"The noblest pleasure is the joy of understanding.”
—Leonardo da Vinci
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel gene therapies for resistant multiple myeloma. For full details of these study abstracts, visit ashpublications.org.
Syed Ali Abutalib, MD
Kenneth C. Anderson, MD
CARTITUDE-1 Trial: Ciltacabtagene Autoleucel
ABSTRACT 177: Phase Ib/II CARTITUDE-1 study: Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy, in relapsed or refractory multiple myeloma (ClinicalTrials.gov identifier NCT03548207).1
Background: Subjects have been treated with this construct using single-agent lymphodepletion with cyclophosphamide, with manageable toxicities (LEGEND-2 study2); these results were presented during the 2019 ASH Annual Meeting & Exposition.
Methods: After conventional lymphodepletion with cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) for 3 days, a single infusion of ciltacabtagene autoleucel at a target dose of 0.75 × 106 (range 0.5–1.0 × 106) CAR-positive viable T cells/kg was administered 5 to 7 days after the start of lymphodepletion. The primary objective of the phase Ib portion (n = 29) was to characterize the safety of ciltacabtagene autoleucel and establish its recommended phase II dose; the primary objective of the phase II portion (n = 68) was to evaluate its efficacy. Median follow-up duration was 8.8 months (range, 1.5–20.4 months), and 41.2% were penta-refractory.
Results: Overall response rate per independent review committee was 94.8% (confidence interval [CI] = 88.4%–98.3%), with a stringent complete response rate of 55.7% (CI = 45.2%–65.8%), a very good partial response rate of 32.0% (CI = 22.9%–42.2%), and a partial response rate of 7.2% (CI = 3.0%–14.3%). Median duration of response was not reached. The 6-month progression-free and overall survival rates (95% CI) were 87.4% (78.9%–92.7%) and 93.8% (86.7%–97.2%), respectively; median progression-free survival and overall survival were not reached.
A total of 10 deaths occurred during the study; 8 were due to adverse events and 2 from progressive disease. The adverse events reported in more than 70% of patients were cytokine-release syndrome (94.8%), with a rate of grade 3 and 4 events of 4.1%, and pancytopenia.
Median time to cytokine-release syndrome onset was 7.0 days (range, 1–12 days), and the median duration was 4.0 days. CAR T-cell–related neurotoxicity was reported in 20.6% of patients; the rate of grade 3 and 4 events was 10.3%.
Clinical Implications: Preliminary phase Ib/II data from CARTITUDE-1 indicate a single low-dose infusion of ciltacabtagene autoleucel leads to early, deep, and durable responses in heavily pretreated patients with myeloma, with a safety profile consistent with the LEGEND-2 study.2 Ciltacabtagene autoleucel has received Breakthrough Therapy designation; the phase II portion of the study is fully enrolled (CARTITUDE-2; NCT04133636), and phase III (CARTITUDE-4; NCT04181827) studies have been initiated. Long term-durability of response, as well as development of late neurologic adverse events, will be defined with further follow-up of these studies.
LUMMICAR-2 Trial: CT053
ABSTRACT 133: Phase Ib/II LUMMICAR-2 Study: Fully human BCMA-directed CAR T cells (CT053) in patients with relapsed or refractory myeloma (NCT03915184).3
Background: CT053 comprises autologous T cells genetically modified with a second-generation CAR incorporating a fully human BCMA-specific single-chain fragment variant (25C2) with high binding affinity. A total of 24 subjects have been treated in phase I studies, with an 87.5% overall response rate, 79.2% complete response rate, and a median duration of response of 21.8 months without inducing immunogenicity.4
Methods: All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/d × 2 days) and fludarabine (25 mg/m2/d × 3 days). A single infusion of CT053 at the targeted 1.5 to 3.0 × 108 CAR-positive T-cell dose was administered after lymphodepletion. Primary objectives for phase Ib (n = 14) were to evaluate the safety and tolerability of CT053 and to identify the recommended phase II dose. The treated subjects had a median age of 59 years (range, 42–73 years), and 64% were penta-refractory. All subjects received bridging therapy.
