Advances in frontline treatment for multiple myeloma may prompt clinicians to rethink how they identify patients with the poorest prognosis, according to a study published in Cancer. Researchers report that patients whose disease progresses within 36 months—not the longstanding 18-month benchmark—should now be considered to have functional high-risk (FHR) multiple myeloma.
Functional high-risk disease has traditionally been defined as myeloma that progresses within 18 months of starting therapy, a group historically associated with survival of less than two years after relapse. However, widespread adoption of quadruplet therapy—combining an anti-CD38 antibody, a proteasome inhibitor, an immunomodulatory agent, and dexamethasone—followed by autologous stem cell transplantation (ASCT) has substantially prolonged remission for many patients.
To determine whether the historical definition remains appropriate, investigators from the University of Alabama at Birmingham and the CoMMiT consortium analyzed outcomes in 310 patients with newly diagnosed multiple myeloma treated with quadruplet therapy plus ASCT. Patients were followed for a median of 41.8 months (3.5 years), during which 66 experienced disease progression.
The researchers evaluated several definitions of FHR disease based on progression occurring within 12, 18, 24, or 36 months after treatment initiation. Their analysis found that progression within 36 months most accurately identified patients whose survival after relapse remained approximately two years or less despite current frontline therapy.
“The current analysis provides validation of FHR36 as the optimal classification for FHR multiple myeloma in the era of QUAD + ASCT, providing a benchmark for future therapies to be explored in this setting,” the authors conclude.
Using the new definition, 16.4% of patients were classified as having FHR36 disease. Many would not have been identified as high risk using conventional staging systems: more than one-third had lower-stage disease according to the second revised International Staging System, and more than half met standard-risk criteria under current International Myeloma Society guidelines.
The study also suggests that T-cell redirecting therapies (TCRTs), including CAR T-cell therapies and bispecific antibodies, may improve outcomes in this population. Although only 11 patients received TCRTs as second-line treatment, outcomes were markedly better than with conventional therapies.
The 12-month second progression-free survival rate was 80% for patients treated with TCRTs, compared with 23% for those receiving other therapies. Overall response rates were 91% versus 47%, respectively. Multivariable analysis showed that TCRT remained associated with improved progression-free survival after adjustment for FHR status.
The authors caution that these findings require confirmation because relatively few patients received TCRTs. Still, they argue that patients meeting the FHR36 definition should be prioritized for early T-cell redirecting therapy and enrollment in clinical trials evaluating novel agents.
“We believe FHR36 should be a standard definition for FHR going forward and that the safety and efficacy of experimental agents should be reported in this important subset of patients or dedicated trials should be designed and conducted for this special population,” the authors write.
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