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The Paradox of Choice: Experts Address Critical Questions for Selecting and Sequencing Therapy for Patients With R/R MM

Paul G. Richardson, MD
Program Director

R. J. Corman Professor of Medicine
Harvard Medical School
Clinical Program Leader
Director of Clinical Research

Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Boston, Massachusetts

Paul G. Richardson, MD, has disclosed that he has received funds for research support from Bristol-Myers Squibb/Celgene, Karyopharm, Oncopeptides, and Takeda and consulting fees from AstraZeneca, Bristol-Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Protocol Intelligence, Regeneron, Sanofi, Secura Bio, and Takeda.

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Nina Shah, MD

Professor of Clinical Medicine
Division of Hematology-Oncology
Department of Medicine
University of California, San Francisco
San Francisco, California

Nina Shah, MD, has disclosed that she has received funds for research from Bluebird Bio, Celgene/Bristol-Myers Squibb, Janssen, Nektar, Poseida, Precision Biosciences, Sutro Biopharma, and TeneoBio and consulting fees for an advisory role from Amgen, CareDx, CSL Behring, GlaxoSmithKline, Indapta Therapeutics, Karyopharm, Kite, Oncopeptides, and Sanofi.

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Peter M. Voorhees, MD

Director, Medical Operations and Outreach Services
Department of Hematology/Oncology
Levine Cancer Institute
Charlotte, North Carolina

Peter M. Voorhees, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Novartis, Oncopeptides, and Secura Bio and has served on the Advisory Board for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Pfizer, and Sanofi.

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Released: August 19, 2021

There is a very exciting array of treatment options currently available for patients with multiple myeloma, calling for careful consideration on how to sequence and strategize therapies to ensure the best outcome for patients. These decisions are becoming an increasingly complex but also arguably very rewarding task, recognizing the real challenges of managing relapsed refractory disease. In this commentary, Paul G. Richardson, MD; Peter M. Voorhees, MD; and Nina Shah, MD, address this important topic.

How should healthcare professionals incorporate anti-CD38 monoclonal antibodies in clinical practice?

Peter Voorhees, MD:
The treatment for relapsed or refractory (R/R) multiple myeloma (MM) is going to change as we incorporate newer therapies into clinical practice. Commonly, patients with R/R MM have been previously treated with an immunomodulatory drug (IMiD)/proteasome inhibitor (PI)–based induction therapy and progress on or after lenalidomide maintenance therapy. Barring any exclusions due to medical history, I would treat this type of patient with an anti-CD38 monoclonal antibody (mAb) in combination with carfilzomib and dexamethasone (Kd) based on data from the phase III CANDOR trial of daratumumab (Dara) plus Kd vs Kd in patients with R/R MM who received 1 to 3 previous lines of therapy. I was struck by the improvement in progression-free survival (PFS) in patients with lenalidomide-refractory disease with the triplet compared with Kd (HR: 0.47; 95% CI: 0.29-0.78).

Nina Shah, MD:
I agree. It is hard to ignore the data with the combination of a PI and an anti-CD38 mAb; the PFS is remarkable in both the CANDOR trial with Dara plus Kd vs Kd and in the IKEMA trial with isatuximab (Isa) plus Kd vs Kd. However, many of us also use an anti-CD38 mAb in combination with pomalidomide and dexamethasone (Pd), because it is convenient. But, even though it is a cross-trial comparison, the median PFS in the APOLLO trial with Dara-Pd was 12.4 months vs 28.6 months seen in CANDOR with Dara-Kd. Similarly, the median PFS in the ICARIA-MM trial with Isa-Pd was 11.53 months vs not yet reached in IKEMA with Isa-Kd. Based on these data, I think we may improve our patients’ outcome by starting with an anti-CD38 mAb plus Kd, even though it requires IV administration.

Paul Richardson, MD:
I agree with this assessment as well. For patients who acquire high-risk cytogenetic abnormalities, such as del(17p), and had received daratumumab as a part of frontline therapy, would that influence your choice? Would you consider isatuximab at relapse in that scenario?