Results: All subjects experienced ≥ grade 3 neutropenia and leukopenia, and 36% of subjects had ≥ grade 3 thrombocytopenia.
No grade 3 or higher cytokine-release syndrome or neurotoxicity was observed. Median time to cytokine-release syndrome was 2 days, with a median duration of 4 days (range, 1–6 days).
A 100% overall response rate was observed in 10 patients, with 2 stringent complete responses, 2 complete responses, 1 very good partial response, and 5 partial responses.
Clinical Implications: Collectively, these results demonstrate that CT053 at a target dose of 1.5 to 3.0 × 108 CAR-positive T cells delivers early and deep responses, including measurable residual disease (formerly known as minimal residual disease) negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory myeloma. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase I studies and support the launch of a pivotal phase II LUMMICAR-2 study. This CAR design contains a fully human BCMA single-chain variable fragment, with an improved therapeutic index. Moreover, these CAR T cells can be produced in 8 to 10 days, enhancing their availability for treatment.
KarMMa Trial: Idecabtagene Vicleucel
ABSTRACT 131: Phase I CRB-401 (KarMMa) study: Idecabtagene vicleucel a BCMA-directed CAR T-cell therapy in relapsed or refractory myeloma (NCT02658929).5
Background: Idecabtagene vicleucel (bb2121) demonstrated a favorable benefit-risk profile, with an overall response rate of 85%, a complete response rate of 45%, and a median progression-free survival of 11.8 months in the first 33 patients treated in CRB-401.6,7
Methods: After lymphodepletion with fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d) for 3 days followed by 2 days of rest, patients received idecabtagene vicleucel at target doses of 50, 150, 450, or 800 × 106 CAR-positive T cells in the dose-escalation phase and 150 to 450 × 106 CAR-positive T cells in the dose-expansion phase. Investigators reported updated safety and efficacy results for 62 patients who received idecabtagene vicleucel in the ongoing CRB-401 study. As of January 14, 2020, 21 patients had received idecabtagene vicleucel in the dose-escalation phase, and 41 patients received it in the dose-expansion phase.
Results: As of the cutoff date, 13 patients were ongoing, and 49 patients had discontinued the study. Reasons for study discontinuation were progressive disease (58%), withdrawal by patients (10%), and death (10%).
Target dose levels of 150 to 450 × 106 CAR-positive T cells were selected for the dose-expansion phase.
The most frequent adverse events were pancytopenia and cytokine-release syndrome (76%). Most cytokine-release syndrome events were grade 1 or 2. In all, four patients had grade 3 cytokine-release syndrome, with no grade > 3 events. Neurologic toxicity occurred in 27 patients (44%) and was primarily grade 1 and 2, with one patient having grade 3 and one having grade 4 neurotoxicity.
Among all 62 patients in the dose-escalation and -expansion phases, the overall response rate was 76%, including 24 patients with at least a complete response and 40 patients with at least a very good partial response. The median duration of response was 10.3 months.
Clinical Implications: Idecabtagene vicleucel demonstrated deep and durable responses in heavily pretreated patients with relapsed or refractory myeloma. Overall, a dose-dependent effect was observed on responses and survival outcomes, with greater efficacy reported at ≥ 150 × 106 CAR-positive T cells. This study achieves remarkable frequency and extent of response in relapsed myeloma, but the median duration of response remains short. Ongoing studies are evaluating strategies to prolong the duration of response, including enriching CAR product for memory T cells, treating patients early in the disease course, and using combination therapies.
This therapy was U.S. Food and Drug Administration–approved for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
Unveiling the Resistance Behind
Anti-BCMA–Directed CAR T-Cell Therapy
ABSTRACT 721: Biallelic loss of BCMA triggers resistance to anti-BCMA CAR T-cell therapy in multiple myeloma.8,9
Background: The median progression-free survival has been less than 12 months. Among the small number of patients re-treated at the time of disease progression with the same CAR T-cell product, responses have been infrequent. This highlights the development of resistance that may preclude the effectiveness of the second infusion and may also underlie relapse following response to the initial CAR T-cell therapy.
