Relapsed/refractory patients,   General MM

Ongoing trials of chimeric antigen receptor (CAR) therapy in multiple myeloma

Throughout January and February, the Multiple Myeloma (MM) Hub are focusing on the topic of chimeric antigen receptor (CAR) therapy. CAR therapy has traditionally been developed using patient-derived T-cells (CAR T-cell therapy) directed at a single cell surface antigen, though new approaches include dual targeting CAR T-cells, allogeneic CAR T-cells, and the use of natural killer (NK) cells instead of T-cells. Most CAR T-cell therapies are aimed at treating patients with relapsed/refractory (R/R) MM (RRMM), however there are some trials in the newly diagnosed (ND) setting. The MM Hub have conducted a thorough search of Clinicaltrials.gov for ongoing studies using CAR approaches to treat MM. This article summarizes some of the most interesting and promising ongoing studies.  

CAR T-cell therapy: phase III trials

Most CAR T-cell approaches for MM target one cell surface antigen, most commonly the B-cell maturation antigen (BCMA). The most clinically advanced trials in MM are using the anti-BCMA CAR T-cell products bb2121 and JNJ-68284528 (JNJ-4528).1,2 Details of these trials are summarized in Table 1. It should be noted that there is an extensive list of other phase I/II trials on anti-BCMA CAR T-cell products not listed here.

Table 1. Phase III trials of anti-BCMA CAR T-cell therapy in RRMM

CAR T product

Trial name

NCT reference

Details of trial

Status

Founding studies

bb21211

KarMMa-3

NCT03651128

Arm A: bb2121 (est. enrolment: 254)

Arm B: SOC therapy – DPd, DVd or IRd (est. enrolment: 127)

Primary outcome: PFS

Recruiting

KarMMa

JNJ-45282

CARTITUDE-4

NCT04181827

Arm A: SOC therapy PVd or DPd

Arm B: JNJ-4528

Primary outcome: PFS

Not yet recruiting

CARTITUDE-1 and LEGEND-2

BCMA; B-cell maturation antigen, DPd; daratumumab, pomalidomide, and low-dose dexamethasone, DVd; daratumumab, bortezomib, and low-dose dexamethasone, est.; estimated, IRd; ixazomib, lenalidomide, and low-dose dexamethasone, PFS; progression-free survival, PVd; pomalidomide, bortezomib, and low-dose dexamethasone, RRMM; relapsed/refractory multiple myeloma, SOC; standard of care

CAR T-cell therapy: non BCMA single target trials in RRMM

Whilst the current phase III trials of CAR T in MM target BCMA, CAR T products targeting other cell surface antigens are also in development. These include CD138 and SLAMF7 and some examples of these are shown in Table 2.

Table 2. Phase I/II studies of single-targeting, non-anti-BCMA CAR T-cell therapy in patients with RRMM

CAR T product (where given)

Phase

NCT reference

Antigen target

Main primary outcome

Patient population

Unnamed product3

I

NCT03958656

SLAMF7 (also known as CS1)

Safety by frequency of AEs

Patients with RRMM (≥3 prior regimens)

ATLCAR.CD138 cells4

I

NCT03672318

CD138

Proportion of participants with DLTs as a measure of MTD

RRMM (up to 2 treatment lines if refractory to both IMiD and PI)

MLM-CAR44.1 T-cells5

I/II

NCT04097301

CD44v6

MTD and recommended phase IIa dose

RRMM (≥4 different prior treatments in 3 treatment lines, or 4 treatments in 2 treatment lines in early relapsing patients)

CAR2 anti-CD38 A2 CAR-T Cells6

I

NCT03464916

CD38

Determine the MTD

RRMM (following prior lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab) or RRMM (within 1 year of high-dose therapy/ASCT in first- or second-line)

Unnamed product7

I

NCT04162340

CD4

Determine toxicity profile by number of AEs

RRMM having exhausted standard therapeutic options

AE; adverse event, ASCT; autologous stem cell transplant, CAR; chimeric antigen receptor, DLT; dose limiting toxicity, IMiD; immunomodulatory agent, MTD: maximum tolerated dose, R/R; relapsed/refractory, PI; proteasome inhibitor

CAR T-cell therapy in different patient settings

As mentioned, bb2121 and JNJ-4528 are two of the most well-studied CAR T-cell therapies for patients with advanced RRMM. However, these agents, amongst others, are also being explored in early lines of therapy, as detailed in Table 3.

