Despite major and continuing treatment interventions, myeloma remains incurable for most patients, and relapse is an expected part of the disease course. At the National Comprehensive Cancer Network 12th Annual Congress: Hematologic Malignancies, Natalie S. Callander, MD, outlined issues in the management of relapsed/refractory multiple myeloma (RRMM).
“More and more myeloma patients are living with relapsed disease, which is a reflection of the drugs that we have available and the advances that we’ve made,” said Dr Callander, of the University of Wisconsin Carbone Cancer Center. “At the same time, given the number of treatment options available, deciding what to do with an individual patient can be overwhelming. 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.”
According to Dr Callander, one of the immediate considerations in treating patients with relapsed disease is distinguishing between biochemical and symptomatic relapse, as studies have shown that patients with biochemical relapse perform significantly better than those with symptomatic relapse, regardless of how they were treated. In addition, said Dr Callander, it’s important to consider whether relapse is occurring on maintenance therapy and how early the relapse has occurred. 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.
As Dr Callander explained, an appropriate evaluation for relapsed myeloma entails:
- Complete blood count with differential
- Analysis of electrolytes, blood urea nitrogen, creatinine, lactate dehydrogenase, and β2-microglobulin levels
- Serum kappa/lambda ratios
- Immunoglobulin test for immunoparesis
- Cytogenetic/fluorescence in situ hybridization (FISH) testing from bone marrow biopsy
- Serum protein electrophoresis test
- Skeletal survey
- Evaluation for secondary amyloidosis (if symptoms suggestive)
Regimens for Relapsed Disease
Given the recent spate of FDA approvals of novel agents for patients with RRMM, choosing the right regimen can be confusing, said Dr Callander, but the many new drugs and drug combinations are “welcome additions.” Four separate phase 3 trials in the early relapse setting with lenalidomide-based treatments all have “excellent data,” she reported, but the POLLUX trial, which tested the daratumumab-lenalidomide-dexamethasone triplet against lenalidomide-dexamethasone control may be the “most intriguing.” Patients receiving the triplet had an overall response rate of 93%, and 22.4% of these patients ended up becoming negative for minimal residual disease.
“We think that’s going to translate into better overall survival and progression-free survival,” she said, “but that remains to be seen.”
To complicate matters further, several bortezomib-based salvage therapies in the early relapse setting have also demonstrated high response rates with survival benefits. Nevertheless, economic analysis of 8 separate phase 3 trials suggests the best benefits in terms of side effect profile and quality-of-life years come from the daratumumab-lenalidomide-dexamethasone triplet, Dr Callander reported.
Frail versus Fit Patients
Fitness also makes a big difference in selecting therapy. For frail patients, Dr Callander offered the following treatment considerations:
- Focus on oral or less frequently administered drugs
- For monoclonal antibodies, consider moving to biweekly or monthly after response is confirmed
- Limit steroids when feasible
- Carfilzomib on weekly schedule (not for patients with class III/IV heart failure)
- Consider agents or classes not previously used
The following agents can be considered for frail patients:
- Add weekly bortezomib to lenalidomide/dexamethasone
- Add weekly carfilzomib to lenalidomide/ 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 just the monoclonal antibody. “You can also consider adding on bortezomib or lenalidomide or pomalidomide-lenalidomide doublet later if you’re not seeing the response that you like.”
Patients who acquire additional cytogenetic/FISH mutations—t(14;16), t(14;20), or del(17p)—tend to relapse earlier regardless of aggressive initial therapy. Moreover, survival after relapse is usually inferior, with one study reporting less than 1-year survival in more than 75% of high-risk multiple myeloma patients after relapse. For fit patients with high-risk myeloma, Dr Callander urged controlling the disease quickly with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) or high-dose cyclophosphamide and considering clinical trials. Elderly or unfit patients with high-risk RRMM, however, are rarely eligible for clinical trials.
“Hopefully, targeted agents will have an impact on this group in the future,” said Dr Callander, who underscored how rapidly the treatment paradigm for RRMM is changing.
“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,” Dr Callander added. “Whoever gives this talk next year, it will be different, because the field is continuing to evolve.”