CARTITUDE-1 results indicate deep and durable responses with cilta-cel for RRMM

Treatment options and prognosis are very limited for patients with relapsed or refractory multiple myeloma (RRMM) who have had at least three prior unsuccessful therapies.¹ In search of novel therapies for this subset of patients, the phase Ib/II CARTITUDE-1 trial was designed (NCT03548207). In this study, the autologous chimeric antigen receptor T-cell (CAR T) therapy, ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M) was assessed for efficacy and safety in patients with RRMM. Cilta-cel possesses two anti B-cell maturation agent (BCMA)-single antibody domains along with the 4-1BB and CD3ζ co-stimulatory domains.¹ Preliminary data from the phase I LEGEND-2 trial (NCT03090659) in China showed that cilta-cel is tolerable and can lead to deep and durable responses in patients with RRMM.¹

The latest results from both phase Ib and II of CARTITUDE-1 were presented by Deepu Madduri et al.¹ during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition and are summarized below. A detailed cytokine release syndrome (CRS)-focused safety analysis from CARTITUDE-1 was also presented² and is included in the summary below.

Study design

• This phase Ib/II trial enrolled N = 113 adult patients (≥ 18 years) with RRMM, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, who had received ≥ 3 prior therapies or were double-refractory to proteasome inhibitors and immunomodulatory drugs and had received previous anti-CD38 treatment
• Primary endpoints:
  • Phase Ib part (n = 29): Safety and to establish the recommended phase II dose
  • Phase II part (n = 68): overall response rate (ORR)
• Cilta-cel dosing:
  • The median administered dose was 0.71 × 10⁶ (range, 0.51–0.95 × 10⁶) CAR+ viable T-cells/kg
• The full study design of CARTITUDE-1 is shown below in Figure 1
• The median turnaround time for cilta-cel was 29 days, with no production failures
• In total, 73 patients received bridging therapy as needed

CAR, chimeric antigen receptor; Cy, cyclophosphamide; Flu, fludarabine; PD, pharmacodynamics; PK, pharmacokinetics.

Results

• In total, 97 out of 113 enrolled patients received cilta-cel infusion. In the phase Ib part of the study, 24 out of 29 patients were ongoing, while 59 out of 68 patients are still on the phase II part of the study
• The patient baseline characteristics are shown below in Table 1. All patients were heavily pretreated with a median of six prior lines. The majority were triple-refractory (87.6%), and a significant proportion was penta-refractory (42.3%). Almost all patients (99.0%) were refractory to the last therapeutic line they received

Table 1. Patient baseline characteristics in CARTITUDE-1¹

Characteristic	N = 97
Allo-SCT, allogeneic SCT; Auto-SCT, autologous SCT; BCMA, B-cell maturation antigen; BM, bone marrow; SCT, stem cell transplantation. *Excluding bone plasmacytomas. Six additional patients had bone plasmacytomas totaling 19.6%; †At least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody; ‡At least two proteasome inhibitors, two immunomodulatory drugs, and one anti-CD38 antibody.
Median age, years (range)	61.0 (43.0–78.0)
Extramedullary plasmacytomas ≥ 1, n (%)*	13 (13.4)
BM plasma cells ≥ 60%, n (%)	21 (21.9)
Median time since diagnosis, years (range)	5.9 (1.6–18.2)
High-risk cytogenetics, n (%)   del17p   t(14;16)   t(4;16)	23 (23.7) 19 (19.6) 2 (2.1) 3 (3.1)
Tumor BCMA expression ≥ 50%, n (%)	57 (91.9)
Median number of prior lines (range)	6 (3.0–18.0)
Previous SCT, n (%)   Auto-SCT   Allo-SCT	87 (89.7) 8 (8.2)
Triple-class, n (%)†   Exposed   Refractory	97 (100.0) 85 (87.6)
Penta-class, n (%)‡   Exposed   Refractory	81 (83.5) 41 (42.3)
Refractory status, n (%)   Carfilzomib   Pomalidomide   Anti-CD38 antibody	63 (64.9) 81 (83.5) 96 (99.0)
Refractory to last therapy line, n (%)	96 (99.0)
Received bridging therapy, n (%)	73 (75.3)

Safety

• With regards to safety, almost all patients (99.0%) experienced Grade 3–4 hematological adverse events (AEs), with the most common being:
  • Neutropenia (94.8%)
  • Anemia (68.0%)
  • Thrombocytopenia (59.8%)
  • Leukopenia (60.8%)
  • Lymphopenia (49.5%)
• The median recovery time of Grade 3–4 cytopenias was 2 weeks for neutropenia and 4 weeks for thrombocytopenia. Late recovery (> 1 month) occurred in 10.3% of patients with neutropenia and 25.8% of patients with thrombocytopenia
• Infections were another common AE, with 57.7% of patients experiencing any grade infections and 19.6% experiencing Grade 3–4 infections (pneumonia, 8.2%; sepsis, 4.1%)
• Frequent nonhematological AEs of any grade (mostly Grade 1–2) were fatigue (37.1%), cough (35.1%), hypocalcemia (32.0%), hypophosphatemia (30.9%), and diarrhea (29.9%)
• In total, 14 deaths were recorded in this study due to:
  • Progressive disease (n = 5)
  • AEs unrelated to cilta-cel (n = 3)
  • AEs related to cilta-cel (n = 6):
    • Sepsis/septic shock (n = 2)
    • CRS/hemophagocytic lymphohistiocytosis (n = 1)
    • Lung abscess (n = 1)
    • Respiratory failure (n = 1)
    • Neurotoxicity (n = 1)

