EHA Education｜Professor Mateos: The future of MM immunotherapy

In recent years, the treatment of multiple myeloma (MM) has made significant progress.
The clinical application of proteasome inhibitors, immunomodulators, monoclonal antibodies and chimeric antigen receptor cells (CAR-T) has made MM's The treatment has entered the era of targeted immunotherapy
.

So with the launch of new immunotherapeutic drugs and the continuous advancement of the number of treatment lines, how should the first-line treatment of MM immunotherapy be positioned? In the EHA education section of this year's EHA annual meeting, Professor Mateos from Salamanca University Hospital in Spain introduced the status and progress of the first-line treatment of MM immunization.
The editor organizes the essence of the content as follows for readers
.

Dr.
María-Victoria MATEOS, Director of Myeloma Program, University of Salamanca School of Medicine, Spain.
Lead of blood clinical trials at University of Salamanca School of Medicine, Spain.
Leader of Spanish Myeloma Collaborative Group (GEM).
Recalling the past, the development of MM treatment MM treatment The overall development can be divided into two stages: the era of traditional chemotherapy and the era of targeted immunity
.

Since 1969, the application of the MP regimen (melphalan + prednisone) opened the stage of traditional chemotherapy for MM.
However, the remission rate of traditional chemotherapy is low, resistance failure is prone to occur, and the prognosis of patients is not ideal
.

In the past ten years, with the advent of new drugs such as immunomodulators and proteasome inhibitors, the treatment of MM ushered in a new century.
The overall remission rate and median survival of patients have been greatly improved
.

Figure 1 The development process of MM treatment However, MM is still incurable to a large extent, and relapse and refractory treatment are the main problems of treatment
.

At present, immunotherapy methods such as CD38 monoclonal antibody and CAR-T have the function of affecting immunosuppressive cytokines and helper cells in the myeloma microenvironment, and can restore the anti-tumor immune effect of host cells through various mechanisms Therefore, it can improve the prognosis of MM patients and bring new hope to the treatment of MM patients
.

Although immunotherapy improves the prognosis of MM patients, the current status of the treatment of MM patients in actual clinical practice is not optimistic
.

A study 1 shows that in the real world, most patients cannot enter the back-line treatment, only 1/3 of the patients receive ≥2 line therapy, and only a few patients receive ≥3 line therapy
.

Moreover, as the burden of disease increases and comorbidities increase, the depth of remission after line treatment is lower, and the interval between no treatments is shorter
.

Therefore, the number of immunotherapy lines continues to move forward to achieve a deeper degree of disease remission at an early stage, thereby improving the survival and prognosis of MM patients
.

Figure 2 The current status of treatment of MM patients Looking at the current situation, the first-line treatment strategy of MM The goal of first-line treatment of MM is to obtain deep remission and long-lasting disease control
.

Minimal residual disease (MRD) is one of the criteria for response to anti-myeloma treatment.
MRD-negative patients with complete remission (CR) are associated with prolonged progression-free survival (PFS) and overall survival (OS)
.

In patients receiving first-line treatment, MRD can be used as a surrogate end point for PFS.
At present, research based on MRD detection to drive clinical decision-making is increasingly recognized by scholars
.

The first-line treatment plan for MM recommended by the EHA-ESMO MM clinical practice guidelines in 2021 is shown in the figure below
.

It can be seen that daratumomab has strongly entered the first-line treatment program for MM
.

Daratumumab is the first fully human CD38 monoclonal antibody marketed in China.
With its deep and long-lasting efficacy (higher remission rate and MRD negative rate) and good safety, it is used in the first-line treatment of MM He emerged and changed the treatment pattern of MM
.

Figure 3 MM first-line treatment options 1 NDMM suitable for transplantation For NDMM patients suitable for transplantation, at least a three-drug combination including bortezomib and dexamethasone is the standard induction treatment plan, among which bortezomib/lenalidomide/ Dexamethasone (VRd) is the triple plan with the best risk-benefit ratio so far (recommended in IB category)
.

The use of daretuzumab has significantly improved the current status of the treatment of MM.
Based on the results of the CASSIOPEIA study, the four-drug regimen of daretuzumab combined with bortezomib, thalidomide and dexamethasone (D-VTd) has been Become a new standard induction protocol before autologous stem cell transplantation (ASCT) (IA recommendation)
.

Phase III CASSIOPEIA study Part 1 2 results showed that D-VTd induction and consolidation therapy before and after ASCT can improve the depth of remission and PFS in patients with NDMM transplantation.
The PFS rate at 18 months in the D-VTd group was significantly better than that in the VTd group (93%).
vs 85%)
.

The updated data 3 of the 17th International Myeloma Symposium (IMW) in 2019 showed that compared with VTd, the ≥CR rate and MRD negative rate after consolidation treatment in the D-VTd group were significantly higher, and PFS benefited more
.

Moreover, patients with ≥CR and MRD negative have more obvious PFS benefits
.

Figure 4 CASSIOPEIA study results 2 NDMM not suitable for transplantation Before 2019, VMP and Rd were the standard treatment options for patients who were not suitable for transplantation of NDMM
.

Based on SWOG S0777 study data 4, lenalidomide combined with bortezomib and dexamethasone (VRd) are approved for the treatment of NDMM patients who are not suitable for transplantation
.

