Part 1: Selecting Treatment Options for Relapsed/Refractory Multiple Myeloma

Natalie Callander, MD (Moderator)

Professor, Hematology/Oncology

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin

CASE DESCRIPTION:

A 55-year-old African American man in a rural community was diagnosed with hyperdiploid multiple myeloma at Revised International Staging System stage II. He had a medical history of hypertension controlled with lisinopril. He received VRd (bortezomib [Velcade] lenalidomide, [Revlimid], dexamethasone) for 4 cycles, followed by autologous stem cell transplant (ASCT). He achieved a very good partial response and received lenalidomide maintenance that was meant to continue until disease progression.

At 3-year follow-up, imaging showed stable disease. His hemoglobin level was 11.3 g/dL, calcium was 9.2 mg/dL, and creatinine was 0.8 mg/dL. His M-protein level in June was 1.2 g/dL, in July it was 1.4 g/dL, and in August was 1.7 g/dL.A fluorescence in situ hybridization assay showed a 17p deletion and hyperdiploidy. He had an ECOG performance score of 0. The patient received Dara-Vd (daratumumab [Darzalex], bortezomib, and dexamethasone).

One year later, an MRI showed new lytic lesions and his ECOG performance score was updated to 2. His hemoglobin level was 11.5 g/dL, calcium was 9.8 mg/dL, creatinine was 1.1 mg/dL. There was an M-protein spike of 1.1 g/dL. β2-Microglobulin was 5.6 mg/L. A repeat bone marrow biopsy was performed and a 17p deletion was found in 50% of cells and it showed hyperdiploidy.

DISCUSSION QUESTIONS:

• What are the key factors that influence your decision making for a patient like this, such as prior therapy, mechanism of action, eligibility for second transplant or CAR (chimeric antigen receptor) T-cell therapy, logistics, chance for long-term response, safety/tolerability, organ involvement, or other?
• What if this patient had mild to moderate renal impairment?
• What are the challenges of treating patients such as this one?

NATALIE CALLANDER, MD: What are the key factors that you have to consider when you’re making your decision for a patient like this? I think one big thing besides risk factors, is that this patient is symptomatic and you don’t necessarily have a long time to choose something. Looking at the B-cell maturation antigen [BCMA]-targeted therapies that are available, belantamab mafodotin [Blenrep] is off the shelf, and so that is something that you could potentially choose quite rapidly and easily. I think we take these factors into account on a daily basis. So, what [prior therapies] have they received?

For this particular individual, you’re not probably going to put them on daratumumab again. You could use it with another drug, but I think a lot more physicians would feel comfortable trying to change the mechanism of action. If the patient had stem cells in the bank, and that was something that was immediately available, that wouldn’t necessarily be a bad decision. There’s always some debate about length of time that a person is stable. This patient would meet my test, so stem cell transplant would be a good choice. What are the patient’s goals? This patient is rural, so are they able to come for a clinical trial that might need a lot of visits?

Are you worried about some of their organs? If the patient had mild to moderate renal impairment?

AHMAD MATTOUR, MD: For belantamab, there’s no dose adjustment for mild to moderate renal impairment.¹ It has not been established for severe impairment or requiring dialysis. I know that for a fact, because I had a patient who was on dialysis, and we were debating whether we could start them on belantamab, and the answer was no, because we don’t have the data.

CALLANDER: Right. I think those data are coming. I would agree with you. As far as we know, this patient doesn’t have any renal toxicity, and does not appear to be renally cleared, but you are operating in a data-free zone. I think some of the drugs that we would normally consider—we’ve certainly used carfilzomib [Kyprolis] in people who have renal impairment, and even on dialysis; I’m sure some of you have, too. This patient’s creatinine level isn’t that bad, but a lot of times what is frustrating for me, and probably for some of you as well, is you’ll have a patient who has 1 laboratory result that keeps them out of a clinical trial, and so that option goes away, unfortunately.

