BMS and bluebird bio’s BCMA CAR-T Therapy Ide-cel Demonstrates Deep and Durable Responses with Meaningful Quality-of-Life Improvements in Relapsed/Refractory Multiple Myeloma

December 08, 2020 News /BioValleyBIOON/ -- Bristol-Myers Squibb (BMS) and its partner bluebird bio recently presented the latest data on idecabtagene vicleucel (ide-cel, bb2121) at the 62nd Annual Meeting of the American Society of Hematology (ASH). Long-term data from the Phase I CRB-401 study demonstrated that ide-cel treatment in patients with relapsed or refractory multiple myeloma (RRMM) yields sustained, deep, and durable responses, with a median overall survival (OS) of 34.2 months. Data from the pivotal registrational Phase II KarMMa study showed clinically meaningful benefits of ide-cel on health-related quality of life, highlighting its potential value in elderly RRMM patients and those with high-risk RRMM.

ide-cel is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy. The drug is currently under regulatory review in the United States and Europe for the treatment of relapsed/refractory multiple myeloma (RRMM), specifically for adult patients with RRMM who have previously received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. In the United States and the European Union, ide-cel has been granted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) status, respectively.

The safety profile was consistent with previously reported results for CRB-401. The most common adverse events were neutropenia (92%) and cytokine release syndrome (CRS, 76%),Anemia(76%) and thrombocytopenia (74%). The most common grade 3/4 adverse events were neutropenia (89%), leukopenia (61%), anemia (57%), and thrombocytopenia (57%). Most CRS events were grade 1 or 2. Four patients (7%) experienced grade 3 CRS; no grade 4 or 5 CRS events were reported.

In this study, among the 62 patients treated with ide-cel, the overall response rate (ORR) was 76%, with 24 patients (39%) achieving a complete response (CR). The median duration of response (DoR) was 10.3 months. The median progression-free survival (PFS) was 8.8 months, the median overall survival (OS) was 34.2 months, and the median follow-up time was 14.7 months. These results continue to demonstrate the potential of ide-cel to provide deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), addressing the significant unmet medical needs in this patient population.

Analysis showed that ide-cel demonstrated deep and durable responses in patients with RRMM who had received 3 classes of drugs. For patients with poor prognosis (including extramedullary disease, high-risk cytogeneticsHeredityAcademic, HighTumorburden) was subjected to subgroup analysis to evaluate the therapeutic efficacy of ide-cel at the target dose level of 150–450 × 10⁶ CAR-positive T cells.In an analysis of 128 patients, ide-cel demonstrated deep and durable responses in most subgroups, including those at highest risk. The overall response rate (ORR) and complete response (CR) rate in most high-risk subgroups were ≥65% and ≥20%, respectively. Furthermore, the median duration of response (DoR) exceeded 9.2 months, and the median progression-free survival (PFS) exceeded 7.5 months in most high-risk subgroups.

A separate subgroup analysis was conducted in elderly patients to evaluate the outcomes of ide-cel treatment. Multiple myeloma is most commonly seen in the elderly population,DiagnosisThe median age was 69 years. Advanced age has been shown to have a negative impact on prognosis and limits treatment options.。Among the 128 patients treated with ide-cel in the KarMMa study, 45 patients (35%) were aged ≥65 years and 20 patients (16%) were aged ≥70 years. The response rates in both age groups were comparable and consistent with those of the overall population treated with ide-cel across all target dose levels, with an ORR of 84%–90% and a CR rate of 31%–35%.

