Immunotherapy Patient Selection in Myeloma

Transcript:Peter Voorhees, MD: Lenalidomide, dexamethasone, and elotuzumab is typically a regimen that I would use in patients who have had 1 to 3 prior lines of therapy, and are either lenalidomide naive—in other words, they’ve never been treated with lenalidomide before—or they had a lenalidomide-sensitive disease. A good example would be a patient who’s gone through initial induction chemotherapy, has received an autologous stem cell transplant and elected not to go on lenalidomide maintenance therapy, and relapses subsequently. That would be a patient that would potentially be a very good candidate for a combination of lenalidomide, dexamethasone, and elotuzumab. In the non-transplant setting, you may have a patient, for example, who chose to be treated with cyclophosphamide/bortezomib/dexamethasone for a defined period of time. They subsequently relapsed. They’re lenalidomide-naive. That would be another good situation in which to use the combination of lenalidomide/dexamethasone and elotuzumab.

As far as daratumumab monotherapy goes, patients who are what we call, double refractory—and what I mean by that is that they’re at refractory to at least lenalidomide and one of the proteasome inhibitors, bortezomib or carfilzomib—those patients would be excellent candidates for daratumumab therapy. In addition to that, patients who have received at least 3 prior lines of therapy for their disease, and have subsequently relapsed, that would be another good group of patients that would potentially benefit from the use of daratumumab monotherapy. It is important to recognize that there are a lot of studies ongoing right now combining daratumumab with other myeloma therapies, so this advice is likely going to change in the very near future, as we start to see some of these phase III studies with daratumumab read out.

It’s important to realize that the patients that were treated in the ELOQUENT-2 study, had disease that was either never before treated with an IMiD, or had IMiD-sensitive disease. In addition to that, patients were eligible for that study if they had received 1 to 3 prior lines of therapy. Because of that, I would not use the combination of lenalidomide/dexamethasone and elotuzumab in a patient with heavily pretreated disease. In addition to that, I would not use the combination in patients who have lenalidomide-refractory disease. For example, if you have a patient that’s been on lenalidomide maintenance therapy and starts to progress, that’s not the type of patient that I would use lenalidomide/dexamethasone and elotuzumab. Instead, I would use that particular regimen in a patient who either had lenalidomide-sensitive disease, or had not been treated with lenalidomide before. And, again, this is a regimen that you would use in one of the first relapses of the multiple myeloma, as opposed to patients who had been treated with multiple therapies over the course of time. So, patients in their first or second relapse would particularly be the best candidates for that particular platform.

In contrast, importantly, daratumumab has shown activity as a single agent in patients who are not only double refractory—in other words, refractory to lenalidomide and a proteasome inhibitor. We’re not talking about triple refractory disease where patients are refractory to lenalidomide, bortezomib, and either carfilzomib and pomalidomide. You hear about quadruple refractory these days, patients who are resistant to lenalidomide, pomalidomide, bortezomib, and carfilzomib. You saw activity in all of those patients regardless of the number of lines of prior therapy that they had. So, daratumumab is something that will retain activity even in patients with heavily pretreated disease. Thus, I think you can see daratumumab monotherapy being used in patients with double-refractory disease and patients who have been through multiple lines of prior therapy.

In the ELOQUENT-2 study, patients in both arms of the trial were treated until disease progression, provided they were tolerating therapy well. I think that the paradigm in multiple myeloma, for those regimens that are well tolerated, is to treat until disease progression. And that certainly is the case with the lenalidomide, dexamethasone, and elotuzumab combination. So, patients were treated until disease progression. If you want to replicate the benefits for your patients, you need to do it as it was done in the study, which is to treat until disease progression. Similarly in the daratumumab monotherapy studies, patients were treated until disease progression, again, provided they were tolerating it well. So, the recommendation would be to treat until disease progression. I certainly think that there is room for additional research to better understand how to best schedule these particular antibody therapies. But, for the time being, treat to disease progression in accordance with the label.

There’s a unique aspect to monitoring response to therapy for patients that are being treated with myeloma therapeutics that include a monoclonal antibody, such as elotuzumab or daratumumab. Because of the fact that elotuzumab and daratumumab are monoclonal antibodies, a serum protein electrophoresis and serum immunofixation electrophoresis will potentially pick up the monoclonal therapeutic antibody. For example, if you have a patient with free lambda light chain multiple myeloma who you’re monitoring for response, you may see the emergence of a monoclonal IgG kappa antibody on your serum immunofixation electrophoresis. That, in fact, is the therapeutic antibody. For someone who has a free lambda light chain myeloma, that’s not such a relevant issue, because you can measure the free lambda light chains quite readily through other means. However, if you have a patient who has an IgG kappa multiple myeloma, the interference with the IgG kappa daratumumab or the IgG kappa elotuzumab is potentially an issue. There are plans in the works to develop assays that will hopefully become commercially available that will help eliminate that noise; but, it does make it a little bit more difficult to gauge complete response for patients that are being treated with monoclonal antibody therapeutics.

Transcript Edited for Clarity