Treatment options available for an elderly man with multiple myeloma upon first relapse.
Saad Z. Usmani, MD: We want to shift gears and start talking about choosing appropriate therapy for our patients at first relapse. Let’s go to another case. We have a 69-year-old gentleman diagnosed with revised ISS [International Staging System] stage 2, ISS stage 3, lambda light chain myeloma. He got diagnosed with very high levels of the lambda light chains, almost 10,000 mg/L. He also had 9% circulating plasma cells in his peripheral blood. Cytogenetics on the bone marrow biopsy showed a gain of 1q 2 as well as a translocation of 11;14. PET CT scan had no extramedullary myeloma, but several FDG [fluorodeoxyglucose]-avid lesions in the ribs and a collapsed T7 [thoracic spinal nerve 7]. The gentleman is a retired teacher, is generally active, and likes to walk and garden. So they get started on induction with VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] for 6 cycles, get to stringent CR [complete response], MRD [minimal residual disease]-negative. Status is at 10-5. He gets a MEL200 [melphalan 200mg/m^2] auto, and then he’s on maintenance treatment, which is generally well tolerated to treatment. But then, he had a grade 2 peripheral neuropathy after VRd. He came in for a follow-up. Immunofixation was positive for lambda light chains initially, and then the serum-free lambda light chains started to rise. Patient is asymptomatic. He’s being considered a biochemical relapse and he’s still on lenalidomide. He’s now going to be started on treatment to avoid clinical relapse. We have the following choices. This is where the discussion becomes relevant to our lenalidomide-refractory patients. This is a year-and-a-half into lenalidomide maintenance, let’s assume. Which of the following treatment regimens would you pick for this patient? You’ve got pomalidomide [Pomalyst] with bortezomib-dexamethasone [PVd]; you’ve got the 2 anti-CD38s, daratumumab [Darzalex]-Kd [carfilzomib (Kyprolis), dexamethasone], isa [isatuximab (Sarclisa)]-Kd [carfilzomib, dexamethasone], KPd [carfilzomib, pomalidomide, dexamethasone], and anything else. I’ll go to Neha, Urvi, and then Sham. How about that?
Neha Korde, MD: Looking at the treatment options, generally and technically speaking, all of these could be applicable. But for this patient, when you’re looking at the patient in front of you and are figuring out what your options are in this refractory lenalidomide patient, I tend to lean towards an anti-CD38-PI [proteasome inhibitors] combo. Among the choices listed, we have it with carfilzomib. In the past, I’ve used Velcade before the carfilzomib data was mature and out, but 1 of the biggest reasons why I typically go that route is to change up that mechanism of action. So you have a patient that’s essentially coming off of an IMiD [immunomodulatory drug] that is IMiD resistant, and we can talk about it further. Of course, there is data to support, for instance, that this patient could benefit from an anti-CD38 plus pomalidomide, but I think if you’re going for a bang for your buck, I’d probably go with an anti-CD38-PI combo with the carfilzomib.
Saad Z. Usmani, MD: Urvi, what do you think?
Urvi Shah, MD: I agree. This patient also has peripheral neuropathy, so Velcade would not work from VRd previously so I wouldn’t prefer PVd as an option. Then, between dara [daratumumab]-Kd or isa [isatuximab]-Kd, I think both are reasonable options with the best PFS [progression-free survival] benefit with the CANDOR and IKEMA studies. Their PFS benefit is the highest compared to all these options that we are seeing here. The only downside is that patients have to come in the office for IV [intravenous] therapy weekly, and this will last for a while. Whereas, if you do something like dara [daratumumab]-pom [pomalidomide]-dex [dexamethasone] or pom [pomalidomide]-Velcade-dex [dexamethasone], it’s just a shot and oral pomalidomide. Whereas, doing the carfilzomib option, we are committing them to IV weekly, but it has the best PFS.
Saad Z. Usmani, MD: What do you think, Sham?
