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CARTITUDE-2 Cohort B: Results of cilta-cel in patients with early relapsed MM

Jun 16, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM

Patients with multiple myeloma (MM) who experience an early relapse have a poor prognosis, with a median survival of <2 years. This represents a clear unmet need for this group despite the use of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies.1

Ciltacabtagene autoleucel (cilta-cel) has recently been approved in the US and Europe for patients with relapsed/refractory MM based on the CARTITUDE-1 study. After more than 2 years of median follow-up, this phase Ib/II trial reported durable and deepening responses with cilta-cel, with 83% of patients achieving a stringent complete response that led to 27-month progression-free survival and overall survival rates of 54.9% and 70.4%, respectively.2

During the European Hematology Association (EHA)2022 Congress, Niels Van de Donk3 presented an update of the CARTITUDE-2 trial of cilta-cel in patients with MM who experience early relapse. This update covered data from cohort B, which included patients experiencing early relapse following initial treatment with a PI and IMiD (early relapse defined as progression within 12 months of stem cell transplant or within 12 months from start of anti-MM therapy for patients who have not received stem cell transplant).1

Study design1

The endpoints for this study and the overall study design are shown in Figure 1. Patients were given one infusion of cilta-cel 4−6 days after lymphodepletion therapy with fludarabine and cyclophosphamide.

Figure 1. Endpoints and study design*

AE, adverse event; ASTCT, American Society for Transplantation and Cellular Therapy; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; CTCAE, common terminology criteria for adverse events; Cy, cyclophosphamide; DoR, duration of response; Flu, fludarabine; ICANS, immune effector cell-associated neurotoxicity; IMWG, international Myeloma Working Group; MRD, measurable residual disease; NGF, next-generation flow; NGS, next-generation sequencing; ORR, overall response rate; PD, pharmacodynamics; PK, pharmacokinetics.
*Adapted from Agha, et al.1

Results1

Patient characteristics

With a median follow-up of 13.4 months (range, 5.2−21.7 months), 19 patients received cilta-cel, with the last data cut-off in January 2022. Patient characteristics at baseline are shown in Table 1. The median age of patients in this trial was 58 years and 73.7% were male. This cohort included 78.9% of patients who were refractory to last treatment and 15.8% who were triple-class refractory. In addition, 78.9% of patients had received a previous autologous stem cell transplant and one patient was treated in an outpatient setting.

Table 1. Baseline patient characteristics*

Characteristics, % (unless otherwise stated)

Total (N = 19)

Median age (range), years

58 (44−67)

Male

73.7

Black/African American

10.5

Extramedullary plasmacytomas

15.8

Bone marrow plasma cells ≥60%

21.1

High-risk cytogenetic profile

15.8

              Del17p

15.8

Median prior LOT (range)

1 (1−1)

Previous autologous SCT

78.9

Triple-class exposed

21.1

Triple-class refractory

15.8

Refractory status

 

              Lenalidomide

78.9

              Bortezomib

31.6

              Daratumumab

15.8

              Thalidomide

10.5

              Refractory to last line of therapy

78.9

Median duration between diagnosis and enrollment (range), years

1.15 (0.5−1.9)

LOT, line of therapy; SCT, stem cell transplant.
*Adapted from Agha, et al.1

Efficacy

In this population, an overall response rate (ORR) of 100% was achieved (95% confidence interval [CI], 82.4100; Figure 2). The median time to first response was 1.0 month (range, 0.9−9.7 months), while the median time to best response was 5.1 months (range, 0.9−11.8 months). The median duration of response was not reached as of the current data cut-off.

The 12-month progression-free survival rate was 89.5% (95% CI, 64.1−97.3). Out of the whole cohort, 15 were evaluable for measurable residual disease (MRD) assessment and 93.3% of these were MRD negative (95% CI, 68.1−99.8) at a threshold of 105.

Figure 2. Response rates*

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Agha, et al.1

Safety

Neutropenia occurred in 95% of patients, with 90% experiencing Grade 3 or 4. Of the patients experiencing Grade 3 or 4 cytopenias, 16% of cases of thrombocytopenia and 11% of lymphopenia and neutropenia had not recovered to Grade 2 by Day 60. Cytokine release syndrome (CRS) occurred in 84% of patients, with one patient having a Grade 3/4 event (Figure 3). The median time to CRS onset was 8 days (range, 5−11 days) and each event lasted for a median of 3.5 days (range, 1−7 days). Resolution of CRS occurred in all patients, with 63% receiving tocilizumab.

Only one patient experienced Grade 1 immune effector cell-associated neurotoxicity (ICANS) 11 days after infusion, which lasted for 4 days. The sponsor implemented patient management strategies across the cilta-cel clinical trials to reduce the initial incidence of movement and neurocognitive treatment-emergent adverse events reported in the CARTITUDE-1 trial.

Figure 3. Adverse events*

AEs, adverse events; CRS, cytokine release syndrome; ICANS immune effector cell-associated neurotoxicity; MNT, movement and neurocognitive treatment-related adverse event.
*Adapted from Agha, et al.1

One case of a Grade 3 movement and neurocognitive event was recorded. This patient was treated with high-dose methylprednisolone, plasmapheresis, and intravenous immunoglobulin, and was stable at the last data cut-off with a complete response to cilta-cel.4

There was one death recorded on the trial due to progressive disease at Day 158 following cilta-cel infusion.

Conclusion

In patients with MM who experienced early clinical relapse after initial treatment, one infusion of cilta-cel produced promising results. An ORR of 100% was achieved, with 90% of patients reaching at least a complete response. The safety profile was deemed to be manageable with mostly low-grade CRS, and the majority of cytopenias resolved to Grade 2 by Day 60. Cilta-cel represents a good option for the treatment of these higher-risk patients who experienced early relapse and supports continued investigation of the use of cilta-cel in earlier lines of treatment.

  1. Agha ME, Van de Donk N, Cohen AD, et al. CARTITUDE-2, Cohort B: Updated clinical data and biological correlative analyses of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-R cell therapy, in patients with multiple myeloma and early relapse after initial therapy. Oral abstract #S185. Presented at: European Hematology Association (EHA)2022 Hybrid Congress; Jun 12, 2022; Vienna, AT.
  2. Usmani SZ, Martin T, Berdeja JG, et al. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): 2 years post LPI. Poster #8028. Presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; Jun 4, 2022; Chicago, US.
  3. van de Donk N. CARTITUDE-2, Cohort B: Updated clinical data and biological correlative analyses of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-R cell therapy, in patients with multiple myeloma and early relapse after initial therapy. Oral abstract #S185. European Hematology Association (EHA)2022 Hybrid Congress; Jun 12, 2022; Vienna, AT.
  4. van de Donk N, Delforge M, Agha M, et al. Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, in patients (pts) with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2 Cohort B. Presented at: 8th World Congress on Controversies in Multiple Myeloma (COMy); May 15, 2022; Paris, FR.

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