The Impact of CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma

The current landscape of treatment options for patients with newly diagnosed or relapsed/refractory multiple myeloma is quite complex with a significant number of new therapies either recently approved or in clinical trials.

As myeloma is not yet considered curable, a patient will experience a series of relapses and require different treatment regimens at various time points in their course.

Initial Treatment of Multiple Myeloma

Initially patients are stratified as either high or standard risk based on fluorescence in situ hybridization (FISH) results. High risk FISH includes translocations t(4:14), t(14:16), t(14:20), and 17p deletion.¹ In addition, eligibility for hematopoietic stem cell transplant is considered by the clinician at the time of the patient’s diagnosis.Regimens for induction therapy are selected based on these factors, as well as patient comorbidities and goals of care. For patients with symptomatic myeloma, initial chemotherapy often includes 3 or 4 drug regimens including an immunomodulatory drug, a proteosome inhibitor, dexamethasone, with or without a CD38-directed monoclonal antibody. Subsequently, based on response, the patient may undergo stem cell collection and transplant or store the cells for a later transplant. Post-transplant, the patient will go on a maintenance program depending on the risk stratification and response.

Eventually, a patient will develop relapsed/refractory disease and require immediate or delayed treatment. No single salvage regimen is the standard of care. At that point, a clinician will consider clinical trial eligibility, prior treatment, response and duration of response, performance status, transplant eligibility, and comorbidities.

Therapies for Relapsed/Refractory Disease

The paradigm for management of relapsed myeloma is evolving rapidly with a plethora of treatment options based on results of clinical trials. These treatments include novel targets such as agents directed against the B-cell maturation antigen (BCMA), bispecific T cell engagers, antibody drug conjugates, CELmods that target cereblon, among others.²

One explosive area of scientific and clinical research is the investigation of chimeric antigen receptor (CAR) T-cell therapy. CAR T cells are genetically modified T cells employing autologous T cells altered ex vivo to express the antigen binding domain for a B cell receptor that is fused to an intracellular domain of CD3 TCR.³

To date, autologous CAR T-cell therapy against B-cell maturation antigen has been the most studied with dramatic efficacy but there are other targets are under investigation in the relapsed/refractory myeloma space. Many of the initial trials have been carried out in the United States and China. BCMA is a member of the tumor necrotic factor receptor superfamily. It is expressed on plasma cells, plasmablasts and activated B-cells.⁴

CAR T-Cell Clinical Trials

Idecabtagene Vicleucel (Ide-cel)

An important phase 1 trial (NCT02658929) reported by Noopur Raje, MD, et al, investigated ide-cel.⁵ This CAR T therapy involved transduction of autologous T cells with a lentiviral vector encoding a second-generation CAR with an anti-BCMA single-chain variable fragment, a CD137 costimulatory motif and a CD3 zeta signaling domain.

Of importance, eligible patients in the study had received at least 3 previous lines of therapy including a proteosome inhibitor and an immunomodulatory agent or were refractory to both classes. In addition, the dose-expansion phase of the study criteria included prior daratumumab treatment as well as demonstration of refractory disease to the most recent treatment. The primary end point was safety.

Results in the first 33 patients showed an overall response rate (ORR) of 85%, with a 45% complete response (CR) rate. Toxicities seen included a high incidence of hematologic effects with anemia, neutropenia, and thrombocytopenia. Cytokine release syndrome was seen in 76% of patients, primarily grades 1 or 2; neurologic toxicity was seen in 42%. Overall, 85% of patients had a clinical response lasting a median of 10.9 months and the median progression-free survival (PFS) was 11.8 months. Some evaluable patients achieved minimal residual disease (MRD) negative status.

An update on the phase 2 KarMMa trial (NCT03361748) was reported in the New England Journal of Medicine on 128 patients who received ide-cel.^6,7 These heavily pretreated patients demonstrated an ORR of 73% after receipt of a single dose of ide-cel post lymphodeleting agents. Patients received targets of 150-450 × 10-6 CAR T cells.

