CAR-T cell therapy Idecabtagene Vicleucel in the treatment of relapsed and refractory multiple myeloma: results of phase II KarMMa study

Although the treatment of multiple myeloma (MM) has made more progress in recent years, the current main MM treatment drugs (immunomodulators, proteasome inhibitors, anti-CD38 monoclonal antibodies) still cannot avoid disease progression.

MM patients with disease progression have poor survival and low treatment remission rate.
The median progression-free survival (PFS) is only 3-4 months, and the median overall survival (OS) is only 8-9 months.
There is still no standard treatment plan for these patients.

 Chimeric antigen receptor T cells (CAR-T) are a new type of therapy.
Currently, CAR-T therapy targeting CD19 has been approved for the treatment of B-cell lymphoma.

The phase I study showed that the CAR-T drug idecabtagene vicleucel (ide-cel, bb2121), which targets B cell maturation antigen (BCMA), has shown better efficacy in patients with relapsed and refractory MM.

On the basis of this study, a key study (KarMMa study) explored the efficacy and safety of ide-cel in patients with relapsed and refractory MM.

The main results of the research are summarized as follows for the reference of readers.

Research methods The study included ages ≥18 years old, who had received at least 3 MM treatment regimens (including immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies) and the most recently received treatment regimen was invalid (appears within 60 days after the last dose) Disease progression) relapsed and refractory MM patients.

Patients included in the study need to have measurable disease and normal organ function.

 The study included patients who received fludarabine (30mg/m2 per day) and cyclophosphamide (300mg/m2 per day) for 3 consecutive days, and then received ide-cel infusion after stopping treatment for 2 days.

The CAR-T cell dose received by the patient was 150×106, 300×106, and 450×106.

The patients will then be followed up for ≥24 months and will then be included in a separate long-term follow-up study (GC-LTFU-001; NCT03435796).

 The primary endpoint of the study was the overall response rate (ORR) (partial response [PR] or better response) assessed by the Independent Review Committee (IRC).

Secondary endpoints include complete remission (CR) or strict complete remission (sCR), treatment onset time, duration of remission, PFS, OS, minimal residual disease (MRD), safety, pharmacokinetics, and immunogenicity .

Study Results 01 Patient Characteristics The study included 140 patients who underwent leukocyte separation from December 13, 2017 to November 13, 2018, of which 128 patients received ide-cel infusion and 12 patients were receiving ide-cel Withdraw from the study before infusion (including 1 patient whose CAR-T cell preparation failed).

As of the data deadline (January 14, 2020), 62 patients are still receiving ide-cel treatment.

The median age of 128 patients receiving ide-cel infusion was 61 years (range: 33-78 years), and the median time from diagnosis was 6 years (range: 1-18 years).

65 patients (51%) had high tumor burden (≥50% bone marrow plasma cells), and 50 patients (39%) had extramedullary diseases.

Twenty-one patients (16%) had stage III disease, and 45 patients (35%) had high-risk cytogenetic factors (including del(17p), t(4;14), t(14;16)).

 A median of 128 patients who received ide-cel infusion received 6 treatments for myeloma (range: 3-16 times), of which 120 (94%) patients had previously received autologous hematopoietic stem cell transplantation.

108 patients (84%) had triple refractory diseases (immunomodulators, proteasome inhibitors, anti-CD38 monoclonal antibodies), and 77 patients (60%) had failed treatment with 5 drugs (bortezomib, carfizoate) Rice, lenalidomide, pomalidomide, daretuzumab), 33 cases (26%) of the disease were five-fold refractory.

During the preparation of CAR-T cells, 112 patients (88%) received bridging therapy with a median duration of 15 days (range: 1-33 days).

After the completion of the bridging treatment, this group of patients underwent baseline characteristics assessment, including the diagnosis and staging of myeloma.

Five of the 112 patients (4%) achieved disease remission after bridging therapy (as shown in the figure below).

02 Remission Among 128 patients who received ide-cel infusion, 4 patients received 150×106 CAR-T cell infusion, 70 patients received 300×106 CAR-T cell infusion, 54 One patient received a 450×106 dose of CAR-T cell infusion.

At a median follow-up of 13.
3 months (range: 0.
2-21.
2 months), 94 of the 128 patients achieved disease remission (73%; 95%CI: 66-81%; P＜0.
001), 42 cases (33%) ) Patients achieved CR/sCR, and 67 (52%) patients achieved very good partial remission (VGPR) or better remission.

The remission rates of the three infusion doses were 50% (2/4), 69% (48/70), 81% (44/54), and the CR/sCR rates were 25% (1/4) and 29%, respectively (20/70), 39% (21/54).

Of the 42 patients who achieved CR/sCR, 33 (79%) patients had MRD negative at the 10-5 level, and the MRD status of the remaining 9 patients (21%) could not be assessed.

Most of the subgroups in the study (elderly patients, patients receiving bridging therapy, patients with aggressive disease, patients with high-risk cytogenetic factors, patients with triple or five-fold refractory disease, and high tumor burden Patients with extramedullary disease and patients with extramedullary disease) have observed a higher disease remission rate (≥50% of patients get disease remission, ≥10% of patients achieve CR or sCR) (as shown in the figure below).

