With significant advances in the treatment of multiple myeloma (MM) during the past decade, the disease is increasingly viewed more as manageable and chronic, not incurable.1 For relapsed/refractory (R/R) cases, a growing range of therapies can now be used at various phases of relapse. At the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, held virtually for the first time, early results were presented from trials investigating chimeric antigen receptor T cell (CAR-T) therapies for patients with R/R MM (Table).
The following presentations are a sampling of the research presented at this year’s meeting.
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 Myeloma2
Researchers reported phase 1b data and initial data from phase 2 of the CARTITUDE-1 study (ClinicalTrials.gov Identifier: NCT03548207) investigating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR-T therapy, in 97 patients with R/R MM.
After lymphodepletion, patients received a single infusion of cilta-cel at a target dose of 0.75×106 (range, 0.5-1.0×106) CAR+ viable T cells/kg. Overall response rate (ORR; primary endpoint) was 94.8% (95% CI, 88.4-98.3). Complete response (CR) was observed in 55.7% of patients (95% CI, 45.2-65.8); 32.0% achieved very good partial response (VGPR; 95% CI, 22.9-42.2), and 7.2% showed partial response (95% CI, 3.0-14.3). Among 52 patients who were evaluable for minimal residual disease (MRD), 94% tested negative at 10-5.
Overall survival rate was 93.8% (95% CI, 86.7-97.2), and 6-month progression-free survival (PFS) rate was 87.4% (95% CI, 78.9-92.7). The 10 deaths that occurred during the study were attributed to adverse events (AEs; n=8) and progressive disease (n=2). The more common AEs were cytokine release syndrome (CRS; 94.8%), neutropenia (90.7%), anemia (81.4%), and thrombocytopenia (79.4%). Neurotoxicity affected 20.6% of patients.
These preliminary findings are of an early, deep, and durable response with cilta-cel in patients with R/R MM, with a manageable safety profile similar to that observed with LCAR-B38M (alternate name for cilta-cel) in the phase 1 LEGEND-2 study (ClinicalTrials.gov Identifier: NCT03090659) conducted in China. Cilta-cel is being studied in other MM populations.
Patient Expectations and Perceptions of Treatment in CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma3
Symptoms associated with MM often contribute to diminished health-related quality of life (HRQOL). CARTITUDE-1 investigators aimed to glean HRQOL-related perspectives from patients regarding their expectations of, and experience with, cilta-cel.
In the phase 2 portion of the study, 36 patients participated in qualitative interviews before treatment and twice after treatment (Day 100 and Day 184). During the pretreatment phase, symptoms that patients reported hoping would be most reduced were pain (25.9%) and fatigue (33.3%), which were the most commonly reported symptoms (affecting 85.2% and 74.1% of patients, respectively). Following treatment, the number of patients reporting pain was reduced by 21.7% at Day 100 and by 29.2% at Day 184; the number reporting fatigue was reduced by 34.8% at Day 100 and by 20.8% at Day 184.
Regarding the impact of MM on relationships (reported to be affected by 92.6% of patients), psychological and emotional functioning (reported to be affected by 88.9% of patients), and activities of daily living (reported to be affected by 66.7% of patients), study participants reported no change or some improvement in:
- Relationships (in 50.0% at Day 100 and in 58.3% at Day 184);
- Psychological and emotional functioning (in 77.3% at Day 100 and in 83.3% at Day 184); and
- Activities of daily living (in 59.1% at Day 100 and in 62.5% at Day 184).
The more common pretreatment expectations were remission (40.7%), extended life expectancy (14.8%), less treatment (11.1%), and cure (11.1%); these expectations were met or exceeded at Day 100 in 78.3% of patients and at Day 184 in 91.7% of patients. In addition, 52.2% of patients at Day 100 and 70.8% of patients at Day 184 reported that their experience with cilta-cel was better than with previous treatments.
Cilta-cel treatment led to a reduction in symptoms of R/R MM and their impact on HRQOL. Such patient feedback can be used to guide clinical decision-making based on patients’ treatment goals and expectations.
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 Study4
In the first 33 patients with R/R MM treated with idecabtagene vicleucel (ide-cel) in the phase 1 CRB-401 study (ClinicalTrials.gov Identifier: NCT02658929), the drug showed a favorable safety profile with an ORR of 85%, a CR rate of 45%, and a median PFS of 11.8 months. The investigators reported updated results for 62 patients with R/R MM in the ongoing study.
After lymphodepletion, patients received a target dose of 50, 150, 450, or 800×106 CAR+ T cells in the dose-escalation phase (n=21) and 150 to 450×106 CAR+ T cells in the dose-expansion phase (n=41). At the cutoff date, 49 patients had discontinued the study, primarily (58%) because of disease progression. More common AEs were neutropenia (92%; 89%, grade 3/4), cytokine release syndrome (76%; 7%, grade 3, and 0, grade 4]), anemia (76%; 57%, grade 3), and thrombocytopenia (74%; 57%, grade 3). Neurotoxicity (primarily grade 1/2) affected 44% of patients. ORR was 76%, with 39% showing CR or better and 65% showing VGPR or better. There was an overall dose-dependent effect, with greater response and survival outcomes observed at ≥150×106 CAR+ T cells.
