Questions surround MRD assessment in MM


Toni Valković, MD, PhD

DUBROVNIK, CROATIA—Clinical trials are needed to answer the many questions related to minimal residual disease (MRD) assessment in multiple myeloma (MM), according to a speaker at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

MM patients are increasingly assessed for MRD, which is a strong prognostic factor and surrogate for overall survival, according to Toni Valković, MD, PhD, of University Hospital Center Rijeka in Croatia.

However, Dr. Valković said MRD assessment has not become a part of routine clinical practice, perhaps because we haven’t determined the best way to utilize MRD assessment in MM patients.

The optimal sensitivity threshold, technique, and timing of MRD assessment are not known, and it isn’t clear how MRD should be used to guide treatment.

What we know

Dr. Valković cited studies showing that MRD negativity is associated with superior survival in MM1, and, when MRD negativity is achieved, high-risk cytogenetics, age, and previous treatment regimens appear to have no further impact on prognosis.2

Dr. Valković went on to explain the benefits and detriments of multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment.3

NGS requires a baseline patient sample, but MFC does not. More cells are required with MFC than with NGS (>5 million vs. <1 million).

With MFC, samples must be processed within 24 to 48 hours, whereas, with NGS, fresh or stored samples can be used. MFC can be done in a few hours, while NGS can take several days.

Despite these differences, both methods provide similar levels of sensitivity for detecting MRD (≥1 in 105).

Dr. Valković also noted that MRD should be evaluated outside the bone marrow as well, which can be done with positron emission tomography-computed tomography (PET-CT).

Research has shown that patients who are MRD-negative according to both MFC and PET-CT have better outcomes than patients who are MRD-positive by MFC, PET-CT, or both.4

What we don’t know

Though he compared MFC and NGS, Dr. Valković said we don’t know the optimal technique for assessing MRD in the bone marrow.

Another uncertainty is the optimal sensitivity threshold. In the POLLUX study5, researchers found that a threshold of 10-4 resulted in lots of patients with MRD negativity, but some of these were false-negatives.

So although 10-4 proved inaccurate, it isn’t clear if the optimal threshold is 10-5 or 10-6, Dr. Valković said.

Likewise, it isn’t clear if PET-CT is the optimal method for evaluating MRD outside the bone marrow.

In a study published in 2017, PET produced false-negatives in MM patients.6 In 11% of patients (26/227), there was evidence of disease with diffusion-weighted magnetic resonance imaging with background signal suppression, but there was no apparent disease with PET. The researchers said low expression of hexokinase-2 was associated with a false-negative PET result.

Finally, Dr. Valković said we don’t know how best to use MRD to tailor therapy in MM patients. He posed the following questions:

  • If patients don’t achieve MRD negativity, should they continue on the therapy?
  • If MRD-negative patients become MRD-positive, should they begin therapy immediately, or should treatment be put off until a biochemical or clinical relapse?
  • Should MRD status be used to determine the number of treatment cycles a patient receives, the timing of transplant, or when to begin and end maintenance therapy?

“There are a lot of issues and unanswered questions related to the optimal techniques for the evaluation of MRD and their sensitivity, the timing for MRD assessment during and after therapy, and its role in the treatment decisions, which should be answered in future clinical studies,” Dr. Valković concluded.

He did not declare any conflicts of interest.

1. Munshi NC et al. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160

2. Paiva B et al. Blood. 2016 Jun 23;127(25):3165-74. doi: 10.1182/blood-2016-03-705319

3. Kumar S et al. Lancet Oncol. 2016; 17 (8):e328-46 doi:

4. Fernandez RA et al. Blood. 2017; 130:3098

5. Dimopoulos MA et al. Haematologica. 2018 Sep 20. pii: haematol.2018.194282. doi: 10.3324/haematol.2018.194282

6. Rasche L et al. Blood. 2017 Jul 6;130(1):30-34. doi: 10.1182/blood-2017-03-774422

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