Micro-classroom No. 17 Professor Zeping Zhou: The value of MRD detection in multiple myeloma

In recent years, the continuous emergence of new drugs and the improvement of detection methods have made the treatment of multiple myeloma (MM) more effective, the past efficacy evaluation standards can no longer meet the current treatment needs, the introduction of higher and more sensitive MM efficacy standards has also become the common pursuit
of experts and scholars at home and abroad.
Minimal residual disease (MRD) is an important independent prognostic factor in the treatment of MM and is increasingly being explored in clinical studies to guide treatment
.
Professor Zhou Zeping of the Second Affiliated Hospital of Kunming Medical University was invited to share the value of
MM MRD testing.

In recent years, MRD detection reflects the residual state of tumors in vivo after treatment, and in recent years has been regarded as an important tool to evaluate the efficacy of MM treatment and judge the prognosis of patients, and domestic and foreign expert consensus and authoritative guidelines have also recommended the inclusion of "MRD negative" in the evaluation criteria
of MM efficacy.
In the 2016 International Myeloma Working Group (IMWG) consensus on MM response and MRD evaluation, MRD-negative efficacy evaluation criteria ¹
were defined for the first time.
The 2017 Chinese MM guidelines used this as a reference and introduced IMWG MRD negative efficacy evaluation criterion ²
.
This year's revised guidelines for the diagnosis and treatment of MM in China also insist on including MRD negative into the efficacy evaluation criteria, and recommend that patients undergo MRD efficacy evaluation after achieving complete remission (CR)³
.

Patients assessed as MRD-negative are expected to achieve better outcomes, and one large meta-analysis4 included progression-free survival (PFS) data from 8098 patients in ⁴⁴ studies and overall survival (OS) data from 4297 patients in 23 studies to assess the effect
of MRD-negative on long-term survival outcomes 。 The results showed that achieving MRD-negative was associated with significant improvements in survival outcomes regardless of disease background (newly diagnosed MM [NDMM] or relapsed/refractory MM [RRMM]), MRD sensitivity threshold, cytogenetic risk, MRD assessment method, depth of clinical response at MRD measurement, and maintenance at MRD assessment
。 Analysis exploring the prognostic value of MRD status on PFS showed that patients with RRD who achieved MRD negative benefited more PFS than MRD-positive patients in transplant-appropriate and transplant-unsuitable NDMM patients and RRMM patients (Figure 1).

Fig.
1 Prognostic value of MRD status on PFS

Based on the strong prognostic value of MRD, it is inevitable to include MRD on the basis of traditional efficacy evaluation, and PFS differences in patients with CR in traditional efficacy assessment after treatment ≥ achieve different MRD status
.
As a monoclonal antibody targeting CD38, daratumab has demonstrated good efficacy in multiple clinical trials, and the association
between ≥ CR and MRD-negative and PFS in patients was evaluated through pooled analysis of four phase III studies (POLLUX, CASTOR, ALCYONE, AND MAIA⁾⁵.
Results showed that achieving a ≥ CR and a negative MRD predicted a better PFS benefit (Figure 2).

Also, daratumab-based regimens resulted in more patients achieving ≥ CR and MRD-negative status compared with standard regimens, and patients who received ≥ CR and MRD-negative after darratumab-based therapy also improved PFS compared with patients who also received ≥ CR and MRD-negative but received standard care, with estimated 48-month PFS rates of 74.
6% and 48.
9%, respectively (Figure 3).

。 This showed that the clinical outcomes of patients with ≥ CR and negative MRD remained heterogeneous
.
To further assess and differentiate differences in patient depth of remission, more sensitive MRD detection
is required.
The IMWG consensus not only recommends a minimum sensitivity of 10-5 or higher based MRD detection, but also proposes the concept of persistent MRD negative, suggesting that next-generation flow cytometry (NGF) or next-generation sequencing (NGS) to detect bone marrow persistent MRD-negative, that is, MRD-negative for more than 1 year, as an indicator
of long-term survival and even functional cure of patients.
The deeper the remission of the patient, the lower the risk of recurrence and the longer PFS may be (Figure 4)⁶
.

