Developments in multiple myeloma over the past year were marked by the approvals of a first-in-class drug for relapsed or refractory disease and a second chimeric antigen receptor (CAR) T-cell therapy, as well as some encouraging news and disappointments on the research front.
New Approvals
Last month, the FDA granted accelerated approval to teclistamab (Tecvayli) for the treatment of triple-class refractory multiple myeloma.
The first approved drug of its kind, teclistamab redirects T cells through B-cell maturation antigen (BCMA) and CD3 to activate the immune system against the cancer. It is indicated for patients who have received at least four prior therapies, including an immunomodulator, a proteasome inhibitor, and an anti-CD38 antibody.
Approval was based on results from the MajesTEC-1 clinical trial, which reported an objective response rate of 63% and median 18.4-month response duration in patients who had received at least three prior lines of anti-myeloma therapy, but no prior exposure to a BCMA-targeted agent. More than 90% of responding patients had ongoing responses at 6 months with teclistamab, and two-thirds had ongoing responses at 9 months.
Earlier in the year, a BCMA-directed CAR T-cell therapy — ciltacabtagene autoleucel (Carvykti) — was also approved for triple-class refractory myeloma. In the phase IB/II CARTITUDE-1 trial, one-time treatment with ciltacabtagene autoleucel resulted in an overall response rate of 98%, with more than three-fourths achieving a stringent complete response. Median duration of response was 21.8 months.
Thumbs Down on a ‘Dangling’ Accelerated Approval
In September, the FDA’s Oncologic Drugs Advisory Committee (ODAC) may have sealed the fate of a dangling accelerated approval in multiple myeloma.
By a clear 14-2 margin, the panel voted that the benefits of melphalan flufenamide (Pepaxto) do not outweigh the risks for patients with relapsed or refractory disease, after data from the confirmatory OCEAN trial showed an increased mortality risk with melphalan flufenamide.
The peptide-drug conjugate had originally been granted accelerated approval based on overall response rates observed in a single-arm phase II trial, and the approval was contingent on further study of the therapy.
“A critical aspect of accelerated approval is that follow-up trials actually confirm the initial benefit,” said ODAC member Mikkael Sekeres, MD, MS, of the University of Miami Sylvester Comprehensive Cancer Center, during the meeting.
“Unfortunately, in this case the follow-up trial flopped,” said Sekeres. “Not only did it not show the magnitude of benefit shown originally, but it potentially showed an increased risk of death in patients, with significant toxicity.”
A Research Win and a Disappointment
Follow-up data from the phase III IKEMA trial of isatuximab (Sarclisa) added to a standard proteasome inhibitor-based regimen demonstrated an “unprecedented” improvement in progression-free survival (PFS) for patients with relapsed multiple myeloma.
Median PFS in the randomized trial improved from 19.2 months with carfilzomib (Kyprolis) and dexamethasone (Kd) to 35.7 months with the addition of isatuximab, a CD38 inhibitor.
“Isatuximab-Kd is now a standard of care for relapsed multiple myeloma,” said Philippe Moreau, MD, of University Hospital Hôtel-Dieu in Nantes, France, who presented the results during a European Society for Medical Oncology virtual plenary.
On the negative front, the phase III ELOQUENT-1 trial found that adding elotuzumab (Empliciti) to lenalidomide (Revlimid) and dexamethasone failed to improve PFS over lenalidomide-dexamethasone alone for patients with newly diagnosed, transplant-ineligible multiple myeloma.
PFS, the study’s primary endpoint, was a median 31.4 months with the addition of the monoclonal antibody versus 29.5 months without it. Response rates (83% vs 79%, respectively) and overall survival (60.4 vs 57.6 months) were similar as well.
Prognostic Role for Circulating Tumor Cells
A prospective study involving 400 patients demonstrated that circulating tumor cell (CTC) levels in newly diagnosed multiple myeloma identified high-risk disease associated with shorter PFS and overall survival.
A CTC level exceeding 5 cells/µL (CTC-high) more than doubled the hazard for disease progression or death and the survival hazard. Patients with CTCs above the cutoff at diagnosis had a 4-year overall survival of 68% versus 92% for patients with lower CTC levels. Bone marrow plasma cells, meanwhile, did not have a significant association with outcome.
A companion study confirmed that CTCs outperformed bone marrow plasma cells for identifying high-risk myeloma, but yielded a different CTC cutoff level for demarcating high-risk disease.
“We believe that these data can open the way to the incorporation of CTC into a wider clinical use for the routine diagnosis of patients with [multiple myeloma],” the authors concluded.
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