18th Congress of EHA
Relapsed or progressive multiple myeloma
Dr Ruben Niesvizky - Weill Cornell Medical College, New York, USA
Welcome, Dr Niesvizky, to the European Haematology meeting. Thank you very much for agreeing to be interviewed. The management of patients with relapsed or progressive multiple myeloma is clearly one of the main themes at this year’s meeting. Why do you think there is so much interest in this at the moment?
There are several dimensions to the interest for looking at patients with relapsed or refractory myeloma. We have made major strides in bringing the newer agents into the front line and that has improved the survival significantly, yet in patients who have relapsed or have active disease after a prolonged remission time, these patients require more attention and they still suffer from all the comorbidities associated with the disease and unfortunately they die so major emphasis has to be made on the care of those patients. We are now very fortunate to have newer agents that have actually changed the outcome of those patients significantly.
Now, you’ve presented data at this meeting from a phase IB/II study in this setting. Can you tell me a bit of the background to that and what your main findings were?
Certainly lenalidomide and dexamethasone is now approved for the patients with relapsed and refractory and these patients have an outcome with progression free survival and overall survival superior to whatever the control was during that time. But certainly there is room to improve and from preclinical data we know that the combination of immunomodulators and proteasome inhibitors can augment the responses, increase significantly the tumour mass kill and therefore, perhaps, improve the survival of the patients. And therefore we started following the steps of previous authors of combining a proteasome inhibitor and lenalidomide and a dexamethasone construct. The initial generation of those studies which were done with bortezomib, lenalidomide and dexamethasone were very gratifying, however toxicity was an issue. You know the majority of the patients with multiple myeloma have advanced disease and they cannot tolerate these types of therapies. Carfilzomib is a second generation proteasome inhibitor which differs from bortezomib in that it has a more specific inhibition to the active modalities of the proteasome, those who actually are in charge of destroying the proteins involving cell survival. And therefore we think that being more specific, a less reversible union to the proteasome can offer better responses and less off-target effects and lesser toxicity. So combining carfilzomib, lenalidomide and dexamethasone was logical in that sense of investigation.
We therefore started a phase I/phase II trial in which we combined carfilzomib, lenalidomide and dexamethasone at escalating doses, starting at a lower dose of each carfilzomib and lenalidomide and we were treating patients in the classic schedule of carfilzomib twice per week on consecutive days for three weeks in a row and one week break with lenalidomide daily for 21 days and dexamethasone once a week. Since cohorts were done at the lower dose we treated small cohorts, varying between six and eight patients in each cohort, to try to identify if there was any toxicity. We did six cohorts and we were able to find a very well tolerated regimen for all the cohorts. Therefore we were able to reach the maximum planned dose without finding a maximum tolerated dose or a dose limiting toxicity. Hence we were able to now expand the final cohort, over fifty patients, to get the maximum tolerated dose or the maximum planned dose at 25mg of lenalidomide, 20mg/m2 and 27mg/m2 of carfilzomib and dexamethasone at 40mg once a week.
We’ve spoken to a number of presenters at this year’s meeting and they all seem to agree with the fact that this new agent is one of the most promising of its kind that they’ve seen so far. Is that view justified in your opinion?
Indeed, we were able to find that it’s quite safe. As I said, we were able to escalate the dose without finding a major dose limiting toxicity. And what was very gratifying is that we can continue the use of these drugs long term, patients receiving up to forty or fifty cycles of these drugs without major toxicity.
And finally this is clearly an evolving area of research in multiple myeloma. Where do we go from here?
Well certainly the field is now open to bringing this combination into the front line. There are already some trials that are championing this type of combination, one at the University of Chicago, the other at the NCI, in which they’re combining the lenalidomide, dexamethasone and carfilzomib but for front line and the results have been outstanding. Similarly, it’s important to compare these combinations against the standard of care and there is a clinical trial comparing lenalidomide dexamethasone versus lenalidomide dexamethasone and carfilzomib front line. More so, we will try to see carfilzomib in other combinations – combinations with cyclophosphamide, with melphalan and even dose escalating carfilzomib to be on the doses that we are using right now.
Dr Niesvizky, thank you very much indeed.