Isartuximab combined with dexamethasone significantly improves the efficacy of patients with relapsed and refractory multiple myeloma

CD38 is expressed in plasmacytoma and is a good target for treatment of multiple myeloma (MM).

Isatuximab (Isatuximab) is a monoclonal antibody that targets CD38.
It has been approved in the United States and the European Union in combination with pomalidomide and dexamethasone for the treatment of relapsed and refractory MM (RRMM).

Dexamethasone is a commonly used steroid drug in the treatment of myeloma and can be used in combination with monoclonal antibodies to prevent infusion reactions (IR).

In addition to direct anti-tumor effects, steroid drugs also have immunomodulatory effects, but the efficacy of steroid drugs in combination with immunomodulatory monoclonal antibodies has not yet been confirmed.

 A phase I/II study explored the safety and effectiveness of ixatuximab as a single-agent regimen in the treatment of RRMM.

In the phase I dose exploration phase of the study, RRMM patients received 3-20 mg/kg of Isartuximab as a single agent.

Studies have shown that Isartuximab is well tolerated in RRMM patients and is effective at doses ≥10 mg/kg, with an overall response rate (ORR; primary endpoint) of 20%-29%.

Subsequent studies did not observe a significant dose-response relationship in the dose range of 10-20 mg/kg.
Pharmacokinetic (PK) analysis supports a dose of 20 mg/kg every week or every 2 weeks.

The study further compared the efficacy and safety of ixatuximab single-agent regimen and ixatuximab combined with dexamethasone regimen in RRMM patients.

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

Research methods The study included RRMM patients ≥18 years of age who were refractory to immunomodulators (IMiD) and proteasome inhibitors (PI) or had previously received ≥3 lines of therapy (including IMiD and PI).

Patients included in the study must have been treated with alkylating agents and have achieved at least minimal remission from previous treatments.

In addition, patients included in the study need to have an ECOG score of 0-2 or Karnofsky score ≥60, measurable disease, and normal organ function.

During the study period, patients were prohibited from receiving anti-tumor drugs other than palliative radiotherapy.

 The patients included in the study were randomly assigned at a ratio of 2:1 and received intravenous injection of 20 mg/kg Isartuximab once a week (1, 8, 15, 22 days of each cycle, 28 days as a cycle), complete After 4 infusions of Isartuximab, the patient will receive an intravenous injection of 20mg/kg Isartuximab once every 2 weeks (on the 1st and 15th days of each treatment cycle).
Receive 40 mg of dexamethasone intravenously or orally on the first 1, 8, 15, and 22 days of each treatment cycle (20 mg for patients ≥75 years of age).

 The initial infusion rate of Isartuximab is 175 mg/h, and it can be increased to 400 mg/h in the absence of IR.

All patients need to receive IR prophylaxis within 15-30 minutes before receiving ixatuximab infusion (diphenhydramine 25-50mg, methylprednisolone 100mg [only ixatuximab single-agent group] , Ranitidine 50mg, Acetaminophen 650-1000mg).

It is forbidden to reduce the dose of Isartuximab during treatment, and the dose of dexamethasone must not be reduced more than 2 times.
After the dose is reduced, the dose cannot be increased to the previous level.

The patients in the study continued to receive treatment until the disease progressed, intolerable adverse events (AE) or withdrew from the study due to other reasons.

 The primary endpoint of the study was the ORR assessed by the Independent Adjudication Committee (IAC), and the secondary endpoints included the duration of remission, clinical benefit rate, progression-free survival (PFS) and overall survival (OS).

Patients with disease progression 60 days after the last treatment were followed up every 3 months until the patient died or the data was cut off.

Patients who have not developed disease progression and have not started other anti-tumor treatments will be followed up every 4 weeks until the patient has disease progression, death or data cut-off.

Results of the study The second phase of the study ended on January 21, 2019.
A total of 165 patients were included for random allocation, of which 109 patients received ixatuximab monotherapy, and 55 patients received ixatuximab combined Dexamethasone treatment.

As of the end of the data, 13 patients (11.
9%) in the single-drug regimen group and 15 patients (27.
3%) in the combined regimen group are still receiving treatment (as shown in the figure below).

The most common reason for stopping treatment was disease progression (64.
2% in the single-drug regimen group, 60.
0% in the combined regimen group).

Patients in the single-drug regimen group received a median of 5 cycles (range: 1-24) of treatment, and patients in the combination regimen group received a median of 7 cycles (range: 1-22) of treatment.

There was no significant imbalance in the baseline characteristics of the two groups of patients.

In the single-drug regimen group and the combined regimen group, 21% and 22% of patients had high-risk cytogenetic factors (del(17p), t(4;14), t(14;16)), respectively.

Patients in both groups had previously received median 4-line (range: 2-10) treatment.

69.
7% and 76.
4% of the patients in the single-drug regimen group and the combined regimen group were respectively resistant to IMiD and PI, and >89% of the patients in the two groups were resistant to the most recent treatment regimen (as shown in the figure below).

01 The ORR of the single-drug regimen group evaluated by IAC was 23.
9% (95%CI: 0.
162-0.
330), and the combined regimen group was 43.
6% (95%CI: 0.
303-0.
577; P=0.
008).

