Assessing and Managing Relapsed/Refractory Myeloma

Suzanne Lentzsch, MD, PhD: It is important that when we initially start treatment for patients with multiple myeloma, we have all the information that guides us later. We need our serum protein electrophoresis, the free light chains, and also a bone marrow test that gives us good information about cytogenetics and FISH [fluorescence in situ hybridization]. This is very important because it provides a baseline for future decisions and for deciding whether the patient has high-risk or standard-risk multiple myeloma. I also want to point out that patients need sufficient imaging. A skeleton survey is not sufficient. In most parts of the world, especially in Europe, instead of a low-dose whole-body CT scan used in the United States, most of the patients get a PET-CT to visualize lytic lesions.

Especially in earlier relapses, it’s standard that patients receive imaging for the bones—best case, a PET [positron emission tomography] or CT also—to follow up on development and activity of lytic lesions. Is there productivity? In relapse situations, I usually also do a bone marrow biopsy, but the importance of the bone marrow biopsy varies. In very old patients, when you see a relapse and the development of new lytic lesions, and you have your cytogenetics and they are not high risk, you might not do a bone marrow biopsy. It changes in younger and older patients. In earlier relapses, you need information on the side of genetics; especially in younger patients. In older patients, where you focus more on the quality of life, you might omit a bone marrow biopsy if you have clear evidence of a relapse.

Patients in early relapse have a lot of options. It’s very difficult to pinpoint what we recommend for the first, second, and third relapses. A lot depends on the initial treatment. A lot also depends on the age and performance status of the patient. For instance, if a patient relapses or has a first relapse, I usually look at their initial response to the initial treatment. What was the duration of the response? Is there any resistance? For instance, patients who developed relapsed multiple myeloma and had prior RVd [lenalidomide, bortezomib, dexamethasone] and relapsed under Revlimid [lenalidomide] would now be good candidates for a CD38 antibody in combination with carfilzomib. I can’t give you a strict recipe. The treatment of relapse patients depends on what the patients had before and if there is any cross-resistance. We usually try to treat patients with a new drug class. For instance, if a patient never had a CD38 antibody initially, that would be the time in the first relapse to initiate a CD38 antibody. If a patient had Revlimid [lenalidomide] before, that patient would be a good candidate for pomalidomide. In the first and second relapses, we are still in a good situation to have treatment options like pomalidomide, carfilzomib, and daratumumab, to manage that situation very well.

Peter Voorhees, MD: One of the most important considerations is to ask: What is the disease refractory to at the time of relapse? In first relapse, at least in the United States, lenalidomide maintenance therapy is often used until disease progression, provided the patient is tolerating it. At first relapse, a lot of patients will have lenalidomide-refractory disease. In that case, we’ll often go to a non-cross-resistant regimen as opposed to a lenalidomide-based regimen. That’s 1 thing that we look at. Past medical history is very important. For example, if you have a patient who has significant coronary artery disease, had a terrible myocardial infarction, and is now suffering from systolic congestive heart failure, that patient might not be the best candidate for a carfilzomib-based regimen. You might have a patient with a long history of suboptimally controlled diabetes mellitus who has painful neuropathy as a result. They may not be a good candidate for a bortezomib-based regimen. That’s important. It’s also important to recognize past toxicities of therapy that they’ve had. If someone had terrible bortezomib-related neuropathy with their initial induction therapy with lenalidomide, bortezomib, and dexamethasone, you may want to avoid a bortezomib-based strategy in the relapse space.

It’s important to look at whether the patient is in clinical relapse vs biochemical relapse. Biochemical relapse is a scenario where the numbers are getting worse, but the patient feels no different and is not experiencing any adverse sequelae of their myeloma progression. Whereas the patient in clinical relapse has new bone pain, for example. They might have renal failure, elevation in their calcium level, or become progressively anemic. With clinical relapse, you need to make sure you choose a regimen that’s going to get their disease under control very quickly. Whereas with patients with biochemical relapse, depending on the pace, you have a lot of different options available to you. You may be able to monitor the situation for a while without necessarily changing therapy. You may be able to tweak therapy a bit rather than completely moving to non-cross-resistant therapy.

We also like to look at standard vs high-risk cytogenetics. For patients with high-risk cytogenetics, we’re going to want to choose regimens that have performed well in that scenario. A good example is deletion 17p. We know that proteasome inhibitor–based therapy has performed well in patients who have deletion 17p. We also know that pomalidomide-based therapy has also worked very well in that setting. We now have emerging data that suggest selinexor is performing well in patients with deletion 17p. There are lots of factors to consider when choosing optimal therapy for a patient with relapsed myeloma.

As far as sequencing therapies, in general, it’s important to move to non-cross-resistant therapies at the time of progression. One of the things that we are often challenged with is a patient in first relapse who’s progressing in the face of lenalidomide maintenance therapy and technically has lenalidomide-refractory disease. The treatment strategies that are most commonly used would be a CD38 antibody, either daratumumab or isatuximab with pomalidomide and dexamethasone, or isatuximab or daratumumab with carfilzomib and dexamethasone. It remains to be seen which of those regimens is best.

Drug-resistance profile is important in the sequencing question. It’s also important that you use the regimens that are available for patients in the right space. As long as you’re doing that and making wise decisions about your treatment regimen based on the factors that I’ve already mentioned, the exact sequence might not make a big difference. For example, if you use a pomalidomide-based strategy in first relapse and a carfilzomib-based strategy in second relapse or vice versa, I don’t know that it’s going to make a big difference for the patients. They’re going to do well under both circumstances.

Transcript Edited for Clarity