MRD Negativity Moves Into the Spotlight as a Potential Surrogate End Point in Multiple Myeloma

Ongoing research efforts are pushing to establish minimal residual disease (MRD) negativity as a surrogate end point for patient outcomes in multiple myeloma clinical trials, and MRD assessment is becoming an increasingly utilized tool to inform real-world clinical decisions, according to a paper published in Clinical Care Research.

The integration of novel therapies and combinations for the treatment of patients with multiple myeloma has led to more durable responses, translating to improved survival. However, it has also shed light on shortcomings with currenxt residual disease testing modalities that have been used to defined complete responses (CRs) in this patient population. Nearly all patients who achieved CRs with such testing experience relapse, suggesting that the standard immunofixation techniques and morphological evaluation of bone marrow provided a “false sense of disease control,” lead study author Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School and program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, and co-authors wrote.¹

As such, MRD assessment was incorporated into the International Myeloma Working Group uniform response criteria based on available data demonstrating the prognostic value of MRD negativity in patients with multiple myeloma.² In January 2016, a white paper collaboration of minds across the myeloma field updated the status of MRD and highlighted that a study-based definition of MRD as a surrogate end point was needed to inform clinical decisions in multiple myeloma.

Subsequently, more research has emerged establishing MRD as a potential regulatory end point for clinical trials and MRD negativity had routinely been incorporated into clinical trial designs. Moreover, these efforts are providing additional insight into the value of MRD assessment at various stages of multiple myeloma.

“Many of these designs have now been implemented, and almost 50 phase 3 trials are currently actively enrolling, using MRD-directed treatment assignment or MRD as an end point,” Anderson, who is a 2014 Giants of Cancer Care® winner in multiple myeloma, and co-authors wrote.¹

Multiple MRD assessment technologies are emerging as potentially employable strategies for clinical trials, drug development, and real-world utility, including next-generation flow (NGF), next-generation sequencing (NGS), blood-based MRD assessment, circulating cell-free DNA assessment, single-cell RNA-sequencing, imaging, and mass spectrometry-based paraprotein analyses. Although these technologies differ, any measurement of tumor burden can “provide consistency when comparing treatment arms or stratifying patient populations into different arms of therapeutic intervention and ultimately in the future in choosing treatment options in real-world practice,” Anderson and co-authors wrote.

However, factors such as prior treatments, other diagnostic tests and risk markers, and patient-related factors, such as symptoms, comorbidities, and quality of life, should be considered when determining how much value MRD assessment holds for an individual patient.

“Determination of MRD at a single point in time may have prognostic significance, but quantitative, accurate, standardized, and sensitive MRD determinations may provide greater information relevant to tumor biology and likelihood of relapse when performed in a sequential fashion over multiple time points during a continuum of care to establish the trend and pace of the change in tumor burden,” wrote Anderson and co-authors.

Despite the estimate that MRD assessment can open opportunities for potential regulatory and clinical uses as a biomarker, factors such as underlying disease, patient heterogeneity, therapeutic context, target of therapy, or a combination of disease parameters must be considered before wide implementation of MRD assessment can be used in the clinical and regulatory settings.

Moreover, with so many ongoing trials incorporating MRD negativity as end points, it is critical to ensure that emerging data regarding MRD is interpretable. The FDA has highlighted issues such as inadequate data, data not proposed for inclusion because of missing or disparate data points, high rates of test failures, incomplete test characteristics, and incomplete planned statistical analysis with MRD assessment in past regulatory submissions. Notably, although NGF and NGS are the most widely utilized MRD technologies currently, the FDA does not have a preference in terms of technology platforms used in clinical trials assessing MRD, stating only that the test must be analytically validated for its context of use in the trial.

The role of MRD assessment as a clinical end point in trials is an important facet of the biomarker’s development in multiple myeloma. With the significant advances that have been made in therapeutics in recent years, the time to reach progression-free survival and overall survival has become very long, which prevents therapies from moving into clinical use in a timely manner, particularly with regard to frontline regimens. Because MRD-negativity status has demonstrated improved survival outcomes, incorporation of MRD negativity as a surrogate end point could expedite therapeutic development for patients with multiple myeloma.

“It would be beneficial for regulatory agencies to use existing data from completed [multiple myeloma] trials to provide industry with guidance on specific timepoints that can be used in prospective [multiple myeloma] trials for evaluating MRD status. Such guidance will of course evolve, but if we wait for future clinical trials to provide definitive validation of MRD as a surrogate end point, valuable years will be lost as we wait for these studies to progress and these data to mature,” Anderson and co-authors wrote.

Ultimately, MRD assessment stands to benefit patients across the spectrum of multiple myeloma, including smoldering, transplant-eligible and -ineligible newly diagnosed, and relapsed/refractory disease states. MRD assessment also appears to have utility in patients with extramedullary disease.

“The pace of advances in targeted and immune therapies in [multiple myeloma] is unprecedented, and this collaborative effort, inspired by a shared commitment to patients, will assure that these advances translate to clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes,” Anderson and co-authors concluded.

References

1. Anderson KC, Auclair D, Adam SJ, et al. Minimal residual disease in myeloma: application for clinical care and new drug registration. Clin Cancer Res. Published online July 28, 2021. Accessed August 17, 2021. doi:10.1158/1078-0432.CCR-21-1059
2. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346. doi:10.1016/S1470-2045(16)30206-6