Expanding Role Seen for Minimal Residual Disease in Managing Multiple Myeloma

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Minimal residual disease is a promising biomarker for guiding the management of multiple myeloma that is becoming increasingly important with the advent of more efficacious therapies, according to emerging data and expert opinion.

With the new treatments that have changed the myeloma landscape, we are already achieving complete responses in a substantial proportion of patients, so it’s the right time to investigate minimal residual disease.
— Jesús F. San-Miguel, MD, PhD

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“The story of minimal residual disease in multiple myeloma is like a revolution,” Jesús F. San-Miguel, MD, PhD, Professor and Director of Clinical & Translational Medicine at the Universidad de Navarra in Spain, commented in an interview. “Although we published our first paper on minimal residual disease in multiple myeloma >15 years ago, I would say that the revolution started probably this past 2 years ago.1 Now, minimal residual disease is being implemented in all clinical trials, and many academic centers are using it routinely.”

Clinical Context

Until recently, minimal residual disease was predominantly used in leukemia, he noted. “You may ask, why did you publish minimal residual disease studies in acute lymphoblastic leukemia [ALL] and acute myeloid leukemia [AML] in the late 1990s and even the 2000s—10 years ago—and not in multiple myeloma? The answer is simple: In multiple myeloma, the treatments were suboptimal. We did not even achieve a complete response by cytologic means. There was no real need to investigate minimal residual disease.”

That has changed with approval of a host of agents for multiple myeloma such as antibodies and small molecules, which have dramatically improved prognosis, reducing residual disease to levels so low it can be detected only with highly sensitive assays and raising the question of redefining goals of therapy. “With the new treatments that have changed the myeloma landscape, we are already achieving complete responses in a high proportion of patients, so it’s the right time to investigate minimal residual disease,” Dr. San-Miguel maintained.

The benefit of complete response mainly comes from the minimal residual disease–negative cases.
— Jesús F. San-Miguel, MD, PhD

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In fact, about 80% of patients with newly diagnosed disease given contemporary combination regimens, with or without the addition of high-dose melphalan and autologous stem cell transplantation, achieve complete response.2 Still, the majority who do ultimately go on to experience a relapse, and among complete responders, those with minimal residual disease detected by a variety of hematologic assays or positron-emission tomography (PET)/computed tomography experience poorer survival.3

Proposed roles for minimal residual disease in managing multiple myeloma therefore include assessing the efficacy of regimens, helping to guide treatment decisions, and estimating survival.3 Additionally, some investigators have suggested that minimal residual disease be used as a regulatory endpoint for drug approval in patients with newly diagnosed disease.4

Recent Meta-analysis

In this context, recent research has focused on strategies for detecting minimal residual disease and defining its association with clinical outcomes. A recent meta-analysis took on this issue, analyzing data from four studies of patients with newly diagnosed multiple myeloma, excluding those undergoing allogeneic transplantation.5 Results showed that patients who were minimal residual disease–negative after therapy had significantly better progression-free survival (hazard ratio, 0.35; P < .001) and overall survival (hazard ratio, 0.48; P < .001) than counterparts who were minimal residual disease–positive.

“This meta-analysis confirms that minimal residual disease negativity is a very important predictor of clinical outcome and supports the value of minimal residual disease as a tool to evaluate the efficacy of treatment,” Dr. San-Miguel commented, noting that the results are consistent with research conducted by his team.

“The findings demonstrate that the information of minimal residual disease is more relevant than the information of complete response,” he added; in fact, preliminary evidence suggests that after removing minimal residual disease–negative patients from the group with complete response, the others have outcomes similar to those who had only a partial response. “In other words, the benefit of complete response mainly comes from the minimal residual disease–negative cases,” he elaborated.

At the same time, the meta-analysis had some limitations, he cautioned. It did not use individual-level patient data. Also, analyses combined minimal residual disease as assessed by different assays.

Minimal Residual Disease Assays

The two main categories of hematologic assays for assessing minimal residual disease, flow cytometric methods and molecular methods, differ in various aspects, which affect their clinical applicability, according to Dr. San-Miguel. Additionally, performance varies within each category.

Flow cytometric methods—conventional, second-generation, and next-generation—differ in their sensitivity. “We have determined that approximately 30% of patients who are minimal residual disease–negative with the old technique, which has a sensitivity of 10–4, become positive with the newer, second-generation technique, which has a sensitivity of 10–5,” he elaborated.6 “Similarly, with the next-generation flow, which has a sensitivity of 10–6, some of the cases that were minimal residual disease–negative are now minimal residual disease–positive.”

