When the US Food and Drug Administration (FDA) halted three Keytruda (pembrolizumab) clinical trials recently because of unexpected deaths, it was cause for concern. This week, the FDA has acted to close further studies involving the whole range of PD-1/ PD-L1 inhibitors combined with the IMiDs Revlimid (lenalidomide) and Pomalyst (pomalidomide) in order to forestall any further unexpected toxicities and/or deaths.
The FDA has placed clinical holds on five Celgene trials. The trials are testing Imfinzi (durvalumab), an anti-PD-L1 antibody, in combination with immunomodulatory and chemotherapy agents in multiple myeloma, chronic lymphocytic leukemia, and lymphoma. A partial hold has been placed by the FDA on trials with PD-1 inhibitor Opdivo (nivolumab), according to Bristol-Myers Squibb. (Patients on a clinical trial with any of these drugs should review the status with their personal doctor to get the best advice about the next steps.)
Unacceptable toxicity
A key problem is that unleashing the immune T-cells with these therapies has allowed the T-cells to attack not just the myeloma, as hoped, but also critical normal tissues, including lung tissues, liver, thyroid, and even heart cells. This is unacceptable toxicity. Recent news about a new CAR-T approach resulting in patient deaths is also a cautionary story.
As I have mentioned, tweaking the immune system for myeloma patients is like fine-tuning a Swiss watch—it must be done with extreme precision. Unfortunately, we are just learning how the normal watch works, so making possibly beneficial changes is largely guesswork. The spring could break or the watch could keep erratic time.
A unique immune system
Let's focus on understanding the immune system in myeloma patients. Their immune systems are very different from those of melanoma patients, for whom Keytruda therapy as a single therapy has been a huge success. Turning the immune system loose on melanoma is enormously helpful.
We need to answer two essential questions: What, exactly, is wrong with the immune system in myeloma patients? And, can it be repaired?
A “favorable immune signature” linked to longer survival has been identified via immune-monitoring using the Next Generation Flow (NGF) technique to assess minimal residual disease (MRD). Achieving such a signature and enhancing this ideal immune surveillance to help control and/or eliminate residual myeloma is our ultimate goal.
In the meantime, we must recover from our disappointment about PD-1/ PD-L1 inhibitors and move on to other immune approaches: anti CD-38 monoclonal antibodies like Darzalex (daratumumab) and many more to come, including bispecific antibodies, which hold great potential.
Echoes of 9/11 in Hurricane Harvey’s Toxic Side Effects
Monday will be the 16th anniversary of 9/11, which, while a man-made tragedy, has much in common with the environmental disasters afflicting the planet in 2017. These tragic events are followed by serious and often life-threatening consequences. For example, toxic exposures unleashed by the 9/11 attacks are blamed for the development of many cancers among first responders, including myeloma.
Now, it turns out that serious toxic exposures may also be a concern in the aftermath of Hurricane Harvey. Houston was “awash in a stagnant brew of chemicals” as more than two dozen current and former toxic Superfund sites were inundated, and more than 40 petroleum and chemical plants were found to be releasing toxic chemicals. Subsequent testing has identified increased levels of the cancer-causing chemical benzene. Benzene has been linked to the causation of myeloma for more than 50 years.
Adaptation or prevention?
Thus, as we worry about the immediate impact of climate change with more intense storms and climate events, broader environmental impacts are forced upon us. From Texas to Churchill, Canada to Antarctica, consequences can be severe and can result in permanent changes. Nature can adapt.
For example, turtle-headed sea snakes become black in toxic waters, but they accumulate the toxic-heavy metals and chemicals only in their darkened skins, and then shed their skins. As the temperatures in the Antarctica waters warm, the growth and pattern of marine life is changing and will undoubtedly change much more.
But how will human beings adapt to these changes? As in many parts of Texas, the livelihood of the whole town of Churchill, Canada, is at stake, after floods washed away its only connecting railroad. When environmental chemicals affect health, we are also forced to pay attention, ask questions, and consider changes. States like California are filling in gaps left by the current Environmental Protection Agency by stepping in to assess toxic risks facing Californians and are recommending precautions.
The Black Swan approach
Much broader programs are required to make disease prevention feasible. Through the IMF Black Swan Research Initiative’s iStopMM project, the IMF is committed to understanding what causes myeloma, and to leading efforts towards true prevention in a time of dramatic challenges and changes.
Learning from tragedies is essential in order to adapt and ensure a better future. Myeloma patients already know about change as they face the daily challenges of dealing with the disease. The IMF is a source of information and support to guide the way forward.
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®.
