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Spotlight

This roundtable series reviews the use of B-cell maturation antigen–targeted treatments in patients with relapsed/refractory multiple myeloma, as discussed by participants at virtual live events.

BCMA-Targeted Therapy in Patients with Multiple Myeloma

In 2017, at the age of 55, an African-American man was diagnosed with multiple myeloma which was hyperdiploid at Revised Multiple Myeloma International Staging System stage II​. He had a history of hypertension controlled with lisinopril​. He received VRd (bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone) for 4 cycles, followed by autologous stem cell transplant (ASCT) and achieved a very good partial response. ​He was to receive lenalidomide maintenance until progression​.

Three years later, imaging showed stable disease. He had an ECOG performance score of 0. Fluorescence in situ hybridization determined that he had a 17p deletion. He received Dara-Vd (daratumumab [Darzalex], bortezomib, and dexamethasone). One year later, a CT skeletal survey showed new lytic lesions and his performance score was changed to 2. He had a 17p deletion in 50% of cells, hyperdiploid.

 Essentially we’re just under 5 years into the treatment of a man with multiple myeloma who is young, had an ASCT, a good response for 3 years, and now is relapsing following therapy.

[Does] somebody want to tell me why they chose anything in particular?

 I chose the triplet regimen. I think ideally I would have maybe sent for chimeric antigen receptor [CAR] T-cell therapy, but it’s hard to come by, it can’t happen right away, and you’ve got to find a center that has a slot. So I thought more practically and that’s why I picked a triplet therapy, maybe pomalidomide [Pomalyst], carfilzomib [Kyprolis], and dexamethasone or something like that.

Maybe they’d get the referral [for CAR T-cell therapy], but in the meantime, I’d start them on something else.

 It’s kind of interesting, isn’t it? I was trying to figure out what combination I would use because, theoretically, if you go by the license indications for CAR T-cell therapy, I’m not quite sure they’d be quite there yet because they’re certainly supposed to be exposed to 3 or 4 lines.

 It depends what you call a “line of therapy”. But they’ve definitely been exposed to lenalidomide and they’re resistant, they’ve been exposed to daratumumab and they’re resistant, and they’ve been exposed to bortezomib and they’re resistant.

 I would definitely not do a doublet. I’d definitely go for a triplet. I think the carfilzomib/pomalidomide is pretty enticing with dexamethasone because you’re substituting both the immunomodulatory drug and the proteasome inhibitor and I know there is activity whenever you go to the new class of each of those drugs.

 So there’s a good chance that that patient [could] still respond.

I mean, honestly, with the CAR T-cell therapy, it puts the patient out of our hands and you still want to maintain, as long as you’re giving effective treatment, it’s nice to continue with the relationship you have. But I would definitely refer the patient to a myeloma specialist and work in conjunction with them. But at the same time, I think that carfilzomib/pomalidomide/dexamethasone is a very effective treatment choice.

 I think these are all reasonable options. I voted for CAR T-cell therapy, but granted the patient is having a symptomatic relapse and you probably need something to bridge him to the CAR T-cell therapy while you wait for the cells to be [infused]. So if he couldn’t go for CAR T-cell therapy right away, then I still have a little hesitation sequencing the belantamab mafodotin [Blenrep] with CAR T cell, so I’d probably give the patient triplet therapy as bridging, and then try to go for CAR T cell.

 I think that’s probably where I would come up, and as you say, what you choose for bridging therapy is 1 thing that is important, and when you refer and how early you refer is also important.

Is a second stem cell transplant an option for this patient?

 One of the things we didn’t have as an option was about potentially a second transplant. Dr Suarez Londono, can you discuss the second transplant for this patient?

 I’m a bone marrow transplanter at NYU. The European Society for Blood and Marrow Transplant did a retrospective analysis on patients that had 17p deletion, and they look into doing an ASCT followed by an ASCT, or autologous transplant followed by [allogeneic] transplant. Although there was no overall survival difference, the relapse-free survival and the progression-free survival were beneficial for the patients that had 17p deletion and had an autologous transplant followed by an allogeneic stem cell transplant.

So I think a referral in this patient with 17p to an allogeneic transplant center makes a lot of sense. There are data that suggest a second transplant makes sense. And even an allogeneic transplant in this setting.

 Okay. And the patient having had 3 years with their initial chemotherapy, a second ASCT is potentially an option as well, isn’t it?

 That’s also a potential option. It [only needs to be] be more than 6 months, [and this patient is] 3 years from the previous ASCT, but it’s still a potential option, just to try to get to a remission. And if there’s access to a clinical trial, this would be an ideal patient, too.

 I think it’s quite interesting that the speed of relapse is one of the other things that’s important when we’re thinking about how we’re going to treat patients. If it’s a slow relapse, then yes, we’ve got time to think about these things, and I think it was Dr Braunstein who mentioned bridging therapy to CAR T cells and so on. But if it’s a quick relapse, then it’s one of those situations where we need to get in there and start treatment relatively quickly.

1. Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. 

. 2015;126(20):2284-2290. doi:10.1182/blood-2015-05-643320

2. Abecma (idecabtagene vicleucel). Prescribing information. Celgene Corporation; 2021. Accessed March 23, 2022. https://bit.ly/3L9VEBi

3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial [published correction appears in Lancet Oncol. 2017;18(10):e562]. 

