Ide-cel provides 51% reduction in the risk of progression or death in R/R multiple myeloma

23rd March 2023

Use of Ide-cel in refractory or relapsed multiple myeloma after two to four prior regimens more than halved the risk of progression or death

Ide-cel therapy for with relapsed and refractory multiple myeloma who had received between two to four previous regimens, significantly prolonged progression-free survival compared to a standard-regimen group, according to a recent and international, open-label, phase 3 trial.

A 2020 study found that the global incidence of multiple myeloma was 160,000 and which led to l106,000 deaths. While autologous stem cell transplantation has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades, nearly all patients will eventually experience disease relapse. Although the introduction of CD38-targeting monoclonal antibodies (MCA), daratumumab and isatuximab, have significantly impacted the management of patients with multiple myeloma, patients who are refractory to CD38 MCA have a poor prognosis. In an earlier, phase 2 trial, ide-cel induced responses in the majority of heavily pre-reated patients with refractory and relapsed multiple myeloma.

In the current study, researchers undertook a phase 3 trial of ide-cel in adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab). Individuals were randomised 2:1 to ide-cel or one of five standard regimens. The primary end point was set as progression-free survival, whereas secondary endpoints included the overall response and survival.

Ide-cel and progression-free survival

A total of 386 patients with a median age of 63 years (60.5% male) underwent randomisation, with 254 assigned to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease.

At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, compared to 4.4 months in the standard-regimen group (Hazard ratio, HR for disease progression or death = 0.49, 95% CI 0.38 – 0.65, p < 0.001). A response was seen in a significantly higher proportion of patients who received ide-cel compared to the standard regimen (71% vs 42%, p < 0.001) and a complete response occurred in 39% and 5% respectively. At the time of publication, overall survival data were immature.

Adverse events of grade 3 or 4 occurred more frequently in the ide-cel group (93% vs 75%) and cytokine release syndrome occurred in 88% of the ide-cel group although this was largely of grade 1 or 2 severity. Neurotoxic effects occurred in 15% of the ide-cel group, with 3% having an event of grade 3 or higher.

The authors concluded that ide-cel treatment gave rise to significantly prolonged progression-free survival and an improved response compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma. 

Citation
Rodrigeuz-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Eng J Med 2023

Elranatamab induces durable clinical response in relapsed multiple myeloma

21st December 2022

Use of elranatamab resulted in a durable clinical and molecular response in patients with relapsed or refractory multiple myeloma

Data presented at the 64^th American Society of Haematology (ASH) conference in New Orleans, showed that elranatamab is efficacious and has a manageable safety profile in patients with relapsed or refractory multiple myeloma (RRMM).

Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterised by the abnormal increase of monoclonal immunoglobulins and which if left unchecked, can ultimately lead to specific end-organ damage. It is an uncommon cancer, with the global, age-standardised rate incidence estimated to be 1·78 per 100 000 people but with a mortality rate of 1·14 (95% UI 1·07-1·21) per 100 000 people in 2020. Most patients present with symptoms related to organ involvement, including hypercalcaemia, renal insufficiency, anaemia, and bone lesions (known as calcium, renal failure, anaemia, and bone lesions [CRAB] symptoms). In contrast, a minority of patients are asymptomatic but are identified through abnormal blood and/or urine tests.

At the ASH conference, data were presented for elranatamab, which is a bispecific antibody that targets expression of B-cell maturation antigen (BCMA) and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. The findings come from the MagnetisMM-1 trial designed to assess the safety and tolerability at increasing dose levels of elranatamab in patients with relapse/ refractory multiple myeloma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose. Within the trial, elranatamab was administered subcutaneously at doses from 80 to 1000µg/kg either weekly or every 2 weeks.

Elranatamab clinical response

A total of 55 patients with a median age of 64 years and of whom, 27% were Black/African American or Asian, received elranatamab at a dose ≥215μg/kg. The median number of prior regimens was 5 (range 2-14) with 91% being triple-class refractory, 69% of whom had prior stem cell transplantation, 29% had a high cytogenetic risk and 24% received prior BCMA-targeted therapy.

After a median follow-up of 12.0 months and including only those with an International Myeloma Working Group (IMWC) confirmed responses, the objective response rate (ORR) was 64% (95% CI 50 – 75%) and with 56% of participants achieving very good partial response (VGPR) or better and 38% achieving complete response (CR) or better. 

Among 35 responders, the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for the median duration of response was 17.1 months (95% CI 10.6 – not estimable). Elranatamab induced durable clinical and molecular responses and 100% (12/12) of evaluable patients with confirmed CR or better achieved minimal residual disease (MRD) negativity at a sensitivity of 1×10^-5 including 2 participants with MRD negativity and ongoing stringent complete response beyond 2 years.

The most common treatment-emergent adverse effects included the cytokine release syndrome in 67% of participants but this was limited to grade 1 (33%) or grade 2 (33%) severity with no grade 3 or higher responses.

The authors concluded that elranatamab induced durable clinical and molecular responses for patients with relapsed or refractory MM, with an ORR of 64% and more than half of these patients (38%) achieving CR or better, and 100% of evaluable patients able to achieve MRD negativity. They added that these results support further development of elranatamab for patients with MM.

Citation
Raje N et al. Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma. Abstract No 158, ASH 2022