Next-Line Therapy Choices in R/R Multiple Myeloma After VRd Plus ASCT

Suzanne Lentzsch, MD, PhD

Professor of Clinical Medicine

Director of the Multiple Myeloma and Amyloidosis Program

The College of Physicians and Surgeons of Columbia University

New York Presbyterian Hospital/Columbia University Medical Center

New York, NY

CASE SUMMARY

A 60-year-old White woman was diagnosed with stage II multiple myeloma. She has a history of being a heavy smoker, with a gain (1q21) cytogenetics and an ECOG performance score of 0. At the time, she was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy, followed by autologous stem cell transplantation (ASCT). She achieved a complete remission with VRd and ASCT, and was minimal residual disease negative, then placed on lenalidomide maintenance therapy.

At a follow-up after 2 years on lenalidomide maintenance, the patient reported having severe fatigue and pain in her back and legs, which disrupted her ability to continue working full time. A PET scan showed vertebral fracture at L1, lesions in both femurs, and an ECOG performance score of 1. Her current lab levels were the following:

• M protein, 1.98 g/dL (rapid increase from prior bloodwork)
• λ free light chain increased from 47.5 mg/dL to 136.7 mg/dL
• Hemoglobin: 9.8 g/dL
• White blood cell counts and platelets: within normal limits
• Creatinine: 1.4 mg/dL (range, 0.59-1.04 mg/dL)
• eGFR: 45 mL/min/1.73m2
• Creatinine clearance: 40 mL/min

SUZANNE LENTZSCH, MD, PHD: Does anyone want to comment why you’re using dara-Kd [daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone], isa-Kd [isatuximab (Sarclisa), carfilzomib, and dexamethasone], or [one of the other regimens]?

ALEXANDER BARSOUK, MD: We’re more familiar with daratumumab. None of those answers would be wrong. Because the patient relapsed after 2 or 3 years, even bortezomib would be reasonable to [reuse]. It’s important to introduce anti-CD38 therapy now because the patient wasn’t treated with that. But any of those combinations are OK. I swayed towards carfilzomib because the patient progressed on lenalidomide and I would think the patient would benefit from switching the mechanism from IMiD [immunomodulatory drug] to proteasome inhibitor. But I think even the regimen with pomalidomide [Pomalyst] would be very reasonable.

LENTZSCH: Is there any reason why somebody would choose dara-Pd [daratumumab/pomalidomide/dexamethasone]?

YACOUB FAROUN, MD: I have used dara-Pd as second-line therapy. It’s [our practice’s] most used regimen for second-line therapy. I agree with Dr Barsouk that introducing anti-CD38 is important in the selection of treatment of relapsed second-line therapy after transplant. Pomalidomide is not lenalidomide; they are not interchangeable, so I think we see efficacy with pomalidomide after lenalidomide progression.

LENTZSCH: Yes, I agree. I also choose dara-Kd. Dara-Pd also would be appropriate. If the patient has any cardiac history, daratumumab, bortezomib, and dexamethasone, for instance, is an absolutely inappropriate regimen. As you all pointed out, an anti-CD38 antibody is important at that point.

DISCUSSION QUESTIONS

• Would you use a monoclonal antibody at first relapse or hold for a later line of therapy for those who haven’t seen one yet? If yes, which do you use? ​
• What backbone partner would you choose for this patient with aggressive early relapse on lenalidomide maintenance?
• Please discuss the patient-, disease-, and therapy-related factors you consider when choosing second-line therapy for a patient like this with aggressive early relapse on lenalidomide maintenance.

LENTZSCH: Would you use a monoclonal antibody at first relapse or do you hold it for later line of therapy for those patients who haven’t seen a CD38 monoclonal antibody? Do you keep it because you might treat the patient with VRd, then switch to KPd [carfilzomib, pomalidomide, and dexamethasone] and leave the CD38 monoclonal antibody for the next relapse? Or do you think the patient needs to be treated at that point?

