The FDA ( U.S. Food and Drug Administration ) has approved Abecma ( Idecabtagene vicleucel; Ide-cel ) as the first B-cell maturation antigen ( BCMA )-directed chimeric antigen receptor ( CAR ) T cell immunotherapy 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 monoclonal antibody.
Abecma is a personalized immune cell therapy approved as a one-time infusion with a recommended dose range of 300 to 460 x 10(6) CAR-positive T cells.
As an anti-BCMA CAR T cell therapy, Abecma recognizes and binds to BCMA, a protein that is nearly universally expressed on cancer cells in multiple myeloma, leading to the death of BCMA-expressing cells.
Despite advances in treatment, multiple myeloma remains an incurable disease characterized by periods of remission and relapse.
Most patients experience relapse following initial therapies, and depth and duration of response as well as survival outcomes decrease with each successive treatment.
Patients with relapsed or refractory multiple myeloma that have been exposed to all three major drug classes ( triple-class exposed ), including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, tend to demonstrate poor clinical outcomes with very low response rates ( 20% to 30% ), short duration of response ( 2 to 4 months ) and poor survival.
The FDA approval of Abecma is based on data from the pivotal phase II KarMMa trial of 127 patients with relapsed or refractory multiple myeloma who had received at least three prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.
The efficacy evaluable population consists of 100 patients who received Abecma within the dose range of 300 to 460 x 10(6) CAR-positive T cells.
Of these patients, 88% received four or more prior lines of therapy and 85% were triple-class refractory.
In the study, the overall response rate ( ORR ) for the efficacy evaluable population ( n=100 ) was 72% ( 95% CI: 62-81 ), and 28% of patients achieved a stringent complete response ( sCR; 95% CI: 19-38 ).
Responses were rapid and durable, with a median time to response of 30 days ( range: 15 to 88 days ) and median duration of response of 11 months ( 95% CI: 10.3 – 11.4 ) for all responders and 19 months ( 95% CI: 11.4 – NE ) for those who achieved sCR.
Of the 28 patients who achieved sCR, an estimated 65% ( 95% CI: 42% - 81% ) had remission lasting at least 12 months.
In patients treated with Abecma in the KarMMa study, the safety profile was well-established with mostly low-grade occurrence of cytokine release syndrome ( CRS ) and neurotoxicity ( NT ), and predictable early onset and resolution.
Cytokine release syndrome of any grade occurred in 85% ( 108/127 ) of patients using the Lee grading system.
Grade more than 3 cytokine release syndrome occurred in 9% ( 12/127 ) of patients, with grade 5 CRS reported in one patient ( 0.8% ).
The median time to onset of CRS was one day ( range: 1-23 days ) and the median duration of CRS was seven days ( range: 1-63 days ).
The most common manifestations of any grade CRS included pyrexia ( 98% ), hypotension ( 41% ), tachycardia ( 35% ), chills ( 31% ), hypoxia ( 20% ), fatigue ( 12% ), and headache ( 10% ).
Neurotoxicity of any grade occurred in 28% ( 36/127 ) of patients, including grade greater than or equal to 3 events in 4% ( 5/127 ) of patients.
One patient had ongoing grade 2 neurotoxicity at the time of death.
The median time to onset of NT was two days ( range: 1-42 days ).
Neurotoxicity resolved in 33 of 36 patients ( 92% ) with a median time to resolution of five days ( range: 1-61 days ).
Hemophagocytic lymphohistiocytosis ( HLH ) / macrophage activation syndrome ( MAS ), potential complications related to excessive immune activation associated with CAR T cell therapies, occurred in 4% ( 5/127 ) of patients, including one patient who developed fatal multi-organ HLH/MAS with CRS and one patient with fatal bronchopulmonary aspergillosis, with HLH/MAS contributing to the fatal outcome.
Three cases of grade 2 HLH/MAS resolved.
In the study, 41% ( 52/127 ) of patients experienced prolonged grade 3 or 4 neutropenia and 49% ( 62/127 ) of patients experienced prolonged grade 3 or 4 thrombocytopenia.
Three patients underwent stem cell transplant for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia, which occurred in the setting of ongoing or prior severe cytokine release syndrome or HLH/MAS.
The most common ( 20% or more ) types of nonlaboratory adverse reactions included CRS, infections, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.
Serious adverse reactions occurred in 67% of patients, with the most common ( 5% or more ) being cytokine release syndrome ( 18% ), general physical health deterioration ( 10% ), pneumonia ( 12% ), infections ( 19% ), viral infections ( 9% ), sepsis ( 7% ), and febrile neutropenia ( 6% ).
The most common grade 3 or 4 nonlaboratory adverse reactions were febrile neutropenia ( 16% ) and infections ( 14% ).
Fatal adverse reactions occurred in 6% of patients. ( Xagena )
Source: Bristol Myers Squibb & bluebird bio, 2021