Micro-classroom No. 16 Professor Ma Yanping: Discussion on maintenance therapy suitable for transplanted NDMM patients

Autologous hematopoietic stem cell transplantation (ASCT) remains the standard of care
for patients with multiple myeloma (TE NDMM) who are candidates for transplantation.
In the era of new drugs, small molecule targeted drugs and immunotherapies are used in the induction, consolidation and/or maintenance therapy phase of TE NDMM, bringing more clinical benefits
to patients.
Professor Ma Yanping of the Second Hospital of Shanxi Medical University was invited to share the exploration
of maintenance treatment regimens after ASCT in TE NDMM patients.

The overall management strategy for patients with TE NDMM includes induction therapy, ASCT followed by induction therapy, consolidation therapy after ASCT, and maintenance therapy
.
Several clinical studies have confirmed that maintenance therapy after ASCT improves the prognosis of patients with TE NDMM and plays an important role in inhibiting residual ^disease1
.
In addition, post-ASCT maintenance therapy can maintain and improve the efficacy of first-line therapy, maintain and/or deepen remission in patients, and prevent/delay disease ^{progression2-7}
.
Therefore, maintenance therapy after ASCT is of great significance
for the treatment of MM.

The choice of drug for maintenance therapy after ASCT has been clearly recommended
by domestic and foreign guidelines.
Among the foreign guidelines, the 2023 V1 version of the National Comprehensive Cancer Network (NCCN) guideline ⁸ recommends the first choice of lenalidomide for maintenance therapy, other recommended regimens include bortezomib and isazomib, and this version of the guidelines has added recommendations for daratumab (Dara) regimen
.
The 2022 Mayo guideline ⁹ and the 2021 European Society of Oncology (ESMO) guideline ¹⁰ both state that lenalidomide is recommended for maintenance therapy in patients with standard-risk MM and a combination of bortezomib or bortezomib is recommended for maintenance therapy
in patients with high-risk MM.
In addition, the esazomib regimen is recommended in ^{ESMO guideline 10}, but it has not been approved for maintenance therapy indications in the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) (Figure 1).

Fig.
1 Recommendations of foreign guidelines for maintenance therapy of TE NDMM

Among the domestic guidelines, the Guidelines for the Diagnosis and Treatment of Multiple Myeloma in China, revised in ²⁰²²¹, optimize the stratified treatment of patients, emphasizing that lenalidomide maintenance therapy is more beneficial for patients with intermediate- and low-risk MM, and maintenance therapy with proteasome inhibitors for 2 years or more
for patients with high-risk MM.
The 2022 Guidelines for Integrated Diagnosis and Treatment of Cancer (CACA) - Multiple ^Myeloma12 recommends maintenance therapy for at least 2 years
, regardless of the depth of response after treatment.

The importance of post-ASCT maintenance therapy for MM can be confirmed
by several studies.
One meta-analysis included three randomised controlled trials aimed at analysing the efficacy
of lenalidomide maintenance therapy.
Of the 1208 MM patients included in the study, 605 received lenalidomide maintenance therapy and 603 received placebo or observation
.
The results suggest that lenalidomide maintenance therapy significantly prolongs progression-free survival (PFS) in the overall population and in patients with standard-risk MM, and improves the prognosis
of patients with standard-risk MM.
However, subgroup analysis of overall survival (OS) showed that patients with ISS stage III MM did not benefit from lenalidomide maintenance ^therapy13
.

Another retrospective analysis included 464 patients receiving lenalidomide maintenance therapy, of whom 83 had high-risk cytogenetic characteristics
.
The median PFS of MM patients with high-risk cytogenetic features was 24.
6 months, significantly lower than that of MM patients without high-risk cytogenetic features (Figure 2)¹⁴
.
Studies have shown limited benefit from lenalidomide maintenance therapy in patients with MM with high-risk cytogenetic characteristics
.

Fig.
2 Use of lenalidomide maintenance therapy in high-risk ^patients14

The choice of maintenance therapy after ASCT in patients with high-risk MM has been explored in multiple clinical studies
.
The TOURMALINE-MM3 study showed that maintenance therapy with isozomib significantly extended 2-year PFS rates in patients with high-risk MM compared with placebo, 46% and 24%, ^{respectively15}
.
The results of the study showed that maintenance therapy with isozomib improved the prognosis
of patients with high-risk MM.

A subgroup analysis combining two clinical studies, GIMEMA-MM-03-05 and EMN01, compared the efficacy
of bortezomib maintenance therapy with lenalidomide maintenance therapy.
The results showed that in the high-risk MM subgroup, bortezomib maintenance therapy significantly prolonged PFS and OS compared with lenalidomide maintenance therapy (Figure 3)¹⁶
.

