ASH 2014

ASPIRE study: Carfilzomib potent addition to multiple myeloma therapy

Prof Keith Stewart - Mayo Clinic, Scottsdale, USA

We already knew carfilzomib, which is an irreversible proteasome inhibitor sold as Kyprolis, we already knew that this was an important drug because it’s already been approved in the United States for the treatment of patients who have failed all other therapies. What we wanted to understand was if we moved it earlier into first relapse or second or third relapse and added it to the standard of care there, the reference treatment of lenalidomide and dexamethasone, whether we could improve outcomes.

And you had a number of different arms, didn’t you?

There were two arms in the trial: this reference treatment which is lenalidomide and dexamethasone and the experimental arm of the trial, the same drugs with the addition of carfilzomib.

What did you find?

This was a very positive study result; there were four take home messages. First, patients, the primary endpoint of the study was met; progression free survival was dramatically longer for the three drug cocktail – 26 versus 17 months, an increase of 8.7 months. Secondly, overall response rate was higher. Third, three times as many patients went into complete remission as with the control. The side effect profile was very good. Finally, patients felt better on the study, they had better quality of life.

What about toxicity with this additional agent?

Yes, it was very encouraging. The side effect profile was surprisingly good considering that patients were on treatment for a lot longer on the three drug cocktail than they were on the reference treatment of Revlimid. They were 88 weeks of treatment versus 50 weeks with the control. So even though patients were on treatment much longer, the same number of patients discontinued treatment due to side effects and there was no increase in deaths due to adverse events on the study.

Now, you had a progression free survival of 26 plus, over 26, months compared to 17 and a bit months with the non-carfilzomib arm. How much of a significant improvement do you think that is clinically?

Well, nine months improvement in relapse is very impressive. In other important trials in myeloma recently if we have achieved a three month improvement people thought that was clinically useful. So now we have a nine month improvement in this study which we think is quite dramatic.

Do you think doctors should change practice, then, as a result of this finding?

I think that this is now the standard of care for patients at first relapse with multiple myeloma. It needs to be made available to patients and doctors worldwide and this three drug cocktail of KRD, Kyprolis, Revlimid and dexamethasone, is the new standard.

So what are your clinical recommendations to doctors at this point?

These drugs are not approved in the front line setting so patients will continue to receive backbone drugs such as bortezomib, lenalidomide, thalidomide in the newly diagnosed setting. But at first relapse, when the first relapse occurs, moving quickly to carfilzomib, either in combination with lenalidomide as here or with other drugs, is the right step.

So could you summarise what you think are the bottom line messages coming out of this then, very, very briefly.

The three important things to know about this study is, one, response rate is higher; two, people stay in remission longer and, three, they feel better while they’re on treatment with better quality of life.

And this is all achieved because this is a new blockbuster drug, are you saying?

Carfilzomib is an excellent drug for myeloma. It needs to be made broadly available worldwide. It is the safer and improved proteasome inhibitor.

And are there any downsides to this in your view?

There are some downsides in that it’s an intravenously delivered drug. The patients have to come to clinic twice a week on the current dosing schedule so there is a convenience factor. But overall the overwhelming benefit of being on the drug makes this something that should be available.