The primary study end point was ORR, with secondary end points of time to response, duration of response, PFS, overall survival, safety, pharmacokinetics and immunogenicity. Hematologic toxicity was common (97%). Cytokine release syndrome occurred in 84%, largely grades 1 or 2. CAR T cells were detected in 59% of evaluable patients at 6 months and 36% at 12 months. Ninety-four of 128 patients had a response with 42/128 with a CR or greater. MRD negative status was confirmed in 33 patients. The median duration of response was 10.7 months and response duration increased with the depth of response. Ide-cel showed persistence in the blood samples with 36% showing detectable CAR T cells at 12 months.

Ciltacabtagene Autocel (Cilta-cel)

CARTITUDE-1 (NCT03548207) was a phase 1b/2 study of JNJ-4528 or cilta-cel. This is a BCMA directed CAR T-cell therapy with 2 BCMA single domain antibodies. At the 2020 American Society of Hematology (ASH) annual meeting, the investigators presented phase 1 and early phase 2 updated data.⁸ The phase 1b portion assessed safety and recommendations for the phase 2 dosing. The phase 2 portion sought to evaluate efficacy in a heavily pretreated relapsed/refractory myeloma population.

Ninety-seven patients who had received a median of 6 lines of therapy were treated and evaluated. The ORR was 94.8% with a single dose of cilta-cel with a stringent CR rate of 55.7%. Fifty-two patients were MRD evaluable, with 94.2 % negative at 10-5. The 6- month PFS rate was 87.4%, with an overall survival rate of 93.8%.

Adverse events reported in over 70% included cytokine release syndrome 94.8%, with grades 3 or 4 in 4.1%. Hematologic toxicity was significant with neutropenia at 90.7%, anemia at 81.4%, and thrombocytopenia at 79.4%. Neurotoxicity was noted in 20.6%, with grades 3 or 4 in 10.3%. Finally, 67% of patients who were evaluated at 6 months had cilta-cel CAR T cells below the level of quantification. The response rates in this group of patients were profound and clinical trials are now looking to move CAR T therapy earlier in the disease with strategies to improve durability of response with decreased toxicity.⁹

Orvacabtagene Autoleucel (Orva-cel)

An additional phase 1/2 clinical trial evaluated orva-cel (JCARH125) lentivirus fully human 4-1BB CAR T-cell therapy in a similar group of patients with relapsed/refractory multiple myelomain the EVOLVE study (NCT03430011). This trial studied BCMA CAR T doses of 300, 450, and 600 × 10-6CAR T cells in patients who had been treated with a median of 6 prior regimens. A 91% objective response rate was noted with a 39% CR rate. Toxicities quite similar to those seen in other BCMA CAR T trials were reported including cytopenias, cytokine release syndrome, and neurologic toxicity with grades 1 and 2 more commonly seen.^10,11

Ongoing and Future CAR T-Cell Studies

Autologous CAR T-cell therapy with BCMA targets demonstrated high response rates in the patients studied with advanced disease but the duration of response remains problematic. In addition, longer follow-up is needed to determine which patients will benefit and at what point in their treatment plan. Strategies to improve duration of response are under investigation in pre-clinical and clinical trials and include the study of other targets such as GPRC5D, SLAMF7, and CD38. Evaluations of the causes of lack of response durability include understanding and preventing antigen escape, use of dual-target antigen CAR Ts, and targeting the immunosuppressive tumor microenvironment.⁴

One clinical trial (ChiCTR1800018143) evaluated a dual-targeted BM38 CAR in 16 patients in a phase 1 dose-climbing trial of a bispecific CAR. A high response rate with a longer duration of stringent complete remissions was seen with manageable toxicities.¹²

Several ongoing clinical trials are examining the efficacy and toxicity of allogeneic donor CAR T cells with gene-editing techniques to moderate or eliminate graft-vs-host disease or rejection. The advantage of this approach is the use of healthier donor lymphocytes as well as timeliness of product availability. One such trial is the phase 1 Universal study (NCT04093596) of ALLO-715 in relapsed/refractory myeloma patients examining safety, efficacy, cell kinetics, and immunogenicity.This is a first-in-human study of a genetically modified anti-BCMA product. Thirty-one patients were treated and evaluated for safety. Cytokine release syndrome was largely grade 1 or 2 and there was no neurotoxicity or graft-vs-host disease. A higher dose of ALLO-715 exhibited greater anti-cancer activity.¹³

