Physicians Debate Second-line Therapies for a Patient With Early-Relapse Multiple Myeloma

Peers & Perspectives in OncologyJuly I 2023
Volume 1
Issue 2

During a Targeted Oncology™ Case-Based Roundtable™ event, Ariel F. Grajales-Cruz, MD, discussed second-line therapy combinations for a patient with early-relapse multiple myeloma after complete remission with bortezomib, lenalidomide, and dexamethasone.

Ariel F. Grajales-Cruz, MD

Ariel F. Grajales-Cruz, MD (MODERATOR)


Moffitt Cancer Center

Assistant Professor

Department of Oncologic Sciences

University of South Florida Health Morsani College of Medicine

Tampa, FL


Alfred M. Kalman, MD

Frantz Francisque, MD

Michael S. Wertheim, MD

Vikas Malhotra, MD

Richard A. Knipe, MD

Uday B. Dandamudi, MD

Harshad V. Amin, MD

Mahender Yellu, MD, MBBS, MHA



  • What is the trigger to initiate second-line therapy for this patient?

KALMAN: She clearly needs therapy because of her early relapse, aggressive relapse, and symptomatic disease. She probably needs a triplet therapy as someone who has failed lenalidomide.

GRAJALES-CRUZ: Absolutely. I agree that a patient like this, with clear new CRAB features—high calcium, renal injury, anemia, bone disease— will have unequivocal evidence of progression, and that needs addressing. Doing the same thing and expecting a different outcome [is not a reasonable option]. At this point, you have to switch gears and try to get some control on the disorders. Most importantly, as time goes on and the disease is left untreated, the [laboratory] numbers are going to get worse, kidneys are going to fail, and the patient’s going to end up having a fracture, which opens the door for more complications.


  • How do you define early vs late relapse?

KALMAN: I think 2 years would be early.

GRAJALES-CRUZ: I agree. Anybody who’s relapsing just 1 or 2 years after transplant falls into the category of an early relapse rather than a late one. If we look at all the data from the IFM/DFCI2009 [NCT01191060],1 DETERMINATION [NCT01208662],2 and FORTE [NCT02203643] trials,3 after transplant we are expecting a longer progression-free survival [PFS]. So, I agree that 2 years is on the shorter end of the spectrum.


  • How do you decide what type of therapies should be used next?

FRANCISQUE: It’s usually based on what the patient received in each line of therapy, and if the patient has a more aggressive disease. That’s why we repeat the cytogenetics, and so on. Also [it depends on] the patient’s comorbidities and which complications they developed in the first line. That’s my approach on deciding.

GRAJALES-CRUZ: Absolutely, I agree. Whenever the patient relapses, we have to know what the patient was exposed to, because it’s not the same thing to be exposed to a drug and be refractory to a drug. Sometimes we can recycle the medications if they’re not refractory, remembering that the definition of refractoriness is progression of disease while on the drug or within 60 days of exposure. So, if the patient is exposed but not refractory, we can consider that.

Another important consideration is comorbidities, and most importantly, as well, the toxicity that could have come from the previous drugs that were used. For example, if the patient develops significant neuropathy after bortezomib and it’s worse after transplant, then potentially a bortezomib-based regimen is not necessarily in the best interest of the patient, even if the patient is still sensitive to it. So, that’s important to take into consideration.


  • If the patient had an aggressive presentation like this one vs a low biochemical relapse, would that sway you into doing something different?

WERTHEIM: I think that makes a difference. This patient is going to be in trouble soon if there is no response, so I would switch therapy and use a triplet. If it is a slow relapse, you could maybe use an elotuzumab [Empliciti] combination, but in this patient, I would use daratumumab [Darzalex] or isatuximab [Sarclisa] with carfilzomib [Kyprolis] and dexamethasone.

GRAJALES-CRUZ: It’s 100% accurate what you described, because chemical relapse vs an aggressive relapse you would treat very differently. There are some patients who get into deep trouble and have no [blood] counts whatsoever, requiring more aggressive approaches like chemotherapy such as DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin]. So, I agree that not all relapses are the same.


  • Whom do you consider the most challenging populations to treat in relapsed/refractory myeloma?

GRAJALES-CRUZ: We’re dealing altogether with an older population, with the median age of diagnosis for multiple myeloma being 69 years…. Most of them, in the United States at least, will have comorbidities: hypertension, diabetes, and on some occasions coronary artery disease. So, [whom] do you think are the most challenging populations to treat in myeloma?

MALHOTRA: I think the TP53-mutated cases are the most aggressive, and patients don’t respond well to a lot of therapies.

GRAJALES-CRUZ: Yes, I agree, the TP53-mutated patients are extremely challenging to treat, and that does not only apply to myeloma; I think any cancer with a TP53 mutation will be challenging altogether. These patients tend to have very short-lived responses and will relapse in no time. Some of them are not chemotherapy sensitive, so that is why you can see relapses after transplant that occur very quickly. I agree completely. Does anybody else have another population who makes them nervous?

KNIPE: Any of the patients with aggressive cytogenetics are more challenging—more comorbidities, patients who are older, we’re talking about short relapse times. The more drugs a patient has seen, the more challenging treating becomes, as well. For the second line, a lot of the patients are getting 4 drugs up front and then transplant, so there is a potential that they’ve already seen a number of drugs, even in second-line therapy.

GRAJALES-CRUZ: Right, patients [who] have some of these abnormalities and combinations—for example, a person with a 1q and a 17p deletion, or a translocation of chromosome 4;14, or 14;16—those are challenging.


