IMiD Sequencing in Multiple Myeloma - Episode 4

The Challenges of Treating R/R Myeloma

A. Keith Stewart, MB, ChB:At time of relapse, therapy has to be incredibly individualized. It has to take in numerous things: age and frailty of the patient or health of the patient and the geography, where and how far they live from the hospital or the clinic. It has to take account of socioeconomic issues in terms of ability to pay or even for parking to come and visit at the hospital. It has to take account of what drugs the patient received in the past or whether they tolerated them, whether they had side effects, how long the remission—if they had a remission—lasted for, and whether they were refractory. All of those factors result in a very individualized approach to relapse. There is no one-size-fits-all.

Having said that, if we take the 7 randomized trials that are available to us, a number of things become clear. In almost every circumstance, using 3 drugs show overall response rates to be higher, death of response to be better, and progression-free survival to be prolonged with 3 drugs versus 2. And I think the vast majority of physicians in the United States have moved to triplet therapies, and they can vary from drug to drug, but that has become the standard.

I would say, again, within that 3-drug cocktail, the combination of a proteasome inhibitor and an immune-modulating drug—so, for example, the combination of carfilzomib with pomalidomide, or perhaps ixazomib with lenalidomide—have become very commonplace. The disrupter is the addition of daratumumab, the monoclonal antibody, which can be combined with great success without an immune modulator—again, lenalidomide but in the United States, often pomalidomide—or it can be combined with bortezomib, both of which show dramatic improvements when the third drug of daratumumab is added. So, in summary, triplet drugs, often with an IMiD and a proteasome inhibitor, but increasingly with the monoclonal antibodies.

One of the major issues we are facing now is that lenalidomide has been used continuously from time of a diagnosis. So, time-of-relapse patients have been exposed to a drug often for a long period of time and have become resistant. Many of the clinical trials we have available to us use lenalidomide as part of the backbone. For our patient who has not been on lenalidomide, the choice is much clearer. It’s usually going to be to move to lenalidomide at relapse with elotuzumab, with ixazomib, with carfilzomib, with daratumumab, take your pick, depending on the individual patient.

For the patient who has been on lenalidomide, which is increasing in number, that is a harder decision. I think at that point, 2 choices exist. One is to use an alkylating agent instead of an immune modulator, something like the combination of cyclophosphamide with carfilzomib or ixazomib, or to switch class of immune modulator and to move to pomalidomide, a much more potent immunomodulator than lenalidomide. And I think in the United States, many people are using pomalidomide, at first relapse, combined with carfilzomib, combined with daratumumab, or combined with other novel agents.

Transcript edited for clarity.