The rapid evolution of multiple myeloma management

Eminent haematology specialist Dr Enrique Ocio is a consultant physician in the haematology department at the University Hospital of Salamanca and clinical researcher at the Cancer Research Centre of the University of Salamanca. He spoke to Danielle Barron about how multiple myeloma treatment is evolving We have advanced a lot in multiple myeloma in the last 20 years and this has completely changed the treatment paradigm. We now continue to look for new targets in myeloma and the last decade has seen even more novel targets be discovered such as deacetylase inhibitors (vorinostat and panobinostat), and second and third generation proteasome inhibitors (such as carfilzomib) and alkylators. More recently we have moved from the era of targeted therapy and are coming into the immunotherapeutic era. I think that’s very interesting because we have seen the approval of novel agents such as daratumumab, the first monoclonal antibody to be approved as a single agent, and before that, elotuzumab, which was approved in combination with lenalidomide and dexamethasone. We know where we are but we don’t know where we will be in the short-term future – things are changing so quickly that the paradigm for treatment of myeloma patients is changing very quickly. The situation no w, with so many agents and drugs that we have available, we have to consider that 30 years ago we just had melphalan and steroids. Now we have more than 10 agents at our disposal. That forces us to think about the ultimate goal of our treatment, and it is something we must reconsider every year. In younger patients, our aim is always to achieve a cure. This is an ambitious aim, but it is what we would like to do. We have to follow two strategies, firstly using the best targeted treatments we have in our treatment armamentarium, and come up with very active combinations, such as multiple immunomodulatory agents with steroids, which is probably the best combination we have. In some instances with young patients, we support the use of the autologous stem cell transplant. So upfront we take a very intensive approach.

The second strategy for patients is to try to treat as soon as possible. My research group are working a lot on this, and for patients with asymptomatic myeloma at high risk of progression to symptomatic this is the best time to treat them. For patients at risk of relapse, we ned to control the disease very well and try to make the disease a chronic condition. Again, we have very active combinations that can help us do this, and these can be used over multiple lines of therapy – I saw one patient yesterday who is on their thirteenth line of therapy and we still have options available for him. Novel drugs with novel mechanisms of action, very directed and targeting very specific mechanisms of the blood cells, such as the BCL-2 inhibitor venetoclax. This is very interesting as it is particularly effective and means you can have the first personalised multiple myeloma therapy. Other targets such as the RAF/ELK proliferative pathways, AKP/JAK/STAT some of these are very important. Some drugs are very specific but may be too specific because by themselves they may only work in a small subset of patients. We either have to identify which patients will respond or be most sensitive to these agents, and also combine them with other types of agents. The other important avenue in myeloma therapy is immunotherapy. First came the monoclonal antibodies such as rituximab, but now we have daratumumab and elotuzumab which are giving very good results. Newer therapies are showing great promises such as
antibody drug conjugates (ADC), which is targeted against BCMA (B cell maturation antigen). These work by inhibiting BCMA but also manipulate the immune system as they carry a toxin which then paralyses and kills the cell. There is very promising preliminary trial data on this. Another approach in immunotherapy is bispecific antibodies. There are many of these being
researched but we don’t have clinical data yet. With these molecules, on one side they are binding to the haemo cell, and on the other they are binding to the T cell, the immune cell.
We have very good data with this construct in other diseases, so I think it is very promising in multiple myeloma. Finally, we have the CAR-T cells, and these are getting a lot of attention. Personally, I think this will be like the future of allogeneic stem cell transplantation in multiple myeloma. We collect the T lymphocytes of a given patient and then manipulate them to express antigens against the haemo cell. These are then reinfused into the patient and go onto attack the myeloma. The results from trials have been really surprising. We have to adapt our approach very few months in light of the news of new developments. We still have patients where we don’t succeed with treatment, but in most patients, we will
achieve cure or its management as a chronic disease. Patients are now more likely to die from another cause rather than their myeloma. We have many drugs, but we are not done yet. In Europe we are doing a very good job with research and it is very important to continue this translational research, bringing these developments in the laboratory as quickly as possible to patients in clinical trials.

I think the future is very bright in multiple myeloma.

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