Evolution of Therapy for Relapsed or Refractory Multiple Myeloma

January 2020 Vol 11, No 1

Categories:

Multiple Myeloma

Keeping up with the numerous 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.

“I would say that in myeloma, a higher variety of medications have been approved in recent years than in any other oncology malignancy,” he said at the NCCN 2019 Annual Congress: Hematologic Malignancies. “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 of the numerous treatment options to use for which patient. The National Comprehensive Cancer Network guidelines for multiple myeloma list 8 preferred regimens alone, in addition to over 20 recommended regimens. But choice of treatment, he says, comes down to personalization.

Factors Contributing to Treatment Selection

According to Dr Castillo, deciding on a course of treatment for relapsed or refractory multiple myeloma often seems like less of a scientific method and more of a “wheel of fortune.” To hone this process, providers should 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. These may include issues related to patient preference (IV vs oral therapy, distance to treatment center) or clinical considerations such as renal insufficiency. Almost half of all patients with myeloma will experience some degree of renal insufficiency, so in these patients, providers should favor cyclophosphamide, proteasome inhibitors, and dose-reduced immunomodulatory drugs, as these medications are more likely to provide efficacy with a lower degree of toxicity, he advised.

“In the relapsed and refractory setting, patient preference has become much more important,” he added.

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

Finally, consider treatment toxicities and comorbidities. Speaking in very general terms, Dr Castillo warns clinicians to be wary of using bortezomib and thalidomide in patients with preexisting neuropathy, carfilzomib in elderly patients and in patients with cardiac issues, daratumumab in patients with pulmonary issues, and immunomodulatory drugs in those with previous thrombotic episodes. Although these drugs are not actually contraindicated, knowing which treatments may result in worse outcomes in certain populations can help clinicians to narrow down the overwhelming number of 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 and dexamethasone has led to improved survival outcomes and time to progression in relapsed or refractory multiple myeloma and has been established as an effective treatment in this patient population. However, according to Dr Castillo, “triplets are the way to go, not only for frontline disease, but also for relapsed disease.”

A number of studies have explored triplet therapy in relapsed or refractory patient populations who had minimal (≤20%) previous exposure to lenalidomide.

In these studies, adding carfilzomib to a lenalidomide/dexamethasone regimen showed promising efficacy in patients after first relapse, as did adding ixazomib—an oral proteasome inhibitor—to lenalidomide/dexamethasone in the relapsed or refractory setting.

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

However, Dr Castillo warned that the applicability of these findings is limited, because the majority of patients in clinical practice will have had higher exposure to lenalidomide.

In patients with relapsed or refractory multiple myeloma and higher previous lenalidomide exposure, adding carfilzomib to dexamethasone led to a “remarkable” PFS benefit compared with combination treatment with bortezomib and dexamethasone. In addition, a sister study showed that the addition of daratumumab to bortezomib and dexamethasone was superior to bortezomib and dexamethasone alone.

Dr Castillo added that certain toxicity trends should also serve to guide treatment. For example, neuropathy tends to be more of an issue in patients receiving proteasome inhibitors, infections are more common with daratumumab combinations, and cardiotoxicity is more prominent with the use of carfilzomib. However, certain side effects, such as diarrhea, tend to occur across the board.

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

Primary Refractory Disease and Looking to the Future

Clinical trials have yet to be designed solely for patients with primary refractory disease. “We treat them with what we already have, but 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,” he said.

However, selected recommendations can guide the treatment of these patients. First, autologous stem cell transplant (ASCT) should be standard in transplantation-eligible patients relapsing after primary therapy that did not include ASCT, and a second ASCT should be considered for patients relapsing after primary therapy that included ASCT with initial remission after 18 months. Finally, allogeneic stem cell transplantation should be considered in patients with high-risk disease who experience early relapse (<24 months) after primary therapy that included ASCT.

According to Dr Castillo, there are a few general rules of thumb to keep in mind: non-lenalidomide triplets should be considered in patients whose disease progressed while receiving lenalidomide maintenance, whereas a lenalidomide-based triplet should be favored in patients who had a prolonged treatment-free survival after lenalidomide-based induction. Consider a triplet with different novel agents in patients with primary refractory disease, he advised, and always consider referring for transplant if no ASCT was performed during induction.

The armamentarium in relapsed or refractory multiple myeloma is expanding all the time and has recently seen the addition of such treatments as novel immunomodulators, proteasome inhibitors, and monoclonal antibodies. According to Dr Castillo, current research is focusing on chimeric antigen receptor T-cell therapies, antibody-drug conjugates, and bispecific T-cell engagers, and these emerging treatments should be on the oncologist’s radar.

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March 2022 Vol 13, No 3
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Last modified: February 17, 2021

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