Similar to previous findings, ide-cel demonstrated a deep and durable response and a favorable benefit:risk profile at target dose levels ≥150×106 CAR+ T cells in patients with R/R MM.
Phase 1/2 Study of the Safety and Response of P-BCMA-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME) with Novel Therapeutic Strategies5
Researchers reported safety and efficacy results in 43 patients with R/R MM treated with P-BCMA-101 (ClinicalTrials.gov Identifier: NCT03288493), an autologous CAR-T therapeutic “targeting BCMA and [comprising] of a high percentage of desirable stem cell memory T cells” that is designed to increase efficacy and minimize toxicity.
Following lymphodepletion, patients initially received dose escalations of a single infusion of 0.75-15×106 cells/kg. Novel strategies were subsequently assessed using a median dose of 0.75×106 cells/kg derived from a modified manufacturing process in 3 exploratory cohorts:
- Biweekly infusion;
- Addition of rituximab or lenalidomide, before and after lymphodepletion, to prevent development of anti-CAR antibodies and enhance T-cell robustness, respectively; and
- Single administration at the lowest dose level.
The overall safety profile was excellent, likely due to gradual expansion of the stem-cell memory T cells (over 2 to 3 weeks compared with the typical 3 days). CRS was observed in 17% of patients. No patient required aggressive measures, such as admission to an intensive care unit, and no deaths or dose-limiting toxicities (DLTs) occurred. Cytopenia/infection and neutropenia grade 3 or higher (79%), thrombocytopenia (30%), and anemia (30%) were the more common AEs.
ORR was 57% among 34 patients who received the initial single administration. In the 4 patients treated with the novel strategies, ORR is 100% thus far, and the safety profile is comparable to the overall sample.
As observed in preclinical results, these data show significant efficacy of P-BCMA-101 at low doses, with low toxicity appropriate for outpatient treatment.
Results from LUMMICAR-2: A Phase 1b/2 Study of Fully Human B-cell Maturation Antigen-specific CAR T Cells (CT053) in Patients with Relapsed and/or Refractory Multiple Myeloma6
CT053 consists of 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. Phase 1 studies (ClinicalTrials.gov Identifiers: NCT03716856, NCT03302403, and NCT03380039) showed an ORR of 87.5%, CR of 79.2%, and a median duration of response of 21.8 months (without inducing immunogenicity) in a sample of 24 patients with R/R MM treated with CT053. Investigators presented safety and efficacy results from the ongoing phase 1b/2 LUMMICAR STUDY 2 (ClinicalTrials.gov Identifier: NCT03915184). Following lymphodepletion, patients received a single infusion at the targeted dose of 1.5-3.0×108 CAR+ T cells.
Of 14 patients treated in phase 1b, in which the main objectives were evaluation of safety and tolerability and a recommended phase 2 dose, hematologic toxicity was the most common grade 3 or higher AE. All patients exhibited grade 3 or higher neutropenia and leukopenia; 36% experienced grade 3 or higher thrombocytopenia within 30 days after infusion. Grade 1 or 2 CRS was observed in 86% of patients, occurring at a median of 2 days following infusion and lasting a median of 4 days. In 10 patients evaluable for at least 2 months of efficacy assessment at cutoff, ORR was 100%. Two patients each showed CR or stringent CR, 1 patient demonstrated VGPR, and 5 patients showed partial response.
Consistent with previous results, current data indicate that CTO53 confers an early and deep response in patients with R/R MM, with an acceptable safety profile. These findings support progression to phase 2 of LUMMICAR STUDY 2.
Two-year Follow-up of Investigator-initiated Phase 1 Trials of the Safety and Efficacy of Fully Human Anti-BCMA CAR T Cells (CT053) in Relapsed/Refractory Multiple Myeloma7
Follow-up results after 24 months were presented from multicenter, exploratory phase 1 trials (ClinicalTrials.gov Identifiers: NCT03716856, NCT03302403, and NCT03380039) investigating the safety and efficacy of CT053 in 24 adult patients (median age, 60.1 years) with R/R MM.
After preconditioning treatment with fludarabine and cyclophosphamide, 21 patients received 1.5×108 CT053 CAR-BCMA T cells, 1 patient received 0.5×108 cells, 1 patient received 1×108 cells, and 1 patient received 1.8×108 cells. Prior to completion of follow-up, 15 patients discontinued the drug due to disease progression (n=13) or to initiate another therapy (n=2).