The addition of daratumomab has also changed the treatment model that is not suitable for transplantation of NDMM.
Based on two large phase III studies (ALCYONE and MAIA studies), daratumumab combined with bortezomib, melphalan and strong Pine (D-VMP) and Daratumomab combined with lenalidomide and dexamethasone (D-Rd) have become a new standard (IA recommendation) for patients who are not suitable for transplantation of NDMM, and obtained EMA in October 2019 Approved
.

In ALCYONE Study 5, with a median follow-up of 40.
1 months, the overall response rate (ORR, 90.
9% vs 73.
9%), ≥VGPR rate, and ≥CR rate of the D-VMP group were significantly higher than those of the VMP group
.

Moreover, the negative rate of MRD in the D-VMP group was 4 times that of the VMP group
.

Compared with the VMP group, the D-VMP group had a higher proportion of patients who remained MRD negative after 6 months and 12 months
.

In addition, the D-VMP group can reduce the risk of death by 40% compared with the VMP group
.

Figure 5 ALCYONE study results The preliminary analysis of the Phase III MAIA study 6 showed that with a median follow-up of 28.
0 months, D-Rd compared to Rd can significantly improve the negative rate of PFS and MRD in patients who are not suitable for transplantation of NDMM
.

After a median follow-up of 48 months, the D-Rd group had significant PFS benefits compared to the Rd group (less than 34 months), and the PFS rates at 48 months were 60% and 38%7
.

Compared with the Rd group, the D-Rd group can achieve a deeper and longer-lasting remission, with higher ORR (93% vs 82%), ≥CR rate (51% vs 29%) and MRD negative rate (31% vs 10%)
.

Figure 6 MAIA study 4-year follow-up results show the future, NDMM treatment continues to make breakthroughs.
In addition to the first-line treatment options for MM currently recommended by the EHA-ESMO MM clinical practice guidelines, there are many other therapies under study, and preliminary results of some programs The results are remarkable and are expected to further improve the prognosis of NDMM patients
.

Figure 7 Future options for the first-line treatment of MM.
For example, the Phase II randomized GRIFFIN study 8 evaluated NDMM patients who are suitable for transplantation, combined with lenalidomide, bortezomib, and dexamethasone (VRd) in combination with daratumomab (D-VRd) The curative effect
.

The results showed that compared with VRd, D-VRd increased the strict CR (sCR, 62.
6% vs 45.
4%) rate and MRD negative rate (51.
0% vs 20.
4%), and the sCR rate and MRD negative rate increased over time
.

Its updated data 9 showed that after 12 months of maintenance treatment, the sCR rate (63.
6% vs 47.
4%) and MRD negative rate (10-5 or 10-6) of the D-VRd group were still higher than those of the VRd group
.

Figure 8 The updated results of the GRIFFIN study Isatuximab is a new generation of CD38-targeted monoclonal antibody.
GMMG-CONCEPT study 10 shows that Isatuximab, carfilzomib, lenalidomide and dexamethasone (ISA-KRD) four drugs are combined to treat high-risk NDMM Patients can have a deep remission, increase the negative rate of MRD and prolong the PFS of patients, but its benefits for high-risk NDMM patients still need to be further confirmed
.

Other immunotherapeutic drugs, such as new proteasome inhibitors, new immunomodulatory drugs, CAR-T, antibody-conjugated drugs (ADC) and bispecific antibodies targeting BCMA, also have good application prospects in the treatment of MM
.

These treatments may gradually advance to the front line in the future, but they need to be verified by more clinical trials
.

Summary Generally speaking, immunotherapy has an impressive effect in the treatment of NDMM, showing a deeper degree of remission and a higher frequency of remission
.

Regardless of whether it is a single agent or a combination therapy, NDMM patients receiving immunotherapy can get long-term benefits
.

Monoclonal antibodies that target CD38, especially daratumumab, have become part of the standard first-line treatment regimens for MM suitable for transplantation and those that are not suitable for transplantation
.

Other first-line treatment options for MM immunity are still being explored
.

Although the optimal timing of immunotherapy has not been determined, more and more evidence suggests that the earlier it is used, the greater the benefit
.

References: 1.
Yong K, et al.
Multiple myeloma: patient outcomes in real-world practice.
Br J Haematol.
2016 Oct;175(2):252-264.
2.
Moreau P, et al.
Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study[J].
Lancet.
2019;394(10192):29-38.
3.
Avet Loiseau H et al, IMW boston september 2019.
oral presentation.
4.
Durie BGM, et al.
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet.
2017;389(10068):519-527.
5.
Mateos MV, et al.
Overall survival with daratumumab, bortezomib, melphalan,and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial.
Lancet.
2020 Jan 11;395(10218):132-141.
6.
Facon T, et al.
Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.
N Engl J Med.
2019 May 30;380(22):2104-2115.
7.
Shaji K.
Kumar et al.
Updated Analysis of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM): The Phase 3 Maia Study.
2020ASH: Poster 2276.
8.
Voorhees PM, et al.
Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.
Blood .
2020 Aug 20;136(8):936-945.
9.
Kaufman JL et al.
ASH2020; abstract 549 (oral presentation).
10.
Weisel K, et al.
EHA2020, S204.
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