But I think of the list that we were given for the polling question, I am not sure I would use selinexor [Xpovio] and dexamethasone [without another agent]. I would probably use it in [a triplet] combination. So, if this patient said they want to get treatment at home, this is a patient I might give something like selinexor, pomalidomide [Pomalyst], and dexamethasone to, which is something that has been published and has a reasonable response rate, and has had some resensitization for pomalidomide.²

MATTOUR: What are your thoughts about challenging with older regimens, such as cyclophosphamide, bortezomib, and dexamethasone, for example?

CALLANDER: I have certainly done it before. In this case, I might not choose that because he has just been on bortezomib, and so I might be a little bit shy about that. But going back to carfilzomib, I’ve certainly used carfilzomib/pomalidomide/dexamethasone and carfilzomib/cyclophosphamide/dexamethasone. I think all of those would potentially be reasonable.

In a symptomatic patient like this, if they are having a lot of symptoms, I’m really looking for a treatment to show a response pretty quickly.

DAHLIA ELKADI, MD: Have you been using bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide [VDT PACE]? I know with cisplatin we would try to avoid it, but have you been using this regimen, with all those other options?¹

CALLANDER: VDT PACE tends to come up for our practice most often for a patient with a condition such as plasma cell leukemia. That regimen is used in that situation almost at diagnosis. It’s challenging to give an older, frail person, though this patient is 55 years old. The way I look at VDT PACE is it’s got to be a bridge to another therapy, because that’s not going to be a regimen you’re going to give 3 or 4 times.

You might say that you want to get [a response to the patient’s myeloma] as fast as you possibly can, but you must have another strategy ready to go after that. Now whether it might be a second ASCT, if you had the stem cells ready, or you’re going to get them on that clinical trial, or consider something like a CAR T-cell therapy, I think VDT PACE has a relatively limited role for most of us.

SAURABH CHHABRA, MD: That was exactly my point, Dr Callander. If this renal impairment is due to myeloma, I think VDT PACE is a bridging therapy to something later, like a clinical trial, or CART-cell therapy, or belantamab mafodotin. You need to try to reverse the pathophysiology of the myeloma, because the belantamab, or another medicine, may not work that quickly.

CALLANDER: If the patient says, “OK, I’m going to get VDT PACE, and now I’m going to go 100 miles away from your center,” you have to make sure, with that kind of regimen, you have excellent communication and you have great follow-up plans. And that person’s going to need growth factor support, they’re just going to need meticulous follow-up. But it’s certainly something you can choose.

CALLANDER: Has anybody used melflufen [Pepaxto], out of curiosity? I think that is a drug that has some utility. It’s under FDA review right now, because there was a randomized trial going on with pomalidomide and dexamethasone vs melflufen and dexamethasone, and there was some excess mortality in the melflufen arm.³ So, all of those trials are on hold right now. You can still get melflufen. The schedule is once a month, which is nice for a rural patient. Currently, it requires a central line to administer it, but I have had some patients on melflufen who have found it well tolerated. The most common serious adverse events are cytopenias.⁴ For a patient who’s going to be far from your center, they have to have some sort of follow-up in terms of [platelet] counts. I haven’t seen the data that the FDA has seen, but my guess is that the problem was that cytopenias may have led to some infections.

_References:

_{1. Blenrep (Belantamab mafodotin). Prescribing Information. GlaxoSmiteKline; 2020. Accessed January 26, 2022. https://bit.ly/3tYNIxz}

_{2. Chen CI, Bahlis N, Gasparetto C, Tuchman SA, et al. Selinexor, pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. Blood (2019) 134 (Supplement_1): 141. doi:10.1182/blood-2019-122907}

_{4. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). FDA. July 28, 2021. Accessed January 26, 2022. https://bit.ly/3fXrFPJ}

_{3. Schjesvold F, Robak P, Pour L, Aschan J, Sonneveld P. OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol. 2020;16(11):631-641. doi:10.2217/fon-2020-0024}