EBMT 2016

Novel agents before and after stem cell transplantation for myeloma

Dr Enrique Ocio - Universidad de Salamanca, Salamanca, Spain

I have a talk in one of the sessions, in the chronic malignancies working party, speaking about how new agents, new drugs, that we have in multiple myeloma, how this will affect the procedure of stem cell transplantation not probably now but probably in the upcoming years. The end of the talk title is beyond 2016.

What kind of novel drugs have you been using?

In fact, there are many novel mechanisms of action that are being used currently in multiple myeloma. Some of them are old ones in which we have a second generation of agents such as proteasome inhibitors or immunomodulatory agents. But what is very important is that in the last year we have the approval of four new drugs in multiple myeloma and even three of them with novel mechanisms of action, that was the deacetylase inhibitors and a couple of monoclonal antibodies, anti-CD38 and anti-SLAMF7. So this is very important because for the first time we have novel agents with novel mechanisms to treat our patients. Moreover, in the near future we will have several other agents come in that are being investigated, other monoclonal antibodies, particularly focussing on immunotherapy and some other targeted agents that target the specific mechanisms of the tumour cells that probably will be in the clinical scenario near.

From your findings, what has made you think that current procedures should change?

One important question that has been raised in the last year is if, with the appearance of all these novel drugs, bone marrow transplantation should remain the standard of care for young multiple myeloma patients. A recent study published and presented at the last ASH meeting by the French group showed that definitely patients that received an autologous transplantation did better, had a better outcome, better survival, than those patients that did not have this autologous transplantation in the first line treatment but at relapse. So this demonstrates that autologous stem cell transplantation has to remain a standard of care for these young myeloma patients.

But, as we have many other drugs and myeloma patients do not achieve the cure, many of them, so myeloma is still considered an incurable disease, it’s important to find or to search for novel strategies to improve the outcome and the prognosis of even these young myeloma patients. In this regard come all these novel strategies, novel agents, that can be positioned in different places in the procedure of autologous transplantation to try to improve them.

Does this happen before or after treatment? How does this affect the timeline?

As I will present in my talk, there are some novel alkylators that could replace melphalan. Melphalan has been the standard of care for this transplantation and there are novel alkylators with novel mechanisms, some, I would say, more fashioned alkylators that could replace, more effective and less toxic. Also we have all these second generations of the currently available agents that could induce more deeper responses with a less toxicity profile. We have carfilzomib, ixazomib, novel proteasome inhibitors which in the induction phase before the transplant could have also a deeper response and go in better situations to the procedure, to the transplantation procedure. Also we have some good data, although much of this data is preliminary because most of these agents have been tested in the relapsed situation, as they are novel first you have to test them in the relapsed situation, in relapsed patients. But now we are moving more and more to the first line scenario. In this regard some of these monoclonal antibodies, for instance, or other drugs such as deacetylase inhibitors that have demonstrated activity in the relapsed situation, they could be moved, for instance, to use in the maintenance setting after transplant to try to keep the disease under control for a long period of time.

Finally, I think I would also mention that some of these agents could be incorporated also as a fourth drug partner in the induction therapy. Up to now we knew that four drug combinations were not better than three drug combinations in the induction, that was with the classical drugs. Now we know that the addition of a novel drug as a fourth drug combined, for instance, with VTD or VRD, bortezomib, lenalidomide, dexamethasone plus a novel drug such as panobinostat, the deacetylase inhibitor, or a monoclonal antibody which would be a revolution in the treatment of myeloma, the monoclonal antibodies, this could enhance more the responses and efficacy of the bone marrow transplantation.

Where would you hope to see these novel drugs in the future?

That’s a very difficult question to answer, in fact, because it depends on what is our purpose for these patients. I’m quite optimistic in this regard and I think our goal should be to try to cure myeloma patients, most importantly, or mainly, those young patients. So we have to optimise very much the treatment of these young myeloma patients, candidates who are autologous stem cell transplantation. Probably in this regard a very good combination with a proteasome inhibitor, a second generation proteasome inhibitor, second generation IMiD, steroids, and probably the addition of a novel agent such as daratumumab, a monoclonal antibody, should be a goal with the best possible induction followed by an optimised conditioning regime for the transplant. Probably a consolidation with some different agents and the maintenance phase, trying to keep the immune system, trying stimulate the immune system to keep the tumour clone under control so with the final aim, probably, of curing the disease in the first line.