Year in Review: Multiple Myeloma

Advances in multiple myeloma treatment this year were marked by the resurrection of a drug that had been previously pulled off the market, new FDA approvals, and research suggesting that an isatuximab (Sarclisa)-based quadruplet could be the new standard of care for transplant-ineligible patients with newly diagnosed disease.

A Second Chance for Belantamab Mafodotin

One of the major stories in multiple myeloma in 2024 was the comeback of belantamab mafodotin (Blenrep) after it had been pulled from the market in 2022.

In 2020, belantamab mafodotin, an anti-B-cell maturation antigen (BCMA) monoclonal antibody, had been granted accelerated approval for the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

When the DREAMM-3 confirmatory trial failed to meet the primary endpoint of progression-free survival (PFS), the FDA requested that GSK, the agent’s developer, withdraw it from the market.

However, results from the DREAMM-7 study, which were presented during an American Society of Clinical Oncology (ASCO) Virtual Plenary, showed that when belantamab mafodotin was combined with bortezomib (Velcade) and dexamethasone, it led to a median PFS of 36.6 months compared with 13.4 months for those who received daratumumab (Darzalex) plus bortezomib and dexamethasone (HR 0.41, 95% CI 0.31-0.53, P<0.00001).

The DREAMM-7 results “are compelling, and support the clinical efficacy of belantamab mafodotin for patients with relapsed/refractory multiple myeloma,” said ASCO discussant Rachid Baz, MD, of the Moffitt Cancer Center in Tampa, Florida, at the time.

In November, GSK announced that DREAMM-7 also met the secondary endpoint of improved overall survival.

Furthermore, a second belantamab mafodotin-containing triplet also demonstrated a PFS benefit in relapsed/refractory myeloma. In the DREAMM-8 study — the results of which were presented during the ASCO annual meeting — estimated 12-month PFS rates were 71% with belantamab mafodotin combined with pomalidomide (Pomalyst) and dexamethasone compared with 51% with pomalidomide, bortezomib, and dexamethasone (HR 0.52, 95% CI 0.37-0.73, P<0.001).

The drug is again under review at the FDA as a treatment for myeloma.

FDA Approvals

In July, the FDA approved subcutaneous daratumumab-hyaluronidase (Darzalex Faspro) in combination with bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

Approval was based on results from the phase III PERSEUS trial in which treatment with the quadruplet led to a significant improvement in the primary endpoint of PFS, reducing the risk of disease progression or death by 60% compared with VRd alone (HR 0.40, 95% CI 0.29-0.57, P<0.0001).

These results, which were presented at the American Society of Hematology annual meeting last year, also included an interim analysis that showed a trend toward improved overall survival in favor of daratumumab-hyaluronidase plus VRd.

The FDA also expanded the labels of two CAR T-cell products for multiple myeloma in April, allowing their use in earlier lines of treatment for relapsed or refractory disease.

Ciltacabtagene autoleucel (cilta-cel; Carvykti) is now approved as a second-line therapy for patients who are refractory to lenalidomide, and whose prior line of therapy also included a proteasome inhibitor. The expanded approval was based on results from the CARTITUDE-4 trial in which a single infusion of cilta-cel reduced the risk of disease progression or death compared with standard care in lenalidomide-refractory patients.

Idecabtagene vicleucel (ide-cel; Abecma) was approved as a third-line option for patients with triple-class-exposed disease (an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody). The extended approval was based on findings from the KarMMa-3 trial, which showed that patients receiving the one-time infusion of ide-cel experienced a significant improvement in PFS.

The FDA’s decision followed a meeting of the agency’s Oncologic Drugs Advisory Committee during which the panel recommended approval of the expanded indications.

Wins for Isatuximab in Newly Diagnosed Disease

Results from two phase III trials presented at ASCO showed that the anti-CD38 monoclonal antibody isatuximab combined with the standard VRd backbone significantly improved outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma.

In the IMROZ trial, the estimated PFS rate at 60 months was 63.2% among patients treated with isatuximab-VRd compared with 45.2% for those treated with VRd alone (HR 0.60, 98.5% CI 0.41-0.88, P<0.001), reported Thierry Facon, MD, of the Centre Hospitalier Universitaire de Lille in France.

Meanwhile, in the BENEFIT trial, Xavier Leleu, MD, PhD, of Centre Hospitalier Universitaire in Poitiers, France, reported that the isatuximab-VRd combination significantly improved minimal residual disease (MRD) negativity rates at 10^-5 at 18 months compared with isatuximab, lenalidomide, and dexamethasone (53% vs 26%; OR 3.16, 95% CI 1.89-5.28, P<0.0001).

The higher MRD negativity rates with isatuximab-VRd were also observed at 12 months at both 10^-5 and 10^-6.

Facon and Leleu agreed that the results from IMROZ and BENEFIT, which were published in the New England Journal of Medicine and Nature Medicine, respectively, supported isatuximab-VRd as a new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma.

Other Multiple Myeloma News in 2024:

Quadruplet Shows ‘Excellent Activity’ in Myeloma Patients Who Defer HSCT

Real World CAR T-Cell Therapy Outcomes ‘Favorable’ in Relapsed/Refractory Myeloma

Refractory Multiple Myeloma Responsive to Immunotherapy Plus Low-Dose Radiotherapy

New Agents for Relapsed/Refractory Myeloma Impress in Early-Stage Clinical Trials

High Response Rate in R/R Multiple Myeloma With Bispecific Antibody

Elotuzumab Misses Mark Again as Frontline Treatment for Multiple Myeloma

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