News involving the treatment of multiple myeloma this year was highlighted by talk of a potential cure with a single infusion of a chimeric antigen receptor (CAR) T-cell therapy, new FDA approvals (including a drug once pulled from the market), and trials demonstrating efficacy and safety of therapies adapted for older, frail patients.
Potential Cure?
A post-hoc analysis of the CARTITUDE-1 trial presented at this year's annual meeting of the American Society of Clinical Oncology led to talk that a single infusion of the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel, Carvykti) offered the "potential of cure" for patients with heavily pretreated relapsed/refractory multiple myeloma.
Among 97 treated patients, 45 were still alive and in long-term follow-up, with a median overall survival (OS) of 60.7 months, reported Peter Voorhees, MD, of the Wake Forest University School of Medicine in Charlotte, North Carolina.
Moreover, 32 patients were alive and progression-free without any further anti-myeloma treatment 5 or more years after treatment with cilta-cel. Of these progression-free patients, 12 from a single center with serial minimal residual disease (MRD) assessments were all MRD-negative and imaging-negative at year 5 or later after cilta-cel without additional therapy.
These results suggest "a potential cure, or at bare minimum, unprecedented durability of complete response," Voorhees said.
Blenrep Completes Comeback
After an odyssey lasting half a decade, the FDA in October once again approved belantamab mafodotin (Blenrep), this time in combination with bortezomib (Velcade) and dexamethasone (BVd) for the treatment of adults with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug.
This approval came 3 years after the drug was pulled from the market over concerns about its efficacy. It was originally granted accelerated approval in 2020 for the treatment of adults with relapsed or refractory disease who had received at least four prior therapies.
The FDA's latest action was based on results from the DREAMM-7 trial, which showed patients treated with the belantamab-based BVd combination had significantly improved progression-free survival (PFS) and OS compared with those who received a combination of daratumumab (Darzalex) plus bortezomib and dexamethasone.
BVd overcame various concerns raised by the FDA's Oncologic Drugs Advisory Committee (ODAC) in July, including ocular toxicities with belantamab mafodotin. ODAC ultimately voted that the risks with the B-cell maturation antigen (BCMA)-targeted agent outweighed the benefits for two proposed indications.
While belantamab mafodotin was approved as part of the BVd combination, it failed to pass muster with the agency in combination with pomalidomide (Pomalyst) and dexamethasone.
The ocular toxicity issue earned belantamab a risk evaluation and mitigation strategy (REMS) from the FDA, as well as a boxed warning.
Other FDA News
The FDA in July granted accelerated approval to linvoseltamab (Lynozyfic) for relapsed/refractory multiple myeloma after at least four prior lines of therapy.
The BCMA-directed bispecific antibody is indicated for adults who have already received a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
The prescribing information for linvoseltamab includes a boxed warning for cytokine release syndrome and neurologic toxicity, including immune effector cell-associated neurotoxicity, and the product will only be available through a REMS program.
Approval of the bispecific T-cell engager was based on results from LINKER-MM1, a phase I/II trial of 80 patients in which linvoseltamab induced objective responses in 70%, with 45% achieving a complete response or better.
Earlier this year, the FDA's ODAC agreed that results from the phase III AQUILA trial provided sufficient evidence of a favorable risk-benefit profile for subcutaneous daratumumab (Darzalex Faspro) in high-risk smoldering myeloma.
If approved, the drug would be the first therapy available to delay progression from smoldering to active myeloma in high-risk patients.
Wins for Older, Frail Patients
Results from the phase II REST trial showed that a modified version of a regimen combining the anti-CD38 monoclonal antibody isatuximab (Sarclisa) with bortezomib, lenalidomide (Revlimid), and limited dexamethasone was safe and effective for older multiple myeloma patients ineligible for autologous hematopoietic stem cell transplantation.
The study, published in Lancet Haematology, found that among 51 patients ages 70 to 88, MRD-negative complete response was observed in 37%, with an overall response rate of 100% and complete response or better in 47%, while 82% had a very good partial response or better.
Median PFS was not reached, while the 12-month PFS rate was 86%. The 12-month OS rate was 90%.
Moreover, the authors said that the modified regimen appeared to mitigate the risk of increased toxicity -- including infection -- that might be expected with the full regimen.
In another trial published in Lancet Oncology, a dexamethasone-sparing regimen involving lenalidomide and the anti-CD38 drug daratumumab was shown to be safe and effective in older, frail patients with newly diagnosed myeloma.
Among 295 patients, median PFS reached 53.4 months for those assigned to lenalidomide-daratumumab plus dexamethasone limited to just the first two cycles of treatment, as compared with 22.5 months for a control group that received lenalidomide plus continued dexamethasone (HR 0.51, 95% CI 0.37-0.70, P<0.0001).
The regimen did not lead to an increased risk of infections, including pneumonia, suggesting a dexamethasone-sparing strategy can mitigate toxicity risks while maintaining the benefits of anti-CD38 antibody therapy.
A study presented at the annual meeting of the International Myeloma Society showed that a modified daratumumab-based combination achieved encouraging results in an older population of transplant-ineligible patients with newly diagnosed multiple myeloma.
The overall response rate following induction therapy with daratumumab, lenalidomide, ixazomib (Ninlaro), and dexamethasone (D-RId) was 92.4%, including a very good partial response or better rate of 69.6% and a complete response or better rate of 22.8% in 79 evaluable patients, reported Andrew J. Yee, MD, of Massachusetts General Hospital Cancer Center in Boston.
After 12 cycles of D-RId, the 12-month PFS and OS rates were 92% and 93.6%, respectively, "which I believe are favorable outcomes for this transplant-ineligible patient population," Yee said.
Yee and colleagues modified D-RId in the trial by reducing the initial lenalidomide dose from 25 mg to 15 mg to improve tolerability and by replacing bortezomib with the oral proteasome inhibitor ixazomib.
Other Multiple Myeloma News in 2025:
- Anti-CD38-Based Quad Improves Outcomes in Transplant-Ineligible Myeloma
- High Response Rate in Myeloma With Novel CAR-T After Anti-BCMA Failure
- Treatment Succeeds for Secondary Cancer After CAR-T, Case Report Shows
- Stopping Bispecific Appears Safe in Relapsed/Refractory Myeloma
- CAR-T Drug for Myeloma Hit With New Boxed Warning
- Undetectable Disease Status in Myeloma Similar With Drug Therapy, Transplantation
- Elranatamab-Based Triplet Effective in Transplant-Ineligible Myeloma
- High Response Rate in Heavily Treated Multiple Myeloma With Novel Drug Combination
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