JCO: BCMA-targeting cilta-cel in relapsed/refractory multiple myeloma in China Phase II outcome, 18-month OS rate of 78.7%

For multiple myeloma (MM), new drugs have sprung up in the past two decades, different proteasome inhibitors, immunomodulators, CD38 monoclonal antibodies, XPO1 inhibitors, etc.
have been listed in China, while BCMA CAR T cell therapy is still mostly in clinical trials in China, only Reindeer Biologics/Innovent Biologics cooperation to develop Iquilency injection and Keji Pharmaceutical's Zevoki Olensai injection have been declared for marketing
.

Ciltacabtagene Autoleucel (cilta-cel), a BCMA CAR T product developed by Janssen in collaboration with Legend, was approved for marketing
in the United States in February 。 CARTIFAN-1 is a pivotal phase II study of cilta-cel in Chinese RRMM patients who have received ≥ 3-line (including PI and IMiD) therapy, and the Journal of Clinical Oncology recently published preliminary efficacy and safety results of the CARTIFAN-1 study at 18-month follow-up, the corresponding author is Professor Chen Saijuan, and the co-first authors are Mi Jianqing, Zhao Wanhong, Jing Hongmei and Fu Weijun
。

Study design

The CARTIFAN-1 study is an ongoing phase II, open-label, confirmatory study to evaluate the efficacy and safety of cilta-cel in patients with RRMM in China who have previously received ≥ 3-line therapy (including PI and IMiD).

Perform apheresis according to the standards of the participating institutions (target 6 X 109 peripheral blood mononuclear cells).

If clinically indicated, patients can be treated with bridging antimyeloma between
apheresis and cleansing.
Circumphosphamide 300 mg/m2 once daily and fludarabine 30 mg/m2 intravenously once daily for 3 days
about 4 to 6 weeks after apheresis.
For patients aged ≥ 70 years with an ECOG score of 1, the investigator may reduce the dose of cyclophosphamide to 250 mg/m2 once daily as appropriate; If creatinine clearance is 40 to 70 mL/min/1.
73 m2, the dose of fludarabine can be reduced to 25 mg/m2 once
daily.
A single infusion of cilta-cel (target dose 0.
75 x 106 CAR [0.
5-1.
0 x 106 CAR]-positive live T cells/kg)
5-7 days after the start of cleansing.

Research results

Patients and treatments

Sixty-four patients were enrolled in the study and received apheresis (Figure 1), of whom 16 patients discontinued the study prior to cilta-cel infusion due to disease progression (n=5), AE (n=3), physician decision (n=2), death (n=2), or refusal to further study
treatment (n=4).
A higher proportion of patients who eventually discontinue from the drug require bridging therapy and an ECOG of 1 are higher
compared with patients who continue to receive cilta-cel therapy.

The median age at enrollment of patients treated with CILTA-CEL (n=58) was 61.
0 years; the median time from diagnosis to CILTA-Cel infusion was 3.
7 years (Table 1).

。 All patients have an evaluative bone marrow biopsy or puncture sample; Plasma cells 30%-60% in 20.
8% of patients, plasma cells ≥ 60% in 16.
7% of patients; Twenty-one patients (43.
8%) had high-risk cytogenetic features (22.
9% T (4,14), 20.
8% Del17P, 0% T (14;16)), and 5 (10.
4%) with extramedullary plasma cell tumors
.

At the time of enrollment, the median treatment line of patients was 4 lines, and 31.
3% were exposed to class III exposures; 85.
4% were refractory to PI, 91.
7% refractory to IMiD, 79.
2% refractory to PI+IMiD, 27.
1% refractory to daratumumab, 18.
8% refractory to Class III, and 97.
9% refractory to the last line
.
Seventeen (35.
4%) patients had previously undergone autologous stem cell transplantation (ASCT).

The median cilta-cel dose was 0.
67 x 10 6 CAR-positive T cells/kg, and only one patient in the study was below the target dose range (0.
42 x 10⁶).

Data as of 07/19/2021, 38/48 patients are still enrolled in the study
.

efficacy

The results of the mitigation assessment based on the Independent Review Committee (IRC) are shown in Table 2
.
At a median follow-up of 18.
0 months, the IRC assessment showed an ORR of 89.
6% and 77.
1% achieving ≥CR
.
The median time to first response was 0.
95 months, to optimal response was 3.
25 months, and to ≥CR was 3.
32 months
.
Of the 40 sample-evaluable patients, 39 (97.
5%) achieved MRD-negative (threshold of 10-5), of which 35 achieved ≥ CR.

Median DOR not reached; Of the 43 responders, 67.
2% had DOR ≥ 18 months
.
At the time of data cut-off, remission continued in 33 (76.
7%) patients (Figure 2), including the patient who received a dose of cilta-cel below the target range who also maintained sCR for 28 months
.
Six patients with PD, four of whom were due to new-onset extramedullary plasmacytoma and/or osteolytic lesions, had optimal remission of sCR (n=4), VGPR (n=1), and stable disease (n=1).

