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

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*

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

Efficacy

In this population, an overall response rate (ORR) of 100% was achieved (95% confidence interval [CI], 82.4–100; 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 10⁻⁵.

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.

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.