CARTITUDE-2 Cohort C: Efficacy and safety of cilta-cel in patients with relapsed/refractory MM

Several therapies targeting B-cell maturation antigen (BCMA) are now available for the treatment of patients with multiple myeloma (MM); therefore, understanding the sequencing of these therapies is important. Ciltacabtagene autoleucel (cilta-cel) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory (R/R) MM.

During the 49th Annual Meeting of the EBMT, María-Victoria Mateos, co-chair of the Multiple Myeloma Hub Steering Committee, presented data from Cohort C of the CARTITUDE-2 trial evaluating the efficacy and safety of cilta-cel in patients with progressive MM exposed to non‑cellular anti‑BCMA immunotherapy.¹ The Multiple Myeloma Hub has previously reported results from CARTITUDE-1 and Cohort B of the CARTITUDE-2 trial. We are pleased to present key results from Cohort C of the CARTITUDE-2 trial here.

Study design¹

The CARTITUDE-2 trial (NCT04133636) is a phase II, multi-cohort study of cilta-cel in patients with R/R MM. The overall study design and the primary and secondary endpoints of CARTITUDE-2 Cohort C are shown in Figure 1.

AE, adverse event; ASTCT, American Society for Transplantation and Cellular Therapy; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel; ciltacabtagene autoleucel; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for AEs, Cy, cyclophosphamide; DOR, duration of response; Flu, fludarabine; ICANS, immune effector cell-associated neurotoxicity syndrome; IMiD, immunomodulatory drug; mAb, monoclonal antibody; MRD, minimal residual disease; NGF, next-generation flow; NGS, next-generation sequencing; ORR, overall response rate; PI, protease inhibitor; RRMM, relapsed/refractory multiple myeloma.
*Adapted from Mateos.¹

Results^1,2

Baseline characteristics

A total of 20 patients were included in Cohort C, of which 65% were exposed to an antibody–drug conjugate (ADC) and 35% to a bispecific antibody (BsAb). Key baseline characteristics for these patients are shown in Table 1.

The median time from last anti-BCMA treatment to cilta-cel infusion was 6.4 months (range, 2.0–24.6 months).

Table 1. Baseline characteristics

ADC, antibody–drug conjugate; BCMA; B-cell maturation antigen; BM, bone marrow; BsAb, bispecific antibody; CR, complete response; IMiD; immunomodulatory drugs ISS, International Staging System; LOT, line of therapy; MM, multiple myeloma; PD, progressive disease; PI, protease inhibitor; sCR, stringent CR; SD, stable disease; VGPR, very good partial response. *Data from Mateos.1 †Data from Mateos, et al.2 ‡Maximum value from BM biopsy and aspirate is selected if both results were available; total cohort (n = 19) and ADC-exposed cohort (n = 12). §All del17p; missing data in eight patients in the total cohort. ‖≥1 PI, ≥1 IMiD, and 1 anti-CD38 antibody. ¶≥2 PIs, ≥2 IMiDs, and 1 anti-CD38 antibody.
Characteristic, % (unless otherwise stated)	Total Cohort C (N = 20)*	ADC-exposed cohort (n = 13)†	BsAb-exposed cohort (n = 7)†
Median age (range), years	62.5 (44–81)	66.0 (44–81)	60.0 (49–71)
Male	60	61.5	57.1
Race
White	95	100	85.7
Black	5	0	14.3
BM plasma cells ≥60%‡	32	33.3	28.6
Extramedullary plasmacytomas	25	38.5	0
High-risk cytogenetic profile§	15	15.4	14.3
Median time from initial MM diagnosis (range), years	6.3 (2.5–16.3)	6.4 (3.6–16.3)	5.0 (2.5–14.5)
Disease stage, ISS
I	40	46.2	28.6
II	20	23.1	14.3
III	40	30.8	57.1
Median number of prior LOTs, (range)	8 (4–13)	8 (4–13)	8 (6–12)
Last line of therapy
Anti-BCMA	30	30.8	28.6
Other treatments	70	69.2	71.4
Response to prior anti-BCMA*
sCR	5	7.7	0
CR	5	0	14.3
VGPR	15	15.4	14.3
SD/PD	75	—	—
Refractory status
Triple class‖	90	84.6	100
Penta-drugs¶	55	53.8	57.1
Anti-BCMA treatment	90	84.6	71.4
To last LOT	95	100	85.7

Efficacy

The data cutoff was June 2022.

• At a median follow-up of 18 months, seven of ten patients were minimal residual disease (MRD)-negative; five in the ADC-exposed cohort and two in the BsAb-exposed cohort.
• The median duration of response was 12.3 months, with an overall response rate (ORR) of 60% in the total cohort.
  • ORR was similar in both the ADC- and BsAb-exposed cohorts (Figure 2).
• Median progression-free survival was:
  • 9.1 months (range, 1.5–13.2 months) in the total cohort
  • 9.5 months (range, 1.0–15.2 months) in the ADC-exposed cohort
  • 5.3 months (range, 0.6 months to not evaluable) in the BsAb-exposed cohort
• Patients responding to cilta-cel showed a shorter median duration of last anti-BCMA exposure versus those not responding to cilta-cel (29.5 days vs 63.5 days).
• Cilta-cel responders showed a longer time from last anti-BCMA treatment to apheresis versus non-cilta-cel responders (161 days vs 56.5 days).

ADC, antibody–drug conjugate; BsAb, bispecific antibody; CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent CR; VGPR; very good partial response.
*Adapted from Mateos.^1
†Percentages may not sum appropriately due to rounding.

Safety

• As shown in Figure 3, the most common adverse events (AEs) were hematologic events.
• Cytokine release syndrome (CRS) of Grade 1 or 2 was observed in 12 of 20 patients, with a median time to CRS onset of 7.5 days (range, 2–10 days).
• Any grade immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in four patients, while Grade 3 or 4 ICANS occurred in three patients.
• The median time to ICANS onset was 9 days (range, 4–13 days) and the median duration was 7 days (range, 4–20 days).
• CRS resolved in all patients, while ICANS resolved in three out of four patients.
• There were no cases of movement and treatment-emergent AEs or parkinsonism reported.
• A total of 12 deaths were reported, due to the following:

• Progressive disease (n = 8)
• COVID-19 pneumonia (n = 2)
• Clostridiodes difficile colitis (n = 1; treatment-related)
• Subarachnoid hemorrhage (n = 1)

ADC, antibody–drug conjugate; AE, adverse event; BsAb, bispecific antibody; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
*Data from Mateos.¹

Conclusion

Findings from Cohort C of the CARTITUDE-2 trial demonstrated a clinical benefit of cilta-cel in patients with R/R MM who were heavily pretreated and exposed to non‑cellular anti‑BCMA immunotherapy. The study highlighted the impact of prior anti‑BCMA therapy on responses to cilta‑cel. The safety profile of cilta‑cel was consistent with that observed in the CARTITUDE-1 trial. The data from Cohort C of the CARTITUDE-2 trial may inform future treatment plans, including sequencing and a washout period between BCMA‑targeted agents.