Adverse events of special interest

• Any CRS grade was experienced by 94.8% of patients with a median time to onset of 7 days and a median duration of 4 days
  • the majority were of CRS Grade 1–2 (89.7%), and in 98.9% of patients with CRS, it was resolved within 14 days from onset
  • 4.1% of patients experienced CRS Grade 3–4, and one patient experienced CRS Grade 5
  • CRS management with tocilizumab, steroids, anakinra, vasopressors, mechanical ventilation, cyclophosphamide, or etanercept was used in 90.7% of patients.^1,2
• Cilta-cel-associated neurotoxicities of any grade were observed in 20.6% of patients, with 10.3% of them being of Grade ≥ 3
• Immune effector cell-associated neurotoxicity syndrome (ICANS) of Grade ≥ 3 developed in 2.1% of patients with 8 days as a median time of onset, and 4 days as median time to recovery. All patients recovered from ICANS
• Other neurotoxicities (12.4% of any grade) resolved in six out of 12 patients, with one patient experiencing Grade 5 neurotoxicity

Efficacy

• The efficacy outcomes of cilta-cel are shown below in Table 2.
• The ORR was 96.9% with a median time to first response of 1 month (range, 0.9–8.5) and with 72.2% of patients with ongoing responses at data cutoff
• At a median follow-up of 12.4 months, the median progression-free survival (PFS) was not yet reached, while 1-year PFS was estimated at 76.6% (95% CI, 66.0–84.3) and 1-year overall survival at 88.5% (95% CI, 80.2–93.5; Table 2)
• 93.0% of evaluable patients achieved MRD negativity at 10⁻⁵, as assessed by next-generation sequencing (NGS), within a median time of 1 month (range, 0.8–7.7)
• After a follow-up of 6 months, most patients had circulating CAR+ T cells below 2 cells/μL

Table 2. Cilta-cel efficacy outcomes from CARTITUDE-1¹

Outcome	N = 97
MRD, measurable residual disease; NGS, next-generation sequencing; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; VGPR, very good PR. *Results on all treated patients (97 patients). Of note, 40 patients were not evaluable primarily due to lack of an identifiable clone in the baseline bone marrow sample.
ORR	96.9%
sCR	67.0%
VGPR	25.8%
PR	4.1%
1-year OS, % (95% CI)	88.5 (80.2–93.5)
1-year PFS, % (95% CI)	76.6 (66.0–84.3)
In patients with sCR In patients with VGPR	84.5 (72.0–91.8) 68.0 (46.1–82.5)
Median PFS, % (95% CI)	NR
MRD assessment by NGS*
Overall MRD negativity at 10−5	54.6%
MRD negativity at 10−5 and sCR	34.0%
MRD negativity at 10−5 and ≥ VGPR	50.5%

CRS biomarkers²

• Cilta-cel CAR+ T cells reached their circulating expansion peak at a median of 13 days (range, 9–55)
• The median time to CRS onset was 7 days (range, 1–12)
• In all patients, interleukin-6 (IL-6), C-reactive protein (CRP), and ferritin circulating levels peaked at 7–14 days postinfusion, coinciding with the time of CRS symptoms. Thus, these might be useful CRS monitoring biomarkers
• No link between CRP or ferritin baseline or peak levels and CRS severity were observed. However, increasing peak levels of IL-6, IL-10, and interferon-γ were associated with higher CRS grade and the need for more intensive CRS management

Conclusions

The phase Ib/II CARTITUDE-1 trial results indicate that the anti-BCMA CAR T-cell therapy, cilta-cel, is tolerable and leads to early, deep, and mainly durable responses in heavily pretreated patients with RRMM. In this patient subset, cilta-cel led to an ORR of 96.9%, with 67.0% of patients achieving a stringent complete response. These responses were durable as 72.2% of patients still have ongoing responses, and the median PFS after a 12.4-month follow-up has not yet been reached. The authors also show that CRP and ferritin levels coincide with CRS clinical onset and are not associated with CRS severity, making them potential biomarkers for CRS monitoring. These results show great promise and provide hope to patients with RRMM who have exhausted all available therapeutic options.

Cilta-cel is under further clinical assessment in other MM patient subsets and as an earlier therapy in the two upcoming trials CARTITUDE-2 (NCT04133636) and CARTITUDE-4 (NCT04181827).