Treatment Goals Based on Relapse Type in Myeloma

Transcript:Ivan Marques Borrello, MD: When patients relapse with myeloma, the types of relapse can be very different. There are patients that have explosive disease, in which case disease control needs to be very rapid. And I think that’s a situation for which cytotoxic chemotherapy, or a proteasome inhibitor combined with an IMiD or even with an alkylating agent, is a very appropriate therapy. Because those are very good in rapidly reducing the disease burden.

In contrast, there’s what we call biochemical relapse. These are patients for whom there are relatively no symptoms, and their relapse is being detected primarily by blood tests, with a slowly rising M-spike. These are patients for whom there is a lot of time to integrate newer therapies. Immunotherapy, in that setting, seems to be a reasonable choice. You’re taking a patient that has minimal symptoms and coming in with a therapy that can take a little bit longer time to respond—but also can be given over a longer period of time. That is a situation for which a therapy, such as ERD, would be a reasonable choice.

We can take lessons from the solid tumors, melanoma, and lung cancer, where there are tyrosine kinase inhibitors, targeted therapies that have shown, for patients whose tumors are expressing certain mutations, a very nice and rapid reduction, but ultimately translating into a relatively short-lived progression-free survival. These are also settings in which checkpoint inhibition has really revolutionized the field. PD-1 blockade has, in contrast, shown, as most immunotherapies do, a slightly longer time to response, but also a longer tail in Kaplan-Meier curves in terms of disease control. And this paradigm, probably best explained in the solid tumor arena, can certainly be applied to other settings, such as in the field of multiple myeloma where, over and over again, we are now seeing that a longer time to response can often translate also into a longer disease-free interval. Monoclonal antibody therapies, whether tumor-targeted or immune-targeted, are reasonable approaches to take in that setting.

​Jatin P. Shah, MD: There are multiple treatment options now for relapsed and refractory myeloma. Importantly, we can think of different classes of drugs. We can think of proteasome inhibitors (bortezomib, carfilzomib, and now ixazomib), IMIDs (lenalidomide and pomalidomide), and now monoclonal antibodies (elotuzumab and daratumumab). However, I want to separate those out a little bit because even though we put those two monoclonal antibodies in the same class, they’re very, very different drugs. So, we want to be very careful when we talk about monoclonal antibodies to really separate them and say we’re talking about elotuzumab or daratumumab, and not lump them all together. Because they’re very different, they work very differently, so I think that’s important for our treating physicians to understand.

Importantly, we also need to not forget that we also have panobinostat, which is an HDAC inhibitor, another good class of drugs that was approved last year, as well. That’s another important treatment option for patients, as well as alkylating-based therapy. I think there are a number of different classes of drugs that we can see. And, importantly, this highlights really an opportunity to talk about the “art of medicine.” That’s a key message here! There are really multiple options for patients, and we have to embrace the art of medicine and art of myeloma management here. And that’s an exciting opportunity for our patients. So, we just have to embrace this as really the art of medicine.

Ivan Marques Borrello, MD: Antibodies currently in multiple myeloma are indicated only in the relapsed setting. This is primarily because that’s where the data have been generated thus far, although it’s not to say that with more data, these may now move into the upfront setting. I think the current indications recommend that they be given at least after one prior therapy, and a lot of the therapies are also being examined in combination. Daratumumab was initially approved as a single-agent therapy. We have seen from earlier studies that combining it with Revlimid and dexamethasone can increase the overall response rate.

At ASCO, we heard yesterday that daratumumab, in combination with Velcade and dexamethasone, showed a dramatic improvement in overall response rate, with significant durability compared to Velcade and dexamethasone alone. And I think data are going to be presented next week at EHA showing daratumumab plus Revlimid, and dexamethasone compared to Revlimid, and dexamethasone alone. It’s going to also show an improvement in overall response rate. Similarly, we’ve seen this with elotuzumab; that in the ELOQUENT study, elotuzumab/Revlimid/dexamethasone (ERD) showed a significant improvement in the overall response rate compared to Revlimid and dexamethasone.

So, summarizing these data: I think what we’re beginning to see is that antibodies are working through a non—cross-reactive mechanism. There is some benefit of synergism that we’re beginning to see, and, ultimately, what the right combination is going to be of all the drugs that are currently available in our armamentarium remains to be determined. But, it will probably include an IMiD; it may or may not include steroids; it may include a proteasome inhibitor, as well as other agents that are currently available.

My personal bias is that drugs that tend to suppress immune responses are probably the ones that will also dampen the response to many of these monoclonal antibodies. As such, it will be interesting, for example, to compare the daratumumab/Velcade/dexamethasone study with the daratumumab/Revlimid/dexamethasone study to see whether there’s going to be differences there. Analogous trials are also going on with elotuzumab, where ERD has obviously already been FDA approved. But, elotuzumab/Velcade/dexamethasone is currently being examined, as well.

Transcript Edited for Clarity