Table 3. Currently recruiting CAR T-cell trials not exclusively for patients with advanced RRMM

CAR T product

Trial name

Phase

NCT reference

Main primary outcome

Patient population

bb21218

 

With lenalidomide maintenance

KarMMa-4

I

NCT04196491

Rate of DLTs

High-risk NDMM defined as R-ISS stage III per IMWG criteria

JNJ-45289

 

Cohort D will also receive lenalidomide maintenance

CARTITUDE-2

II

NCT04133636

Percentage of patients with negative MRD status

Cohort A: PD after 1-3 lines of therapy

Cohort B: Early relapse after frontline therapy

Cohort C: RRMM after PI, IMiD, dara, and anti-BCMA therapy

Cohort D: NDMM after ASCT front-line therapy 

Anti-BCMA CAR T +/- huCART1910

Not listed

I

NCT03549442

Number of AEs

Patients responding to first- or second-line therapy for high-risk MM

ASCT; autologous stem cell transplant, AE; adverse event, BCMA; B-cell maturation antigen, CAR; chimeric antigen receptor, CR; complete response, dara; daratumumab, DLT; dose limiting toxicity, IMiD; immunomodulatory drug, IMWG; International Myeloma Working Group, MM; multiple myeloma, MRD; measurable residual disease, NDMM; newly diagnosed multiple myeloma, PD; progressive disease, PI; proteasome inhibitor, R-ISS; revised International Staging System, RRMM; relapsed/refractory multiple myeloma

CAR T-cell therapy trials with additional agents

One way to maximize the efficacy of CAR T-cell therapy may be to combine CAR T-cells with other agents, such as a gamma secretase inhibitor (GSI). The use of GSI is believed to increase expression of BCMA on the myeloma cell surface, whilst also decreasing the levels of soluble BCMA in circulation, overall leading to increased efficacy of anti-BCMA CAR T.11 Some further examples of these approaches are given in Table 4.

Table 4. Phase I anti-BCMA CAR T approaches in combination with additional agents

NCT reference

Additional agent

Main primary outcome

Patient population

Status

NCT0350257711

Gamma secretase inhibitor (JSMD194)

Determine the MTD

RRMM following ASCT or transplant, ineligible patients with persistent disease after 4 cycles of induction that are refractory to both PI and IMiD therapy

Recruiting

NCT0394347212

Immune inhibitors

Safety (by number of AEs)

RRMM following ≥3 prior therapies including alkylating agents, PIs, and IMiDs with disease progression in the past 60 days

Not yet recruiting

NCT0307032713

Lenalidomide

Determine the MTD of CAR T-cells

RRMM following >2 prior lines of treatment including IMiD and PI with refractory, persistent or progressive disease

Active, not recruiting

AE; adverse events, ASCT; autologous stem cell transplant, BCMA; B-cell maturation antigen, CAR; chimeric antigen receptor, IMiD; immunomodulatory drug, MTD; maximum tolerated dose, PI; proteasome inhibitor, R2PD; recommended phase II dose, RRMM; relapsed/refractory multiple myeloma

CAR T-cell therapy: dual/multiple target

Whilst targeting one cell surface antigen has proven efficacious so far, it is hypothesized that targeting more than one antigen may increase efficacy of CAR T therapy further. Targeting more than one antigen increases coverage and eradication of myeloma cells before resistance can develop or antigen escape occurs.14

Results from some dual targeting approaches have already been presented at medical congresses, such as the SZ-CART-MM02 study (NCT03455972), presented during the 45th meeting of the European Society for Blood and Marrow Transplantation (EBMT). The treatment regimen included induction therapy and autologous stem cell transplant, followed by the administration of anti-CD19 and anti-BCMA CAR T-cells in patients with high-risk NDMM. Read more on the MM Hub here.15

Examples of trials using dual-targeting approaches for patients with RRMM can be found in Table 5.

