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2023-08-04T12:18:09.000Z

BCMA-targeted therapies for multiple myeloma part II: CAR T cells

Aug 4, 2023
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Learning objective: After reading this article, learners will be able to cite the main novel therapeutic strategies targeting BCMA being investigated in multiple myeloma.

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Multiple B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapies are currently under investigation for their application in relapsed/refractory multiple myeloma (MM). Here, we summarize the latest on BCMA-targeted CAR T-cell therapies, presenting their up-to-date clinical data.1

In part I of this article series, we covered the latest updates on BCMA antibody-drug conjugates and BCMA-targeted bispecific antibodies which can be found here.

BCMA CAR T-cell therapy

CAR T-cells are autologous CD3+ T-cells that are engineered to contain an extracellular ligand binding domain. These domains are most commonly a single-chain variable fragment of a monoclonal antibody that recognizes tumor-associated antigens on malignant cells. Once activated, it initiates signaling through T-cell activation, the release of proinflammatory cytokines, and cytosis.2

Prior to reinfusion of the modified autologous T-cells, the patient undergoes lymphodepleting conditioning chemotherapy, usually with fludarabine and cyclophosphamide to decrease endogenous T-cells and increase levels of proliferative cytokines interleukin-7 and interleukin-15; thus, creating the most favorable environment for CAR T-cells to expand and action. Similar to bispecific antibodies, there is a risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, with rates of immune effector cell-associated neurotoxicity syndrome tending to be higher with CAR T-cells.2

Two autologous BCMA-targeting CAR T cells have been approved, and multiple are still in clinical development; these are summarized in Table 1.

Table 1. BCMA-targeted CAR T-cell therapy*

BCMA CAR T-cell therapy

Drug information

Latest clinical trial data

ARI0002h

A second-generation academic BCMA-directed CAR-T cell therapy that contains a 4-1BB co-stimulatory domain and a humanized scFv targeting BCMA.

(NCT04309981)

ORR: 96.0%

sCR: 44.4%

VGPR: 18.6%

Median PFS and OS: not reached

CRS: 87.0%3

CC98633

 

An investigational, BCMA-directed CAR T-cell product with a fully human CAR construct manufactured using the NEX-T process.

(NCT04394650)

ORR: 95.1%

>6-month response rate: 75.0%

CRS, any grade: 81.5%

CRS Grade3/4: 1.5%4

Ciltacabtagene autoleucel
(JNJ-68284528, cilta-cel)

Cilta-cel uses a lentiviral vector to create a construct with a CD3ζ activation domain with 4-1BB co-stimulatory domain. The antigen binding domain contains bispecific scFvs targeting VHH1 and VHH2, two distinct BCMA epitopes which increase binding and specificity for BCMA.

Additional information:
Cilta-cel is FDA approved for R/R MM after four or more therapy lines, including a PI, an IMiD, and an anti-CD38 mAb.

CARTITUDE-1

(NCT03548207)

ORR: 97.9%

Median PFS: 34.9 months

36-month estimated OS: 62.9%5

CARTITUDE-4 (NCT04181827)
As-treated population

ORR: 99.0%

≥CR: 86.0%

12-month PFS rate: 90.0%

SAE: 44.2%6

Equecabtagene autoleucel
(CT103A)

Uses a lentiviral vector containing a CAR construct with a fully human scFv, CD8a hinge and transmembrane, 4-1BB costimulatory- and CD3z activation- domains.

Additional information:
Received both regenerative medicine advanced therapy and fast-track designation from the FDA for the treatment of patients with RRMM.

FUMANBA-1
(NCT05066646)

ORR: 96.0%
≥CR: 74.3%

12-month PFS: 78.8%
CRS: 93.2%
ICANS: 1.9%7

GC012F

A BCMA and CD19 dual-targeting CAR T-cell therapy.

(NCT04935580)

ORR: 93.1%

Median DOR: 37.0 month

MRD negativity: 100%

MRD negativity at 12 months: 78.6%

Median PFS: 38.0 months

CRS event: 86%

CRS ≥Grade 3: 7.0%8

Idecabtagene vicleucel
(Ide-cel, bb2121, abecma)

A second-generation CAR with a lentiviral vector to transduce a BCMA-targeting scFv fused to 4-1BB co-stimulatory and CD3ζ signaling domains.