Peter Voorhees, MD:
For patients who received daratumumab-based induction therapy followed by lenalidomide maintenance therapy, I would consider them to be daratumumab or anti-CD38 mAb exposed, but not refractory. In this case, I would still consider an anti-CD38 mAb combination therapy.

Nina Shah, MD:
I agree; however, we know now that using one anti-CD38 mAb after another is not necessarily beneficial in a refractory setting. To address the issue of treatment selection for patients acquiring a del(17p): In a subgroup analysis of the CANDOR trial, Dara-Kd did show a PFS benefit with Dara-Kd vs Kd in patients with high-risk cytogenetics. In a subgroup analysis of the IKEMA trial, there was also a PFS benefit with Isa-Kd vs Kd in patients with high-risk cytogenetics.

Peter Voorhees, MD:
For a patient who received daratumumab maintenance every 2 months after induction and transplant and then progressed, going to a regimen using the alternative anti-CD38 mAb may not be as effective. A phase I/II trial of 32 patients who received isatuximab with or without dexamethasone after progression on previous daratumumab therapy showed a disease control rate of 37.5% with isatuximab and 63.6% with the addition of dexamethasone. In this study, the response signal was not very strong, with a best overall response of minimal response (MR) in 1 patient and stable disease in 17 patients.

I would favor a pomalidomide/PI/dexamethasone triplet for somebody progressing on anti-CD38 mAb maintenance.

Paul Richardson, MD: I agree. There was nothing to suggest a strong signal in that study; however, in a retrospective analysis of patients with R/R MM treated at the MD Anderson Cancer Center, 67% of patients (10 out of 15) achieved MR or better with isatuximab plus Pd given after previous daratumumab. I agree that these data should be approached with caution until we know more. In general, switching to a different class of agents would make more sense to me.

With many approved agents with a novel mechanism of action, how should healthcare professionals use anti–B-cell maturation antigen (BCMA) targeted agents in clinical practice?

Peter Voorhees, MD: Belantamab mafodotin is an antibody–drug conjugate (ADC) that targets BCMA and is conjugated to a microtubule disrupting agent, monomethyl auristatin phenylalanine. It was approved based on the randomized phase II DREAMM-2 trial for patients with R/R MM after ≥4 previous lines of therapy, including an anti-CD38 mAb, a PI, and an IMiD. In this trial, patients were heavily pretreated with a median of 7 previous lines of therapy, with 65% of the patients refractory to carfilzomib, 87% refractory to pomalidomide, and 100% refractory to daratumumab. Despite this, the overall response rate (ORR) was 31% with 2.5 mg/kg dosing, with 19% of patients achieving very good partial remission (VGPR) or better. Of importance, although the PFS in the 2.5mg/kg arm was only 2.8 months, the median duration of response was 11 months, which is similar to what was seen in the KarMMa trial with idecabtagene vicleucel.

The phase II KarMMa trial led to the recent FDA approval of idecabtagene vicleucel (ide-cel), a BCMA-targeted, CAR T-cell therapy. In this trial, 140 patients with R/R MM were enrolled if they had previously received ≥3 regimens, including regimens that contained an IMiD, a PI, and an anti-CD38 mAb, and if they were refractory to their last line of therapy. The ORR was 73% with ide-cel therapy, which is impressive in this group of heavily pretreated patients with a median of 6 previous lines of therapy, and 39% who had extramedullary disease. While the ORR is higher than with belantamab mafodotin in a similar patient population, the median duration of response was similar at 10.7 months. The median PFS with ide-cel was 8.8 months.

When selecting between these 2 anti-BCMA targeted therapies, one thing that I highlight is the adverse event (AE) profiles of each agent. For belantamab mafodotin, ocular toxicities, particularly keratopathy, was seen in 71% of patients, but not all those patients experienced clinical symptoms related to this keratopathy. Of these patients, 22% had blurred vision, and 14% of patients had dry eyes. Fortunately, this appears to be a reversible toxicity, but not surprisingly, keratopathy was the most common cause for dose delays, which occurred in 47% of patients, as well as dose reductions in about a quarter of the patients.