A strategy to combat the issue of persistence of the CAR T is under study with bb212117. This is a modified CAR T product in which T cells are co-cultured with a phosphatidylinositol 3-kinase inhibitor to expand memory T cells. CRB 402 (NCT03274219) is a phase 1 dose escalation trial of bb212117 in patients with heavily pretreated relapsed/refractory disease. Forty-six patients in the initial report received escalation doses of 150, 300, or 450 × 10-6with primary end points of adverse events and dose-limiting toxicities. T cell analysis was performed to assess for long-lasting memory T cell formation.¹⁴ An update at the 2020 ASH annual meeting reported on 74 patients with significant ORRs and a median duration of response of 17 months. Enrichment for memory T cells correlated with improved patient responses.¹⁵

Clinical trials with CAR T-cell therapy for patients with relapsed/refractory multiple myeloma are enrolling at a rapid pace. Strategies to enhance persistence of the CAR T cells, identify mechanisms of resistance, evaluate new targets, minimize toxicities, and determine which patients will most benefit remain under intense investigation.

_References:

_{1. Moreau P, Kumar S, San Miguel, et al.Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group. Lancet Oncol. 2021;22(3):e105-e118. doi:10.1016/S1470-2045(20)30756-7}

_{2. Richardson P, San Miguel J, Anderson K.Interpreting clinical trial data in multiple myeloma: translating findings to the real world setting. Blood Cancer J. 2018;8(11):109. doi:10.1038/s41408-018-0141-0}

_{3. Neelapu S, Tummala S, Shpall E. Chimeric antigen receptor T-cell therapy- assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. doi:10.1038/nrclinonc.2017.148}

_{4. Wudhikarn K, Mailankody S, Smith EL. Future of CAR T cells in multiple myeloma. Hematology Am Soc Hematol Educ Program. 2020;2020(1):272-279. doi:10.1182/hematology.2020000111}

_{5. Raje N, Berdeja J, Lin Y, et al. Anti-Bcma CAR-T cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380:1726-1737. doi:10.1056/NEJMoa1817226}

_{6. Munshi N, Anderson L, Shah N, et al. Idecabtagene vicleucel (ide-cel: bb2121), a BCMA-targeted CAR-T cell therapy in patients with relapsed and refractory multiple myeloma: initial KarMMa results. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503}

_{7. Munshi N, Anderson L, Shah, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705-716. doi:10.1056/NEJMoa2024850}

_{8. Berdeja J, Madduri D, Usmani S, et al. Update of CARTITUDE-1: a phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505}

_{9. Madduri D, Berdeja J, Usmani S, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 177. https://bit.ly/3diI1QV}

_{10. Mailankody S, Htut M, Lee K, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a Phase 1/2 multicenter study (EVOLVE). Blood. 2018;132(suppl 1):957. doi: 10.1182/blood-2018-99-113548}

_{11. Mailankody S, Jakubowiak A, Htut M, et al. Orva-cabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients with relapsed/refractory multiple myeloma: update of the phase 1/2 EVOLVE study. J Clin Oncol. 2020;38(suppl 15):8504. doi:10.1200/JCO.2020.38.15_suppl.8504}

_{12. Li C, Mei H, Hu Y, et al.A bispecific CAR T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Blood. 2019;134(suppl 1):930. doi:10.1182/blood-2019-130340}

_{13. Mailankody S, Matous J, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 129. https://bit.ly/3u2hTRa}

_{14. Berdeja J, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-Bcma CAR T cell therapy. Blood. 2019;134(suppl 1):927. doi:10.1182/blood-2019-126660}

_{15. Alsina M, Shah N, Radje N, et al. Updated results from the phase I CRB-402 study of anti-Bcma CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 130. https://bit.ly/3u62oI8}