The median PFS was not achieved (Figure 3A), with PFS rates of 77.
0% and 66.
8%
at 12 and 18 months, respectively.
The median OS was not reached, with an 18-month OS rate of 78.
7% (Figure 3B).

In addition, the ORR > was 80% in most patient subgroups, and M protein was significantly reduced in 45 patients with significant CAR–T cell expansion and ≥ disease evaluation

security

All patients developed an AE (TEAE; Table 3).

The most common haematologic TEAE are anaemia (100%), leukopenia (97.
9%), neutropenia (97.
9%), lymphopenia (95.
8%), and thrombocytopenia (87.
5%)
.
Grade 3/4 anemia occurred in 52.
1% of patients, and 31.
3% received red blood cell transfusions
.
Among patients with grade 3/4 thrombocytopenia (n=26), 14 received platelet transfusions, 15 recovered to grade ≤2 on day 30, and 20 to grade
≤2 on day 60.
Of the 46 patients who developed grade 3/4 lymphopenia, 43 recovered to grade
≤2 on day 60.
Among patients with grade 3/4 neutropenia (n=47), 38 recovered to grade ≤2 on day 30 and to grade
≤2 on day 60.
The most common non-hematologic TEAE were CRS (97.
9%), elevated AST (68.
8%), hypocalcemia (66.
7%), hypokalemia (62.
5%), elevated ALT (54.
2%), and hypoalbuminemia (50.
0%)
.

CRS developed in 47 patients, of which 17 (35.
4%) were grade 3/4 (Appendix Figure A3, online only).

The median duration of onset was 7 days and the median duration was 5 days
.
Of the 52 reported CRS events, 47 (90.
4%) had subsided by data cut-off; Five CRS events in five patients had not resolved
at the time of death.
Forty-six patients (95.
8%) received supportive care for CRS, with tocilizumab (91.
7%), analgesics/anti-inflammatory drugs (79.
2%), supplemental oxygen (58.
3%), corticosteroids (41.
7%), intravenous fluids (39.
6%), and/or vasopressors (18.
8%)
.
A second CRS developed in 5 patients and hemophagocytic lymphhistiocytosis
in 3 patients.

After Cilta-cel infusion, 2 grade 1 immune effector cell-associated neurotoxic syndrome events occurred in 1 patient (2.
1%); In one other patient, other neurotoxicity, grade 1 memory impairment, and grade 2 leukoencephalopathy
developed.
No patients developed motor and neurocognitive TEAE
.

Forty-one patients (85.
4%) developed infection, of which 37.
5% (n=28) were grade
3/4.
The most common infections were pneumonia (35.
4%), upper respiratory tract infection (33.
3%), and shingles (18.
8%)
.
HBV reactivation occurred in 5 (10.
4%) patients, and new HBV infection
occurred in another 3 (6.
3%).
The median time from infusion to all eight HBV events was 205 days, with a median duration of 129 days
.
No patients developed COVID-19 infection
.

Hypogammaglobulinaemia after Cilta-cel infusion is common: approximately 70% of patients have ≥ 1 minimum immunoglobulin G (IgG) measurement < 400 mg/dL
in the first 200 days.
IgG levels gradually recovered in most patients, but remained at < 400 mg/dL in 6 (20%) patients and <200 mg/dL
in 3 (10%) after day 400.

Ten patients died after CILTA-Cel infusion (Figure 1): 2 occurred within the first 30 days (before the first disease assessment) and the remainder within 60 days (n=4) or > 100 days (n=4).

。 Eight deaths were assessed by investigators as treatment-related: bleeding at grade 4 thrombocytopenia, inability to transfuse platelets (day 7); sudden cardiac death with hemoglobin< 50 g/L without blood transfusion (day 9); Septic shock (day 35); Liver failure (day 39); pneumonia (day 47); Grade 4 thrombocytopenia with intracranial hemorrhage, insufficient platelet transfusion (day 58), multiple organ failure (day 172), and pulmonary mycosis (day 199).

Deaths unrelated to treatment were due to pneumonia (day 287) and PD (day 335).

conclusion

A single infusion of cilta-cel resulted in early, deep, and durable remission in Chinese patients with a median of 4 lines of prior therapy, with an ORR of up to 89.
6%.

Of the patients who achieved ≥ CR (n=37), 35 also achieved MRD-negative
.
In addition, the median DOR, PFS, and OS were not reached
at data cutoff.

There is still a high unmet need for effective treatment options in patients with RRMM in China, with an approved ORR of only 29% to 36%.

The results of the CARTIFAN-1 study confirm the results of its Phase I Legend-2 study and are consistent with
those of the US Phase Ib/II CARTITUDE-1 study.
These studies suggest that CILTA-CEL has a positive risk-benefit profile in this class of severely pretreated patients with relapsed/refractory disease, providing potential treatment options
that can meaningfully improve clinical outcomes.

References

Jian-Qing Mi, Wanhong Zhao, Hongmei Jing,et al.
Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1).
J Clin Oncol .
2022 Oct 21; JCO2200690.
doi: 10.
1200/JCO.
22.
00690.