The Black Swan Research Initiative® (BSRI®), the International Myeloma Foundation’s innovative approach to finding a cure for myeloma, has entered a very exciting time. The project’s first phase – which began with the official launch in 2013 – has been successfully completed. We are now beginning Phase Two of our work to identify treatments that will cure myeloma.
Phase One of the Black Swan Research Initiative: a recap
The goal of Phase One of the BSRI was to establish the best methods for detecting and monitoring Minimal Residual Disease (MRD), which we believe is key to curing myeloma. In recent years, dramatic advances in myeloma treatment made it possible to destroy all but a tiny amount of diseased cells in many patients. Lingering, but hidden cells caused relapse. Only by wiping out all the myeloma could a patient be cured.
The BSRI team realized that existing testing methods were inadequate to measure and identify those cells – a stumbling block for attaining a cure. We had to be able to measure myeloma at a very low level in order to track and treat remaining disease. If we could do so, we could determine a) whether or not any cells remained at all (MRD-negative) or b) which treatment would work best on the cells that remain.
With the support of the BSRI, an extremely sensitive flow cytometry method for MRD detection has been developed by Drs. Alberto Orfao, Bruno Paiva, and team leader Prof. Jesús San Miguel, working at the Universities of Salamanca and Pamplona. This new flow cytometry test is able to detect myeloma cells in the bone marrow at the highly sensitive level of one in a million cells.
Extremely accurate method for measuring myeloma
“Next-Generation Flow” (NGF), as this new method is called, is highly reproducible, with a computer software package that takes just 12 minutes to run. We estimate the total cost of the test will be under $150. The NGF test can be done at centers around the world. In addition, it compares extremely favorably to a molecular or DNA sequencing technique called “Next-Generation Sequencing” (NGS).
Although NGS is also sensitive at a level of approximately one in a million cells, just 88 percent of patients had a bone marrow sample that allowed the DNA sequencing technique to be used, according to our analysis. That left out a sizeable 12 percent of patients. And in myeloma patients who had enough material to perform both NGF and NGS tests, the NGF method was actually positive in a few more cases versus the sequencing method. The NGS method will cost approximately $1,000 per test.
Black Swan Research Initiative: Phase Two
With the most sensitive and accurate MRD measuring tool in place, the BSRI investigators are now poised to begin Phase Two. In the next few months we will be introducing Next-Generation Flow and other types of MRD testing to correlate in what we call “cure” trials. The CESAR trial is launching now in Spain; the US ASCENT trial will begin within a few months at multiple institutions in the US, with Dr. Shaji Kumar of the Mayo Clinic as the principal investigator.
The goal is that these trials will lead to a sustained MRD-negative status for the patient. If we are not able to detect any residual disease at the level of one in a million cells, we feel this is an excellent indicator of sustained MRD-negative. If the patient continues to be MRD-negative for one year, three years, or five years off treatment, then this would indicate that the patient is potentially cured.
Both trials will be conducted in patients who have high-risk smoldering myeloma. We believe if we start early, this is the type of patient who will be amenable to a cure. Starting treatment early means there is less myeloma and fewer mutations or extra or missing chromosomes. Using an aggressive approach to treat these patients as part of the initial therapy, we believe that a significant percentage of these patients will indeed be cured.
What percentage are we predicting? In these trials, we think that as many as 30 to 50 percent of the patients will be cured through an aggressive strategy consisting of carfilzomib, lenalidomide, dexamethasone, autologous stem cell transplant, and – in the US ASCENT trial – the introduction of daratumumab. We believe the anti-CD38 monoclonal antibody will provide that extra bit of treatment that could allow the eradication of many, if not all, resistant clones.
Of course, not every patient will achieve an MRD-negative status. What about the patients who remain MRD-positive? The study of these patients constitutes a huge and very important part of the BSRI. We are now embarking on detailed studies of patients with residual myeloma and asking: What is the nature of the residual clones? What are their molecular characteristics? What are their immune features? What are the drug sensitivity features?
We want to be able to better understand these resistant cells and come up with the best treatment strategies to eradicate the resistant disease – even for the patients who have quite resistant sub-clones. This represents a huge opportunity to introduce new drugs in development and come up with new combinations and new therapies. Those trials will start in 2016.
And so, this is truly an exciting time for the Black Swan Research team. Its membership is rapidly expanding to include representatives from around the world who are contributing through lab-based research and upcoming clinical trials. Stay tuned for many more exciting new details in the coming months.
Black Swan Research Initiative resources