A. Keith Stewart, MB, ChB: At the time of progression, we assume that drug resistance has emerged within the myeloma clone, and that can sometimes make it difficult to use the same drug or same class of drugs even again at that stage of the disease. Nevertheless, since we have more potent versions of some of these agents, we can sometimes switch from lenalidomide, for example, to the drug pomalidomide. The targets of those drugs are the same. It’s the protein cereblon to which they bind. However, pomalidomide is a more potent drug and can perhaps overcome resistance even when cereblon levels have been suppressed or less available. So, we do see one strategy of switching from lenalidomide to pomalidomide at time of relapse.
The same hypothesis applies to the proteasome inhibitors. If a patient has had bortezomib and has not tolerated or progressed on the drug, we do have other effective agents in that class that are probably more potent, such as carfilzomib. And now we have daratumumab, which is a completely novel mechanism of action and can be combined safely with either a proteasome inhibitor or an immune modulator.
Where we struggle a bit is knowing how to put those 3 pieces of the jigsaw together. But I think a very common approach at first relapse would be the use carfilzomib/pomalidomide or pomalidomide/daratumumab as the first relapsed choice of therapy.
In addition to daratumumab, there are other monoclonal antibodies available to us, such as elotuzumab. Elotuzumab targets a cell surface protein that is different. It is a very well-tolerated drug. It is more convenient. It is given only every 2 weeks. It tends to be particularly suited, I think, for the less fit or perhaps patients who have less convenience in their schedule to receive daratumumab.
Phase III clinical trials have shown that the addition of elotuzumab to lenalidomide, as an example, can result in prolonged progression-free survival for many patients. And I think it’s a drug that we should use more often and we should probably use, particularly, in a less fit and perhaps more frail population, in which it would be a very attractive choice.
At the ASCO 2018 meeting, we heard the results of the OPTIMISMM trial, which was a large phase III trial in which the drugs bortezomib and dexamethasone were compared with the 3-drug combination of pomalidomide, bortezomib, and dexamethasone. This trial, perhaps not surprisingly, again showed that 3 drugs were better than 2. The combination of pomalidomide, bortezomib, and dexamethasone had a higher response rate, deeper responses, and a longer progression-free survival by about 4 months when compared with the control arm. This was particularly evident at first relapse, in which the PVd combination completely outperformed the 2-drug cocktail, with a median progression-free survival of about 20 months for the 3-drug regimen.
This cements that 3-drug cocktail concept at first relapse in our heads, and I think it has now caught on in the United States and across the world where 3 drugs—particularly with pomalidomide and carfilzomib, for example, pomalidomide and Velcade (bortezomib), as shown in this study—are now commonly employed.
Since we use the drug bortezomib in induction, it is common to switch to that also at relapse. One option we have today is carfilzomib, a very potent proteasome inhibitor, probably one of the most potent drugs we have in myeloma. It is, however, a bit inconvenient, and it has to be given twice weekly today. The other, ixazomib, can be given as an oral proteasome inhibitor. It is, therefore, more convenient and can be perhaps tolerated for longer.
At this meeting, we heard from the ARROW clinical trial. The ARROW clinical trial looked at the convenience of carfilzomib, which was traditionally given twice a week, and compared that regimen with a once-week dosing schedule that had been predefined for tolerability. It was an important change in our practice management since it showed that once-weekly carfilzomib was actually better tolerated and more effective than a twice-weekly dosing. So, this, I think, will catch on very quickly and will become a standard of care in multiple myeloma.