2021 EHA Big Coffee Talks Professor Fu Weijun: First Look at the Progress of MM&AL Immunotherapy

At the upcoming 26th European Society of Hematology (EHA) Annual Meeting (June 9-17, 2021), a number of studies on MM immunotherapy will be announced soon
.

Yimaitong is the first to sort out some of the highlights of immunotherapy in MM and light chain amyloidosis (AL), and specially invited Professor Fu Weijun from Shanghai Changzheng Hospital to give a wonderful interpretation.
Let's see it! The progress of daratumomab combination regimen in MM&AL [S180] CASSIOPEIA study: DARA maintenance therapy brings significant survival and remission benefits to NDMM patients.
The interim analysis of the second part of CASSIOPEIA shows that among NDMM patients who are suitable for transplantation, Compared with the observation group, the PFS of DARA maintenance treatment was significantly prolonged, and the depth of remission and the negative rate of MRD were significantly increased, and it was safe and tolerable
.

CASSIOPEIA is a two-part, open-label, randomized, phase III study
.

After receiving DARA+bortezomib, thalidomide, and dexamethasone (D-VTd) or VTd induction therapy in Part 1, the patients who achieved ≥PR were re-randomized into groups and received DARA maintenance treatment or observation respectively.
Compare the two The efficacy of the group
.

The median follow-up time was 35.
4 months.
Compared with the observation group, the PFS of the DARA maintenance group was significantly longer (Table 1), and showed consistent PFS advantages in most subgroups
.

The PFS benefit of DARA maintenance therapy is more obvious in patients with VTd induction/consolidation therapy (HR 0.
32, 95% CI 0.
23–0.
46); in patients with D-VTd induction/consolidation therapy, regardless of whether DARA is used for maintenance in the future There was no significant difference in the benefits of PFS after treatment (HR 1.
02, 95%CI 0.
71–1.
47)
.

Compared with the observation group, more patients in the DARA group reached ≥CR and MRD negative (10-5) (Table 1)
.

In patients who have not previously received DARA treatment and those who have received DARA treatment, the proportion of infusion-related reactions (90% of grade 1/2) with DARA in the maintenance phase is 54.
5% and 2.
2%, respectively
.

Compared with the observation group, there were no new safety events in DARA maintenance treatment (Table 1)
.

Table 1: Comparison of efficacy and safety between DARA maintenance group and observation group [S189] ANDROMEDA study: D-VCd treatment of newly diagnosed AL can achieve faster and deeper relief.
The updated results of ANDROMEDA study further support: in newly diagnosed AL patients Among them, the D-VCd regimen is superior to the VCd regimen (it is faster to reach ≥VGPR, and a higher proportion of patients achieve hematological CR, ≥VGPR and major organ remission, and the safety is good)
.

ANDROMEDA is an ongoing open-label, randomized, controlled, phase III clinical trial
.

388 newly diagnosed adult patients with AL were randomly assigned to receive DARA+bortezomib, cyclophosphamide and dexamethasone (D-VCd) or VCd treatment at a 1:1 ratio
.

This EHA conference updated the latest data of ANDROMEDA research
.

As of November 2020, the median treatment time for the D-VCd group and VCd group were 18.
5 and 5.
3 months, respectively, and 40% of D-VCd patients were still receiving treatment
.

The hematological CR rate, VGPR rate, and major organ remission rate of the D-VCd group were significantly higher than those of the VCd group (Table 2)
.

In addition, among patients in remission, the median time from randomization to ≥VGPR (0.
56 months) in the D-VCd group was shorter than that in the VCd group (0.
82 months)
.

Table 2: Comparison of hematology and organ remission data between D-VCd and VCd groups.
71 patients died (D-VCd, 31; VCd, 40)
.

Starting from the 7th cycle, in the D-VCd group, ≥5% of patients had no grade 3/4 treatment-related adverse events (TEAE)
.

After the sixth cycle, no systemic infusion-related reactions were seen in the D-VCd group
.

The progress of bispecific antibodies in RRMM [S191] Talquetamab (GPRC5D/CD3 double antibody) RP2D treatment of RRMM, clinical remission rate is high, well tolerated In RRMM patients, Talquetamab RP2D is 405μg/kg SC per week
.

Under this RP2D, the ORR was 63%, and no dose-limiting toxicity occurred
.

Talquetamab has a good prospect in RRMM
.

This study reports the first phase 1 human body in which Talquetamab was administered to RRMM patients (the previous median number of treatment lines was 5.
5 lines) at the recommended phase 2 dose (RP2D, intravenous 0.
5-180μg/kg or subcutaneous 5.
0-800μg/kg) Research results are updated
.

No dose-limiting toxicity occurred under RP2D
.

The most common AEs at the RP2D dose were cytokine release syndrome (CRS, 79%; 4% was grade 3), neutropenia (64%), anemia (57%), and dysgeusia (57%)
.

32% of patients reported infections, 7% reported neurotoxicity, and 75% of patients had skin-related AEs
.

ORR was 63%, 50% achieved VGPR; 53% of triple refractory patients and 100% of five refractory patients achieved remission; the median time to the first remission was 1.
0 month, and the remission was durable and progressed over time Deepen
.

In the in vitro cytotoxicity test, Talquetamab was administered with RP2D, and its exposure was maintained above the maximum effective concentration (EC) target level, and sustained T cell activation was observed
.

[S193] Teclistamab (BCMA/CD3 double antibody) used RP2D to treat RRMM patients, with deep and long-lasting remission.
Teclistamab used 1,500μg/kg SC weekly RP2D to treat RRMM patients.
It is well tolerated, with an ORR of 65%, and it is worthy as a monotherapy And in conjunction with other drugs for further research
.