Figure 3 Subgroup analysis of two clinical studies, GIMEMA-MM-03-05 and EMN011111111116

In recent years, with the deepening of clinical exploration, a number of studies have confirmed that Dara maintenance therapy can significantly improve the depth of remission and improve the survival benefit
of patients 。 The CASSIOPEIA study is a randomized, open-label, phase III study conducted in TE NDMM, which consists of two parts: Part 1 randomizes patients with TE NDMM to Dara plus bortezomib, thalidomide, and dexamethasone (D-VTd) or VTd to receive 4 cycles of induction therapy before ASCT and 2 cycles of consolidation therapy after ASCT; Part 2 randomized 886 patients with post-consolidation efficacy assessment in partial response (PR) and above to Dara maintenance and observation groups for maintenance therapy for 2 years or until the patient developed disease progression
as prescribed by the International Myeloma Working Group (IMWG).
The results of this study suggest that Dara maintenance therapy significantly improves PFS and depth of
remission in patients treated with VTd induction/consolidation therapy.
In the VTd group, patients in the Dara maintenance group who continued treatment for 1 year had a higher negative rate of minimal residual disease (MRD) than in the observation group, at 35.
7% and 21.
4% (Figure 4)^17-18
.

FIG.
4 RESULTS OF CASSSIOPEIA ^{17, 18}

The GRIFFIN study was a multicenter, randomized, open-label, phase II study conducted in TE NDMM, in which patients were randomized to Dara plus bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd, receiving 4 cycles of induction therapy before ASCT and 2 cycles of consolidation therapy after ASCT; Patients in the D-VRd group received D-R maintenance therapy and patients in the VRd group received R maintenance therapy for 2 years
.
The latest results from the GRIFFIN study showed that the depth of remission progressed over time, with the deepest remission in the D-VRd group occurring at the end of maintenance therapy in this study (≥ complete response [CR] rates were 83% and 60%, respectively).

At all follow-up time points, the D-VRd group was consistently more effective than the VRd group (Figure 5)¹⁹
.

FIG.
5 GRIFFIN STUDIED REMISSION IN THE D-VRD GROUP AND THE VRD ^GROUP19

The MRD negative rate in both groups also gradually increased over time, and the negative MRD rate in the D-VRd group was significantly higher than that in the VRd group
at one year of maintenance therapy and at the end of the study.
In both groups, 14% and 10% of patients with end-stage MRD-positive patients on consolidation therapy turned negative for MRD at the end of 2 years of maintenance therapy
.
Although PFS was not achieved in either group, it can be seen from the curve that PFS is longer in the D-VRd group, especially after 1 year of maintenance therapy (Figure 6)¹⁹
.

FIG.
6 THE LATEST RESULTS OF THE GRIFFIN ^STUDY19

This result further confirms that D-R maintenance therapy after D-VRd induction/consolidation therapy significantly prolongs the survival benefit
of patients.
Based on the GRIFFIN study, the 2023 V1 NCCN guidelines include daratumumab in other regimen recommendations
for maintenance therapy.

A summary of the above findings is shown
in Table 1.

Table 1 Summary of important clinical studies on maintenance therapy after ASCT

summary 

Post-ASCT maintenance therapy in patients with TE NDMM can deepen remission, prevent or delay disease progression, and improve the survival benefit of patients, and post-ASCT maintenance therapy is of great significance for MM treatment

The results of clinical studies showed that maintenance therapy with ASCT later natomide could significantly improve PFS in patients with standard-risk MM, and the benefit was limited in patients with high-risk MM.
Maintenance therapy with ishazomib or bortezomib significantly improves PFS in patients with high-risk MM

CASSIOPEIA studies have shown that Dara maintenance therapy significantly improves PFS and depth of remission in patients with VTd-inducing/consolidation therapy MM; The updated results of the GRIFFIN study show that D-R maintenance therapy can deepen the depth of response, MRD negative rate and significantly prolong PFS in patients with D-RVd induction/consolidation therapy MM

Domestic and foreign guidelines recommend lenalidomide for maintenance therapy for patients with standard-risk MM, and bortezomib or combination therapy for maintenance therapy for patients with high-risk MM.
Based on the latest results of the GRIFFIN study, the NCCN 2023 V1 guideline adds the recommendation of daratumumab for maintenance therapy after ASCT in patients with TE NDMM, providing more evidence-based medical evidence for the clinical treatment of patients with MM