. 2017;18(10):1327-1337. doi:10.1016/S1470-2045(17)30578-8

4. Dimopoulos M, Weisel K, Moreau P, et al. Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse. 

. 2021;35(6):1722-1731. doi:10.1038/s41375-020-01021-3

5. Gagelmann N, Eikema DJ, de Wreede LC, et al. Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT. 

. 2021;56(1):210-217. doi:10.1038/s41409-020-01007-w

During a live virtual event, Faith E. Davies, MD, discussed treatment options for a patient with multiple myeloma who relapsed after multiple lines of treatment including autologous stem cell transplant. 

Part 1: Reviewing Late-Line Options for Relapsed/Refractory Multiple Myeloma

Have you used belantamab mafodotin (Blenrep)? If so, what was your experience?

 If you haven’t used belantamab, what reservations do you have about it, or any difficulties [in accessing it]?

 None of my patients have reached the point of resorting to these kinds of therapies. We have belantamab and the chimeric antigen receptor [CAR] T-cell therapy. There [are no studies] comparing between them. Is there any logic to picking one over the other?

 We were fortunate to have belantamab in trials a number of years ago, and I think that the best thing about it is it’s just available. The patients who respond to it seem to respond quite well and quite fast. We have had patients who were burning through [other treatments], and then they had 1 or 2 doses of belantamab and had a significant improvement in their myeloma.

The biggest issue with CAR T cells is it takes a while to get those cells manufactured, so you have to have a patient who’s stable enough so that you can harvest or phorese those T cells, and then they have to be manufactured. If you [start seeing] a patient who is on steroids or has just had a drug like bendamustine for their myeloma, that patient may have very poor lymphocyte counts, collecting cells to even manufacture the CAR T cells is quite difficult.

Even if you get over that hurdle, and you get the CAR T cells collected, it takes 4 to 6 weeks to have the cells manufactured for that patient. Then the patient must stay in some reasonable shape. They don’t need to go into remission, but you have make sure that they don’t start having kidney problems, or other problems. For some of these patients, that is really difficult.

One of the biggest advantages of belantamab is that it has a different mechanism of action. I have used belantamab first for unstable patients. Another fortunate thing is that we have some ophthalmologists on site because we had studies going on, and the Risk Evaluation and Mitigation Strategy program.

There are reports of patients who have relapsed post–CAR T-cell therapy getting belantamab and responding to that, which I think points [to using] the BCMA [B-cell maturation antigen] therapies that we have, and the ones that are coming.

I don’t think we know how to sequence [these later-line options], if there’s something that would be bad to do, or deleterious to do. I don’t believe that if you have belantamab before trying to go to CAR T-cell therapy, that it is going to spoil it, but getting it through a clinical trial often prevent us from giving any other BCMA-directed therapy. Now that the commercial CAR T-cell therapy is available, I think we will soon figure out whether there are types of patients who don’t do well with CAR T-cell therapy based on what treatments they’ve had before.

 I agree with you completely. In my limited experience, I’ve given belantamab to 5 or 6 patients, and I’ve seen responses in roughly half of the patients. But my problem has been that none of my patients were able to get more than 2 doses, because after 2 doses, either they progressed, or they developed grade 2 keratopathy or other conditions. We had to hold treatment, and while they waited, either there was concern that they would progress even if there was no objective evidence of it, or they did progress and they had to go on to another treatment.

It is tough to choose between belantamab and CAR T-cell therapy. The data look good with CAR T cell, but it’s hard to get to CAR T cells at this point, whether from clinical trials or commercially. It’s hard to use belantamab before CAR T cell from a clinical trial perspective, but I think I probably wouldn’t hesitate using belantamab even as a bridging therapy after the patients went through apherisis, before they go on to commercial CAR T-cell therapy. Right now, we can’t do commercial CART cell because we just don’t have slots.

 I have another question about the real-world data. You have these 2 drugs that you can use in the same patient scenario, but in the real world, which one of them easier to get authorized or approved to start on the patient?

 What more and more of us are saying is that if you think you might have a patient for CAR T-cell therapy, the way things are going right now, it would be good to have them seen by a center than can deliver CAR T cells, because the waiting times are long. What we can’t do, and I think Dr Chhabra will agree with this, is call a treatment center and say that you want them to have CAR T-cell therapy in a week. It’s not going to happen. Unfortunately, it will be months before they will be able to have cells collected, let alone manufactured. So, it’s a tough situation if you want CAR T cells. And, as Dr Chhabra said, the clinical trials that are accruing right now are limited, and the access to the commercial CAR T cells is limited. 

During a live virtual event, Natalie Callander, MD, discussed real-world experience with the efficacy of belantamab mafodotin and whether it can be chosen instead of chimeric antigen receptor T-cell therapy. 

Part 2: Choosing Between BCMA and CAR T-Cell Therapy in Multiple Myeloma

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.

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?

 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?

 For belantamab, there’s no dose adjustment for mild to moderate renal impairment.

 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.

 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.

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

 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.

 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?

 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.

 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.

 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.

 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.

 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.

 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.

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

During a live virtual event, Natalie Callander, MD, discussed possible treatment options for a patient who relapsed several years after successful treatment of multiple myeloma with bortezomib, lenalidomide, and dexamethasone. 