FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy in the United States, accounting for 1.8% of all cancers and 17% of all hematologic malignancies (1). Patients who are refractory to major classes of available antimyeloma therapies such as triple class refractory [refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 mAb], or penta-refractory (refractory to 2 PIs, 2 IMiD agents, and an anti-CD38 mAb) demonstrate low response rates to salvage therapies and have poor overall prognosis (2). Therefore, there is a substantial need for new therapies for treatment of patients with myeloma that is refractory to main classes of agents such as proteasome inhibitors, immunomodulatory agents and anti-CD38 antibodies.

Idecabtagene vicleucel is the first chimeric antigen receptor (CAR) T-cell product approved for the treatment of multiple myeloma. On March 26, 2021, after a priority review, the FDA granted regular approval to idecabtagene vicleucel for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 mAb. The efficacy of idecabtagene vicleucel was established in KarMMa (NCT03361748), a single-arm, multicenter trial, based on the overall response rate (ORR), complete response (CR) rate, and the duration of response (DoR) in an advanced patient population. Preliminary data from this trial was the basis for breakthrough therapy designation (BTD) in multiple myeloma, which was granted over 3 years prior to licensure. Herein, we provide a summary of the FDA clinical review and rationale for regular approval of this marketing application.

Idecabtagene vicleucel is a genetically modified T-cell product consisting of autologous T cells transduced with a lentiviral vector (LVV) expressing a CAR targeting the B-cell maturation antigen (BCMA; ref. 3). The CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for BCMA, a human CD8α hinge and transmembrane domain with the 4–1BB and CD3ζ chain T-cell intracellular signaling domains. Binding of the anti-BCMA CAR to BCMA-expressing target cells leads to signaling through the CD3ζ and 4–1BB domains, and subsequent CAR T-cell activation. Antigen-specific activation results in CAR T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

The recommended dose is a single infusion of 300–460 × 10⁶ CAR-positive T cells. To facilitate CAR T-cell engraftment and expansion, lymphodepleting chemotherapy is administered prior to infusion. Cyclophosphamide 300 mg/m² i.v. and fludarabine 30 mg/m² i.v. are administered for 3 days. Idecabtagene vicleucel is administered 2 days after completion of lymphodepleting chemotherapy.

The basis of approval was a single-arm, open-label, multicenter phase II trial [KarMMa (NCT03361748)] in adults with relapsed and refractory multiple myeloma, with a primary efficacy endpoint of ORR per independent response committee (IRC) based on International Myeloma Working Group (IMWG) Consensus Criteria, 2016 (4). Eligible patients had received at least three prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor and anti-CD38 antibody with disease that was refractory to the most recent line of therapy. The study required an Eastern Cooperative Oncology Group performance status (ECOG PS) < 2, creatinine clearance (Cr Cl) >45 mL/minute and hepatic transaminases ≤ 2.5 times the upper limit of normal. Study participants were required to have absolute neutrophil count (ANC) ≥1,000 cells/mm³ and platelet count of ≥50,000/mm³ in the absence of growth factor or transfusion support, respectively. All patients had measurable disease by IMWG 2016 criteria (4) at enrollment.

Antimyeloma bridging therapy was permitted between leukapheresis and up to 14 days prior to initiation of lymphodepleting chemotherapy. Therapies to which patients were not previously exposed could not be used as bridging. However, patients could receive antimyeloma agents they were exposed to in different combinations. All patients were hospitalized for 14 days after CAR T-cell infusion to monitor for potential cytokine release syndrome (CRS) and neurotoxicity.

Of the 135 patients who underwent leukapheresis for the 300 and 450 million dose cohort, 100 patients treated with idecabtagene vicleucel at a dose of 300–460 × 10⁶ CAR⁺ T cells constitute the efficacy evaluable population. The manufacturing failure rate was 1.5%. Ten patients were not treated following leukapheresis, primarily due to progressive disease, death, adverse reactions (AR) and study withdrawal. Two patients died from septic shock and general physical health deterioration after receiving lymphodepletion and prior to receiving idecabtagene vicleucel. The leukapheresis population (n = 135) included 23 patients treated outside of the recommended dose range of 300–460 × 10⁶ CAR⁺ T cells (at dose ranges between 277–300 × 10⁶ and 460.2–518.4 × 10⁶ CAR⁺ T), including 15 patients with an objective response.

Table 1 summarizes the characteristics of the efficacy population. In the efficacy evaluable population (n = 100), the median age was 62 years, 36% were ≥65 years. Only 6% of the efficacy evaluable population was Black or African American. Ninety-five percent of the patients were refractory to an anti-CD38 antibody, 85% were triple class refractory, and 26% were penta-refractory. Although the trial eligibility allowed enrollment of patients after three or more prior lines of therapy, only 12% of the efficacy population had received three prior lines of therapy with remaining 88% having received ≥4 prior lines of therapy (Table 1).

