FDA Approves Ide-Cel for Triple-Class Exposed R/R Multiple Myeloma

FDA

The FDA has approved idecabtagene vicleucel (ide-cel; Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.^1,2

The regulatory decision is supported by data from the phase 3 KarMMa-3 trial (NCT03651128), in which, at an estimated median follow-up of 15.9 months, treatment with the CAR T-cell therapy (n = 254) led to a median progression-free survival of 13.3 months (95% CI, 11.8-16.1) vs 4.4 months (95% CI, 3.4-5.9) with standard regimens (n = 132; HR, 0.49; 95% CI, 0.38-0.64; P < .0001), translating to a 51% reduction in the risk of disease progression or death.

Moreover, ide-cel also demonstrated a significant improvement in overall response rate (ORR) vs standard regimens, with 71% (95% CI, 66%-77%) of patients achieving a response vs 42% (95% CI, 33%-50%) of those who received standard regimens (P < .0001). Thirty-nine percent of patients in the ide-cel arm had a complete or stringent complete response vs 5% of those in the standard regimen arm.

Notably, the responses achieved with the CAR T-cell therapy also proved to be durable, with a median duration of response (DOR) of 14.8 months (95% CI, 12.0-18.6) in those who experienced a partial response or better, and those who achieved a complete response or better experienced a median DOR that was even longer, at 20 months (95% CI, 15.8-24.3).

“Abecma has demonstrated a progression-free survival benefit three times that of standard regimens in relapsed or refractory multiple myeloma, and we are now bringing the promise of cell therapy to patients earlier in their treatment journey,” Bryan Campbell, senior vice president and head of Commercial, Cell Therapy at Bristol Myers Squibb, stated in a press release. “This approval underpins our commitment to addressing the unmet needs of more patients living with multiple myeloma by improving upon the current treatment paradigm, and we remain steadfast in our pursuit of innovation and advancing cell therapy research to deliver potentially transformative therapies.”

About KarMMa-3: Eligibility Criteria, Treatment, Objectives

The open-label, multicenter, randomized, controlled study enrolled adult patients with relapsed/refractory multiple myeloma who had previously received 2 to 4 therapies, including an IMiD, a PI, and daratumumab (Darzalex), and were refractory to their most recent regimen. Patients had achieved a minimal response or better to at least 1 previous treatment regimen and had an ECOG performance status up to 1.

If patients had serum creatinine clearance under 45 mL/min, serum aspartate aminotransferase or alanine aminotransferase greater than 2.5 times the upper limit of normal, or a left ventricular ejection fraction under 45%, they were excluded.

Study participants were randomly assigned 2:1 to receive ide-cel (n = 254) or standard regimens, which could have included any of the following: daratumumab, pomalidomide (Pomalyst), and dexamethasone (DPd); daratumumab, bortezomib (Velcade), and dexamethasone (DVd); ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone (IRd); carfilzomib (Kyprolis) and dexamethasone (Kd); or elotuzumab (Empliciti), pomalidomide, and dexamethasone (EPd). The selection of the standard regimen was based on the patient's most recent therapy received and investigators identified the regimen prior to randomization.

Five days prior to the target infusion date for ide-cel, patients in that arm received lymphodepletion in the form of cyclophosphamide at 300 mg/m² daily for 3 days plus fludarabine at 30 mg/m² daily for 3 days. For disease control between apheresis and 14 days before chemotherapy was initiated patients were allowed to receive up to 1 cycle of bridging therapy with DPd, DVd, IRd, Kd, or EPd.

The trial's primary end point was PFS by independent review committee assessment and based on International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Other key efficacy end points include ORR and overall survival.

Baseline Characteristics

The median patient age is 63 years (range, 30-83), and most were male (61%), White (65%), and had Revised International Staging System stage I or II disease (80%). Just under half of patients (42%) had high-risk cytogenetics and 24% had extramedullary disease.

The median number of previous lines of therapy received was 3, with a range of 2 to 4 lines. Specifically, 30% of patients had received 2 prior lines, 37% received 3 prior lines, and 32% received 4 prior lines. The majority of patients were refractory to an anti-CD38 monoclonal antibody (95%) and triple-class refractory (66%). Five percent of patients were penta-drug refractory. Moreover, 85% of participants had previously undergone autologous stem cell transplant.

Additional Information

Ninety-eight percent of the patients who underwent randomization (n = 254) received leukapheresis; 2% of them did not complete the treatment due to patient withdrawal (n = 2), toxicity (n = 1), or they did not meet lymphodepletion criteria (n = 2). Ten percent of patients did not receive ide-cel infusion because of death (n = 4), toxicity (n = 4), physician decision (n = 7), not meeting lymphodepletion criteria (n = 6), or manufacturing issues (n = 3). Moreover, 1.2% of patients received non-conforming product.

In the 249 patients who underwent leukapheresis, the overall manufacturing failure rate was 2.4%. Three of the 6 patients received CAR-positive T cells that failed to meet the product release specifications for ide-cel and there was an inability to manufacture the product for the remaining 3 patients.

Safety Data

There are boxed warnings for the product with regard to cytokine release syndrome (CRS), neurologic adverse effects (AEs), hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia, and secondary hematologic malignancies.¹

The safety population was comprised of 222 patients who received ide-cel at doses ranging from 175 x 10⁶ CAR-positive T cells to 529 x 10⁶ CAR-positive T cells.² The median dose received was 445 x 10⁶ CAR-positive T cells.

Serious toxicities were experienced by 43% of patients.

The most common grade 3 or 4 adverse effects reported in at least 10% of patients who received ide-cel on the study include febrile neutropenia (51%), coagulopathy (2.7%), diarrhea (2.3%), nausea (0.9%), abdominal pain (0.5%), pyrexia (9%), fatigue (1.4%), edema (0.5%), chills (0.5%), CRS (4.1%), hypogammaglobulinemia (0.9%), any infection (16%), reduced appetite (1.8%), encephalopathy (3.6%), dizziness (1.8%), dyspnea (1.8%), hypoxia (6%), hypotension (2.3%), and hypertension (7%).

The most common grade 3 or 4 laboratory abnormalities that worsened from baseline in at least 10% of patients in the ide-cel arm included decreased lymphocytes (98%), leukocytes (96%), neutrophils (96%), platelets (59%), hemoglobin (52%), phosphate (45%), and sodium (11%), and increased triglyceride (21%), alanine aminotransferase (13%), and Gamma-glutamyltransferase (10%).

Grade 3 or 4 laboratory abnormalities that were observed in less than 10% of patients who received ide-cel but were still determined to be clinically important were increased aspartate aminotransferase, decreased potassium, decreased albumin, increased alkaline phosphatase, decreased calcium, increased glucose, increased activated partial thromboplastin time, decreased fibrinogen, increased bilirubin, and hypomagnesemia.

References

1. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 4, 2024. Accessed April 5, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx
2. Abecma. Prescribing information. Bristol-Myers Squibb; 2024. Accessed April 5, 2024.