Sham Mailankody, MD: Same here. Although pomalidomide is different from lenalidomide you would probably want to steer clear for some time, in somebody who’s been on lenalidomide for an extended period of time, for the reasons that Neha mentioned. So I think a non-IMiD regimen would be reasonable, and the choices that you guys listed would be isa [isatuxmiab]-carfilzomib-dex [dexamethasone] or dara [daratumumab]-carfilzomib-dex [dexamethasone]. Daratumumab is subQ [subcutaneous] injection, isatuximab is IV, and carfilzomib is IV regardless of the regimens used. The other thing I would point out, particularly with the pandemic, as more data has become available for carfilzomib—although the studies very strictly looked at twice weekly dosing of carfilzomib—I think most of us are using carfilzomib once a week in this setting to make it easier for patients. Although there isn’t a head-to-head comparison of every scenario, the twice weekly regimen would probably work to minimize toxicities and patient burden by doing the twice weekly regimen. As Dr Shah said, it is a challenge to have these patients come every week for IV infusion, for what might be a pretty long period of time, but it also has the best data.
I would plug a patient like this for clinical trials. This is a patient who presented with what, on the brand new criteria for plasma cell leukemia, would be considered plasma cell leukemia with 9% plasma cells. These are patients that, unfortunately, tend to have a more aggressive biology, so these patients might benefit from early treatments of novel mechanisms like CAR [chimeric antigen receptor] T-cells, or bispecifics, or other immunologic modalities. If they are readily available, I would definitely strongly consider patients, like this person, with otherwise good performance status and good functioning status to go on these clinical trials and potentially get a longer benefit.
Saad Z. Usmani, MD: I’m going to bring up a couple of other options because this patient has translocation 11;14. We have, even though it’s not FDA [Food and Drug Administration] approved yet, we have the BELLINI study data, right? So we have venetoclax [Venclexta]-bortezomib-dexamethasone [VVd] as a potential combination. There’s even activity with carfilzomib that’s been reported and let’s not forget selinexor [Xpovio]. So selinexor-bortezomib-dexamethasone [XVd]. I didn’t want to bring this up, but again, it was a positive trial in the BOSTON study and specifically had a lot of lenalidomide-exposed, lenalidomide-refractory patients as well. At the very least, the lenalidomide-refractory patients had similar PFS benefit compared to the rest of the patients. What are your thoughts around the small molecules?
Sham Mailankody, MD: I definitely agree with you about venetoclax for these patients. About 15% to 20% of patients have 11;14 translocation, and, again, to be clear, this is not currently FDA approved. But the data, as we see it, is fairly clear that for this subgroup of patients with 11;14 translocations, we see good responses. It may be a challenge sometimes to get this in patients with 1 prior line, but certainly it’s something to keep in the back of your mind for a patient like this who has a 11;14 translocation. As you think about different treatment options, I think venetoclax by itself, or, as Dr Usmani alluded to, in combinations of some of the early studies would be beneficial for this specific subgroup of patients with 11;14 translocation. It’s well tolerated.
Saad Z. Usmani, MD: Perhaps this is something to look forward to, but something that’s not available at this point.
Sham Mailankody, MD: Correct.
Saad Z. Usmani, MD: Selinexor. Any takers for selinexor?
Urvi Shah, MD: I think there is a role when there are other options that are not working or you have very few options. There have been a few patients who were very refractory and then responded to selinexor well, but the role is in a certain small population.
Saad Z. Usmani, MD: OK. Would you think about selinexor in any high-risk patients? If this patient was progressing after 4 months of lenalidomide maintenance, would you think of a selinexor-like mechanism for those patients?
Urvi Shah, MD: If there’s a CNS [central nervous system] disease, I think selinexor might have some CNS benefit.
Saad Z. Usmani, MD: OK. Yeah, typically circulating plasma cell patients do well.
Urvi Shah, MD: Yeah.
Saad Z. Usmani, MD: We’ll leave selinexor alone. I just wanted to bring that up for parity, I guess.
Transcript edited for clarity.