Physicians Examine Efficacy and Tolerability of Frontline Combinations for Transplant-Eligible Multiple Myeloma

Saulius K. Girnius, MD (MODERATOR)

Medical Director, Cellular Therapy Program

Good Samaritan Hospital

TriHealth

Cincinnati, OH

EVENT REGION Ohio and Michigan

PARTICIPANT LIST Wajahat Khan, MD | Baidehi Maiti, MD, PhD | Madan L. Arora, MD | Srividya Viswanathan, MD | Molly Gallogly, MD, PhD | Mark H. Knapp, MD | Neeraj Mahajan, MD | Faisal Musa, MD

CASE SUMMARY

A 54-year-old woman presented with laboratory results including the following:

• Hemoglobin: 7.0 g/dL
• B2 Microglobulin: 6 mg/dL
• Albumin: 3.2 g/dL
• Calcium: 11.3 mg/dL
• Lactate dehydrogenase: 200 U/L
• Creatinine clearance: 45 mL/min
• Bone marrow: 22% monoclonal plasma cells
• Serum kappa free light chains: 240 mg/L
• Serum monoclonal protein: 5 g/dL

She had no cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities and had an ECOG performance status of 1. PET/CT scans showed multiple bone lesions in her vertebrae without extramedullary disease. Her diagnosis was Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG-κ myeloma, and she was identified as being eligible for autologous stem cell transplant (ASCT).

DISCUSSION QUESTIONS

• What are the available triplet regimen and quadruplet regimen options for patients with transplant-eligible newly diagnosed multiple myeloma?
• How do you decide between quadruplet and triplet?
• What factors impact use of quadruplet vs triplet?
• For a patient who is eligible for transplantation, do you initiate treatment with a quadruplet or triplet regimen?

KHAN: Now we are using KRd [carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone] in some high-risk myeloma patients, especially with 17p deletion, and nobody is using any more CyBorD [cyclophosphamide, bortezomib (Velcade), and dexamethasone]; it is out of context except in patients with acute renal failure.

MAITI: We would also consider VRd [bortezomib, lenalidomide, and dexamethasone] as front line, or CyBorD if they’re ineligible for lenalidomide, and then we’ll do the quadruplet, which is daratumumab [Darzalex]/VRd [D-VRd] as first line in high-risk myeloma.

GIRNIUS: That summarizes what I use as well. What factors impact the use of quadruplet or triplet?

ARORA: In community practice, I want to use quadruplet [therapy with] daratumumab [in the] first line, but for transplant-eligible patients, it’s not approved with VRd. It’s [FDA]-approved with thalidomide, and…in the US, we don’t use thalidomide.¹ Therefore…I stay with VRd. But if it is approved, we would like to go to quadruplet for transplant-eligible patients. For transplant-ineligible patients, it is approved with…lenalidomide,² but for transplant-eligible patients, it is not approved yet.

GIRNIUS: Have you had any luck getting the quadruplet, even without FDA approval?

ARORA: I have not tried.

GIRNIUS: In newly diagnosed multiple myeloma, transplant-eligible, has anyone had any success in the real world?

MAITI: I have used D-VRd for high-risk myeloma as initial treatment. I do not recall getting a pushback.

GIRNIUS: In my experience, I’ve had no issues except some insurances require 21-day cycles rather than 28-day cycles based on the GRIFFIN trial [NCT02874742]. What type of comorbidities…would prevent you from using a quadruplet?

VISWANATHAN: It is pretty well tolerated, but my only concern would be the cell collection when they are going for ASCT. I try to send them to the transplant team as soon as they are diagnosed, when I start them on the frontline therapy. But what has your practice been with regard to that? That’s my concern, but otherwise I have not had any issues in terms of tolerance.

GIRNIUS: If you look at the data from the GRIFFIN trial, there does not appear to be…a difficulty in collecting stem cells, usually with either [cyclophosphamide] mobilization or plerixafor [with] G-CSF [granulocyte colony–stimulating factor] mobilization on trial, there weren’t any difficulties.³ Has anybody had any difficulties outside of a clinical trial, when you’re dealing with a more frail patient population with more medical comorbidities?

GALLOGLY: I’m more on the transplant side, but I would say that we have not had any issues getting our patients with myeloma to mobilize after either a quadruplet or a triplet.

VISWANATHAN: Thank you, that’s helpful.

GIRNIUS: What type of comorbidities would prevent you from using the quadruplet? Would frailty play a role in this?