Table 5. Dual antigen targeting CAR T-cell trials for patients with RRMM

CAR T product (where given)

Phase

NCT reference

Antigen targets

Main primary outcome

Patient population

Status

BCMA-CS1 cCAR T cells14

I

NCT04156269

BCMA and CS1

Number of patients with DLT

RRMM having exhausted standard therapeutic options

Recruiting

BCMA-CD19 cCAR T cells16

I

NCT04162353

BCMA and CD19

Number of AEs

RRMM having exhausted standard therapeutic options

Recruiting

Unnamed17

I/II

NCT03767751

BCMA and CD38

Number of patients with AEs and SAEs

 

Recruiting

AE; adverse event, BCMA; B-cell maturation antigen, BM; bone marrow, cCAR; compound chimeric antigen receptor, DLT; dose limiting toxicity, MTD; maximum tolerated dose, PB; peripheral blood, RRMM; relapsed/refractory multiple myeloma, SAE; severe adverse event

Allogeneic CAR T-cell therapy

Allogeneic CAR T-cell therapies are generated from healthy donor T-cells, as opposed to traditional CAR T therapy which uses the patient’s own T-cells (autologous). This approach is hypothesized to overcome some of the challenges experienced with traditional CAR T therapy such as the potentially long time between apheresis and product manufacturing, during which time a patient’s condition can deteriorate. Read more about allogeneic CAR T therapy, the differences between allogeneic and patient-derived approaches, and the advantages and limitations on the MM Hub here.

In April 2019, the United States (U.S.) Food & Drug Administration (FDA) approved an Investigational New Drug (IND) for UCARTCS1, an allogeneic CAR T therapy targeting CS1, for the treatment of RRMM.18 Subsequently, in January 2020, the U.S. FDA approved an IND application and granted Orphan Drug Designation to PBCAR269A, another allogeneic CAR T-cell therapy.19  In preclinical models, the pharmaceutical company responsible for the development of PBCAR269A reported no evidence of graft-versus-host disease (GvHD). GvHD is a common cause of non-relapse mortality following stem cell transplant, one of the key treatments used for MM, which CAR T has the potential to replace or consolidate. Further information on these trials, and other allogeneic CAR T-cell approaches for RRMM, are shown in Table 6.

Table 6. Allogeneic CAR T-cell clinical trials for patients with RRMM

CAR T product and NCT reference

Study name

Phase

Antigen target

Main primary outcome

Patient population

Status

PBCAR269A20

NCT04171843

PBCAR269A-01

I/IIa

BCMA

MTD

RRMM following 2 prior therapies, including IMiD, PI, and anti-CD38 antibody

Not yet recruiting

UCARTCS121

NCT04142619

MELANI-01

I

CS1

Safety by number of AEs and SAEs

RRMM

Recruiting

ALLO-71522

+/- ALLO-647 (an anti-CD52 mAb)

NCT04093596

UNIVERSAL

I

BCMA

DLTs

RRMM after >3 prior therapies including PI, IMiD, and anti-CD38 antibody

Recruiting

AE; adverse event, BCMA; B-cell maturation antigen, IMiD; immunomodulatory drug, mAb; monoclonal antibody, MM; multiple myeloma, MTD; maximum tolerated dose, PI; proteasome inhibitor, RRMM; relapsed/refractory multiple myeloma, SAE; serious adverse event

CAR NK-cell therapy

NK cells are being investigated as an alternative to traditional T-cell approaches, in order to overcome common adverse events of CAR T therapy, such as cytokine release syndrome. There is currently one trial in China investigating CAR NK cells for patients with MM that is listed as ‘recruiting’ on the clinical trials database. NCT03940833 is a phase II study of anti-BCMA CAR-NK 92 cells in patients with RRMM. The primary outcome is occurrence of treatment-related adverse events (TRAE).23

Re-infusion of CAR T following previous CAR T therapy

One trial, that is currently listed as active but not recruiting, is also investigating the use of anti-BCMA CAR T cells as a treatment for patients with recurrence and progression following previous CAR T-cell therapy. NCT03672253 is a phase I trial using anti-BCMA CAR T-cells  in patients with RRMM, with a primary outcome of the occurrence of TRAEs.24

Regulatory approvals

Whilst no CAR T-cell therapy is currently approved by either the U.S. FDA or the European Medicines Agency (EMA) for use in patients with MM, several significant regulatory designations have been granted, making an approval of a CAR T product in MM likely in the coming months/years, subject to further data being presented. Some of the most significant regulatory designations are shown in Table 7 below.

