Idecabtagene Vicleucel in relapsed and refractory multiple myeloma

April 2021 Pharma News Tom Feys

The B-cell maturation antigen (BCMA)–directed CAR T cell idecabtagene vicleucel (ide-vic) induced responses in a majority of heavily pre-treated patients with relapsed refractory multiple myeloma (RRMM) with a quarter of patients obtaining a minimal residual disease (MRD) negative status. Unfortunately, toxicity is an issue with almost all patients experiencing grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome (CRS).

Editor’s pick by Achiel van Hoof, haematologist, AZ Sint-Jan

Despite treatment advances in multiple myeloma, relapses are common.1-6 No standard of care has been established for patients who have disease progression despite receiving the three main classes of myeloma therapy; immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies. Chimeric antigen receptor (CAR)–modified T cells are a promising new treatment, and CD19-directed CAR T cells are approved for B-cell cancers.7,8 The B-cell maturation antigen (BCMA)–directed CAR T cell idecabtagene vicleucel (ide-cel, also called bb2121) previously showed promising efficacy in a phase 1 study involving RRMM patients.9 These results prompted the phase II KarMMa study in which the efficacy and safety of ide-cel was assessed in patients with triple-class-exposed RRMM.10

The study enrolled 140 adult patients with measurable disease after at least three previous regimens, 128 patients received ide-cel target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells (12 patients discontinued the study before infusion). Patients were heavily pre-treated with a median of 6 previous antimyeloma regimens (94% had received previous a autologous HSCT). A total of 108 patients was triple refractory, 77 had a disease that was penta-exposed, and 33 patients even had penta-refractory disease.11

At a median follow-up of 13.3 months, 73% had a response (p<0.001), including a complete response or better in 33%. At the target doses of 150×106, 300×106, and 450×106 CAR+ T cells, a response was observed in 2 of 4 patients, in 48 of 70 patients, and in 44 of 54 patients, respectively. A CR or better was observed in 1 of 4 patients, in 20 of 70 patients and in 21 of 54 patients. The median time to first response was 1.0 month, with a median time to a complete response or better was 2.8 months. Efficacy after a single ide-cel infusion was encouraging, with a median response duration of 10.7 months, a median progression free survival (PFS) of 8.8 months, and a median overall survival (OS) of 19.4 months across treated patients. The median response duration and PFS were longer at the 450×106 dose (11.3 months and 12.1 months, respectively). Increased depth of response was also associated with improved response durability. In fact, patients with a complete or stringent complete response had a longer median response duration at 19.0 months. MRD negativity was evaluated in bone marrow aspirates by next-generation sequencing with a minimum cut-off of 10−5 nucleated cells, and was confirmed in 33 patients (i..e 26% of all 128 patients who were treated and 79% of the 42 patients who had a CR or better.

Adverse events (AEs) were reported in all 128 patients treated with ide-cel, with grade 3 or 4 events occurring in 127 patients (99%). Most AEs, with the exception of hypogammaglobulinemia and infections, occurred within the first 8 weeks after infusion. Most grade 3 or 4 events were hematologic toxic effects, including neutropenia (89%), anaemia (60%), and thrombocytopenia (52%), and were at least partially related to the lymphodepleting chemotherapy administered before ide-cel infusion. DRS was reported in 84%, including 5% who had events of grade 3 or higher. Neurotoxic effects developed in 18% and were of grade 3 in 3%; no neurotoxic effects higher than grade 3 occurred. A total of 44 treated patients (34%) died during the study, with most deaths (27) attributed by the investigator to complications of myeloma progression. Three patients died within 8 weeks after ide-cel infusion from ide-cel–related AEs. One patient died between 8 weeks and 6 months from an ide-cel–related AE.

Exploratory end points included levels of cytokines and soluble BCMA (sBCMA) as well as tumour BCMA expression. Nearly all tumours expressed BCMA, a finding that supports the use of ide-cel in RRMM without restriction based on tumour BCMA expression. Baseline sBCMA levels were elevated in treated patients and decreased rapidly after infusion in patients who had a response, with nadir values achieved within 3 months. Achievement of undetectable sBCMA levels increased with depth of response. Nearly all patients who could be evaluated had elevated sBCMA values (97%) and still had detectable levels of tumour BCMA (93%) at the time of myeloma progression, findings that suggest that BCMA antigen loss is an uncommon mechanism of escape from ide-cel.

Ide-cel showed durable persistence in blood, with 36% of evaluable patients having detectable CAR+ T cells at 12 months. Higher CAR+ T-cell expansion was associated with increased depth of sBCMA reduction. Median CAR+ T-cell expansion increased at higher target doses and was associated with longer PFS. The presence of these cells did not guard against recurrence; it is unclear whether the myeloma cells became resistant to the CAR T cells or the T cells became functionally compromised in some way.

In summary, Ide-cel induced responses in a majority of heavily pre-treated patients with RRMM. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. Determination of long-term disease-free survival with ide-cel requires additional follow-up.

References

  1. Braggio, E., et al. Cancer Cell, 2015
  2. Nijhof, I.S., et al. Drugs, 2018
  3. Chari, A., et al. N Engl J Med, 2019
  4. Fulciniti, M., et al. Biomed Res Int, 2015
  5. Gandhi, U.H., et al. Leukemia, 2019
  6. Mikhael, J., et al. Clin Lymphoma Myeloma Leuk, 2020
  7. Holstein, S.A., et al. Clin Pharmacol Ther,2020
  8. Sidana, S., et al. Blood adv, 2019
  9. Raje, N, et al. N Engl J Med, 2019
  10. Munshi, N.C., et al. N Engl J Med, 2021
  11. Kumar, S., et al. Lancet Oncol, 2016
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