At the International Myeloma Working Group (IMWG) Summit in June, the most active work group focused on immunotherapy, primarily CAR T-cell therapies and BiTEs (bi-specific T-cell engagers). The myeloma researchers who joined the immunotherapy work group determined that in order to move forward with these treatments, it is imperative to:
- Grade and manage toxicities with CAR T-cell therapies, especially cytokine release syndrome (CRS)
- Define and evaluate resistance to anti-BCMA therapies, including CAR-T cell therapies, monoclonal antibodies, and BiTEs.
In the news, we have information to help with both of these. First, a new report identifies a “Pause Button” that can stop CAR-T-cell-induced CRS in its tracks. Right now, a combination of dexamethasone and an anti-IL-6 agent (tocilizumab) can be used to reduce inflammation. A team from Stanford University proposes the use of a commercially available agent called dasatinib, which has produced very promising results in mouse studies. Dasatinib is an FDA-approved tyrosine kinase inhibitor. Used to treat chronic myelogenous leukemia, dasatinib also strongly shuts down T-cell activation.
The studies showed that dasatinib rapidly and (importantly) reversibly blocks CAR T-cells’ anti-tumor and anti-inflammatory effects. This is potentially most valuable for avoiding life-threatening, CRS-induced neuro (brain) toxicity. Clinical trials are needed, but this emergency back-up “pause button” might be a potential life saver.
The second item in the news is a type of CAR T-cell therapy that includes a BiTE approach. This approach shows promise in treating dangerous brain tumors called glioblastomas. The infused CAR T-cells directed against the cancer also contain a combination antibody. The combination uses CD3 molecules to grab onto other T-cells, causing the tumor region to be flooded with tumor-killing chemicals coming from the activated T-cells. This is the BiTE feature.
These are early data, but they illustrate the potential to ramp up the ability of CAR T-cells to eliminate tumors. Clearly, there will be much more to come on this and other novel approaches.
A caution about combined immune approaches in myeloma
This week, the results of a study combining the anti-PD-1 inhibitor pembrolizumab with pomalidomide plus dexamethasone were reported in The Lancet. This randomized KEYNOTE-183 trial comparing pembrolizumab + pomalidomide + dexamethasone versus pomalidomide + dexamethasone alone was halted early by the FDA in July 2017 because of an increased risk of death in the triple-therapy patient population. This was disappointing because an early phase II study in relapsed/refractory myeloma had proven the regimen to be safe and showed promising results.
It turns out that PD-1 blockade is much safer in patients with lower tumor burden and less impaired immune systems. There were two deaths in the KEYNOTE-183 study, linked to inflammation of the heart (myocarditis) and a severe skin-related allergic reaction (Stevens-Johnson syndrome). Other reactions included lung inflammation (pneumonitis) and thyroid gland inflammation (hyperthyroidism). But the main point was that the problems emerged in patients with very advanced, high-risk disease. This is an extremely important caution for the future. Further studies are required to identify patients who can safely benefit from PD-1 blockage with pembrolizumab.
Staying safe in the sun
As we ponder the pros and cons of different immune therapy combinations, it is important to stay safe in the sun during these hot summer months. Two recent reports offer guidance. In the New York Times, Dr. Lawrence F. Eichenfield says, “sun protection makes sense” because of the increased risk of sunburn, aging of skin, and, of course, skin cancer—especially in myeloma patients, who have an underlying increased risk. The first steps toward protection include:
- Staying in the shade
- Avoiding the most intense hours of sun exposure
- Wearing a hat and using sun-protective clothing and bathing suits
The next step is to review the options for sunscreens. There are several new cautions about sunscreens. According to a recent study, some sunscreen chemicals are absorbed into the bloodstream and may be harmful. Several vacation destinations (including Hawaii, Palau, and Key West) have begun banning sunscreens because they damage coral reefs. The chemicals of concern are oxybenzone, octinoxate, and parabens. If they are killing coral reefs, this certainly raises the real concern of harm to your body.
An alternative is to use what are called “blocking” sunscreens that rely on titanium dioxide and zinc oxide, which are not absorbed into the blood stream. But, for the environmentally conscious among us, these agents do wash off and can bleach coral. So, cover up and use as little sunscreen as possible. In general, a sunscreen with broad UVA and UVB coverage and a SPF of 30 (or greater) is fine.
Summer heat and the future
As we reflect upon the fact that heat waves indicate global climate change, there is a piece of unexpected good news. Scientists have discovered that there is a huge aquifer of freshwater off the northeast coast of the U.S., from New Jersey up to Massachusetts. This aquifer is big enough to fill a billion Olympic-size swimming pools. It is thought the water came from melting of a glacier in the past.
If other such aquifers exist, capturing melting fresh water from glaciers in some fashion may be feasible. Many small lakes are the result of glacier melt. Maybe we should try to create some bigger ones?
This just in: 9/11 first responders fund clears the Senate
In a 97-to-2 vote, the Senate approved the 9/11 First Responders Fund bill this week. Comedian Jon Stewart, an emotional advocate, and New York firefighters and police officers leapt to their feet in the usually quiet chamber to lead a standing ovation. As the culmination of a lengthy fight, this $10.2-billion bill means financial stability for those patients with myeloma linked to the exposures. Great news indeed!
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®.