On July 27, 2016, the new response criteria from the IMF’s International Myeloma Working Group (IMWG) incorporating minimal residual disease (MRD) testing was published in The Lancet Oncology. Achieving consensus by more than 200 of the world’s top myeloma researchers on these criteria marks a significant accomplishment, two years in the making, by lead author Dr. Shaji Kumar of Mayo Clinic and his IMWG colleagues. The new response criteria update those set by the group in 2006.

“The treatment landscape for multiple myeloma has been radically transformed during the past decade by the introduction of several new drugs with different mechanisms of action,” writes Dr. Kumar. High rates of complete response in myeloma patients treated with the new drugs called for new categories to identify responses that are deeper than those conventionally defined as complete response.

The publication of the new response criteria also represents an important step forward for the IMF’s mission to find a cure. As you may know, MRD testing has been a crucial element of our Black Swan Research Initiative® since its inception in 2012. We have been pleased to see that in the four years since then, MRD testing in myeloma has been embraced by the rest of the myeloma research community. But with the publication of the new response criteria, MRD testing has now taken its place as the gold standard of disease measurement – much as we envisioned – and one which now allows us to determine exactly where a patient stands in the course of the disease and how effective treatment has been.

What, exactly, is MRD negative, MRD positive?

In the new IMWG MRD response criteria, exact definitions are spelled out for what constitutes a patient considered to be “MRD negative”: at what level and with which tests. Either Next-Generation Sequencing (NGS) or Next-Generation Flow (NGF) can be used, with a cutoff which has to be at least less than 1 in 100,000 cells, but hopefully less than 1 in 1,000,000 cells. There are two additional categories in the new response criteria to measure MRD: one in which PET/CT scanning is also negative and a “sustaining MRD negative” category in which the MRD negative testing remains negative after one year – a key endpoint.

Having “sustained MRD negative” as an endpoint in clinical trials provides an important yardstick to point the way to the achievement of cure – which is defined as an MRD negative level sustained at three years and five years. It is wonderful to have this framework for clinical trial design.

MRD testing in the clinic

But what about MRD testing in the clinic? I very much appreciate and understand the patient perspective that “confirming MRD negative status” would be very reassuring. And I know from talking to patients that they are rightfully anxious to take this next step. However, I have to point out a couple of challenges in the short term:

1. Currently, “routine” MRD testing is not fully set up and standardized. Nor is there an accepted reimbursement plan. The fact that a sample can be sent to one laboratory and get one answer (let’s say “negative”) and another lab with a different answer (let’s say “positive”) is very disturbing. This issue needs to get sorted out before routine testing is recommended.  We hope that standardization and quality controls for NGF will be in place for a significant number of laboratories in the US within six to nine months, and, the Black Swan research team has been working nonstop to make that happen.

2. We need to fully understand the significance of “MRD negative” and “MRD positive” test results. If, for example, a patient is on maintenance therapy, doing well, and is “MRD negative,” is it safe to stop maintenance or maybe continue for a further six months or longer? We don’t know. If such a patient has an “MRD positive” test result, what does that mean? Should maintenance be changed or is everything actually just fine in terms of achieving ongoing benefit with the same maintenance? These are very important questions, which along with many others, need to be answered in top priority clinical trials.

“These revised response criteria will be used in clinical practice, research, and in regulatory studies that lead to the approval of new drugs by agencies worldwide,” explained Dr. S. Vincent Rajkumar of Mayo Clinic, who called the paper “another landmark accomplishment for the IMWG.”

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