The median treatment onset time for patients in the study was 1.
0 months (range: 0.
5-8.
8 months), and the median time to CR/sCR was 2.
8 months (range: 1.
0-11.
8 months). The median duration of remission was 10.
7 months (95%CI: 9.
0-11.
3), and the median duration of remission was 11.
3 months (95%CI: 10.
3-11.
4) in patients who received 450×106 doses of ide-cel (below Figure A).

The duration of relief prolonged as the depth of relief increased.

For patients with the best degree of remission of PR (27 cases), VGPR (25 cases), and CR/sCR (42 cases), the median duration of remission was 4.
5 months (95%CI: 2.
9-6.
7) and 10.
4 cases, respectively Months (95%CI: 5.
1-11.
3), 19.
0 months (95%CI: NE-11.
3) (Figure B below).

 The median PFS of the patients in the study was 8.
8 months (95%CI: 5.
6-11.
6), and the median PFS of the patients who received 450×106 doses of ide-cel was 12.
1 months (95%CI: 8.
8-12.
3), reaching The median PFS of CR/sCR patients was 20.
2 months (95%CI: 12.
3-NE) (Figure C below).

The median OS of the patients in the study was 19.
4 months (95%CI: NE-18.
2), and the 12-month OS rate was 78% (Figure D below).

However, due to the lack of survival data for 85 patients (including 39 patients who received 450×106 doses of ide-cel) in the study, overall survival data is not perfect.

Twenty-eight patients continued to receive ide-cel treatment after the disease progressed, of which 6 patients (21%) achieved disease remission again, and these 6 patients received ide-cel treatment with a higher dose than the initial dose after the disease progressed.

03 Safety All 128 patients who received ide-cel infusion reported adverse events, of which 127 (99%) patients had ≥3 grade adverse events (as shown in the figure below).

Except for hypogammaglobulinemia and infection, most adverse events occurred within the first 8 weeks after infusion.

Most of the adverse events of grade ≥3 were hematological adverse events, of which 114 (89%) had neutropenia, 77 (60%) had anemia, and 67 (52%) had thrombocytopenia.

After 1 month of ide-cel infusion, 52 patients continued to develop neutropenia ≥ grade 3, and recovered to grade 2 or lower after a median of 1.
9 months (range: 1.
2-5.
6 months) of treatment Adverse events of grade 2; 62 patients continued to develop thrombocytopenia ≥ grade 3, and recovered to grade 2 or lower adverse events after a median of 2.
1 months (range: 1.
2-13.
8 months) of treatment.

In the study, there were 4 cases of bleeding events ≥3 grade, which were brain, gastrointestinal, conjunctival, and postoperative bleeding events.
The cerebral hemorrhage event occurred after the patient's disease progressed.

88 patients (69%) developed infections, of which 28 patients (22%) developed ≥ grade 3 infections.

Most patients received treatment with antimicrobial drugs, growth factors, and immunoglobulins.

107 (84%) patients developed cytokine release syndrome (CRS), most of which were grade 1-2 CRS.

Five patients (4%) developed grade 3 CRS, one patient (1%) developed grade 4 CRS, and one patient (1%) developed grade 5 (300×106 level) CRS.

The median time to CRS after treatment was 1 day (range: 1-12 days), and the median duration of CRS was 5 days (range: 1-63 days).

For CRS, 67 patients (52%) received tocilizumab treatment, and 19 (15%) patients received glucocorticoid treatment.

Under the three infusion doses, 50% (2/4), 76% (53/70), 96% (52/54) of the patients developed CRS, 0% (0/4), 6% (4/70) ), 6% (3/54) of patients had CRS ≥ Grade 3.

In the study, 23 patients (18%) had neurotoxicity events, of which 4 patients (3%) had grade 3 neurotoxicity events, and no neurotoxicity events of grade 4-5 were observed.

The median time to neurotoxic events after treatment was 2 days (range: 1-10 days), and the median duration of neurotoxic events was 3 days (range: 1-26 days).

At the 3 infusion doses, 0% (0/4), 17% (12/70), 20% (11/54) of the patients had neurotoxic events, 0% (0/4), 1% (1%) /70), 6% (3/54) of patients had neurotoxicity events ≥3.

 In the study, 44 patients (34%) who received ide-cel died, and most of the patients (27 patients) died of complications caused by disease progression.

Three patients (2%) died within 8 weeks after the occurrence of ide-cel infusion-related adverse events (bronchopulmonary aspergillosis, gastrointestinal bleeding, CRS), and 1 patient (1%) was related to ide-cel infusion Death within 8 weeks to 6 months after the occurrence of adverse events (cytomegalovirus pneumonia).

Five patients (4%) died after 6 months of treatment due to unrelated adverse events, and another 8 patients (6%) died after disease progression.

 The incidence of adverse events observed in the KarMMa study is basically consistent with previous studies.

All patients receiving ide-cel treatment ≥3 grade CRS incidence rate does not exceed 6%, although the incidence of ≥3 grade hematological adverse events is relatively high, but the duration is relatively short.

Research conclusions: Most patients with relapsed and refractory MM achieved disease remission after ide-cel treatment, and 26% of them achieved MRD negative status.

Almost all patients treated with ide-cel have grade 3-4 adverse events, and the most common adverse events are hematological toxicity events and CRS.

Reference: Nikhil C.
Munshi, Larry D.
Anderson, Jr.
, Nina Shah, Deepu Madduri, et al.
Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.
N Engl J Med 2021;384:705-16.
; DOI:10.
1056/ NEJMoa2024850 stamp "read the original", we make progress together