Fig.
2 Effect of different MRD states on PFS in patients with ≥ CR

Fig.
3 PFS results of patients with different treatment regimens and efficacy evaluation results

Figure 4 Influence of different MRD detection depths on PFS

Patients who obtain persistent MRD negative have a better survival prognosis
.
Persistent MRD negative has a higher prognostic value
for patients with NDMM who are not candidates for transplantation.
The MAIA and ALCYONE studies showed that in NDMMs that were not suitable for transplantation, the duration of MRD-negative ≥ 12 months benefit more
PFS in patients with less than 12 months.
Also, patients who also achieved MRD-negative and received daratumumab-based therapy benefited more from PFS than those in the control group, which was also associated with a higher proportion of patients who achieved persistent MRD-negative (Figure 5)⁷
.

Fig.
5 Duration of MRD negative and effect of treatment regimen on PFS in patients who are not suitable for transplantation NDMM

For transplant-eligible NDMM patients, persistent MRD negative is also associated
with longer PFS.
The GRIFFIN study showed that at a median follow-up of 38.
6 months, patients with persistent MRD-negative ≥ 6 months or ≥ 12 months had a longer
PFS compared with those who did not achieve persistent MRD negative.
Patients treated with daratuzumab (D-VRd) also had a higher proportion of persistent MRD-negative compared with VRd (bortezomib + lenalidomide + dexamethasone) (Figure 6)⁸
.

Fig.
6 Duration of MRD negative and effect of treatment regimen on PFS in patients with transplantation NDMM

In recent years, not only more and more clinical studies have used MRD as a surrogate endpoint for MM, but also explored more ways to guide treatment decisions based on MRD status
.
MASTER Study ⁹ is a multicenter, single-arm, phase II clinical trial evaluating the feasibility
of guiding consolidation therapy based on MRD status during the treatment of NDMM with daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd).
。 At the end of D-KRd induction, after autologous hematopoietic stem cell transplantation, and after D-KRd consolidation therapy every 4 cycles (up to 8 cycles), patients with MRD status were detected by NGS, and patients with negative MRD assessment for 2 consecutive times entered treatment-free observation and MRD monitoring
.
Results from a median follow-up of 25.
1 months showed that under this strategy, the MRD-negative rate of patients after consolidation therapy reached 80% (Figure 7), the highest among reported NDMMs, with a 2-year PFS rate of 87% and a 2-year OS rate of 94%.

Fig.
7 MRD negative rate of patients at each stage of treatment in MASTER study

Preliminary results from a Phase II study of MRD status-guided maintenance therapy were also reported at this ^{year's IMS Annual Meeting10} that evaluated
MRD-negative status after stopping maintenance therapy in patients who have been persistent MRD-negative for > 3 years.
The first batch of 15 patients was included, and if ≥ 8 patients were still negative for MRD at the end of Year 1, the second cohort of 35 patients
was continued.
The primary endpoint was persistent MRD negative rate
1 year after discontinuation.
Preliminary results showed that patients had a 6-month sustained MRD negative rate of 94% and 88% at 12 months, respectively, and a 12-month PFS rate of 94%.

Current results demonstrate the feasibility of discontinuing maintenance therapy in patients with persistent MRD-negative > 3 years.

This is the first time this strategy has been reported in a clinical trial, and mature data from the full cohort will help establish guidance for continued MRD-driven maintenance therapy discontinuation, and subsequent long-term follow-up data are expected
.

summary 

The emergence of new therapies has made the treatment of MM more effective, requiring more sensitive measures
of depth of remission.
MRD has become an important tool to evaluate the efficacy and prognosis of MM.

MRD negative is associated with longer PFS, and persistent MRD negative has a higher prognostic value; In NDMM and RRMM, patients receiving daratumab-based therapy had higher rates of MRD-negative and sustained MRD-negative rates;

More and more studies are exploring the guidance of clinical treatment decisions based on MRD status, and in the future, MRD may play a role
in determining the timing, consolidation, maintenance, and duration of treatment of MM autologous hematopoietic stem cell transplantation.