Table 7. Regulatory designations for CAR T therapy in MM

CAR T product

Regulatory approval body

Designation

Link to article

bb212125

EMA

PRIME

Read more

bb212126

U.S. FDA

Breakthrough therapy

Read more

JNJ 452827

EMA

PRIME

Read more

JNJ 452828

U.S. FDA

Breakthrough therapy

Read more

CT05329

U.S. FDA

RMAT

Read more

P-BCMA-10130

U.S. FDA

RMAT

Read more

EMA; European medicines agency, FDA: Food & Drug Administration, PRIME; priority medicines designation, RMAT; regenerative medicine advanced therapy, U.S.; United States

Conclusions

There are multiple different approaches being investigated to increase the efficacy of CAR T therapies in MM. Whilst some CAR constructs are in promising phase III trials, others are in early stage phase I studies. Regardless of this, ultimately CAR T therapy promises a new treatment option for heavily pretreated patients with MM, with the potential to move into earlier lines of therapy. The next few years will seek to answer the unknown questions, bringing clarity and potentially regulatory approvals, allowing patients with myeloma to access this new therapy.

References
  1. Clinicaltrials.gov. Efficacy and Safety Study of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3). https://clinicaltrials.gov/ct2/show/NCT03651128 [Accessed 2020 Jan 21]
  2. Clinicaltrials.gov. A Study Comparing JNJ-68284528, a CAR-T Therapy Directed Against B-cell Maturation Antigen (BCMA), Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Participants With Relapsed and Lenalidomide-Refractory Multiple Myeloma (CARTITUDE-4). https://clinicaltrials.gov/ct2/show/NCT04181827 [Accessed 2020 Jan 21]
  3. Clinicaltrials.gov. T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03958656. [Accessed 2020 Jan 21]
  4. Clinicaltrials.gov. Study of ATLCAR.CD138 Cells for Relapsed/Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03672318 [Accessed 2020 Jan 21]
  5. Clinicaltrials.gov. Study of CAR T-cell Therapy in Acute Myeloid Leukemia and Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT04097301 [Accessed 2020 Jan 21]
  6. Clinicaltrials.gov. Study to Evaluate the Safety and Efficacy of Anti-CD38 CAR-T in Relapsed or Refractory Multiple Myeloma Patients. https://clinicaltrials.gov/ct2/show/NCT03464916 [Accessed 2020 Jan 21]
  7. Clinicaltrials.gov. CD4-specific CAR T Cells (CD4 CAR T Cells) for Relapsed/Refractory T Cell Malignancies. https://clinicaltrials.gov/ct2/show/NCT04162340 [Accessed 2020 Jan 21]
  8. Clinicaltrials.gov. A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM) (KarMMa-4) (KarMMa-4). https://clinicaltrials.gov/ct2/show/NCT04196491 [Accessed 2020 Jan 21]
  9. Clinicaltrials.gov. A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-cell Maturation Antigen (BCMA) in Participants With Multiple Myeloma (CARTITUDE-2). https://clinicaltrials.gov/ct2/show/NCT04133636 [Accessed 2020 Jan 21]
  10. Clinicaltrials.gov. Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03549442 [Accessed 2020 Jan 21]
  11. Clinicaltrials.gov. BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03502577 [Accessed 2020 Jan 22]
  12. Clinicaltrials.gov. BCMA Chimeric Antigen Receptor Expressing T Cells Therapy for Relapsed/Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03943472 [Accessed 2020 Jan 22]
  13. Clinicaltrials.gov. BCMA Targeted CAR T Cells With or Without Lenalidomide for the Treatment of Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03070327 [Accessed 2020 Jan 22]
  14. Clinicaltrials.gov. BCMA-CS1 Compound CAR (cCAR) T Cells for Relapsed/Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT04156269 [Accessed 2020 Jan 22]
  15. Shi X. et al. Tandem auto-SCT and combined infusion of CD19 and BCMA-specific CART cells for high risk MM. Abstract OS12-1 and oral presentation. 2019 March 27. 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
