April 15, 2021
Achieving a cure for myeloma is what every patient wants, and it is the ultimate goal of all myeloma researchers. In 2012 the IMF established the Black Swan Research Initiative (BSRI) with the sole purpose of searching for a cure. Great progress has been made, but it takes time to know if excellent, deep remissions will be sustained in the long term.
Central role of testing for MRD (minimal residual disease)
A first step for the BSRI team was to establish reliable, sensitive methods to assess low levels of myeloma after very successful treatment. The initial goal was to achieve “MRD undetected.” That means zero evidence of myeloma at a level of zero out of a million cells counted in the bone marrow after a patient receives the current best therapies. A sequencing method of testing (next-generation sequencing) became available, and a flow cytometric method (next-generation flow) was developed by a team of Spanish researchers at the University of Salamanca. Both allowed documentation of this deep level of response known to lead to outstanding remissions and improved survival in myeloma patients.
Conducting cure trials
At the same time as testing was being refined, clinical trials were launched to give decisive treatment to patients with early disease: those with high-risk smoldering multiple myeloma (HR SMM). Dr. María-Victoria Mateos and her colleagues at the University of Salamanca in Spain conducted the CESAR trial in which 90 HR SMM patients received a combination of carfilzomib, lenalidomide and dexamethasone (KRd) and an autologous stem-cell transplant (ASCT). This trial went very well and now four years later a majority of patients are still at that “MRD undetected” level.
In addition, a similar trial, the ASCENT trial, is being conducted in the U.S. with Dr. Shaji Kumar and myself as principal investigators. Therapy in this trial for HR SMM patients is KRd + daratumumab (+/- ASCT) and accrual is still ongoing. As with the CESAR trial, results have been excellent.
The need for patience
Are patients in these trials being cured? The next step in this research is to look more closely for any evidence of myeloma remaining anywhere in the body. Using whole-body PET/CT scanning, a small number of patients in these trials achieved low levels of MRD have been found to have myeloma in soft tissue sites outside the bone marrow that was used for MRD-testing evaluations. This led to intense research for even more highly sensitive MRD testing in blood samples that would be positive no matter where the myeloma is located.
Great progress is now being made and sensitivity at a level of zero out of 100 million may be achievable with new blood testing methodology. In addition, very sensitive testing for the myeloma protein levels in the blood has been introduced using a new mass spectrometry approach. Again, some patients at an “MRD undetected’ level in the bone marrow tested positive with this mass spectrometry technique. Since these patients remain in remission, only time will tell what will happen with ongoing follow-up out to five years and beyond.
New research explores mechanisms of resistance
Today, about half of the patients in both trials remain in remission, with negative testing using every method at our disposal. The focus has now turned to those patients with very low levels of myeloma remaining. Why have these myeloma cells not been eradicated by otherwise successful treatment? And why are these patients still in remission without new disease progression?
We are learning more and more about the genetic and molecular mechanisms of resistance to current therapies. In some cases, genes are activated (called chromatin activation) and allow myeloma cells to survive. Myeloma cells also trigger immune reactions to prevent clean-up by the normal immune response. Many cells are involved in this process. They include T cells, which can become “exhausted,” hence the benefit from administering engineered, active T cells, CAR T cells, to help eradicate myeloma cells.
Other cells, such as monocytes or macrophages (normally, scavenger cells that clean up cancer cells or other types of damaged cells or tissues) are involved. They get reprogrammed so that they are unable to kill myeloma cells, but instead produce chemicals which increase myeloma growth! Tackling this problem will be important.
In addition, cells called “natural killer cells” get depleted. Re-enhancing their anti-myeloma capacities can also be helpful. Members of the BSRI team and other researchers are studying all these different aspects of the micro-environment to assess possible solutions.
Great progress has been made in achieving long-lasting, deep remissions for about half of the patients in the cure trials. Documenting that there is no residual disease hiding somewhere remains a challenge. Thus, patience and longer follow-up are required.
In those patients with low levels of myeloma remaining, we are learning how to potentially eradicate these cells—either directly with therapy against the myeloma cells and/or tuning up the anti-myeloma immune response to either control or eliminate residual disease.
In the meantime, all myeloma patients can be offered new combinations of therapy that can achieve deep responses for a majority and truly long-lasting remissions for an ever-increasing number of patients. Even patients with higher-risk disease can achieved better outcomes if the “MRD undetected” level of response is achieved.
The good news is that the IMF’s Black Swan approach is bringing a level of optimism for all patients.
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.