This study reported on Teclistamab (venous [n=84], 0.
3-19.
2μg/kg, once every two weeks; 19.
2-720 μg/kg, once a week or SC[n=72], 80.
0-3000μg/kg, every Once a week
.

Increasing dose ≥38.
4 μg/kg) The updated results of the first phase I human study in the treatment of RRMM patients (previously the median number of treatment lines was 5) to determine RP2D and its safety and tolerability under RP2D
.

No dose-limiting toxicity occurred under RP2D
.

The most common AEs are CRS (70%; no grade 3/4 events) and neutropenia (60%)
.

The curative effect can be evaluated in 40 patients, with an ORR of 65% (≥VGPR rate: 58%; ≥CR rate 30%)
.

The median time to first remission was 1.
0 month; at a median follow-up of 5.
3 months, the median duration of remission had not been reached, and 88% of remission patients were still continuing treatment and the degree of remission continued to deepen over time
.

Among the 14 patients with evaluable MRD, 9 CR patients reached MRD negative (10-6)
.

Under RP2D, Teclistamab was continuously exposed and exceeded the target level during the entire dosing interval, and sustained T cell activation was also observed
.

Application of CAR-T therapy in RRMM [S190] Preliminary results of CARTITUDE-2 study: Cilta-cel treatment of RRMM can obtain early and deep remission.
A single infusion of RP2D Cilta-cel for RRMM patients can achieve remission in 1 month.
, 1.
9 months can reach the best remission, ORR is as high as 95%, and the degree of remission is deep, and the safety is controllable and manageable
.

CARTITUDE-2 is a multi-cohort, phase II study designed to evaluate the safety and effectiveness of Cilta-cel in various clinical situations in MM patients, and to explore the applicability of outpatient medication
.

The EHA conference reported the preliminary results of group A (progressive MM patients who have previously received 1-3 lines of treatment)
.

As of February 2021, 20 patients had received Cilta-cel treatment with an ORR of 95%, of which 75% reached ≥CR and 85% reached ≥VGPR
.

The median time to the first remission and the best remission were 1.
0 and 1.
9 months, respectively; the median duration of remission was not reached
.

At the data cutoff date, all MRD-evaluable patients were MRD-negative
.

Common (≥20%) hematological AEs are neutropenia, thrombocytopenia, anemia, lymphopenia and leukopenia
.

CRS occurred in 85% of patients, and 10% had grade 3/4
.

Neurotoxicity occurred in 20% of patients (all grade 1/2)
.

Three patients developed immune effector cell-related neurotoxicity syndrome (ICANS)
.

Experts comment that MM is one of the common hematological malignancies, and the exploration of its research methods has always been a hot area, especially the rapid development of immunotherapy in the field of MM
.

At present, most of the immunotherapy research of MM focuses on targets such as CD38 and BCMA
.

The monoclonal antibody targeting CD38 is the pioneer of MM immunotherapy, and DARA is the representative drug
.

Since it was approved in the United States in 2015, it has been widely used in clinical practice.
In April this year, it obtained new indications in China
.

Whether it is NDMM or RRMM, DARA is in a crucial position among them
.

A number of research results announced at this EHA conference have further confirmed the above-mentioned status of DARA
.

The results of the second part of the CASSIOPEIA study corroborated the advantages of DARA in the maintenance treatment of NDMM patients
.

In addition to MM, the DARA joint program also shows advantages in other areas, and AL is one of them
.

In January 2021, the D-VCd regimen was approved for newly diagnosed AL patients.
With the announcement of the updated results of this ANDROMEDA study, the D-VCd regimen has become the new standard regimen for the treatment of AL patients
.

I believe that with the improvement of the late-stage data of DARA subcutaneous injection formulations and various new combination programs, the application prospects of DARA in the field of MM and even blood will be broader
.

Driven by the CD38 monoclonal antibody, but also the birth of the field of the MM many new immunotherapy, including bispecific antibodies, antibody drug conjugate, CAR-T cell therapy
.

This EHA conference announced two bispecific immunoglobulin G4 antibodies, which have good performance in RRMM.
Among them, Teclistamab targets BCMA and CD3, and Talquetamab targets new targets GPRC5D and CD3, and both can be administered subcutaneously.
They are convenient and fast, and have certain application prospects.
They can be further developed in the next step, such as combined therapy
.

In MM, CAR-T cell therapy mainly targets BCMA, which has shown significant efficacy
.

The EHA conference announced the preliminary results of the CARTITUDE-2 study of Cilta-cel for the treatment of RRMM.
In the previous RRMM patients treated with 1-3 lines, the efficacy is significant, and the safety is controllable and manageable
.

Cilta-cel contains a dual BCMA epitope binding part, which has high affinity.
Its other research results are also relatively optimistic.
It has been included in China’s breakthrough therapeutic drug identification and is expected to be launched in the United States this year.
It is also expected that CAR-T therapy will be available in China.
Accessibility brings more immunotherapy options for RRMM patients
.

Professor Fu Weijun, Shanghai Changzheng Hospital, Member of the Hematology Committee, Member of the All-Army Hematology Working Group, Deputy Editor-in-Chief of "Chinese Internal Medicine Yearbook", Chief Editor of Hematology Reference 1.
Moreau P, et al.
2021EHA.
Oral S180.
2.
Kastritis E, et al.
2021EHA.
Oral S189.
3.
Krishnan AY, et al.
2021EHA.
Oral S191.
4.
van de Donk NWCJ, et al.
2021EHA.
S193.
5.
Agha M, et al.
2021EHA.
Oral S190 .
Poke "read the original text", we make progress together