Establishing a Treatment Plan for Triple-Class Refractory Myeloma

Peter Voorhees, MD: At the time of first relapse, the majority of patients, at least in the United States, will have lenalidomide-refractory disease again by virtue of the fact that they’ve been on lenalidomide maintenance until disease progression. A lot of patients will fit in that category. The majority of patients in first relapse won’t have triple-class refractory disease. Typically, patients who have had 2 prior lines of therapy and then subsequently progressed will often be double refractory. But once you’ve gone through 3 prior lines of therapy and that third line of therapy has stopped working, the majority of patients are then becoming triple refractory.

There was a nice study, the MAMMOTH trial, that was spearheaded by Luciano Costa at the University of Alabama at Birmingham School of Medicine. They looked at this question specifically in patients with CD38-antibody refractory disease. It’s a little different. It’s not taking everybody with relapsed and relapsed/refractory disease. But for those who were CD38-antibody refractory, only 21% of them were not triple refractory. Everybody else was at least triple refractory. In fact, 25% of the patients were what we call penta-refractory, which basically means a disease that’s refractory to a CD38 antibody, lenalidomide, pomalidomide, and 2 proteasome inhibitors. Time is the biggest risk factor for developing triple-class refractory disease. The longer you have disease and have been on these therapies, the more time for the disease to find a workaround and develop resistance to those treatments. Most of us would agree that patients with high-risk multiple myeloma will develop triple-class refractory disease faster than patients with standard-risk disease.

Suzanne Lentzsch, MD, PhD: Patients with triple-class refractory multiple myeloma pose a challenge for treatment. Those patients are usually resistant to pomalidomide, lenalidomide, ixazomib, bortezomib, daratumumab, and isatuximab. We know those patients have remissions that last much shorter. Nevertheless, we thankfully had a couple of new approvals over the last year, which makes it much easier to treat patients with triple-class refractory multiple myeloma. Those drugs include selinexor, melflufen, and Blenrep. The options of those patients have broadened significantly.

We know that multiple myeloma is a disease that is relapsing. All patients experience multiple relapses before they become resistant. We know that the goal of the treatment is to postpone the relapses and use the best-available regimen. It is important to point out that in patients who are triple-class refractory, we need to switch the class and go to a new class. Options include Blenrep [belantamab mafodotin], selinexor, melflufen, and elotuzumab, which is also a good option, especially for patients who are older. Those new options have different toxicity profiles. It is important to discuss with the patient what the most suitable regimen would be for them and what is most appropriate based on prior cytotoxicities.

Triple-class refractory patients usually have a shorter duration of response. You can expect a duration of response of progression-free survival in patients to last several years—a median of 5 years—when they are initially treated and receive the transplant. This may be many more years with CD38 antibodies. The progression-free survival in patients with triple-class refractory multiple myeloma is much shorter. We know that can it last from 4 months, when they receive melflufen, to 6 months, when they receive selinexor. The difference is not too significant. It reflects that triple-class refractory multiple myeloma is a challenge for treatment and characterized by a much shorter duration of progression-free survival.

Sometimes you can see that there’s a change in biological behavior. Patients tend to have a much faster proliferation of the multiple myeloma cells. There’s also a higher tumor burden. They can have many more lytic lesions. Because of the multiple treatments patients receive, it is challenging to find the optimal doses of the treatment. They might start a fourth- and fifth-line treatment already with thrombocytopenia or neutropenia, which poses a further challenge to treat and find optimal doses for patients who are refractory.

It’s very difficult to tell a patient in their third, fourth, or fifth relapse what their prognosis is. What would be more honest is to say, “We know from clinical trials in which selinexor was used as a single agent that the median progression-free survival is 4.2 months.” When I discuss with my patients their prognosis, I usually discuss it based on the treatment I suggest. It’s very difficult to know what the options are after the treatment. For instance, a patient might change their prognosis by getting a BCMA BiTE [bispecific T-cell engager] or a CAR [chimeric antigen receptor] T-cell treatment. I would be hesitant to give a prognosis for patients who received their third- or fourth-line treatment. I would stick more to certain drug combinations I’m giving and rely on data that were obtained in clinical trials.

Peter Voorhees, MD: The goal of therapy is obviously to get the disease under control, and this is particularly relevant for patients who are in clinical relapse and suffering from symptoms related to their disease progression. As I mentioned previously, durability of remission does shorten over the course of time. We always need to be cognizant of quality-of-life issues, but we need to be particularly cognizant of quality-of-life issues in this circumstance. Aside from navigating benefit as far as response to therapy and durability of that response, we have to be very careful about mitigating any adverse effects related to that treatment.

Transcript Edited for Clarity