The ORR in the efficacy evaluable population was 72% [95% confidence interval (CI), 62%–81%; Table 2]. The lower limit of the 95% CI was greater than the prespecified null hypothesis rate of 50% for ORR. The stringent complete response rate (sCR) was 28% (95% CI, 19%–38%), the lower limit of the 95% CI was greater than the prespecified null hypothesis rate of 10% for CR.

Overall, the ORR in the leukapheresis population (n = 135) was 64% (95% CI, 56%–72%) with a stringent CR rate of 24% (95% CI, 17%–32%). Confirmation of efficacy in the leukapheresis population indicates that ORR and CR rates are robust.

The minimum follow up duration for all responder patients was 9 months. The response duration tended to be longer in patients with sCR as compared with VGPR and PR. Of the 72 patients who achieved any response, median duration of response was 11 months (95% CI, 10.3–11.4) and an estimated 35% maintained a response for at least 12 months. With a median follow up of 10.7 months in patients with sCR, the estimated median DoR was 19 months (95% CI, 11.4–NE) and an estimated 65% maintained a response for at least 12 months.

Minimal residual disease (MRD) was assessed in the bone marrow samples using a validated next-generation sequencing ClonoSEQ assay. An MRD threshold of 10^–5 was used. MRD negativity—defined as the proportion of patients with CR or sCR and who are MRD negative at any timepoint within 3 months prior to achieving CR or sCR until the time of progression or death—was observed in 75% (95% CI, 55%, 89%) of the sCR patients. Overall, 21% (95% CI, 13%–30%) of the efficacy-evaluable patients attained MRD negativity.

An exploratory analysis was performed to evaluate for dose–response relationship. Within the dose range of 300–460 × 10⁶ CAR⁺ T cells, there is a dose–response relationship noted with numerically higher ORR, sCR rate and median DOR with 440–460 × 10⁶ CAR⁺ T cells compared with 300–340 × 10⁶ CAR⁺ T cells. An ORR of 79% (95% CI, 65%–90%) and sCR rate of 31% (95% CI, 19%–46%) was observed with 440 to 460 × 10⁶ CAR-positive T cells whereas an ORR of 65% (95% CI, 51%–78%) with sCR rate of 25% (95% CI, 14%–39%) was observed in 300 to 340 × 10⁶ CAR-positive T cells.

Safety was evaluated in all 127 patients who received an infusion of idecabtagene vicleucel at a dose range of 150.5–518.4 × 10⁶ CAR⁺ T cells in KarMMa. All patients experienced at least one adverse reaction (AR), and serious ARs were reported in 67% of patients. The most common ARs are shown in Table 3. The fatal AR rate was 6%. Causes of death included CRS with hemophagocytic lymphohistiocytosis (HLH/MAS), lower GI bleeding with grade 4 thrombocytopenia, bronchopulmonary aspergillosis, and CMV pneumonia. The prescribing information for idecabtagene vicleucel contains boxed warnings for cytokine release syndrome (CRS), neurologic toxicities, HLH/MAS, and prolonged cytopenia. Other warnings and precautions in the prescribing information include hypersensitivity reactions, serious infections, hypogammaglobulinemia, secondary malignancies, and, due to the potential for neurologic events, restrictions on driving and other activities.

CRS occurred in 85% of the treated patients and grade ≥3 events occurred in 9% (5). Median time to CRS onset was 1 day (range, 1–23 days). CRS resolved in the majority of patients (99%) with a median time to resolution of 7 days (range, 1–63 days). One patient had fatal CRS. Overall, 54% received tocilizumab and 15% received corticosteroids in addition to tocilizumab for CRS management.

Neurotoxicity occurred in 28% of patients treated with idecabtagene vicleucel in KarMMa with grade 3 events in 4% of the patients. The most common neurologic toxicities (≥5% incidence) included encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%). Seizure was reported in one patient, which was grade 1 and self-limited. All neurologic toxicities occurred within 60 days of treatment and 94% of the patients with neurotoxicity had CRS. Neurologic toxicities were managed with corticosteroids and antiseizure medications. Additional neurologic toxicities reported in other idecabtagene vicleucel trials include cerebral edema, grade 3 myelitis, and grade 3 parkinsonism.