GRAJALES-CRUZ: It seems that all of us chose a CD38- directed therapy in combination with carfilzomib, either with daratumumab or isatuximab. Most importantly, I think a message I would take from this polling question is lenalidomide was not listed among the answers.

If the patient is relapsing after maintenance with lenalidomide, doing lenalidomide in combination with something else so early in the game is not necessarily the best answer. Is it a wrong answer? No, but it would probably give a better PFS if we used completely different drugs to change it up, change the biology, and try to target a different clone that is clearly taking the lead on the disease, per se.


  • 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?

GRAJALES-CRUZ: What is the common practice for you nowadays, in terms of relapse? The poll showed dara-Kd [daratumumab, carfilzomib, dexamethasone] vs isa-Kd [isatuximab, carfilzomib, dexamethasone], so I just want to confirm that is the case.

DANDAMUDI: I’m not holding back on any CD38 monoclonal antibodies. I use them mainly in the postrelapse phase. With the newer data, I’m using them up front also.

GRAJALES-CRUZ: Absolutely. Now we have a lot of data, based on the GRIFFIN [NCT02874742]4 trial to bring those CD38 drugs early in the game with daratumumab. Isatuximab also has 2 [ongoing] clinical trials, both in the transplant-eligible and -ineligible populations for first-line therapy, so we’ll see how those pan out. But I agree that CD38 antibodies make sense early in the game, rather than holding them. That’s standard, it seems.


  • When you think of an anti-CD38 monoclonal antibody, either daratumumab or isatuximab, what combinations do you favor? Do you use a proteasome inhibitor or an immunomodulatory drug?

AMIN: I use a proteasome inhibitor, especially in a patient like this who is already lenalidomide refractory. Even in the first line, I use it, because it’s easy to start quickly with a proteasome inhibitor as sub-q [subcutaneous] treatment and get insurance authorization, and quicker than going through the REMS [Risk Evaluation and Mitigation Strategies] program for lenalidomide or pomalidomide [Pomalyst].

GRAJALES-CRUZ: When you combine, for example, daratumumab, do you combine it with carfilzomib or bortezomib?

AMIN: If it’s a first line, I combine it with bortezomib, but in the lenalidomide-refractory [category], I combine it with carfilzomib. But with CD38, like other colleagues said, I use it more in the first line nowadays, especially in transplant-eligible patients.

GRAJALES-CRUZ: It brings up the same topic that we discussed earlier, the definition of refractoriness vs exposure, because nowadays we have a lot of patients who, based on the GRIFFIN trial, will receive daratumumab up front.4 That doesn’t necessarily mean they’re refractory to that CD38, because if they just use it for induction and… underwent transplant with lenalidomide maintenance, for example, we can definitely revisit the CD38 option at a later time.


  • How important is the convenience or the logistics of the drug that is going to be used?

GRAJALES-CRUZ: We touched on age, comorbidities, and performance status, but I wanted to know how important for you is the convenience of the drug that is going to be used? For example, IV [intravenous] vs sub-q, the cost, the reimbursement, etc; does it play into your decision-making?

DANDAMUDI: Nowadays I’m not using any IV at all, especially with the daratumumab. I’m using daratumumab and hyaluronidase [Darzalex Faspro] most of the time, and that’s the main reason I don’t like the isatuximab.

GRAJALES-CRUZ: Is it because of the chair time, or is it because of infusion-related reactions?

DANDAMUDI: Infusion-related reactions, chair time, patient convenience; all these things favor the daratumumab sub-q.

GRAJALES-CRUZ: Does anybody else have a similar or different opinion about that?

YELLU: I’ve been using mostly daratumumab and hyaluronidase. I don’t remember when I last used the IV daratumumab; it’s been a while. I think one of the key things is the institutional [situation]; sometimes they want to prefer certain drugs in that class, and we’ll probably go with that. But I have not used isatuximab. The daratumumab and hyaluronidase has been getting better and better. Now after 2 treatments, for the third treatment they watch for only 30 minutes, which is convenient for the patient.

GRAJALES-CRUZ: I think that also revolves around the idea of what we’re comfortable with, because the more we use a drug, the more familiar with it we are, so that also plays into the equation.


  • What are your thoughts about the efficacy and safety of isa-Kd in the IKEMA (NCT03275285) trial?

GRAJALES-CRUZ: Based on [the data from IKEMA], what do you think about the efficacy and safety of the regimen altogether?5,6 And how do you compare this to other triplet regimens that you use in this setting?

KNIPE: The data are impressive. The median PFS is out at 42 months, that’s great [95% CI, 27.1-not calculable].6 I compare it to other triplets…none of them will ever go head-to-head, so we’ll probably never know the right answer to that question. You just cross-compare it with other trials, but the safety was impressive.

GRAJALES-CRUZ: Right, unless we have head-to-head trials comparing these—but I don’t think we’re ever going to see those trials. For example, dara-Kd vs isa-Kd, because one company is not going to pay for the other compound. Unfortunately, we are left to the cross-trial comparisons to some extent.


1. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750

2. Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

3. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/ S1470-2045(21)00535-0

4. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/ blood.2020005288

5. Moreau P, Dimopoulos MA, Mikhael J, et al; IKEMA study group. 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

6. Moreau P, Dimopoulos MAC, Mikhael J, et al. VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Ann Oncol. 2022;33(6):664-665. doi:10.1016/j.annonc.2022.04.013

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