duration of their response?

Treatment toxicity and patient comorbidities should also be considered. Speaking in general terms, Dr Castillo warns clinicians to be wary of using bortezomib (Velcade) and thalidomide in patients with preexisting neuropathy, carfilzomib (Kyprolis) in patients with cardiac issues and in elderly patients, daratumu­mab (Darzalex) in patients with pulmonary issues, and IMiDs in those with thrombotic episodes.

Although these drugs are not contraindicated, knowing which treatments may result in worse outcomes in certain populations can help to narrow down the options.

“Every intervention that we have will be related to some toxicity,” he said. “So, we need to make sure that the benefit we provide to our patients is higher than the potential toxicity.”

Triplet Therapy After Relapse

Combination treatment with lenalidomide (Revlimid) and dexamethasone has extended survival and time to progression in relapsed or refractory multiple myeloma. However, “triplets are the way to go, not only for frontline disease, but also for relapsed disease,” Dr Castillo says.

Many studies have explored triplet therapy in patients with relapsed or refractory disease who had minimal (≤20%) previous exposure to lenalidomide. In these studies, adding carfilzomib to a lenalidomide-dexamethasone regimen showed promising efficacy after first relapse, as did adding the oral proteasome inhibitor ixazomib (Nin­laro) to the lenalidomide-­dexamethasone regimen in the relapsed or refractory setting.

Daratumumab added to a lenalidomide-dexamethasone regimen has dem­onstrated significant improvements in progression-free survival (PFS), and elotuzumab (Empliciti), when added to the combination therapy in patients with minimal lenalidomide exposure, has also shown promising efficacy.

However, Dr Castillo warned that the applicability of these findings is limited, because many patients in clinical practice will have had higher exposure to lenalidomide. In patients with previous lenalidomide exposure, adding carfilzomib to dexamethasone led to a ­“remarkable” PFS benefit versus the combination of bortezomib-dexamethasone. In addition, evidence has shown that adding daratumumab to bortezomib-­dexamethasone was superior to bortezomib-dexamethasone alone.

Dr Castillo added that certain toxicity trends should also serve to guide treatment. For example, neuropathy is often more common in patients using proteasome inhibitors; infections are more common with daratumumab combinations, and cardiotoxicity is more prominent with carfilzomib therapy. Certain side effects, such as diarrhea, occur across the board.

For patients in second relapse or later, “pomalidomide-based regimens are an important resource,” but providers should remain vigilant about the risk of neuropathy, Dr Castillo advises.

Primary Refractory Disease

Clinical trials have yet to be designed solely for patients with primary refractory disease. “We don’t have clinical data supporting specific approaches in this type of patient, besides getting them to transplant early and using a triplet or even a quadruplet as data accumulate,” Dr Castillo said. He listed recommendations to guide the treatment of these patients:

  1. First, autologous stem-cell transplant (ASCT) should be standard in transplant-eligible patients with relapsed disease after primary therapy that did not include ASCT.
  2. A second ASCT should be considered for patients relapsing after primary therapy that included ASCT with initial remission after 18 months.
  3. Finally, allogeneic stem-cell transplantation should be considered in patients with high-risk disease and early (<24 months) disease relapse after primary therapy that included ASCT.

General Rules of Thumb

Dr Castillo also listed a few general rules of thumb:

  1. Consider nonlenalidomide triplets in patients whose disease progressed during lenalidomide maintenance, but a lenalidomide-based triplet is advised in those patients who had a prolonged PFS after lenalidomide-based induction.
  2. Consider a triplet with different novel agents in patients with primary refractory disease.
  3. Always consider referring for transplant if no ASCT was performed during induction.

According to Dr Castillo, current research in multiple myeloma is focusing on CAR (chimeric antigen receptor) T-cell therapies, antibody-drug conjugates, and bispecific T-cell engagers, and these emerging treatments should be on all providers’ radar.

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