This article was developed by Janssen Oncology following a discussion with Dr Edmond Chan and Dr Maximilian Merz about the treatment landscape for multiple myeloma (MM), and what minimal residual disease could mean for the researchers, regulators, clinicians and most importantly patients who are part of the MM community.

The multiple myeloma (MM) treatment landscape has seen significant advances over recent years, substantially improving patient and survival outcomes.^[1],[2] These advances mean people diagnosed with MM are living better and for longer than ever before^[3] – a much-needed positive trend. Because of these advances, however, demonstrating meaningful overall survival (OS) of novel therapeutics is not always feasible or practical, and this can limit indications for newer medicines.^[4] That is why, on the path to finding a cure for the thousands of people diagnosed with MM each year,^[5] some scientists are seeking other ways to demonstrate efficacy.

One route to enabling a shift away from a hyperfocus on OS is to consider minimal/measurable residual disease (MRD)-negativity (the absence of any measurable MM cells), as a surrogate endpoint to OS and to demonstrate efficacy of new drugs in clinical trials. Through advancing science and adopting MRD as a surrogate endpoint in research, we can offer real hope to patients too, by potentially reshaping the myeloma treatment landscape and aiding clinical practice through better prognostication and treatment decisions.^[6]

Why is overall survival the gold standard in research?

In MM, as in many other therapeutic areas, OS benefit evidence remains the gold standard endpoint and is a crucial outcome considered for approval, indications, and reimbursement of medicines. However, this endpoint is becoming increasingly longer and more difficult to demonstrate as other non-treatment-related factors and other independent factors, like comorbidity and lifestyle choices, start to impact life expectancy.^[4]

These non-treatment factors can prevent mature and meaningful OS evidence from being available during regulatory or reimbursement assessments for medicines. Consequently, some novel treatments may not have their indications fully realised, which could deny patients access to life-saving medicine. For this reason, it is essential to explore surrogate endpoints to determine whether a therapy improves patient outcomes.

MRD negativity is associated with improved clinical outcomes^[7],[8]

Dr Maximilian Merz, Leipzig University, Germany, relays the importance of MRD in MM and its relevance outside of the research space too:

Dr Merz adds, “MRD negativity directly translates into longer progression-free survival (PFS) and OS on most retrospective analyses. We lack prospective real-world data at the moment, but based on retrospective analyses, we can say that MRD negative patients live longer than MRD positive patients.”

Indeed, two meta-analyses found that MRD-negative patients had better OS than MRD-positive patients.^[7],[8] With this growing strength of evidence, it is unsurprising that MRD negativity is included in the International Myeloma Working Group (IMWG) response criteria guidelines for MM.^[9] The undeniable prognostic value of MRD negativity supports its use as a clinically valid surrogate biomarker for PFS and OS in MM and should be leveraged to this end.^[6]

Dr Chan adds, “if we take the broadly accepted definition of a ‘cure’ as disease-free and not needing treatment for 10 years, I think MRD could be a tool for measuring this.”

So, how do we measure MRD?

Perhaps the best available testing methods for MRD are next-generation sequencing (NGS) and next-generation flow (NGF), which are considered similar in their ability to detect and quantify MRD.^[10] Imaging tools (PET-CT, MRI) can also provide additional prognostic information.^[11]

NGF and NGS have their own advantages and disadvantages, says Dr Merz. For example, NGF is more broadly available, carries lower costs, and the baseline sample requirements are easier to fulfil, though it does require fresh bone marrow samples.^[9] NGF is feasible in almost 100% of patients,^[12] and efforts from the EuroFlow consortium to harmonise MRD testing mean standardised methods are increasingly available.^[13]

In comparison, NGS has a high sensitivity threshold (10^-5)*, and the stability of DNA makes it easier to store samples for analysis at a later date.^[9] But it can be more costly and is feasible in slightly fewer patients (90%).^[9]

That said, assessing MRD may not be for everyone, admits Dr Chan: “from a practical point of view, requiring repeat bone marrow testing for NGS or NGF may be less reasonable in elderly or frail people, while younger patients may be more willing to undergo this.”

He adds, “We are only really at the beginning of detecting MRD – methods, like mass spectrometry, are evolving and improving all the time. MM is a heterogeneous and multi-compartmental disease. So, if we can accurately assess sustained MRD throughout and there is none, this could indicate a cure.”

Dr Chan believes that in the future, there may be less invasive measurement options that allow for a full body assessment, “I think routine monitoring for peripheral blood will become a norm for patients with multiple myeloma, and then we’ll be able to show if an indicator in your peripheral blood suggests that a patient’s disease activity has increased.”

The question remains, with enhanced and more accurate ways of measuring MRD – how does this impact patients’ lives?

In clinical practice, MRD testing may aid in prognostication and help patients and their healthcare professionals make informed decisions regarding subsequent treatment guided by the MRD-negativity results.^[14] Though treatment guidance for MRD is currently unclear, Dr Chan states, “Logically, it makes sense if someone loses sustained MRD negativity; it’s a sign of early relapse. This identification could allow for earlier medical intervention and may translate into a greater chance of survival.”

However, currently, there is a shortage of data that support clinical decision-making based on MRD. That said, Dr Merz is confident that MRD positivity or negativity can be used to guide treatment decisions:

In this scenario, patients with high-risk MM typically refers to a more aggressive form of the disease that is associated with genetic changes and is less responsive to treatment, which means patients are more likely to relapse sooner, compared to standard-risk.^[15]

Analysis of recent prospective trial data show MRD response-adapted therapy in patients with newly diagnosed MM allowed confident and successful treatment discontinuation.^[13] Dr Merz describes his excitement behind this practice-defining research, “I think this is one of the most important studies that implemented MRD negativity to guide treatment, especially in different subgroups of myeloma patients. For the first time, we saw that if you have standard-risk disease or the absence of high-risk myeloma, you can decrease treatment intensity if you have sustained MRD negativity.” This highlights the possibility of MRD negativity in shaping treatment decisions, though, Dr Merz adds “there is a clear need for more prospective real-world data to strengthen the level of evidence, but these are steps in the right direction.”

Cross-sector collaboration will be required to firmly establish the clinical utility of MRD negativity as a surrogate endpoint for survival. Progress has been made, but more needs to be done at the clinical or research level to strengthen the evidence base. Dr Chan believes:

With this strength of evidence, both Dr Merz and Dr Chan agree, health technology assessment bodies will be more likely to accept MRD as a surrogate endpoint in MM treatments – potentially delivering a new wave of management in MM.

One step closer to a cure in MM

With each new development, we are an inch closer to finding a cure for MM, and Dr Merz remains hopeful, adding, “We are still at the beginning of detecting MRD, but if we compare myeloma treatments from where we were 10 years ago to where we are now, we are much closer to the cure.”

Now is the time to move beyond relying on OS evidence to enable timely patient access to new and emerging cancer medicines.^[6] With advances in MRD measurements, it may be possible to detect MRD levels even more accurately and determine if someone is completely free of any myeloma cells.

Both Dr Chan and Dr Merz agree that MRD negativity should be the goal of every treatment and that it is central to understanding if people are disease-free or, effectively, cured. With a growing evidence base, clinicians may be able to use MRD status to shape clinical decisionmaking. Beyond this though, sustained MRD negativity ultimately offers hope to patients that we are one step closer to a potential cure for MM.

* Sensitivity (10^-5) is equivalent to one malignant cell per 100,000 normal cells.^[9]