Methods: Investigators studied one of the resistance mechanisms using longitudinal single-cell transcriptomic and bulk genomic analysis. This patient had relapsed or refractory IgG lambda myeloma with hypodiploidy and a complex karyotype with t(8;12) (q24;q14), clonal t(11;14) (q13;q32), and clonal deletion 13. The patient received 150 × 106 CAR-positive T cells (idecabtagene vicleucel) and achieved a partial response, with a duration of response of 8 months. The patient was re-treated with 450 × 106 CAR-positive T cells at relapse, but no response was noted.
Results: Investigators did not observe infused CAR T cells with single-cell RNA sequence after the second infusion, but a limited expansion was confirmed using reverse transcription polymerase chain reaction.
The soluble BCMA level (produced predominantly by myeloma cells) was high before the first CAR T-cell infusion and dropped significantly to a very low level, coinciding with clinical response; however, it remained low even at the time of relapse, with an increased burden of myeloma, indicating a lack of BCMA production by myeloma cells.
At the time of relapse, imputation of copy number alterations single-cell RNA sequence showed that the majority of myeloma cells had a deletion of 16p, including the BCMA locus located on 16p13.13. Deep whole-exome sequencing identified a subclonal nonsense mutation (p.Q38*) in BCMA that creates an early stop codon in the BCMA gene.
Clinical Implications: These results identify biallelic loss of BCMA locus as a potential resistance mechanism to BCMA-targeting therapy. They highlight the need to investigate soluble BCMA as a potential indicator of BCMA loss at relapse and to carry out detailed transcriptomic or genomic analysis to confirm mutations. Moreover, these data also demonstrate the ability of myeloma cells to survive without BCMA expression. Although the frequency at which treatment-induced loss of BCMA occurs, the growing number of BCMA-targeting therapeutic modalities under development suggests it may be more common in the future. These experimental studies highlight the need to develop strategies that can overcome this resistance mechanism, such as targeting alternative myeloma antigens, either alone or in combination with anti-BCMA–directed therapy.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy. Dr. Anderson is Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics and Kraft Family Professor of Medicine at the Harvard Medical School.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Anderson has been an advisor or consultant for Amgen, Janssen, Pfizer, Sanofi, Oncopeptides, and Precision Biosciences.
REFERENCES
1. Madduri D, Berdeja JG, Usmani SZ, 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. 2020 ASH Annual Meeting & Exposition. Abstract 177. Presented December 5, 2020.
2. Wang BY, Zhao WH, Liu J, et al: Long-term follow-up of a phase 1, first-in-human open-label study of LCAR-B38M, a structurally differentiated chimeric antigen receptor T cell therapy targeting B-cell maturation antigen, in patients with relapsed/refractory multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract 579.
3. Kumar SK, Baz RC, Orlowski RZ, et al: Results from Lummicar-2: A phase 1b/2 study of fully human B-cell maturation antigen-specific CAR T cells (CT053) in patients with telapsed and/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 133. Presented December 5, 2020.
4. Jie J, Hao S, Jiang S, et al: Phase 1 trial of the safety and efficacy of fully human anti-BCMA CAR T cells in relapsed/refractory multiple myeloma. Blood 134(suppl 1):4435, 2019.
5. Lin Y, Raje NS, Berdeja JG, et al: Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: Updated results from phase 1 CRB-401 study. 2020 ASH Annual Meeting & Exposition. Abstract 131. Presented December 5, 2020.
6. 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 380:1726-1737, 2019.
7. Munshi NC, Anderson LD Jr, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.
8. Samur MK, Fulciniti M, Aktas-Samur A, et al: Biallelic loss of BCMA triggers resistance to anti-BCMA CAR T cell therapy in multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 721. Presented December 7, 2020.
9. Samur MK, Fulciniti M, Samur AA, et al: Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun 12:868, 2021.