The 9 patients who completed 24 months of follow-up demonstrated stringent CR (n=8) or CR (n=1). ORR of the full sample was 87.5%, including 79.2% who showed CR (n=3) or stringent CR (n=16). A median PFS of 18.8 months was observed; the 6-month PFS rate was 87%, and the 12-month PFS rate was 60.9%.
The more common grade 3 or higher AEs were hematologic toxicities, including leukopenia (83.3%), neutropenia (85%), lymphocytopenia (79.2%), and thrombocytopenia (20.8%). Low-grade CRS occurred in 62.5% of patients. All CRS events resolved in 2 to 8 days, with 9 patients receiving tocilizumab 4-6 mg/kg. In a patient who experienced grade 3 neurotoxicity and simultaneous grade 2 CRS, full recovery occurred after 3 days of appropriate treatment. Serious AEs, such as lung infection, gastroenteritis, and hematologic toxicity, occurred in 25% of patients. Of 8 deaths that occurred by the cutoff date, 1 was due to a serious AE (bone morrow failure and neutropenic infection) and disease progression and 7 were due to disease progression.
CT053 was well tolerated and demonstrated excellent efficacy in patients with R/R MM, with an early, deep, and durable response observed, with a duration of response of 21.8 months.
Universal: An Allogeneic First-in-human Study of the Anti-BCMA ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma8
Allogeneic CAR-T cell therapy provides several advantages over autologous CAR-T therapy. In this open-label, phase 1 trial (ClinicalTrials.gov Identifier: NCT04093596), 15 adult patients with R/R MM received 1 of 3 dose levels of ALLO-715, an anti-BCMA that is genetically modified to reduce the risk of graft-vs-host disease and “permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion.”
Common grade 3 or higher AEs included anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%); there were 4 episodes of grade 3 or higher infection. One patient developed pneumonia and died due to conditioning. As of the data cutoff date, no DLT, graft-vs-host disease, or neurotoxicity had been reported. For the 4 patients who experienced grade 1 or 2 CRS, resolution occurred naturally.
Median follow-up was 2 months (range, 0-10 months); initial responses were observed on Day 14. Greater anticancer activity occurred at higher doses, with 3 of 5 patients who received 320×106 CAR+ T cells showing at least VGPR (compared with those who received 40×106 or 160×106 CAR+ T cells) and testing negative for MRD. ALLO-715 cell expansion occurred at all dose levels.
Initial results show promise for the anticancer activity of ALLO-715 at higher cell doses. ALLO-715 and ALLO-647 appear to have manageable safety profiles. Higher doses will be explored in future cohorts.
Summary of Type, Patient Characteristics/Interventions, and Secondary Outcomes of Selected Studies
The availability of a greater number of therapies has improved disease outcomes in patients with R/R MM in recent years. The various CAR-T agents presented at ASH 2020 represent the potential for further expansion of the range of options to facilitate increased survival and improvements in quality of life in this patient population. For most trials presented here, investigation will advance into the next phase, with additional groups of patients with R/R MM, to further elucidate the safety and efficacy of these promising agents. Therapeutic options with lower toxicity and high efficacy, including those amenable to outpatient therapy, represent especially appealing targets for further investigation.
Several study authors declared affiliations with the pharmaceutical industry. Please see the original references for a full list of authors’ disclosures.
- Bazarbachi AH, Al Hamed R, Malard F, Harousseau J-L, Mohty M. Relapsed refractory multiple myeloma: a comprehensive overview. Leukemia. 2019;33(10):2343-2357. doi:10.1038/s41375-019-0561-2
- 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. Blood. 2020;136(Suppl 1):22-25. doi:10.1182/blood-2020-136307
- Cohen AD, Hari P, Htut M, et al. Patient expectations and perceptions of treatment in CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel in relapsed/refractory multiple myeloma. Blood. 2020;136(Suppl 1):13-15. doi:10.1182/blood-2020-136383
- 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. Blood. 2020;136(Suppl 1):26-27. doi:10.1182/blood-2020-134324
- Costello CL, Cohen AD, Patel KK, et al. Phase 1/2 study of the safety and response of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (R/R) multiple myeloma (MM) (PRIME) with novel therapeutic strategies. Blood. 2020;136(Suppl 1):29-30. doi:10.1182/blood-2020-142695
- 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 relapsed and/or refractory multiple myeloma. Blood. 2020;136(Suppl 1):28-29. doi:10.1182/blood-2020-139802
- Hao S, Jin J, Jiang S, et al. Two-year follow-up of investigator-initiated phase 1 trials of the safety and efficacy of fully human anti-BCMA CAR T Cells (CT053) in relapsed/refractory multiple myeloma. Blood. 2020;136(Suppl 1):27-28. doi:10.1182/blood-2020-140156
- Mailankody S, Matous JV, 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. Blood. 2020;136(Suppl 1):24-25. doi:10.1182/blood-2020-140641
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Reviewed January 2021