Sustained MRD in patients with newly diagnosed and relapsed/refractory MM

This article summarizes key results from analyses of sustained minimal residual disease (MRD) negativity from the MAIA and ALCYONE trials in newly diagnosed (ND) multiple myeloma (MM) and the POLLUX and CASTOR trials in relapsed/refractory (R/R) MM. In addition, a discussion between Mohamad Mohty, Salomon Manier, and Nizar Bahlis about these findings from a live virtual journal club organized by the International Academy for Clinical Hematology (IACH) is covered below.

Results from the MAIA¹ (NCT02252172), ALCYLONE² (NCT02195479), POLLUX³ (NCT02076009), and CASTOR⁴ (NCT02136134) trials investigating daratumumab-based combination treatment regimens have previously been reported, which confirmed that deep and durable response rates are feasible in patients with ND MM and R/R MM. Despite this, the majority of patients relapse and require subsequent therapies, indicating that there is a disconnect between achieving a complete response (CR) and long-term remission. Therefore, there is a need for more sensitive detection methods that accurately assess disease state and likelihood of relapse. Achieving MRD negativity is known to be associated with longer progression-free survival (PFS) and overall survival (OS), and therefore has the potential to act as a marker of these established clinical endpoints. Furthermore, the ability to maintain MRD negativity may correlate with deeper clinical responses and improved long-term outcomes.

Sustained MRD negativity in ND MM: MAIA and ALCYONE trials⁵

At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Jesus San-Miguel presented analyses from the MAIA and ALCYONE phase III trials in patients with ND MM who were ineligible for autologous hematopoietic stem cell transplant, looking specifically at the predictive role of MRD negativity and durability.⁵ The MAIA study investigated outcomes of patients treated with dara-Rd (daratumumab + lenalidomide + dexamethasone) as frontline therapy, compared with Rd (lenalidomide + dexamethasone) alone.¹ The ALCYONE study compared patients treated with dara-VMP (daratumumab + bortezomib + melphalan + prednisolone) vs VMP (bortezomib + melphalan + prednisolone) only.² Both of these combinations of daratumumab are now approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Details of the eligibility criteria, study designs, patient characteristics, and endpoints can be found on the Multiple Myeloma Hub for both the MAIA and ALCYONE trials.

The rate of MRD negativity was a secondary endpoint in both trials and was defined as the proportion of patients with negative MRD at any timepoint, assessed using next-generation sequencing of bone marrow aspirates. Sustained MRD negativity was defined as the maintenance of MRD negativity in bone marrow confirmed ≥ 6 or ≥ 12 months apart, with a sensitivity threshold of one tumor cell in 100,000 normal cells (MRD at 10⁻⁵).

MRD negativity rates are shown in Table 1 for the intention to treat (ITT) population and patients who achieved a CR or better (≥CR). Key findings from the analyses were:

• Median follow-up time was 36.4 months (range, 0.0–49.9 months) in MAIA and 40.1 months (range, 0.0–52.1 months) in ALCYONE.
• In both populations, significantly higher MRD negativity rates and sustained MRD negativity were seen in patients treated with daratumumab-based combinations compared with regimens not including daratumumab.
• Patients with sustained MRD negativity lasting ≥ 6 months showed improved PFS in both studies separately and when data were pooled compared with patients who did not maintain MRD negativity for ≥ 6 months, and this relationship was also observed in patients with sustained MRD negativity lasting ≥ 12 months.
• Estimated rates of time to subsequent anticancer therapy were mostly higher in patients who obtained MRD at any time vs MRD-positive patients and in patients with sustained MRD negativity lasting ≥ 6 or ≥ 12 months compared with those without durable MRD negativity.
• Moreover, improved PFS was observed in patients who achieved ≥CR and MRD negativity compared with patients who were MRD positive or achieved a very good partial response or worse (HR, 0.19; 95% CI, 0.14–0.26; p < 0.0001).

Table 1. Sustained MRD negativity and TTSAT rates in the MAIA and ALCYONE trials in patients with ND MM*

Sustained MRD negativity in R/R MM: POLLUX and CASTOR trials⁶

Study details and key findings have previously been reported on the Multiple Myeloma Hub for the ongoing phase III POLLUX and CASTOR trials investigating combination treatment of patients with R/R with dara-Rd and dara-Vd, respectively, both of which have FDA and EMA approval. Assessment of MRD using next-generation sequencing was a secondary endpoint in both studies, and these analyses were published in the Journal of Clinical Oncology by Herve Avert-Loiseau and colleagues.⁶ Sustained MRD negativity was defined as for the ND MM studies above and evaluated in patients who obtained ≥CR to account for different sustained MRD negativity rates between treatment arms.