HLH/MAS is a hyperinflammatory syndrome caused by activation of lymphocytes and macrophages that produce high levels of cytokines resulting in immune-related organ failure (6). Five out of 127 (4%) patients treated with idecabtagene vicleucel developed HLH/MAS. Two patients had fatal HLH/MAS: one patient with fatal HLH/MAS in the setting of CRS and another patient who died from bronchopulmonary aspergillosis with ongoing HLH/MAS that caused prolonged neutropenia. Three patients had grade 2 HLH/MAS that resolved. Two patients had overlapping neurotoxicity with HLH/MAS.

Prolonged cytopenia was defined as grade 3 or 4 neutropenia or thrombocytopenia that was persistent for more than 1 month after receiving idecabtagene vicleucel. Overall, 61% of patients developed prolonged cytopenia. The median time to cytopenia recovery was approximately 2 months. Of the three patients (2.4%) who underwent stem cell transplantation for hematopoietic reconstitution, two died from complications of prolonged cytopenia, that is, lower GI bleeding and bronchopulmonary aspergillosis, and the third patient recovered from neutropenia.

Newly diagnosed hypogammaglobulinemia occurred in 41% of patients, which included patients with either an IgG <500 mg/dL on post-treatment laboratory testing or a documented treatment emergent adverse event. In the treated population, 61% of patients received IVIG (intravenous immunoglobulin) therapy for serum IgG level less than 400 mg/dl as needed to maintain an IgG level above 400 mg/dL.

Please refer to the prescribing information of idecabtagene vicleucel for information regarding management of these toxicities (7).

Overall, there was a dose toxicity relationship demonstrated with idecabtagene vicleucel with higher rates of overall CRS (96% vs. 79%), Grade 2 CRS (40% vs. 23%), Grade 3 neurotoxicity (8% vs. 1.4%), HLH/MAS (8% vs. 1%) and prolonged neutropenia (49% vs. 34%) in the 450 × 10⁶ compared with the 300 × 10⁶ CAR⁺ T-cell dose cohorts, respectively.

This is the first FDA approval of a BCMA-targeted CAR T-cell therapy for multiple myeloma. Approval was supported by results of a single arm, open label, multi-center study demonstrating ORR of 72% (95% CI, 62%–81%) and CR rate of 28% (95% CI, 19%–38%) with durability in a relapsed and refractory population. This product received breakthrough therapy designation with more than 5 meetings between the Agency and Applicant during the span of product development.

The Applicant had proposed a target dose of 450 × 10⁶ within a range of 150–540 × 10⁶ CAR⁺ T cells. However, the actual administered dose ranged from 150.5 to 518.4 × 10⁶ CAR⁺ T cells. Additional analyses were performed to identify a dose range that was efficacious. Only four patients were treated in the 150 × 10⁶ CAR⁺ T-cell dose cohort in KarMMa. In addition, of the two responders in this dose cohort, response was durable in only one patient. For the remainder of the dose ranges, we analyzed efficacy at smaller dose range subsets in increments of 10 million and compared the lower bounds of the 95% CI for ORR against the criteria for efficacy (ORR >50%). The majority of the patients were treated between 300–310 and 450–460 × 10⁶ CAR⁺ T-cell dose and the efficacy of these two dose ranges were supported by a lower bound of 95% CI exceeding null for both ORR and CR rate. Doses below 300 and above 460 × 10⁶ CAR⁺ T cells had limited sample size with inadequate data to support efficacy. Although the dose range of 310–450 × 10⁶ CAR⁺ T cells had limited sample size such that the lower bounds of the 95% CI were below the proposed null, this dose range was considered efficacious based on extrapolation of the efficacy observed in the dose ranges below (300–310 million) and above this dose range (450–460 million).

The Applicant's proposed indication for this product was the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Although patients with R/R myeloma who had received at least three prior lines of therapy were eligible for the study, 88% of the efficacy evaluable population had received four or more lines of therapy with a median of 6 prior lines of therapy. Given the limited data to establish the benefit risk in patients who received 3 prior lines, the indication was restricted to patients after at least 4 prior lines of therapy.

In consideration of granting regular approval to idecabtagene vicleucel in relapsed or refractory myeloma, the review team considered the magnitude of benefit observed, specifically the determination that median DOR was 11 months in all responders with an ORR of 72% and response duration of at least 12 months in an estimated 65% of the stringent CR patients (sCR rate of 28%). This magnitude of treatment effect constituted clinical benefit in the indicated patient population. Idecabtagene vicleucel is a single infusion administration which eliminates need for repeated administrations potentially improving patient compliance and convenience.

