Is it possible to boost the immune system for myeloma patients?
The answer is a definite maybe! As myeloma evolves, it does so within the complex immune microenvironment of the bone marrow. The most well-known impact is the reduction in normal plasma cells and reductions in normal immunoglobulin production, causing reduced normal gamma globulins as part of the SPEP (serum protein electrophoresis) pattern. But there are many other effects of the disease which result in reduced or abnormal immune responses. The most well-documented feature of myeloma is the reduced ability to fight infections. Fortunately, this is often not too severe, despite reduced immunity and immunoglobulin levels, while some patients with recurrent infections can benefit from intravenous gamma-globulin infusions, others may benefit from ongoing antibiotic use.
So how can normal immune function be recovered in myeloma patients? This has been extensively investigated for several decades. For example, when it was first demonstrated that interferons (α and β) were helpful in myeloma treatment, chemicals (such as poly ICLC) were developed to trigger the body to produce more helpful interferons. This proved to be of limited value because the immune system became exhausted: only so much interferon could be produced. Likewise, many vaccine approaches attempting to trigger the immune system to reject the myeloma failed because complex inhibitory factors could not be overcome.
Now we have many new immune approaches emerging. One that is the farthest along is elotuzumab (anti-SLAM F7 monoclonal antibody), which triggers natural killer (NK) cells in the bone marrow to attack myeloma cells. This antibody has not worked by itself, but is working well in combination with Revlimid® plus dexamethasone, as well as with Velcade® and dexamethasone (in smaller studies). It seems that increased destruction of the myeloma, which occurs with the combination approaches, is key. This is also what we are seeing with the anti-CD38 monoclonal antibodies (daratumumab, SAR 650948, and MOR 202). With these anti-CD38 antibodies, there is direct killing of the myeloma cell plus recruitment of surrounding NK cells and macrophages to help mop up damaged myeloma cells.
So what we are seeing are new immune methods to reduce the myeloma rather than just modulate the immune response. Reducing the myeloma is actually the key to success. Reducing the myeloma decreases production of all the complex immune inhibitor factors and allows the immune system to bounce back. In patients who have excellent response, after ASCT, we see bounce-back of the normal plasma cells with production of mini monoclonal spikes (called oligoclonal spikes), which is a good sign – actually a very good sign - excellent response and potential long remission. Another feature of the recovering immune system is an increase in T-lymphocytes, which produce interleukin-17 (IL-17): these are called Th-IL-17. This is not something that is normal. This is a reaction to myeloma and successful treatment. Whether this reaction can be usefully enhanced has not been investigated. Whether additional immune enhancement can convert excellent response to cure is a tantalizing but unanswered question.
So is it possible to boost the immune system? Yes, by treating the myeloma and removing inhibitory factors! Whether tweaking, triggering or enhancing the immune system as a sole form of treatment can work remains to be seen. But it is very exciting that immune methodologies are providing a new way forward and allowing us to understand how immune manipulation can help. I am sure there will be many updates to come on this topic!
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®.