Similarly, the median duration of response (DoR) in patients who achieved disease remission across the two age groups (10.7 months for patients aged ≥65 years and 11.0 months for patients aged ≥70 years) was comparable to that of the overall ide-cel–treated population. The median progression-free survival (PFS) was 8.6 months (95% CI: 4.9–12.2) in patients aged ≥65 years and 10.2 months (95% CI: 3.1–12.3) in patients aged ≥70 years. Furthermore, no new safety signals were observed.。

In the analysis of the impact on health-related quality of life (HRQoL) measurements in patients with relapsed/refractory multiple myeloma (RRMM), ide-cel was associated with clinically meaningful improvements in quality of life (QoL) without impairing any HRQoL domains. From baseline through month 3 to month 15 of the study, most functional and symptom scores showed clinically meaningful improvements in patients, with statistical significance (p<0.05) achieved across different subscales at various time points throughout the follow-up period.

ide-cel is the first BCMA CAR-T cell therapy globally to enter the regulatory review process. Its mechanism involves engineering patients’ T cells to express a chimeric antigen receptor (CAR) targeting BCMA. The manufacturing process includes isolating T cells from each patient’s blood and transducing them with a lentiviral vector encoding the BCMA-specific antigen receptor.CarrierT cells are modified to express the BCMA receptor on their surface. During treatment, patients with multiple myeloma (MM) first receive preconditioning chemotherapy with two agents (cyclophosphamide and fludarabine) to deplete existing T cells in the body, followed by infusion of bb2121. Once infused back into the patient, ide-cel begins to seek out and kill cells expressing BCMA.

ide-cel is part of a co-development, co-commercialization, and profit-sharing agreement between Bristol-Myers Squibb and bluebird bio. The parties’ comprehensive clinical development program for ide-cel includes multiple clinical studies in earlier-line treatment of multiple myeloma (MM), including newly diagnosed MM (KarMMa-2, KarMMa-3, KarMMa-4).

In addition to ide-cel, Bristol-Myers Squibb and bluebird bio are also developing the second-generation anti-BCMA CAR-T therapy bb2127, a product further developed on the basis of the first-generation CAR-T therapy ide-cel. It incorporates a PI3K inhibitory signal to produce a CAR-T product enriched with “memory T cells,” a longer-lived and more potent T-cell subset with improved anti-TumorActivity.

Multiple Myeloma (MM) is the second most common hematologic malignancy, after non-Hodgkin lymphoma.Tumor. In recent years, despite significant advances in chemotherapy, proteasome inhibitors, immunomodulatory thalidomide derivatives, and CD38-targeted antibodies, nearly all patients eventually experience relapse. Therefore, there is an urgent need for new treatment regimens. The MM market is projected to reach $29 billion by 2027.

Investigational Immunotherapies for Multiple Myeloma Targeting BCMA (Source: PMID: 31277554)

B-cell maturation antigen (BCMA) is an extremely important B cellBiomarker, widely expressed on the surface of MM cells, has become a focus in recent years for MM and other hematologic malignanciesTumora highly popular target for immunotherapy. Currently, there are more than 20 immunotherapies developed against BCMA, mainly divided into three categories: chimeric antigen receptor T-cell therapy (CAR-T, BMS/bluebird bio,Novartisrepresented by), bispecific antibodies (BsAb, represented by Amgen), antibody-drug conjugates (ADC,GlaxoSmithKlineas a representative).

This August,GlaxoSmithKline(GSK) The BCMA-targeting antibody-drug conjugate (ADC) Blenrep (belantamab mafodotin, GSK2857916) has received approval in the United States and the European Union for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM) who have previously received multiple therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

Notably, Blenrep is the first BCMA-targeted therapy approved globally. Data from the pivotal Phase II DREAMM-2 study showed that in patients with relapsed/refractory multiple myeloma (R/R MM) who had been heavily pretreated (median number of prior therapies: 7), the overall response rate (ORR) was 31% (n=30/97) in the 2.5 mg/kg dose group and 34% (n=34/99) in the 3.4 mg/kg dose group, representing clinically meaningful outcomes. Data from the DREAMM-1 study demonstrated an ORR of 60% with Blenrep treatment in BCMA-positive R/R MM patients. (Bioon.com)

Original Source: Bristol Myers Squibb and bluebird bio Present Data Highlighting Anti-BCMA CAR T Cell Therapy, Ide-cel, in Relapsed and Refractory Multiple Myeloma at ASH 2020