KHAN: In general, daratumumab is a well-tolerated drug, so if you do a quadruplet vs triplet, I don’t think you’re adding any major toxicities by adding daratumumab. In my opinion, there are no major comorbidities which would prevent me from using daratumumab in a pretransplant or even nontransplant setting.

GIRNIUS: For a patient who’s eligible for transplantation, do you initiate treatment with a quadruplet or triplet regimen?

KNAPP: For patients who are higher risk, I would consider treating them with the quadruplet. I don’t always do that for a lower-risk patient.

KUMAR: For younger patients with minimum comorbidity, I would tend to use quadruplet, but other than that, for high-risk patients, [I would use] triplet.

MAITI: If the patient is frail, I would probably lean more toward triplet rather than quadruplet. We could consider D-Rd [daratumumab, lenalidomide, and dexamethasone] or even for very elderly and frail [patients], we’d probably go with…bortezomib-dexamethasone if they have a lot of renal dysfunction, or lenalidomide-dexamethasone. Those could be options.

MAHAJAN: If somebody is very high risk, we’ll use the quadruplet; otherwise, triplet. Our patients and community are more average, not like [especially fit patients] who go for the clinical trials or to the academic center. Even arranging the triplet is a hassle for [the patient] to come in twice a week [for] bortezomib and then weekly daratumumab, and then trying to…make sure they get lenalidomide. There may be a bit better data with the quadruplet, but the logistics and then the practicality and then the tolerability for average 75-year-old patients are not easy. That‘s mainly for younger, healthier, and very high-risk…[and] transplant-eligible patients.

GIRNIUS: So…you still consider, for transplant-ineligible [patients, it] sounds like you would take a step back and reassess the quality of life and other issues.

MAHAJAN: Daratumumab is becoming the main backbone of the first line. Whether you use D-Rd or D-Vd [daratumumab, bortezomib, dexamethasone] depends on comorbid [conditions] and the patient situation.

GIRNIUS: What do you consider an adequate successful treatment response in your patients following induction therapy in the real-world setting? We’re looking at transplant-eligible newly diagnosed multiple myeloma.

GALLOGLY: From the transplant center, we’re looking for at least a VGPR [very good partial response] prior to transplant, so VGPR or CR [complete response generally our requirement. That’s our goal. [Also,] not having a new problem that precludes transplant [since] we want them to still be eligible.

MUSA: [My goal is a] good response, obviously. Either a VGPR, PR [partial response], or CR.

DISCUSSION QUESTIONS

• How do you manage adverse events for patients receiving induction therapy? Does it differ for triplet versus quadruplet therapy?

KHAN: In my personal experience with daratumumab-VRd, as opposed to VRd, hematological toxicities, especially anemia, are a bit more pronounced than with VRd alone. But there are not too many nonhematological toxicities compared with VRd alone.

KUMAR: I’ve only used [the] quadruplet in 1 patient so far, and I didn’t have any experience with the worsening toxicity. I see that neutropenia was more [in the trial data], but I have not noticed much.

MAITI: I’ve only had a couple of patients with high risk whom I treated with D-VRd, and I did not see any dose-limiting toxicities per se. Just a little more pronounced cytopenias, compared with [what I’ve seen] more commonly [when] I’ve used VRd.

KNAPP: I also have only had a couple of patients, but I’ve not seen much additional toxicity from the daratumumab, in addition to VRd.

GIRNIUS: Dr Gallogly, I’ll target this question to you, since you’re doing the transplants. Have you noticed any difference in infection, whether it’s atypical infections [such as] fungal, after transplant, or within day 100?

GALLOGLY: So far in our experience, in our center, I would say no, I haven’t. We see a large range of patients coming to us from several different physicians, and I haven’t noticed any additional types of infections or frequency, although I haven’t looked in a specifically statistical way.

GIRNIUS: Is anybody adding IVIG [intravenous immunoglobulin] for these patients once they have a hypogammaglobulinemia?

KUMAR: Not unless they have a recurrent infection.

GALLOGLY: I haven’t had issues with recurrent infections, so I haven’t added IVIG.

KUMAR: I have heard varied recommendations. What do you do in this situation? Most of the patients with daratumumab have low immunoglobulin G.

GIRNIUS: I use a lot of daratumumab-VRd. I’ve used a lot of daratumumab with other regimens, and I agree, you see these patients with immunoglobulins of 200 mg/dL, neutrophil counts of 1.9 × 10⁹/L, 1.2 × 10⁹/L, lymphocyte counts [low], and the vast majority of them don’t have any significant complications. All of a sudden, when I was seeing patients, and I’ve had patients with bispecifics, and before their immunoglobulin goes below 400 mg/dL, they’re having Pseudomonas infections, the trials are showing Pneumocystis jirovecii pneumonia, adenovirus, and so forth.