Additional information:
Ide-cel is approved by the FDA and EMA for RRMM after four or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 mAb.

KARMMA-3

(NCT03651128)

ORR: 71.0%

CR: 39.0%

Median PFS: 13.3 months

AE Grade≥3: 93.0%

SAE: 52.0%9

 

KARMMA-2 (Cohort 2c) (NCT03601078)

ORR: 87.1%

≥CR: 74.2%

Median PFS: 30.7 months

CRS: 58.1%

Neutropenia: 90.3%10

MCARH171

A second-generation CAR T composed of a humanized scFv, a 4-1BB co-stimulatory domain, and a truncated epidermal growth factor receptor safety signal.

(NCT03070327)

ORR: 64.0%

Median DOR: 106 days

CRS Grade 1/2: 40.0%

CRS Grade 3: 20.0%11

Orvacabtagene autoleucel

(JCARH125, orva-cel)

Contains a lentiviral CAR construct with a fully human scFv, an optimized spacer, and 4-1BB co- stimulatory and CD3ζ activation domains.

Additional information:
Commercial development has been halted in favour of a second-generation CAR T (CC-98633) in the hope that bridging therapy wont be needed due to its more rapid production time.

EVOLVE

(NCT03430011)

ORR: 92.0%

≥VGPR: 68.0%

Grade ≥3 CRS: 3.0%

Grade ≥3 infections: 14.0%

Grade ≥3 neutropenia: 55.0%12

Zevorcabtagene autoleucel
(CT053, zevor-cel)

A second-generation CAR utilizing a fully-human BCMA-specific scFv (25C2) with high binding affinity to BCMA bound to 4-1BB co-stimu- latory and CD3ζ activation domains.

LUMMICAR-1 (NCT03975907)

ORR: 100.0%

Grade 1/2 CRS: 91.7%

≥Grade 3 neutropenia: 100.0%13

 

LUMMICAR-2 (NCT03915184)

ORR: 100.0%

Grade 1/2 CRS: 86.0%

≥Grade 3 neutropenia: 100.0%14

AE, adverse event; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICANS, immune effector cell-associated neurotoxicity syndrome; ide-cel, Idecabtagene vicleucel; IMiD, immunomodulatory agent; mAb, monoclonal antibody; MMAF, monomethyl auristatin-F; MRD, measurable residual disease; ORR, overall response rate; OS, overall survival; PI, proteosome inhibitor; PFS, progression-free survival; RRMM, relapsed/refractory multiple myeloma; SAE, serious adverse event; sCR, stringent complete response; scFv, single-chain variable fragment; TEAE, treatment-emergent adverse event; VGPR, very good partial response.
*Adapted from Paul, et al.2

CAR T-cell therapy in combination and bispecific CAR T cells

Combinations of multiple CAR T-cell therapies and CAR T cells targeting multiple antigens are currently in development, with the most popular combination being BCMA and CD19. CD19 expression has been found on a small component of MM cells considered to be less differentiated, and as a result, they may lack usual markers such as BCMA.2

BM38 is a bispecific CAR T-cell therapy that targets BCMA and CD38 and is currently under evaluation in a phase I clinical trial.

Allogenic BCMA CAR T-cells

Allogenic CAR T-cell therapy has multiple advantages over autologous CAR T-cells, including its immediate availability, improved product standardization, redosing and combination treatments, and potential cost savings with a more scalable manufacturing process.2 ALLO-715 is under investigation and a summary of the ongoing phase I trial (NCT04093596) can be found on the Multiple Myeloma Hub.

BCMA CAR natural killer cells

Natural killer (NK) cells are innate immune effector cells independent of antigens and human leukocyte antigen molecules that recognize abnormal cells through a combination of surface stimulatory and inhibitory receptors that target ligands on target cells. NK cells are being investigated as an alternative to T cells for CAR constructs. A significant advantage of this treatment strategy is the ability to transplant mature NK cells into a different host without loss of function or the occurrence of graft-versus-host disease. Several trials are currently investigating these agents.2

Conclusion

BCMA-directed therapies are highly efficacious; however, no agent has proven curative. Each class of agent has its own logistical challenges and unique safety profile. It is thought that T-cell stimulating agents used earlier in therapy may lead to more robust and durable responses, and several studies are currently considering the optimal sequencing of treatment, including trials of BCMA-targeted therapies in newly diagnosed patients with MM. Should a patient progress on a BCMA-targeting therapy, it is still unclear whether benefit could be derived from alternative BCMA-directed therapy. While further research is required to answer these questions, BCMA-directed therapies remain a critical and long-awaited addition to the treatment armamentarium of relapsed/refractory MM.

