Can patients who are eligible for NDMM transplantation benefit from VRD consolidation therapy?

In recent years, the introduction of proteasome inhibitors and immunomodulators has significantly improved the treatment outcome of patients with multiple myeloma (MM), increased the remission rate, and prolonged progression-free survival (PFS) and overall survival (OS)
.

Autologous hematopoietic stem cell transplantation (HDM/ASCT) after high-dose melphalan pretreatment is still an indispensable basic treatment for newly diagnosed and suitable transplant patients with multiple myeloma (TE-NDMM)
.

Lenalidomide maintenance therapy has now become the standard treatment for NDMM
.

The status of consolidation therapy after induction and intensive treatment in patients with TE-NDMM still needs prospective clinical studies to evaluate
.

Based on this, some researchers have explored the role of consolidation therapy in patients with TE-NDMM in randomized, controlled clinical trials
.

Research methods The EMN02/HOVON95 trial is a randomized, open-ended, phase III study conducted by the European Myeloma Network (EMN)
.

The efficacy of TE-NDMM patients who were randomly given bortezomib, lenalidomide, and dexamethasone (VRD) for 2 cycles of consolidation treatment or no consolidation treatment after induction and intensive treatment were compared, followed by lenalidomide maintenance treatment
.

The primary study endpoint is the patient's PFS
.

Research results 1.
Consolidation treatment The clinical trial from February 2011 to April 2014 enrolled 1503 MM patients aged ≤65 years from 172 EMN centers, of which 1500 met the inclusion criteria; 1197 patients Was randomly assigned for the first time (R1) (stratified by ISS staging) to receive bortezomib, melphalan, prednisone (VMP) (N=495) or HDM (1 or 2 ASCT; N=702) Treatment
.

878 patients were eligible for a second random assignment (R2) and received 2 cycles of consolidation therapy (N=451) or no consolidation therapy (N=427)
.

At a median follow-up of 74.
8 months, the pre-treatment adjusted median PFS of the VRD consolidation treatment group was significantly longer than that of the non-consolidation treatment group, which were 59.
3 months and 42.
9 months, respectively (HR: 0.
81; P=0.
016) (Picture 1)
.

Calculating from R2, the 5-year PFS rates of patients in the consolidation treatment and non-consolidation treatment groups were 50% (95% CI, 45% to 54%) and 41% (95% CI, 37% to 46%), respectively
.

There is no significant interaction between R1 and R2, indicating that no matter what treatment the patient receives at R1, they can benefit from consolidation therapy after R2 (Figure 2)
.

Figure 1: The median PFS of patients in the consolidation treatment group and the non-consolidation treatment group after adjustment before treatment Figure 2: The effect of consolidation treatment on the PFS of patients from R2 1) R1 to VMP group patients; 2) R1 to single Or double ASCT patients; 3) Single ASCT patients; 4) Double ASCT patients include the revised International Staging System (R-ISS) staging, cytogenetics and previous treatments in most of the pre-defined subgroups.
It is observed The risk of disease progression and death was significantly reduced in patients who received consolidation therapy compared with those without consolidation therapy (Figure 3)
.

Multivariate analysis showed that R-ISS staging was stage III (HR 2.
0, 95% CI, 1.
41-2.
86) and 1q amplification (HR 1.
67; 95% CI, 1.
37-2.
04) were the patients with poor PFS from R2 Prognostic factors
.

Figure 3: Pre-defined subgroups of patients with PFS forest plot from R2 onwards.
The percentage of CR patients with curative effect ≥ complete remission (CR) after consolidation treatment and without consolidation treatment before the start of maintenance treatment were 34% and 18%, respectively (P< 0.
001)
.

The proportion of patients with curative effect ≥ CR in the consolidation treatment group and the non-consolidation treatment group (including maintenance treatment) was 59% and 46%, respectively (P<0.
001)
.

2.
Maintenance treatment In this clinical trial, a total of 847 patients started lenalidomide maintenance treatment, including 428 cases (95%) in the consolidation treatment group and 419 cases (98%) in the non-consolidation treatment group
.

There was no significant difference in the median duration of maintenance treatment, which were 35.
7 months and 31.
8 months, respectively (P=0.
24)
.

At a median follow-up of 73.
4 months, the median PFS of patients in the consolidation treatment and non-consolidation treatment groups from the start of maintenance treatment were 57.
5 months and 42.
3 months, respectively (P=0.
04)
.

At 4 years after R2, the OS rates of patients in the consolidation and non-consolidation treatment groups were both 81%-82%; and at 6 years, the OS rates in the consolidation and non-consolidation treatment groups were 76% (95% CI, respectively).
71%-79%) and 69% (95% CI, 64%-73%)
.

3.
Toxicity and side effects, 96% of patients who were randomly assigned to the consolidation treatment group by R2 completed 2 cycles of VRD treatment
.

Overall, the patient’s toxic and side effects are controllable, and the incidence of grade 3 or 4 adverse events (AE) is 28%, mainly neutropenia (13%), thrombocytopenia (12%) and infection ( 5%)
.

The cumulative incidence of second primary malignancies (SPM) (excluding superficial skin cancer) in the consolidation treatment and non-consolidation treatment groups at 6 years was 5% and 6%, respectively
.

4.
Minimal Residual Disease (MRD) This clinical trial uses 8-color flow cytometry at the beginning of R2 and maintenance treatment to treat CR or strict complete remission (sCR) or very good partial remission (VGPR) patients with bone marrow samples Perform MRD testing
.

The MRD negative rates of patients in the consolidation treatment and non-consolidation treatment groups before the start of maintenance treatment were 74% and 70%, respectively
.

Regardless of whether the patient was assigned to the consolidation or non-consolidation treatment group at R2, patients who reached MRD negative had a longer median PFS from the start of maintenance treatment
.

The median PFS of patients who were assigned to the MRD-negative and positive MRD group without consolidation treatment was 85.
3 months and 39.
3 months, respectively (P＜0.
001); the patients who were randomly assigned to the MRD-negative and positive MRD groups received the consolidation treatment group from The median PFS at the start of maintenance treatment was 70.
1 months and 50.
6 months, respectively (P=0.
008)
.

Research conclusions The research results show that two cycles of VRD consolidation treatment in TE-NDMM patients after induction and intensive treatment can significantly improve the trend of patients with PFS and OS
.

References: Pieter Sonneveld, Meletios A Dimopoulos, Meral Beksac, et al.
Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma.
J Clin Oncol.
2021 Sep 14; JCO2101045.
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