EBMT 2024: Latest updates from CARTITUDE-2 and CARTITUDE-4

Ciltacabtagene autoleucel (cilta-cel), a BCMA-directed chimeric antigen receptor (CAR) T-cell therapy, is approved for the treatment of relapsed/refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Cilta-cel is currently under investigation as part of the CARTITUDE trials for expanding indications in MM and impact on patient-reported outcomes (PROs).

Here, we summarize presentations by Tessa Kerre and Roberto Mina from the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) on the latest data from CARTITUDE-2 and CARTITUDE-4, respectively.

CARTITUDE-2¹

Study design

The phase II CARTITUDE-2 trial (NCT04133636) evaluated the safety and efficacy of cilta-cel in:

• patients with 1–3 prior lines of therapy (cohort A; n = 20);
• patients with 1 prior line of therapy who relapsed ≤12 months after transplant or antimyeloma treatment initiation (cohort B; n = 19); and
• the primary endpoint was negative measurable residual disease (MRD) at a sensitivity of 10⁻⁵.

Results

• The majority of patients experienced MRD negativity after treatment in both cohorts, with ≥50% achieving sustained MRD negativity at 12 months (Table 1).
• Overall response was higher in cohort B (Figure 1).
• Efficacy rates were largely comparable between cohorts A and B at 24 months posttreatment initiation (Table 1).
• In both cohorts, hematologic treatment-emergent adverse events were most common, with neutropenia occurring in approximately 95% of patients in both cohorts; almost all events were Grade 3/4.
• Cytokine release syndrome was common in both cohorts, at 95% and 84.2% in cohorts A and B, respectively, with the majority Grade 1/2 and able to be resolved.

Table 1. Efficacy data from CARTITUDE-2*

CR, complete response; DoR, duration of response; MRD, measurable residual disease; OS, overall survival; PFS, progression-free survival. *Data from Kerre.1
Outcome, % (unless otherwise specified)	Cohort A (n = 20)	Cohort B (n = 19)
MRD negativity ×10−5	100	93.3
Sustained MRD negativity ×10−5 at ≥12 months	50	61.5
MRD in ≥CR	85	68.4
24-month DoR rate	73.3	70.5
24-month PFS rate	75	73
24-month OS rate	75	84

CR, complete response; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Kerre.¹

CARTITUDE-4²

Study design

• The phase III CARTITUDE-4 (NCT04181827) trial evaluated the safety and efficacy of cilta-cel in patients with lenalidomide-refractory MM after 1–3 prior lines of therapy (n = 99) versus a standard of care (SoC) regimen (n = 66).
• The primary endpoint was progression free survival.

Results

• Baseline PROs were largely comparable between cohorts.
• Global health status (GHS) improved in the cilta-cel arm by the end of the follow-up period but not in the SoC arm (Figure 2)
  • A least squares mean change from baseline in GHS of 10.1 was recorded in the cilta-cel arm vs −1.5 points in the SoC arm.
• In the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, improvements were largely observed in the cilta-cel arm, with the sole improvement in the SoC arm being emotional functioning (Table 2).
• Improvements in pain and fatigue were also observed in the cilta-cel arm compared with the SoC arm, with improvements in 51.5% and 54.6% of patients, respectively.

*Adapted from Mina.²

 Table 2. EORTC QLQ-C30 LS mean change from baseline to Month 12*

cilta cel, ciltacabtagene autoleucel; LS, least squares; SoC, standard of care. *Adapted from Mina.2
Functional scale	LS mean change from baseline
	Cilta-cel (n = 99)	SoC (n = 66)
Cognitive	0.5 (−2.4, 3.5)	−7.5 (−11.2, −3.9)
Emotional	9.5 (6.6, 12.5)	2.2 (−1.3, 5.7)
Physical	6.5 (3.8, 9.1)	−2.1 (−5.0, 0.7)
Role	7.7 (3.7, 11.7)	−1.7 (−6.3, 2.9)
Social	6.1 (2.1, 10.0)	−0.1 (−4.2, 4.0)

Key learnings1,2

High rates of MRD negativity were achieved following treatment with cilta-cel from the first line, regardless of functional high-risk status. Treatment with cilta-cel resulted in numerically higher improvements in PROs including pain, fatigue, and GHS compared with SoC therapies. Cilta-cel is delivered in a single infusion which may contribute to improved PROs over time versus continual administration with SoC.