Summer Updates: More about “dara” …and ideas about what may cause myeloma
In an important paper published recently in the journal Blood, researchers from the Netherlands and Belgium correlate the response to daratumumab (dara), the anti-CD38 monoclonal antibody, to the level of CD38 expression on the myeloma cells and whether or not complement inhibitory proteins (CIPs) CD55 and CD59 emerge with treatment. A separate report in Blood from a joint Danish, Netherlands, Italian, and US team summarizes the findings of a phase I/ II study combining dara with lenalidomide + dexamethasone to show that the combination produces responses in 81% of patients versus approximately 30% with dara alone. These results led to the development of the POLLUX trial, which recently confirmed the approximately 80% response rate for the combo with 78% of patients still in remission at close to 2 years. The results of the combination of dara with bortezomib (Velcade®) and dexamethasone (the CASTOR trial) were reported at ASCO in June this year and have just been published in the New England Journal of Medicine. In this case, the response rate was 82.9% but with shorter follow-up thus far.
The bottom line is that our understanding of how dara works, and its benefits—when used alone and in combinations—is evolving rapidly. The results are extremely exciting because of the depth and durability of responses in many patients. The Netherlands team point out how important the surface CD38 levels are and that if the inhibitory proteins (CIPs) emerge, a drug called ATRA (All Trans Retinoic Acid) can be considered to reduce the inhibition. The next step will be to understand why some patients do not respond to even the best combinations. In the meantime, it is challenging for both physicians and patients to keep up with all the new data.
Treatment outpacing reimbursement
Patients have alerted us to a specific problem which has emerged recently: insurance coverage and reimbursement for dara used as part of combinations. Although Janssen has submitted very rapidly to the US Food and Drug Administration to receive “Breakthrough Therapy” status for acceptance of the combination results, which I blogged about here, appropriate review will naturally take time.
This lag between awareness of new and emerging data and regulatory approval is the inevitable consequence of the rapid evolution of exciting, unexpected, and better-than-expected treatment results. This problem was anticipated during discussions at the IMWG Summit in June. It was proposed that new treatment strategies must include multiple “follow-on” studies to document the benefit and safety of the best combinations to support regulatory approval and facility patient access and reimbursement.
Access may affect outcomes
An interesting new study looks at how access to new drugs and combinations may affect outcomes. An article by Dr. Luciano Costa and colleagues from the University of Alabama evaluates what can be broadly described as “social class” and myeloma survival. The finds are intriguing although not definitive.
Survival is progressively worse if a patient has Medicaid (the US health program for the poor) versus private insurance; is unmarried, and lives in a poor neighborhood. A combination of these “three strikes” results in a four-year anticipated survival of <47% versus approximately 71% if these factors are not present.
It is proposed that lack of drug access is a key component for this poor survival, but factors from delay in diagnosis, testing, and other aspects of care may well contribute. More work needs to be done!
Cancer in 9/11 responders
As we move through August toward September, we have learned the World Trade Center Health Registry, run by the New York City Department of Health, will publish a new report next month about cancers developing among first responders to the 9/11 attacks, which occurred 15 years ago this September. CNN notes that as of June 30, 2016, more than 5,400 people have been diagnosed with cancers linked to the 9/11 attacks. The numbers are now increasing at a rate of approximately 1,500 per year, and the actual number is most likely higher because many people have not enrolled in the federal health program, which is the source of current statistics.
Prior to the release of the full report, some details can be found on the World Trade Center Health Program website. Among the top 15 so-called “certified” cancers, there are now over 100 cases of myeloma. The ongoing assessment is to attempt to correlate each cancer with specific site exposures. This raises the question: “What causes myeloma?” Certainly a number of the site toxins are linked to cancer.
Bone cancers always with us?
On the flip side, it is interesting to note that bone cancers have been around for a long, long time, as the New York Times reports in an article about a 1.7-million-year-old skeleton found in South Africa. Cancer-causing factors were present then, as now, including UV radiation, radon gas seeping from granite, plus viruses and hormones, which can have an impact. A particularly interesting idea is that fire and smoke may have been a trigger factor for infections such as tuberculosis and even cancer. Inhaling smoke in confined spaces, such as huts or caves, can lead to significant exposures. Many years ago, as at the 9/11 event, smoke and fumes can contain cancer-causing chemicals.
The possible connection between infection and cancer is also intriguing. British science journalist Ed Yong has written a recent book called “I Contain Multitudes,” in which he highlights how microbes are a major part of the human body. Disturbing this “microbiome” can have far reaching effects, since, as Yong writes, our bodies are “continuously built and reshaped by the bacteria inside us!” So, a lot to think about as we ponder what is causing myeloma in the modern world.
In the coming months, I will be providing updates as we proceed with the iStopMM project, in which we will be assessing all the individuals who are screened in Iceland to learn what environmental exposure may have contributed to causing their MGUS, SMM or active myeloma.
As always, we’ll be keeping you posted on both these aspects and the many new immune therapies which are emerging!
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®.