Is MRD ready for prime time in multiple myeloma?

MRD negativity has implications for speeding drug approvals, developing more sensitive assays, and future treatment management, Dr Landgren said.

No—MRD is not ready for prime time

Dr Richardson acknowledged that MRD assessment is important. However, he pointed out a number of caveats regarding how MRD assessment would be applied in clinical practice to support his position.

“I’d simply suggest to you that, in day-to-day practice, the definition [of MRD] is somewhat fluid,” he said. “And it varies, obviously, between diseases and technology used.”

For most malignancies, Dr Richardson said, 10⁹ to 10¹⁰ malignant cells are undetectable with conventional methods. These may or may not lead to a full clinical relapse within months or even years.

Using a sensitive technique to determine the presence of MRD could permit analysis of treatments that induce a greater depth of response or identify patients at risk of early relapse who need further treatment.

Dr Richardson enumerated hematologic malignancies that utilize MRD as secondary endpoints—acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma.

In chronic myeloid leukemia, MRD is used as a primary endpoint that dictates practice.

“And I would applaud the field in that area because, obviously, molecular response accepted as an endpoint by FDA for second-generation TKIs has been a bedrock of that approval process, and it now applies in clinical practice,” Dr Richardson said.

“Obviously, that’s where we’d like to be, but I’d suggest to you, just again, with a certain amount of moderation and a certain amount of caution, that we may not be quite there yet.”

Dr Richardson suggested that MRD assessment in MM is less advanced than in leukemia and lymphoma.

“[W]e are currently at the point where MRD assessments are clearly secondary endpoints, an important research tool,” he said.

Some “remarkable combination therapies,” he added, have abrogated some of the “extraordinary genetic complexity” in MM.

“The critical point here, though, is that, while we’re more successful in terms of these triplets and quadruplets and now with the introduction of monoclonal antibodies and similar approaches, we’re able to throw a bigger net around the disease,” Dr Richardson said.

“We’re not able to eradicate it completely, and cure remains, in myeloma, frankly, evasive. And I think that’s a critical point.”

Dr Richardson reviewed various strategies for molecular response monitoring, from flow cytometry to polymerase chain reaction and next-generation sequencing, noting that there is variance in applicability and sensitivity.

For example, the limits of detection among 91 labs ranged from 0.10% to 0.001%.

Dr Richardson returned to the “very robust” meta-analysis by Munshi and colleagues discussed by Dr Landgren.

While the authors’ analysis demonstrated that MRD is predictive of both longer PFS and OS, they concluded that the evidence supported MRD as an endpoint and research tool in clinical trials.

“So I would humbly suggest perhaps it’s not ready for clinical prime time yet,” Dr Richardson said.

He also referred to the IFM Study Group trial described by Dr Landgren, calling it a “critical forward effort.”

“[W]hat’s so interesting is that there was no difference in overall survival,” Dr Richardson said. “Now, that’s a very important point as we soberly look at these data and judge what they mean for each patient.”

And so Dr Richardson stood by his assessment that MRD is not yet a standard of care but may be one day.