PRERNA MEWAWALLA, MD: At first relapse, I always use a CD38 monoclonal antibody if they haven’t already been on it in the past.

BARSOUK: I also agree with this. I would use one CD38 antibody or another. Historically, we’ve been more and more familiar with daratumumab, but isatuximab is also coming into play. In terms of choice between pomalidomide and carfilzomib, comorbidities play a role but so do the patient’s convenience and the quality of life. If [a patient] wants to be on a mostly oral regimen, only coming to the office every 2 weeks and then once a month for daratumumab, then for carfilzomib, the regimen is a little bit more tedious. But we use that as well.

LENTZSCH: Are you using twice weekly carfilzomib or once a week?

BARSOUK: We use twice weekly because this is for a patient who has relapsed and you want to give them the best option, especially if it’s a young patient. For somebody older, then maybe we’ll do once a week. But we’re trying to stick to a standard schedule. What would you recommend?

LENTZSCH: I use it for patient convenience and our infusion center is [short on] infusion chairs. I use it once a week and I go up to 56 mg/m².

VARADI: We are as well. Everybody is getting the carfilzomib once a week, and at the 56 mg/m² dose. In a few patients who tolerate well, I try to give 70 mg/m² once a week. When they stabilized, there are 2 or 3 patients whom I started to give isatuximab, and the isatuximab is every 2 weeks. After a while I try also to give the carfilzomib if they are stable and have a very good response, together with the [isatuximab] twice a month, so they come in every 2 weeks.

QUN DAI, MD: I use an antibody for the first relapse. I would not reserve this for later because you want to get a good drug in the front so the patient can get a deep response and go on to transplant. Regarding choice of the backbone, whether proteasome inhibitor or IMiDs, I agree. I want to see when the patient relapsed on the lenalidomide. I was in more favor of a proteasome inhibitor but I am also looking at the patient’s comorbidities to help to make a drug choice.

LENTZSCH: What is the strongest factor that makes you use a different backbone? For instance, we say a CD38 monoclonal antibody is important. But what influences your decision whether you use pomalidomide over carfilzomib?

FAROUN: I think every patient is different. [Data show] that triplet therapy in relapsed/refractory disease is much better than doublet therapy. In the studies, there was not a lot of information about cytogenetics, and which agent is effective. For example, we know that with 1q21 abnormalities, isatuximab may be more effective than others.¹ But I cannot delineate which one is better. Daratumumab [can be given] subcutaneously, and hopefully, isatuximab, when it comes out subcutaneously might also be appealing. Carfilzomib once a week at 70 mg/m2, and later on when they have good response, every other week. I have that done many times. But the idea is that triplet is better than doublet.

LENTZSCH: I agree. There is a majority that [believes] at this point the patient should have received a CD38 monoclonal antibody, at least in the first line. I would not keep it for a later line because it’s important that you induce the deepest remission up front that lasts for a longer time.

CASE UPDATE

The patient was started on Isa-Kd and achieved a very good partial response.

LENTZSCH: Have you used isa-Kd?

GABOR VARADI, MD: I am using it.

LENTZSCH: What is your experience and why did you do this?

VARADI: The first patient I used it in, [it was] because he didn’t like the subcutaneous daratumumab and he was willing to get an intravenous infusion. Since I see that it’s quite effective and if the patient has an infusion port already, it’s not a problem to administer. I saw that the results are really good. It’s a very effective regimen, so I started to use it.²

LENTZSCH: So you have a positive experience.

FAROUN: I have used this regimen, however in third-line therapy after progression on daratumumab. I found that isatuximab is not [the same as] daratumumab. These are different agents, so I have good success; patients who are progressing or not responding to daratumumab respond to isa-Kd.

LENTZSCH: OK, interesting. Has anybody combined isatuximab with other partners, with pomalidomide, for instance?

VARADI: Not yet.

_References:

_{1. Martin T, Richardson PG, Facon T, et al. Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA. Haematologica. 2022;107(10):2485-2491. doi:10.3324/haematol.2022.280660}

_{2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4}