For ide-cel, 84% of patients experienced cytokine release syndrome (CRS), but the majority of these were grade 1 and 2 in severity. Neurotoxicity also occurred in 18% of patients who received ide-cel. In addition, hematologic toxicity is common with ide-cel but resolves over time, and infections occurred in 70% of patients, as you would expect in this patient population, but only 27% of patients had grade 3 or 4 infections.

If a patient is a candidate for CAR T-cell therapy, I would work toward that goal; however, I would avoid using ide-cel in frailer patients, particularly for patients with significant cardiopulmonary or neurologic disorders who would not tolerate CRS or neurotoxicity well. For a patient with severe cardiopulmonary comorbidities, ide-cel therapy would be very challenging. It is also not well suited for patients with rapid relapse who are in need of immediate therapy, unless you have a viable option to control the disease before and after apheresis for T-cells. For patients who are not good candidates for CAR T-cell therapy and do not have preexisting eye disease or specific concern regarding ocular toxicities, I think that belantamab mafodotin is an appropriate therapy.

Data on the efficacy of a BCMA-targeted strategy after progression on an alternate BCMA-targeted strategy are in evolution. I would argue that biallelic deletion of BCMA would predict resistance to all BCMA-targeted strategies. In the absence of that mechanism of resistance, I think there is a role for the use of an alternate BCMA-targeted strategy for someone who's relapsed on a different BCMA-targeted therapy.

Nina Shah, MD: Ciltacabtagene autoleucel (cilta-cel) is another BCMA-directed CAR T-cell product, which is not yet FDA approved but was studied in the phase Ib/II CARTITUDE-1 study that included 113 patients with R/R MM and at least 3 previous therapies. It is similar to ide-cel, in theory and in mechanism of action, but it does have some differences. At a median follow-up of 18 months, the ORR with cilta-cel was 98%, with the VGPR or better rate being 95%. The duration of response was 21.8 months (95% CI: 21.8-not estimable), and at an 18-month data cutoff, the overall survival was approximately 81%.

Similar to other BCMA CAR T-cell trials, 95% of patients in the CARTITUDE trial experienced a CRS event, most of which was grade 1/2, and 20% of patients had neurotoxicity.

Paul Richardson, MD:
I think ide-cel is favorable in terms of tolerability and cilta-cel is impressive in terms of efficacy. I also agree with you that it’s important to consider the toxicities of CAR T-cell therapy vs ADC therapy when choosing among anti-BCMA targeted agents.

When would you consider a selinexor-based approach for patients with R/R MM?

Peter Voorhees, MD:
Selinexor is a small-molecule inhibitor of exportin 1 approved in combination with bortezomib and dexamethasone after ≥1 previous, per the BOSTON trial, and in combination with dexamethasone after ≥4 previous therapies (including ≥2 PIs, ≥2 IMiDs, and anti-CD38 mAb), per the STORM trial.

The phase III BOSTON trial included 402 patients with R/R MM after 1-3 previous therapies and assessed treatment with bortezomib and dexamethasone (Vd) with or without selinexor. In this trial, patients were less heavily pretreated than with the other trials we have discussed, with a median of 2 prior lines of therapy and 19% of the patients having previously received 3 lines of therapy. The ORR was 76% with selinexor plus Vd vs 62% with Vd alone, and this translated into an improvement in median PFS from 9.46 months with the doublet to nearly 14 months with the triplet.

In the BOSTON trial, selinexor was administered at 100 mg once weekly with Vd compared with a dose of 80 mg twice weekly in the STORM trial with dexamethasone. When selinexor was given on a once-weekly basis, the overall rate of AEs was reduced, including hematologic AEs and gastrointestinal AEs like nausea, decreased appetite, diarrhea, and vomiting. This is important to keep in mind when you’re using selinexor in your practice.

Another trial, the phase I/IIb STOMP trial, is exploring a number of different selinexor-based triplets, including with daratumumab or pomalidomide. These data are also promising and suggest that selinexor can be successfully combined with various backbones for additional treatment options for patients with R/R MM.

