As treatments for multiple myeloma have improved, so have methods for assessing a patient’s response to therapy. Minimal residual disease (MRD) is considered a valuable prognostic factor for survival. MRD can be evaluated in several ways: next-generation sequencing; positron emission tomography–computed tomography (PET-CT); whole-body, low-dose CT and whole-body, low-dose magnetic resonance imaging; and multiparameter flow cytometry (MFC).
A study published in May 2019 in American Journal of Hematology looked at whether using a combination of PET and MFC to evaluate minimal residual disease (MRD) had a beneficial effect on progression-free and overall survival in 103 patients with newly diagnosed multiple myeloma. The authors found that there was a significant difference in overall survival between groups who were negative on both PET-CT and MRD as assessed by MFC, or negative on PET but positive for MRD, versus patients who scored positive on PET-CT. Those patients who tested negative with one or both methods tended to do better in overall survival.
Michael Thompson, MD, PhD, a multiple myeloma oncologist at Aurora Health Care in Milwaukee, Wisconsin, who was not involved with the study, said the study is important because “it allows a way to better assess patient response to therapy and gain more information about the biology of the disease, going beyond just looking at bone marrow at [a] single site.” Joshua Richter, MD, an oncologist at Mount Sinai in New York, New York, who also was not involved with the study, said this study affirms the benefits of a multimodal approach for assessing MRD. “Some patients only express [the disease] in the blood, while others only show it in the marrow, or only outside the marrow with extramedullary disease. The reality is that when we’re not comprehensive with these analyses, we can sometimes miss relapses,” he said.
Dr Richter emphasized that the most important result of the study was “bringing to light the necessity to have very comprehensive evaluations when we’re evaluating response to treatment.” Even in the baseline data, there were discrepancies between people who were negative in the marrow and positive in the PET scan, highlighting the heterogeneity of multiple myeloma. Each individual patient’s journey through the disease is completely unique, noted Dr Richter. “We need to take that into account when we’re deciding the treatment course, assessing response and relapse.” And, said Dr Thompson, the study subjects were treated for their multiple myeloma with a variety of different therapies: “If you met the MRD or PET end points, it didn’t matter which treatment you got — that’s an interesting point.”
The study does have several limitations, which the authors acknowledged. For one, the technology they used to assess MRD, multiparametric flow cytometry or MFC, is “a little bit old,” said Dr Richter. While there are a variety of ways to assess MRD currently, next-generation flow (NGF) and next-generation sequencing are considered more sensitive. Dr Richter added that the evaluation options used at any particular practice can vary.
Another big limitation is that this is a retrospective study. “We really need more prospective data, so that we can use this to determine treatment decisions,” said Dr Richter. How does the information gleaned in this study help oncologists better manage patients? There are still many questions to be answered in this realm. For example, if someone is MRD-positive or PET-positive, is it best to continue treatment, change treatment, or give no treatment? One study might look at patients who are MRD-positive or PET-positive at the end of the treatment, giving some of them additional treatment to see if this can change outcomes. Some studies like this are currently being designed and conducted, but prospective studies take years to yield results. A group of studies, noted Dr Thompson, would be most helpful to assess multiple treatment options — individual studies may not yield much helpful information on their own, since there are a number of treatment hypotheses to test within these different groups.
To experts, the big question in the field is: what level of treatment is necessary to make patients better and keep them in remission? “We know that at a basic level, the deeper a remission people get into, the better they’ll do,” said Dr Richter. For instance, if you give a group of patients a treatment, and some end up MRD-positive and some MRD-negative, the MRD-negative patients will do better. While they don’t yet know for sure that additional treatment for the MRD-positive patients will make for better outcomes, many myeloma specialists suspect achieving an MRD-negative status may be key. “We’re exploring that right now,” said Dr Richter.
Assessing the level of remaining disease in multiple ways “allows us to achieve the goal of total disease remission in ways that we haven’t before,” he added. The zero line, the level at which there is zero detectable disease, is continuing to drop as physicians use more and more sophisticated methods to measure it. A “zero” doesn’t mean the disease is gone — it means the amount of disease detected is zero. As detection improves, that “zero” means less and less actual disease remains undetected in the body.
“Ultimately, if we can use these [imaging and sequencing] technologies along with our therapies to find out who’s in really deep remission, not only can we find the patients who don’t need continual treatment (most patients with multiple myeloma do), but perhaps we will use these modalities one day to find the path to cure. Our ‘zero’ level will be so refined that we can say we have cured someone,” said Dr Richter. This study, he said, is an important part of the understanding of the path leading to a cure.
“The authors are to be applauded for getting out more information in this very hot area of research,” concluded Dr Thompson. “This, as well as the other studies before [it], will help design trials to move patient care forward and decrease toxicities.”
Alonso R, Cedena MT, Gómez-Grande A, et al. Imaging and bone marrow assessments improve minimal residual disease prediction in multiple myeloma. Am J Hematol. 2019;94(8):853-861.