In general, there are differences that exist across programs in allowance of bridging therapy based on the study population, disease characteristics and manufacturing time. Key aspects of the protocol that ensured that the efficacy assessment based on ORR was not confounded by the effects of bridging include restricting bridging to therapies that were received prior to study enrollment and requirement for restaging postbridging and prior to CAR T-cell administration. Eighty-seven percent of the treated population required bridging therapy; reflecting the refractory nature of the treated population and the median time from leukapheresis to product availability of 33 days. The median duration of bridging therapy was 15 days with range of 1–33 days. The ORR to bridging therapy was low at 4%. Out of the 100 efficacy-evaluable patients, four did not have measurable disease after receiving bridging. Patients without measurable disease after bridging were considered unevaluable for the purpose of efficacy assessment as it would be difficult to isolate the treatment effect of CAR T-cell therapy in a single-arm trial. A randomized comparator with a time-to -event endpoint would be necessary to characterize efficacy in these patients. These patients were included in the denominator for calculation of response rates.

To ensure safety of the study participants, investigators and the study staff underwent training in the management of CRS and neurotoxicity. All study participants underwent in-patient monitoring for 14 days posttreatment followed by close outpatient follow up. The protocol required that tocilizumab be available for CRS management prior to CAR T-cell infusion and included detailed management guidelines for CRS and neurotoxicity. To inform prescribers regarding the life-threatening and fatal adverse reactions, the label includes a boxed warning for CRS, neurologic toxicities, HLH/MAS and prolonged cytopenia. FDA determined that a Risk Evaluation and Mitigation Strategy (REMS) was necessary to ensure the safe use of idecabtagene vicleucel and maintain a favorable benefit risk profile. Given the new safety signal of HLH/MAS and prolonged cytopenia with fatal outcomes despite rescue hematopoietic stem cell transplantation, the Applicant's proposed REMS training material was modified to include education material for providers regarding these toxicities in addition to CRS and neurotoxicity.

The prescribing information for idecabtagene vicleucel recommends that patients receiving this product should be monitored at least daily for 7 days following infusion at a certified health care facility. Furthermore, patients should remain within proximity of that health care facility for at least 4 weeks following infusion to ensure prompt evaluation and management of toxicities. The feasibility and logistics of product handling at these facilities was considered by the manufacturing review team.

The safety data from this trial has to be evaluated in the context of the relatively strict eligibility criteria for the study population. Only 7% of the patients had creatinine clearance <45 mL/minute and 2.4% had an ECOG PS 2. Few patients (3%) ≥75 years or older were enrolled to characterize the efficacy and safety in this age group. Similarly, only 5% of the treated population was African American limiting the safety and efficacy data in this subgroup. The postmarketing observational study described below will collect additional safety and efficacy data from patients treated with idecabtagene vicleucel in the real-world setting.

There are two main potential safety concerns related to the viral vector with idecabtagene vicleucel. The first is the possibility of vector integration into the host genome resulting in either activation of cellular proto-oncogenes or disruption of a tumor suppressor gene resulting in the development of secondary malignancies. The second concern is the generation of replication-competent lentivirus during the manufacturing process for idecabtagene vicleucel that may result in uncontrolled proliferation of genetically modified T cells. These concerns warrant long-term safety follow up posttreatment.

Therefore, a postmarketing requirement (PMR) study was issued that requires 15 years of follow-up for patients treated with idecabtagene vicleucel to assess its long-term toxicities. This observational PMR will also capture the incidence and severity of CRS, HLH/MAS, prolonged cytopenia including the number of patients who require rescue stem cell transplantation and the outcomes in terms of hematopoietic reconstitution and survival. Also, since all grade 3 neurological toxicities in KarMMa occurred in patients ≥65 years (older adults), this study will also capture the incidence and severity of neurologic toxicities in older adults.

Multiple myeloma has two-three-fold higher incidence in the African American compared to the White population with a higher disease related mortality (8, 9) Approximately 20% of the population diagnosed with myeloma in the US is African American. However, in Study KarMMa, only 5% of the treated population were Black or African American. Underrepresentation of this racial minority occurred despite 73% of the KarMMa study population enrolling from U.S. sites. To address this issue, the FDA recommended a post marketing commitment study to further characterize the efficacy and safety of idecabtagene vicleucel in the African American/Black population from ongoing studies.

The efficacy results from the KarMMa trial have established the clinical benefit of idecabtagene vicleucel in patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy with previous exposure to a proteasome inhibitor, immunomodulatory agent and anti-CD38 antibody therapy. Key safety issues include CRS, HLH/MAS, neurologic toxicity, and prolonged cytopenia. The magnitude and durability of response, and rigorous risk mitigation measures support an overall favorable benefit‐risk profile in the indicated patient population with limited therapeutic options (refer to Table 4). Idecabtagene vicleucel represents a new therapeutic option for patients with relapsed and refractory multiple myeloma.

No disclosures were reported.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.