  1. Moreau P, Touzeau C. T-cell redirecting bispecific antibodies in multiple myeloma: A revolution? Blood. 2022;139(26):3681-3687.DOI: 10.1182/blood.2021014611
  2. Paul B, Rodriguez C, Usmani SZ. BCMA‐targeted biologic therapies: The next standard of care in multiple myeloma therapy. Drugs. 2022;82(6):613-631.DOI: 10.1007/s40265-022-01697-0
  3. de Larrea CF, Gonzalez-Calle V, Cabañas V, et al. Results from a Pilot Study of ARI0002h, an academic BCMA-directed CAR-T cell therapy with fractionated initial infusion and booster dose in patients with relapsed and/or refractory multiple myeloma. Blood. 2021;138 (Suppl. 1):2837. DOI: 10.1182/blood-2021-147188
  4. Costa LJM. Results from the first phase I clinical study of the B-cell maturation antigen (BCMA) Nex T chimeric antigen receptor (CAR) T-cell therapy CC-98633/BMS-986354 in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Oral abstract #366. 64th American Society of Hematology Annual Meeting and Exposition; Dec 10, 2022; New Orleans, US.
  5. Munshi N. CARTITUDE-1 final results: Phase Ib/II study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. Oral abstract #S202. European Hematology Association 2023 Congress; Jun 10, 2023; Frankfurt, DE.
  6. Einsele H. First phase III results from CARTITUDE-4: Cilta-cel versus standard of care (pvd or dpd) in lenalidomide-refractory multiple myeloma. Oral abstract #S100. European Hematology Association 2023 Congress; Jun 10, 2023; Frankfurt, DE.
  7. Li C. CT103A, a novel fully human BCMA-targeting CAR T-cells in patients with relapsed/refractory multiple myeloma: Updated results of phase Ib/II study (FUMANBA-1). Poster #P867. European Hematology Association 2023 Congress; Jun 9-11, 2023; Frankfurt, DE.
  8. Du J. Updated results of a phase I, open-label study of BCMA/CD19 dual-targeting FASTCAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). Poster #P869. European Hematology Association 2023 Congress; Jun 9-11, 2023; Frankfurt, DE.
  9. Rodríguez-Otero P. Idecabtagene vicleucel (ide-cel; bb2121) versus standard regimens in triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): Phase III randomized controlled trial (RCT) KarMMa-3. Oral abstract #BA02-7. 5th European CAR T-cell Meeting; Feb 10, 2023; Rotterdam, NL.
  10. Alsinia M. Idecabtagene vicleucel (ide-cel) in patients with an inadequate response to frontline autologous stem cell transplantation (ASCT): Results from KARMMA-2 cohort 2c. Poster #P871. European Hematology Association 2023 Congress; Jun 9-11, 2023; Frankfurt, DE.
  11. Mailankody S, Ghosh A, Staehr M, et al. Clinical responses and pharmacokinetics of MCARH171, a human-derived BCMA targeted CAR T-cell therapy in relapsed/refractory multiple myeloma: Final results of a phase I clinical trial. Blood. 2018;132(1):959. DOI: 10.1182/blood-2018-99-119717
  12. Mailankody S. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Update of the phase I/II EVOLVE study (NCT03430011). Oral abstract #8504. 2023 American Society of Clinical Oncology Annual Meeting. May 31–Jun 4, 2023. Chicago, US.
  13. Chen W, Fu C, Cai Z, et al. Results from Lummicar-1: A phase I study of fully human B-cell maturation antigen-specific CAR T-cells (CT053) in Chinese subjects with relapsed and/or refractory multiple myeloma. Blood. 2020;136(1):49-50. DOI: 10.1182/blood-2020-140727
  14. Kumar S, Caz, R, Orlowski R, et al. Results from Lummicar-2: A phase Ib/II study of fully human B-cell maturation antigen-specific CAR T-cells (CT053) in patients with relapsed and/or refractory multiple myeloma. Blood. 2020;136(1):28-29. DOI: 10.1182/blood-2020-139802

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