14.
7% of patients in the single-drug regimen group achieved partial remission (PR), 9.
2% of patients achieved very good partial remission (VGPR), and the clinical benefit rate was 43.
1%; 23.
6% of patients in the combined regimen group achieved PR, 20.
0% of patients The patient achieved VGPR and the clinical benefit rate was 54.
5% (as shown in the figure below). Subgroup analysis showed that the ORRs of patients with dual resistance to IMiD and PI in the single-drug regimen group and the combination regimen group were 23.
7% and 38.
1%, respectively; the ORRs of patients with previous treatment lines ≥3 were 22.
8% and 41.
2%, respectively; prior treatment The ORRs of patients with lines ≥ 4 and resistant to ≥ 2 PIs and ≥ 2 IMiDs were 19.
6% and 39.
3%, respectively; the ORRs of patients with high-risk cytogenetic factors were 4.
3% and 16.
7%; the ORRs of patients with standard risk They were 31.
6% and 58.
3%, respectively.

 The median time to remission of the single-drug regimen group and the combined regimen group were 1.
0 month (range: 1-9) and 1.
0 month (range: 1-11), respectively, and the median time to remission was 2.
0 months, respectively (Range: 2-10) and 2.
1 months (Range: 2-12).

The median duration of remission in the single-drug regimen group was 9.
3 months (range: 5.
6 to not reached), and the combined regimen group was 14.
1 months (range: 11.
3-19.
2).

The median PFS of the single-drug regimen group was 4.
9 months (95%CI: 4.
9-17.
3), and the combined regimen group was 10.
2 months (96%CI: 4.
9-17.
3; P＜0.
04) (as shown in the figure below).

 At a median follow-up of 12.
9 months (range: 1-23), 50 patients (45.
9%) in the single-drug regimen group died, with a median OS of 18.
9 months (95%CI: 13.
6-23.
1) and 12 months of OS The rate was 63.
5% (95%CI: 54.
4-72.
7).

At a median follow-up of 13.
4 months (range: 1-24), 22 patients (40.
0%) in the combined regimen group died, and the median OS was 17.
3 months (95%CI: 15.
4 to not reached; P=0.
19), The 12-month OS rate was 73.
8% (95%CI: 62.
0-85.
6) (as shown in the figure below).

72 patients (66.
1%) in the single-drug regimen group and 26 (47.
3%) patients in the combined regimen group received follow-up anti-tumor therapy.
The median time to the next treatment was 5.
8 months (95%CI: 4.
9- 8.
9) and 15.
2 months (95%CI: 6.
7-18.
4). The commonly used treatment options for these patients are dexamethasone, PI, IMiD, alkylating agents, and daratumumab.

02 In the safety study, >91% of patients had adverse events (TEAE) during treatment ≥1 grade.

13.
8% of the patients in the single-drug regimen group and 18.
2% of the patients in the combined regimen group had grade ≥3 TEAEs that may be related to the therapeutic drugs (as shown in the figure below).

The most common TEAEs are IR and hematological abnormalities.

In the two groups, 44 patients (40.
4%) and 22 patients (40.
0%) developed IR, most of which were grade 1-2.

There were 5 patients (4.
6%) in the single-drug regimen group and 2 patients (3.
6%) in the combined regimen group with ≥3 grade IR.

In the study, 6 patients (3.
7%) discontinued treatment due to IR, and most of the IR (98.
6%) occurred during the first infusion, and no IR occurred after the third infusion.

The incidence of grade ≥3 neutropenia (18.
3% and 13.
0%) and grade ≥3 infection (22.
0% and 21.
8%) was similar in the two groups.

 The incidence of mental and gastrointestinal-related TEAEs in the combined regimen was higher, and the main reason for the higher mental-related TEAEs was the higher incidence of insomnia (1.
8% vs 25.
5%).

The most common gastrointestinal TEAEs in the combined regimen group were diarrhea (20.
0%), nausea (14.
5%), and dyspepsia (7.
3%).

 There were 51 (46.
8%) patients and 25 (45.
5%) patients in the single-drug regimen group and the combined regimen group that had serious TEAEs.

The most common serious TEAEs are respiratory tract infection, disease progression, and IR.

The 14 patients (12.
8%) in the single-drug regimen group and 6 patients (10.
9%) in the combined regimen group had serious TEAEs associated with the treatment drug.

 Thirteen patients (11.
9%) in the single-drug regimen group and 5 patients (9.
1%) in the combined regimen group discontinued treatment due to TEAE. 19 cases of TEAE resulted in deaths (15 cases in the single-drug regimen group, 4 cases in the combined regimen group), of which 2 deaths were related to ixatuximab treatment (1 case of respiratory infection and 1 case of sepsis), and no death was related to dexamethasone Metone treatment related.

The conclusion of the study is that the combination of dexamethasone and ixatuximab can improve the efficacy of RRMM patients, and the ORR can be increased from 23.
9% to 43.
6% (P=0.
008).

The results of the study showed that the addition of dexamethasone improved the efficacy of ixatuximab without adversely affecting safety.

References: Meletios Dimopoulos, Sara Bringhen, Pekka Anttila, Marcelo Capra et al.
Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma.
Blood (2021) 137 (9): 1154–1165.
; https:/ /doi.
org/10.
1182/blood.
2020008209 stamp "read the original", we make progress together