We are here at ASH 2012, give an overview of where we are with multiple myeloma.
Multiple myeloma is the second haematological disease in frequency after non-Hodgkin’s lymphoma. In fact, multiple myeloma now in 2012 remains as an incurable disease. However, significant advances have occurred in the treatment of multiple myeloma, especially due to the introduction of novel agents for the treatment of these patients. The first novel agent introduced for the treatment of myeloma patients was thalidomide in the’90s; thereafter proteasome inhibitors were introduced so that bortezomib has been the first proteasome inhibitor introduced into the clinic and treatment of myeloma patients. More recently, novel immunomodulatory drugs such as lenalidomide and oral immunomodulatory drugs, more potent and less toxic than thalidomide, and more recently we have a second generation of proteasome inhibitors such as carfilzomib or MLN9708, an oral proteasome inhibitor and also we have a second generation of immunomodulatory drugs such as pomalidomide.
How have we progressed with combination therapy?
At the beginning obviously these novel agents were evaluated as single agents in the setting of relapsed and refractory myeloma patients, very heavily pre-treated myeloma patients. And these novel agents as single agents resulted effective so the next step was to combine them in order to obtain a synergistic effect in order to gain a significant benefit in terms of efficacy, in terms of overall response rate but especially in terms of progression free survival in overall survival because we can’t forget that our objective should be to prolong the progression free and overall survival of our myeloma patients. This way, novel agents in basic combinations resulted in into the clinic, into the most common regimens used in clinical practice. For example, now, at the present time, around the world the proteasome inhibitor plus immunomodulatory drugs plus corticosteroids in combination resulted in the first option of therapy for all myeloma patients.
You’ve made big progress with efficacy using these agents, tell us more about the toxicity – how are you reducing that?
It’s absolutely logical to think that the introduction of novel agents is also associated with a new toxicity profile. Fortunately novel agents in basic combination have a specific toxicity profile and, for example, bortezomib induced peripheral neuropathy, lenalidomide and thalidomide induced thrombotic events. So, the toxicity profile is clearly different and we know, really, how to manage these side effects. For example, in cases of bortezomib related peripheral neuropathy we know at the present time that it is very important to reduce the dose as soon as peripheral neuropathy appears. Concerning thrombotic events and immunomodulatory drugs, we know that all patients receiving IMiDs need thromboprophylaxis with Herpadin or aspirin in order to avoid the development of thrombotic events. Other important ways to optimise the toxicity profile of these novel agents is, for example, the sub-cue formulation of bortezomib, that we really know that peripheral neuropathy rates significantly decrease with the sub-cue formulation of bortezomib.
How do these new agents fit in with using transplants?
It’s a very interesting question. At the present time, in 2012, I think that autologous stem cell transplant remains the standard of care for young myeloma patients of new diagnosis. So, all patients younger than 65 years usually receive an autologous stem cell transplant after induction therapy with a novel agent based combination. Why? Because we know that novel agents basic combination as induction followed by autologous stem cell transplant are complimentary strategies rather than alternatives. So the debate about transplant at the beginning or transplant at the moment of relapsed disease, the answer to this debate will come from randomised trials that are being evaluated at the present time in order to compare autologous stem cell transplants as far as part of the first line of therapy or at the moment of relapsed disease.
What are the latest findings in optimising therapy for elderly patients?
For older patients the optimisation is coming from the use of novel agent based combinations, especially bortezomib and lenalidomide based combinations but using bortezomib, for example, in a weekly schedule because we know that for elderly patients the weekly administration of bortezomib resulted in a significant reduction of the adverse events but the continuous treatment is able to maintain the efficacy. Concerning lenalidomide, always in elderly patients it would be combined with low dose dexamethasone. High dose dexamethasone in elderly patients resulted in very, very toxic. The safety formulation of bortezomib, again, is another important way to optimise the treatment of elderly myeloma patients.
What are the leading agents to be used in combination therapy?
I think that the leaders, the key players, in the treatment armamentarium of our myeloma patients are proteasome inhibitors, bortezomib, and the novel proteasome inhibitors, carfilzomib and MLN9708, and immunomodulatory drugs, lenalidomide and pomalidomide, that is the new immunomodulatory drugs. And of course we have novel agents that are coming, more experimental drugs such as monoclonal antibodies, elotuzumab and daratumumab, and probably other novel agents that will be incorporated in the future to the treatment of myeloma patients.
What is the take home message for the physician?
Fortunately we have on our hands a large amount of novel drugs, most of them are now in clinical trials but probably in the near future we will have the opportunity to have, in the clinical practice, significant amounts of novel agents that could contribute to optimise the treatment of myeloma patients because we will have the opportunity to choose different drugs with a different mechanism of action at different times of the evolution of the disease.
What are your recommendations for the ever improving treatment of multiple myeloma?
The first important message is to include patients into clinical trials if it’s possible because it’s the only way to complete the correct knowledge of these novel agents and it’s the correct way for these drugs to be incorporated into clinical practice in the future. So this is the first important message and the second important message is that the combination of novel agents that we have now currently approved, bortezomib and lenalidomide, corticosteroids, alkylating agents, can clearly contribute to improve the outcome of our myeloma patients.