Accumulating evidence shows that the deeper the extent of flow cytometric minimal residual disease negativity in multiple myeloma, the better patients’ prognosis, he noted. “This is similar to what has been reported for chronic myeloid leukemia,” whereby prognosis is good for patients having a hematologic response, better for those having a cytogenetic response, and best for those having a molecular response.

Molecular methods of assessing minimal residual disease—allele-specific polymerase chain reaction and, more recently, next-generation sequencing—can similarly achieve 10–5 and 10–6 sensitivity.7 The use of allele-specific polymerase chain reaction has been limited by factors such as processing time, and accessibility, but with the next-generation sequencing is gaining popularity.

“The major advantage of next-generation sequencing is that you don’t need to process the sample immediately; you can keep the sample frozen and do it 1 week later or 1 year later,” Dr. San-Miguel commented. “By contrast with flow you need to process the sample in 24-72 hours, but the counterbalance is that you have the results on the same day, and you can make the clinical decision immediately. And on top of this, you have not only the information on the malignant clone, you can have the information also on the immune system, because you are studying it in parallel to the minimal residual disease.”

But we should not forget that as important as the minimal residual disease evaluation inside the bone marrow, we should investigate minimal residual disease outside the bone marrow by CT-PET. In the transplant setting it has been demonstrate that patients who achieve a negative CT-PET enjoy a significantly longer survival.

The cost of next-generation sequencing or next generation flow or CT-PET could be justified if it were shown to have sufficient impact on care and outcomes, according to Dr. San-Miguel. “[Minimal residual disease] investigation is inexpensive if you compare it with the cost of even a single cycle of treatment. And if you use this to make treatment decisions, that is of clear value,” he said.

“Few academic centers are using next-generation sequencing because most of the studies of this technique have been generated by commercial companies,” he noted. “By contrast, next-generation flow is becoming more and more popular, because individual centers do it. At a recent meeting, over 30 centers showed that they are currently using it.”

Using Minimal Residual Disease in Practice

At present, his clinic assesses minimal residual disease status in three multiple myeloma treatment settings, Dr. San Miguel said. “For every patient who achieves complete response, we do minimal residual disease to evaluate the quality of the response,” he explained. “And in the transplant setting, we do it before transplant and after transplant. Then we also do a control assessment during maintenance to demonstrate the patient has sustained minimal residual disease negativity.”

“For us, minimal residual disease is very valuable, and it also helps us to make decisions,” he added. For example, “if I have a patient with high-risk cytogenetics who is in complete remission but is minimal residual disease–positive, I know he has a poor prognosis and I will not stop treatment at all.”

Looking 5 or 10 years down the line, “I think, to achieve minimal residual disease negativity will be a clear endpoint, and this should be combined with imaging techniques also to have PET negativity,” Dr. San-Miguel concluded. “In other words, in the future, we will evaluate the myeloma both inside and outside the bone marrow.” ■

Disclosure: Dr. San-Miguel has served on advisory board for Takeda, Celgene, Novartis, Amgen, Janssen-Cilag, BMS, Sanofi, Roche and MSD.


1. San Miguel JF, Almeida J, Mateo G, et al: Immunophenotypic evaluation of the plasma cell compartment in multiple myeloma: a tool for comparing the efficacy of different treatment strategies and predicting outcome. Blood. Mar 1;99(5):1853-6, 2002.

2. Mailankody S, Korde N, Lesokhin AM, et al: Minimal residual disease in multiple myeloma: Bringing the bench to the bedside. Nat Rev Clin Oncol 12:286-295, 2015.

3. Paiva B, van Dongen JJ, Orfao A: New criteria for response assessment: Role of minimal residual disease in multiple myeloma. Blood 125:3059-3068, 2015.

4. Landgren O, Iskander K: Modern multiple myeloma therapy: Deep, sustained treatment response and good clinical outcomes. J Intern Med 281:365-382, 2017.

5. Landgren O, Devlin S, Boulad M, et al: Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: A meta-analysis. Bone Marrow Transplant 51:1565-1568, 2016.

6. Flores-Montero J, Saboja-Flores L, Paiva B, et al: Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. March 10, 2017 (early release online).

7. Avet-Loiseau H: Minimal residual disease by next-generation sequencing: Pros and cons. Am Soc Clin Oncol Educ Book 35:e425-e430, 2016.