IMiDs in Relapsed/Refractory Multiple Myeloma - Episode 4

Preferred IMiDs Regimens Based on Line of Therapy

Two experts highlight their preferred treatment options for RRMM based on each line of therapy the patient will need.

Jonathan L. Kaufman, MD: The preferred regimens for patients with first relapse, or second-line therapy, are typically triplet combinations. I base the recommended regimen on what the patient is currently on and what type of relapse it is. Is it early during therapy or several years down the line? At our center, patients are most commonly on lenalidomide as maintenance therapy, so we consider these patients lenalidomide-refractory. In the lenalidomide-refractory setting, there are 2 lines of therapy, one combination with a monoclonal antibody—whether it’s daratumumab, isatuximab, or elotuzumab—with pomalidomide, or a monoclonal antibody with a proteasome inhibitor. In the monoclonal antibody with proteasome inhibitor, we only use isatuximab and daratumumab, and we can consider using carfilzomib or bortezomib.

We have found at our site that patients who are over 2.5 years from diagnosis to the time of first relapse respond very nicely to the combination of daratumumab, pomalidomide, and dexamethasone. In a retrospective review of our own data, we have progression-free survival [PFS] that far outweighs the progression-free survival that’s published in the clinical trials. In contrast, those patients who progress early, within 2.5 years of diagnosis, typically have a short response to the combination of daratumumab, pomalidomide, and dexamethasone. We don’t know if another therapy is more effective, but we know this one is not routinely effective. In these situations, our most common regimen we’d use in the second line is a combination of daratumumab, carfilzomib, and dexamethasone, which leads us to third-line therapy.

What do we do for third-line therapy? If we’ve used a monoclonal antibody that targets CD38 in the second-line therapy, we typically use that drug until progression. In the third line, that patient’s going to be refractory to a monoclonal antibody targeting CD38. They’ll be refractory to daratumumab or isatuximab. We typically don’t continue the monoclonal antibody in the next line of therapy. If somebody had daratumumab, pomalidomide, and dexamethasone, in the third line of therapy—that next line of therapy—is going to be proteasome inhibitor based. We would use carfilzomib and dexamethasone. Carfilzomib and dexamethasone is reasonable in this situation. Also, we can use carfilzomib, dexamethasone, and cyclophosphamide. That’s a very well-tolerated regimen.

A third regimen we consider for the third line is a proteasome inhibitor plus the exportin or XPO1 inhibitor selinexor. Whether we use carfilzomib or bortezomib really depends on the patient and prior toxicities of therapy. If a patient was progressing on second-line carfilzomib-based therapy with a monoclonal antibody, then I would use a pomalidomide-based combination. Again, in these situations, it’s rare that I would use the pomalidomide and dexamethasone. You could consider pomalidomide, dexamethasone, and selinexor, or pomalidomide, dexamethasone, and cyclophosphamide. Despite there not being data, we can use the combination of pomalidomide, dexamethasone, and elotuzumab in this situation. While there are data for that combination in this setting, we don’t have a lot of data in the post-daratumumab refractory or post-CD38 refractory setting.

Once the patient has had those 3 lines of therapy, they’re typically exposed to lenalidomide, bortezomib, and dexamethasone and are refractory to carfilzomib, pomalidomide, and daratumumab or isatuximab. This puts us into that fourth-line setting where we’ll use belantamab mafodotin, the antibody-drug conjugate. If I haven’t used selinexor, I’ll use a selinexor combination at this point. This is when we start looking at doing the CAR [chimeric antigen receptor] T-cell therapy. I hadn’t mentioned it before, but at each line of therapy, we always consider if there is a clinical trial available.

Joshua Richter, MD: As we go from relapse 1 to 2 to 3 and 4—although patient-related and disease-related factors are critical at picking an optimal regimen—what has to sit at the top are treatment-related factors, what therapy and what classes of drugs you are refractory to. In the United States, most patients get treated with a lenalidomide-based therapy up front and stay on it until progression. If they didn’t receive lenalidomide or were not on lenalidomide at the time of relapse, then a lenalidomide-based therapy is optimal at first relapse, with regimens such as KRd [carfilzomib, lenalidomide, dexamethasone], VRd [bortezomib, lenalidomide, dexamethasone], IRd [ixazomib, lenalidomide, dexamethasone], ERd [elotuzumab, lenalidomide, dexamethasone], and DRd [daratumumab, lenalidomide, dexamethasone].

If you are not lenalidomide-refractory in the first relapse, the majority of these therapies have shown median progression-free survival of around 20–26 months, except the POLLUX study. Daratumumab, lenalidomide, and dexamethasone had a median PFS of over 44 months. For the patients who are daratumumab and lenalidomide naïve or sensitive, I will pick something like daratumumab and lenalidomide at first relapse. If you are refractory to lenalidomide and not refractory to a CD38, we have several options at first relapse. Using pomalidomide as a base, you can use isatuximab, pomalidomide, and dexamethasone, or daratumumab, pomalidomide, and dexamethasone. If a patient has a more aggressive relapse, we consider combining an anti-CD38 and carfilzomib, either isatuximab, carfilzomib, and dexamethasone, or daratumumab, carfilzomib, and dexamethasone.

When you have gone beyond that in the third line, if you have not yet received carfilzomib, a carfilzomib regimen may work. An example would be carfilzomib, cyclophosphamide, and dexamethasone. If you have not yet received pomalidomide, you can get pomalidomide, cyclophosphamide, dexamethasone. Then we start moving to our later-line therapies—with drugs such as selinexor and belantamab mafodotin, or some of the newer approved CAR T cells, such as idecabtagene vicleucel and ciltacabtagene autoleucel—all along evaluating the risks and benefits of using clinical trials as an option to help mitigate some of the risk at that stage.

This transcript has been edited for clarity.