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Treatment Considerations for Relapsed or Refractory Multiple Myeloma

March 2018, Vol 8, No 3

Despite major advances in treatment interventions, multiple myeloma remains incurable in the majority of patients, and relapse is an expected part of the disease course. At the 2017 NCCN Hematologic Malignancies Congress, Natalie S. Callander, MD, a hematologist at the University of Wisconsin Carbone Cancer Center, Madison, outlined issues in the management of relapsed or refractory multiple myeloma.

“More and more patients with myeloma are living with relapsed disease, which is a reflection of the drugs that we have available and the advances that we’ve made. At the same time, given the number of treatment options available, deciding what to do with an individual patient can be overwhelming,” Dr Callander said.

“It’s important to remember that we’re still losing about 10% to 15% of patients in the first year, so if you are having trouble with relapsed/refractory patients, you’re not alone,” she added.

Treatment Considerations

One of the first considerations in treating patients with relapsed disease is distinguishing between biochemical and symptomatic relapse, because studies have shown that patients with biochemical relapse perform significantly better than those with symptomatic relapse, regardless of how they were treated, Dr Callander said.

In addition, it is important to consider whether relapse is occurring with maintenance therapy and how early the relapse has occurred, she said.

Finally, determining the extent of the relapse (ie, 1 bone lesion vs 6 bone lesions) will make a difference in the course of treatment, which is why a thorough examination is recommended.

An appropriate evaluation for relapsed multiple myeloma entails:

  • Complete blood count with differential
  • Analysis of electrolytes, blood urea nitrogen, creatinine, lactate dehydrogenase, and beta-2-microglobulin levels
  • Serum kappa to lambda ratios
  • Immunoglobulin test for immunoparesis
  • Cytogenetic testing with FISH (fluorescence in situ hybridization) from bone marrow biopsy
  • Serum protein electrophoresis test
  • Skeletal survey
  • Evaluation for secondary amyloid­osis (with suggestive symptoms).

Regimens for Relapsed Disease

Given the recent FDA approval of novel agents for relapsed or refractory multiple myeloma, choosing the right regimen can be confusing, but the new drugs and drug combinations are “welcome additions,” said Dr Callander.

Four separate phase 3 clinical trials in the early-relapse setting with lenalidomide (Revlimid)-based treatments all have “excellent data,” she said, but the POLLUX study, which assessed disease control with daratumumab (Darzalex) plus lenalidomide and dexamethasone triplet therapy versus lenalidomide plus dexamethasone, may be the “most intriguing.” Patients receiving the triplet regimen had an overall response rate of 93%, and 22.4% of these patients were negative for minimal residual disease.

“We think that’s going to translate into better overall survival and progression-free survival, but that remains to be seen,” she said.

Several bortezomib (Velcade)-based salvage therapies in the early-relapse setting have also demonstrated high response rates, with survival benefits. However, economic analysis of 8 phase 3 clinical trials indicates that the regimen of daratum­umab plus lenalidomide and dexamethasone has the best benefits in terms of side effects and quality-­adjusted life-years.

Frail versus Fit Patients

Fitness also makes a big difference in selecting therapy for multiple myeloma. For frail or elderly patients, Dr Callander offered the following treatment considerations:

  • Focus on oral or less common drugs
  • With monoclonal antibodies, consider transitioning to biweekly or monthly administration after confirmed response
  • Limit steroids use when feasible
  • Consider carfilzomib (Kyprolis) on weekly schedule (not for patients with New York Heart Association class III or IV heart failure)
  • Consider drugs or drug classes not previously used.

The following drugs can be considered for frail and elderly patients:

  • Lenalidomide plus dexamethasone
  • Pomalidomide (Pomalyst) plus dexamethasone
  • Bortezomib plus cyclophosphamide
  • Carfilzomib plus cyclophosphamide
  • Add weekly bortezomib to lenalidomide plus dexamethasone
  • Add weekly carfilzomib to lenalidomide plus dexamethasone
  • Add dexamethasone to lenalidomide
  • Daratumumab monotherapy.

“In elderly patients, I tend to use daratumumab as monotherapy,” said Dr Callander, who noted a 40% response rate with the monoclonal antibody monotherapy. “You can also consider adding on bortezomib or lenalidomide or pomalidomide-lenalidomide doublet later, if you’re not seeing the response that you like,” she added.

High-Risk Patients

Patients with t(14;16), t(14;20), or del17p mutations tend to have their disease relapse earlier than patients without these mutations, regardless of aggressive initial therapy. Futhermore, survival after relapse is usually inferior, with one study reporting a <1-year survival in more than 75% of patients with high-risk disease after relapse.

For fit patients with high-risk multiple myeloma, oncologists should control the disease quickly with a regimen of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide, or high-dose cyclophosphamide, and encourage patients to participate in clinical trials, urged Dr Callander. However, elderly or unfit patients with high-risk relapsed or refractory multiple myeloma are rarely eligible for clinical trials.

“Hopefully, targeted agents will have an impact on this group in the future,” said Dr Callander, underscoring how rapidly the treatment paradigm is changing for relapsed or refractory multiple myeloma. New drugs being investigated for this setting include venetoclax (Venclexta) and chimeric antigen receptor (CAR) T-cell therapies.

“There are so many new agents available, and so many exciting treatments in development, including CAR T-cell therapy and venetoclax, and with molecular analysis and targeted therapy, curative treatments may one day be possible,” said Dr Callander. “Whoever gives this talk next year, it will be different, because the field is continuing to evolve,” she added.

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