I haven’t had issues with daratumumab [like] I’ve had with bispecifics, so…I would follow what everybody else has done. Post transplant, I haven’t seen any more opportunistic infections.

DISCUSSION QUESTION

• What are the available treatment options for patients with transplant-eligible multiple myeloma in the consolidation and maintenance setting?

GIRNIUS: Does anybody do 2 cycles of consolidation [with] triplets or quadruplets before going to maintenance, or do you tend to go just to maintenance, or do you listen to what the transplant center says?

GALLOGLY: Typically after transplant, I’ve gone straight to maintenance.

ARORA: I would listen to the transplanter’s recommendations, talk with them personally, and whatever they suggest, we follow.

GALLOGLY: We don’t do it routinely. I had the same question… whether anyone has actually compared with and without that consolidation, because we typically will go right to maintenance, but we sometimes do get an IMiD [immunomodulatory drug] and daratumumab approved as maintenance, as most patients will have a little bit of residual disease that we can measure. As long as we see that there’s still disease there, we’re able to get both of them. We have a lot of patients for whom we’ve given IMiD plus daratumumab in the maintenance setting, following the GRIFFIN trial.

GIRNIUS: In the maintenance setting, then, what do you typically use for maintenance?

KNAPP: In the maintenance setting, I’m typically using lenalidomide when I’ve given VRd initially. In a couple of patients, I’ve given D-VRd; I have tried to use daratumumab with lenalidomide, and so far I haven’t had any trouble getting it. In the past, I have used bortezomib on a couple of higher-risk patients.

GIRNIUS: Has anybody used ixazomib [Ninlaro]?

VISWANATHAN: I have had a patient on pomalidomide [Pomalyst] and ixazomib. The patient had a high-risk disease and was very young. But it was on the recommendation of the transplant team.

GALLOGLY: I guess that [it may be used] when patients can’t get insurance coverage for the lenalidomide, or they have intolerance.

GIRNIUS: In what situation do you use 2-drug maintenance?

MAITI: I have used Rd in a patient who we induced with D-VRd [and] the 2-drug bortezomib and lenalidomide maintenance in a high-risk patient after transplant.

GIRNIUS: Is anybody else using 2-drug maintenance?

ARORA: Occasionally [I use] lenalidomide-dexamethasone, but nothing else.

KHAN: I have used lenalidomide-bortezomib in a patient with a 4;11 translocation.

GIRNIUS: I presented you some data for high-risk genetics based on the FORTE trial [NCT02203643]. Does that change anybody’s approach when you look at cytogenetics, to make you consider using 2-drug vs 1-drug therapy?

ARORA: If there’s amplification of 1q along with…other high-risk cytogenetics, the data are for using 2 drugs as opposed to 1 drug.

MAITI: Yes, I think the data would persuade me to use 2 drugs with high-risk cytogenetics.⁴ What I found interesting is that in the previous trial, the [IFM/DFCI2009 trial (NCT01191060)], although, with the transplant, the MRD [minimal residual disease] negativity was higher…and the PFS [progression-free survival] was higher, it didn’t quite translate into OS [overall survival].⁵ Would you expect the higher MRD [undetectable status] to translate to higher OS?

GIRNIUS: A lot of trials have demonstrated that high rates of MRD correlate with overall survival. This is across different drug types, and this is across different lines of therapy as well. I’m not involved in any discussion with the FDA, but some of my mentors in the past are, and I know there’s a push of trying to use MRD negativity, or, more importantly, sustained MRD negativity, as a surrogate for OS.

MAITI: But in this particular trial…it did not translate to OS, right?

GIRNIUS: It did not, but it was also 10^-5 [sensitivity].⁵ And in the United States, we use more 10^-6, so I think that’s one of the criticisms. This was [from] the French trials, [where] they ended up using multicolor flow [cytometry], and that can detect a 10^-5 [MRD].

_REFERENCES

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_{2. FDA approves daratumumab for multiple myeloma ineligible for autologous stem cell transplant. FDA. June 28, 2019. Accessed October 31, 2023. https:// tinyurl.com/245tvktd}

_{3. 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}

_{4. Mina R, Musto P, Rota-Scalabrini D, et al. Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial. Lancet Oncol. 2023;24(1):64-76. doi:10.1016/S1470-2045(22)00693-3}

_{5. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;136(suppl_1):39. doi:10.1182/blood-2020-134538}