I think triplet combinations using weekly selinexor dosing strategies are very active and better tolerated than selinexor/dexamethasone with twice-weekly dosing, and selinexor-based triplets can be considered as strategies to bridge to CAR T-cell therapy or for patients who may not be eligible for CAR T-cell therapy or belantamab mafodotin.

Nina Shaw, MD:
I agree. When I use selinexor in clinical practice, I use it in combination with other agents, because the weekly dosing is more tolerable than twice weekly. If a patient cannot tolerate any of those combination options, then I generally do not use selinexor. For patients who can tolerate a selinexor-based combination, I usually use it with carfilzomib/dexamethasone (off label) and some patients have a good response. There was an analysis at ASH 2020, showing that prior PI exposure did not negate the benefit of selinexor plus bortezomib plus dexamethasone in the BOSTON trial, which was very helpful information to have.  

When would you consider treatment with melphalan flufenamide for patients with R/R MM?

Peter Voorhees, MD:
Melphalan flufenamide, or melflufen, is a peptide drug conjugate with a lipophilic peptide carrier and an alkylator payload. The lipophilic peptide carrier allows it to readily traverse the cell membrane, and once inside the cell, aminopeptidases that are heavily enriched in several different malignancies, including multiple myeloma, cleave the peptide carrier off the alkylator payload, which then releases melphalan into the myeloma cell nucleus and where it alkylates the DNA and leads to apoptosis.

The phase II HORIZON trial investigated melphalan flufenamide with dexamethasone in patients (N = 157) with R/R MM and ultimately led to FDA approval of this particular regimen. In this trial, the patients all had to have ≥2 previous lines of therapy, including an IMiD and a PI, and refractoriness to pomalidomide and/or an anti-CD38 mAb. The ORR was 29% in the intention-to-treat population and 26% in patients with triple-class refractory disease. The median PFS was 4.2 months for all comers, and it was 3.9 months for those with triple-class refractory disease. In this study, the median overall survival was approximately 11.5 months.

Hematologic toxicity, including grade 3/4 neutropenia and grade ≥3 thrombocytopenia, is quite common with melphalan flufenamide, suggesting that these aminopeptidases are also in myeloid precursors. Of importance, however, with transfusion support and growth factor support, the rates of high-grade bleeding events and infection events were low, suggesting that this is a manageable toxicity.

Regarding melphalan flufenamide, I think the optimal patient is someone with alkylator-sensitive disease with good baseline blood cell counts. Patients with low counts may be more vulnerable to the hematologic toxicity with melphalan flufenamide. For a patient who has had a long remission after high-dose melphalan therapy with autologous stem cell transplant, and hasn't had an alkylating agent for many years, I think that melphalan flufenamide would be an excellent option, for a patient with good counts.

Paul Richardson, MD:
Of importance, we presented data at both ASCO and EHA showing that patients could have previous exposure to an alkylator and be responsive to melphalan flufenamide. But I think it is fair to say that, in fact, although those responses are real, our data from the alkylator-naive group are particularly impressive, and especially if patients have not had a previous transplant. However, there was recently an FDA alert stating that unpublished results of the phase III OCEAN trial suggested that there was an increased risk of death associated with melphalan flufenamide/dexamethasone vs pomalidomide/dexamethasone in patients with R/R MM after 2-4 lines of previous therapy. There is now a partial clinical hold on all trials of melflufen, and healthcare professionals should discuss the risks and benefits of continuing therapy with melphalan flufenamide with their patients.


Paul Richardson, MD:
We are now in an era where patient preference can help to dictate treatment choice in multiple myeloma. We have at least 15 options that are currently approved for this disease, and we will have probably at least 2 more coming this year, for a total of close to 20 options for treatments as we go into 2022. So patient choice clearly really matters here, and we now have the tools to meet the diverse needs of our patients.

Your Thoughts?
How is your treatment of R/R MM changing as new agents are approved? Share your challenges in the comment box below.

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