MRD was assessed at the time of suspected CR and at 3 and 6 months following confirmed CR in POLLUX and at 6 and 12 months following the first treatment dose in CASTOR. MRD was further evaluated every 12 months after CR in both studies.

Table 2 presents the rates of sustained MRD negativity. Key results were:

• Patients were followed up for a median follow-up time of 54.8 months (range, 0.0–61.9 months) in POLLUX and 50.2 months (range, 0.0–58.6 months) in CASTOR.
• Patients treated with daratumumab-based combinations had a ≥ 4-fold higher MRD negativity rate compared with control treatments within the ITT population and those obtaining ≥CR in both studies.
• A higher proportion of patients treated with daratumumab achieved sustained MRD negativity for ≥ 6 months in both studies compared with the control arms in both the ITT population and patients achieving ≥CR, which was also the case for patients who achieved sustained MRD negativity for ≥ 12 months.
• At 36 months, > 80% of patients who achieved sustained MRD negativity lasting ≥ 6 months had not progressed, regardless of treatment.
• Notably, across all patients treated with daratumumab (n = 537), PFS was prolonged in those with sustained MRD negativity lasting ≥ 6 or ≥ 12 months compared with patients who did not achieve sustained MRD negativity.
• Median time to subsequent anticancer therapy was longer for patients with sustained MRD negativity lasting ≥ 6 months.

Table 2. Sustained MRD negativity rates in the POLLUX and CASTOR trials in patients with R/R MM*

Journal club discussion: What could be the role of sustained MRD in MM?

Concept of sustained MRD

• It was highlighted that the MRD data from the POLLUX and CASTOR studies were the first showing that this depth of response was worthy of investigation in an R/R setting, and furthermore, that durability of MRD negativity has the potential to be a prognostic marker for long-term outcomes.
• The panellists discussed the use of an MRD sensitivity threshold of ≥ 10⁻⁵, i.e., one tumor cell in 100,000 normal cells, the level recommended by the International Myeloma Working Group.
  • A deeper threshold would likely be better in identifying patients with the best prognosis; however, this is limited by current technology and would require a large number of cells for accurate assessment, risking patients being considered as not MRD negative if results were inconclusive or missing.
  • It was agreed that a sensitivity threshold of 10⁻⁵ is a good compromise currently, although this may change with developing technology.
• The use of OS as a primary endpoint in clinical trials was reviewed, alongside concerns that an improvement in OS may not be seen despite the sustained MRD rates, as variables after trial completion cannot be controlled, such as comorbidities.
• Alongside MRD assessment from the bone marrow, imaging evaluation may help define MRD negativity more precisely.
• The panel discussed how frequently MRD should be assessed, as the 6 and 12-month cut-off points were established following previous guidelines on MM monitoring. Newer techniques, such as those involving circulating biomarkers, are not as invasive and therefore less of a patient burden, particularly if they can be performed less often.
• It was noted that in the clinical trials presented, MRD was assessed in patients with suspected CR in addition to the ITT population and that this would translate easily to clinical practice.

Outcomes of patients who achieve sustained MRD

• The panellists considered what action might be taken when a patient achieves sustained MRD and whether treatment can then safely be stopped.
  • There are currently no data that address this; although clinical trials are in progress, therefore caution would currently be recommended.
  • However, in a subanalysis from the MAIA trial, patients with sustained CR > 18 months, who subsequently had to suspend Rd for any reason, maintained their response, which is a promising sign if it also translates to MRD.
  • It was speculated that knowledge around sustained MRD negativity status might allow clinicians to feel more confident in reducing or stopping treatment if a patient experiences severe adverse events than if the patient was MRD positive.
• Furthermore, data are also not yet available surrounding patients who lose their sustained MRD negativity status and become MRD positive; therefore, it is unknown whether initiating or changing therapy would be advised in this case.
  • The impact of early intervention at biochemical relapse rather than symptomatic relapse was considered, given that all the studies discussed included asymptomatic patients. Notably, MRD-positive patients treated with daratumumab-based regimens had improved outcomes when compared with control patients within these trials.
• It was agreed that in the future, and when supported by evidence from clinical trials, sustained MRD may become helpful in clinical practice and be incorporated into monitoring guidelines and therapeutic decisions alongside novel agents in the R/R setting, such as bispecific antibodies and chimeric antigen receptor T-cell therapy.

Final conclusions

The POLLUX and CASTOR studies were the first to report MRD in the relapsed setting, adding to the evidence around MRD negativity in ND MM. Maintenance of MRD negativity was associated with survival benefits regardless of the treatment regimen across all four studies, although a greater proportion of patients achieved deeper and more durable responses with daratumumab-based therapy regimens. Expert discussion on the assessment of MRD negativity revealed several areas where further data are needed, however the panel were in agreement that sustained MRD negativity is likely to be a useful indicator of prognosis in the future.