  16. Clinicaltrials.gov. BCMA-CD19 cCAR in Multiple Myeloma and Plasmacytoid Lymphoma. https://clinicaltrials.gov/ct2/show/NCT04162353 [Accessed 2020 Jan 22]
  17. Clinicaltrials.gov. A Feasibility and Safety Study of Dual Specificity CD38 and BCMA CAR-T Cell Immunotherapy for Relapsed or Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03767751 [Accessed 2020 Jan 22]
  18. Intrado. Precision BioSciences Announces FDA Acceptance of IND for PBCAR269A, a BCMA Targeted Genome Edited Allogeneic CAR T Therapy Candidate for Multiple Myeloma. https://www.globenewswire.com/news-release/2020/01/13/1969425/0/en/Precision-BioSciences-Announces-FDA-Acceptance-of-IND-for-PBCAR269A-a-BCMA-Targeted-Genome-Edited-Allogeneic-CAR-T-Therapy-Candidate-for-Multiple-Myeloma.html [Accessed 2020 Jan 16]
  19. Global Banking & Finance review. FDA Clears the IND for UCARTCS1, the First Allogeneic CAR-T to Treat Multiple Myeloma Patients. https://www.globalbankingandfinance.com/fda-clears-the-ind-for-ucartcs1-the-first-allogeneic-car-t-to-treat-multiple-myeloma-patients/  [Accessed 2020 Jan 16]
  20. Clinicaltrials.gov. A Dose-escalation Study to Evaluate the Safety and Clinical Activity of PBCAR269A in Study Participants With Relapsed/Refractory Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT04171843 [Accessed 2020 Jan 16]
  21. Clinicaltrials.gov. Study Evaluating Safety and Efficacy of UCART Targeting CS1 in Patients With Relapsed/Refractory Multiple Myeloma (MELANI-01). https://clinicaltrials.gov/ct2/show/NCT04142619 [Accessed 2020 Jan 22]
  22. Clinicaltrials.gov. Safety and Efficacy of ALLO-715 BCMA Allogenic CAR T Cells in in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL) (UNIVERSAL). https://clinicaltrials.gov/ct2/show/NCT04093596 [Accessed 2020 Jan 22]
  23. Clinicaltrials.gov. Clinical Research of Adoptive BCMA CAR-NK Cells on Relapse/Refractory MM. https://clinicaltrials.gov/ct2/show/NCT03940833 [Accessed 2020 Jan 22]
  24. Clinicaltrials.gov. CAR-T Re-treatment for Refractory/Relapsed Multiple Myeloma. https://clinicaltrials.gov/ct2/show/NCT03672253 [Accessed 2020 Jan 22]
  25. OncLive. FDA Grants BCMA CAR T-Cell Therapy Breakthrough Designation in Myeloma.http://www.onclive.com/web-exclusives/fda-grants-bcma-car-tcell-therapy-breakthrough-designation-in-myeloma [Accessed 2020 Jan 22]
  26. Pharmaceutical Technology. bb2121 receives EMA PRIME eligibility and FDA BTD for multiple myeloma. https://www.pharmaceutical-technology.com/news/bb2121-receives-ema-prime-eligibility-fda-btd-multiple-myeloma/ [Accessed 2020 Jan 22]
  27. Pharmaphorum. EU regulators to fast-track Janssen’s multiple myeloma CAR-T. https://pharmaphorum.com/news/eu-regulators-to-fast-track-janssens-multiple-myeloma-car-t/ [Accessed 2020 Jan 22]
  28. PR Newswire. Janssen Announces BCMA CAR-T Therapy JNJ-4528 Granted U.S. FDA Breakthrough Therapy Designation for the Treatment of Relapsed or Refractory Multiple Myeloma. https://www.prnewswire.com/news-releases/janssen-announces-bcma-car-t-therapy-jnj-4528-granted-us-fda-breakthrough-therapy-designation-for-the-treatment-of-relapsed-or-refractory-multiple-myeloma-300970825.html [Accessed 2020 Jan 22]
  29. CARsgen Therapeutics. CARsgen Announces Investigational CAR-T Therapy CT053 Granted RMAT Designation by the U.S. FDA for R/R Multiple Myeloma. Press release 28th October 2019. http://www.carsgen.com/media/news?id=BskN4xpfq8 [Accessed 2020 Jan 22]
  30. Myeloma Research News. FDA Grants Poseida’s P-BCMA-101 RMAT Status for Treatment of Multiple Myeloma. https://myelomaresearchnews.com/2018/11/19/fda-grants-poseidas-p-bcma-101-regenerative-medicine-advanced-therapy-multiple-myeloma [Accessed 2020 Jan 22]
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!
100% of people found this article informative