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Experts Answer Pressing Questions on Recent Advances in Treatment of Relapsed/Refractory Multiple Myeloma

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: researcher: Bristol-Myers Squibb/Celgene, Karyopharm, Oncopeptides, Takeda; consultant: AstraZeneca, Bristol-Myers Squibb/Celgene, GlaxoSmithKline, Karyopharm, Novartis, Oncopeptides, Sanofi, Secura Bio, Takeda.

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Natalie S. Callander, MD

Professor of Medicine
School of Medicine and Public Health
University of Wisconsin
Director, Myeloma Clinical Program
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin

Natalie S. Callander, MD, has no relevant financial relationships to disclose.

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Noopur Raje, MD

Director, Center for Multiple Myeloma
Massachusetts General Hospital Cancer Center
Professor of Medicine
Harvard Medical School
Boston, Massachusetts

Noopur Raje, MD: researcher: 2seventy bio; consultant/advisor/speaker: Amgen, Bristol-Myers Squibb, Bluebird, Caribou Biosciences Celgene, GlaxoSmithKline, Immuneel, Janssen, Merck, Millennium, Novartis, Pfizer, Sanofi, Takeda.

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Released: August 18, 2022

Key Takeaways

  • The potential for delayed neurotoxicity and immune effector cell-associated neurotoxicity syndrome is an on-target toxicity of BCMA-targeted CAR T-cell therapy that correlates with disease burden
  • Patients with multiple myeloma treated with anti-CD38 antibodies or some of the BCMA targeting strategies may have diminished responses to the COVID-19 vaccine, and additional strategies should be implemented to prevent SARS-CoV-2 infection and promptly treat any infections that occur

In this commentary, Paul G. Richardson, MD; Natalie S. Callander, MD; and Noopur Raje, MD, answer pressing audience questions regarding the efficacy and safety of approved and investigational treatments for relapsed or refractory (R/R) multiple myeloma (MM) from a recent symposium titled, “Advances in Relapsed/Refractory Myeloma: Keeping Pace With a Rapidly Evolving Treatment Landscape” presented during the 2022 American Society of Clinical Oncology Annual Meeting.

Is B-cell maturation antigen (BCMA) expressed in the brain, and how does that relate to the delayed neurotoxicity seen in patients treated with BCMA-targeted agents?

Noopur Raje, MD:
As additional agents are developed that target BCMA, we are seeing more patients who are developing delayed neurotoxicity. This is an on-target toxicity because BCMA is expressed in the basal ganglia and the caudate nucleus; this is why patients develop a parkinsonian-like syndrome.

The phase Ib/II CARTITUDE-1 study (NCT03548207) looked at the safety and efficacy of ciltacabtagene autoleucel CAR T-cell therapy in patients (N = 97) with R/R MM. In the CARTITUDE-1 trial, 20.6% of patients developed immune effector cell-associated neurotoxicity syndrome (ICANS), and 12.4% developed other neurotoxicities that included movement and neurocognitive changes, nerve palsy, and peripheral motor neuropathy. These additional neurotoxicities occurred after the resolution of cytokine-release syndrome and/or ICANS.

Over time, we’ve developed mitigation strategies for CAR T-cell therapy–induced neurotoxicities, such as reducing the tumor burden in patients prior to CAR T-cell therapy. We've consistently seen that if patients have very high tumor burdens, they are more likely to develop early ICANS, and they can then go on to develop delayed neurotoxicity.

The good news is that in follow-up studies like the phase II CARTITUDE-2 trial (NCT04133636) and others, we haven't seen much delayed neurotoxicity. There has been one case in CARTITUDE-2, and we have seen it rarely with idecabtagene vicleucel. It is something for all of us to watch out for, although it is our hope that as we move these treatments closer to the frontline, we are going to be able to mitigate this even more.

Is the ocular toxicity seen with the antibody–drug conjugate belantamab mafodotin treatment an on-target or off-target effect?

Paul G. Richardson, MD:
Ocular toxicity, including keratopathy and blurred vision, seen with belantamab mafodotin treatment is an off-target effect, and the toxicity does not seem to be BCMA dependent. The cause of the ocular toxicity/corneal epithelial damage is the MMAF cytotoxic payload. 

What are your thoughts on gamma secretase inhibitors (GSIs) being used in combination with antibody–drug conjugates or CAR T-cell therapy for MM treatment?

Natalie S. Callander, MD:
One cohort of patients with R/R MM in the phase I/II DREAMM-5 study (NCT04126200) are receiving belantamab mafodotin in combination with the GSI nirogacestat. Patients in this dose-expansion cohort are receiving low-dose belantamab mafodotin, 0.95 mg/kg every 3 weeks, with nirogacestat 100 mg twice daily continuously. In preliminary results, the response rate with this combination was 60%, and 20% of patients had a very good partial response. Treatment was reasonably well tolerated. Seventy percent of patients experienced an ocular event, diarrhea, or hypophosphatemia. In most cases, these adverse events were grade 1/2; 10% of patients experienced grade 3 diarrhea, hypophosphatemia, or keratopathy and 20% experienced other grade 3 ocular toxicities.

At the 2021 American Society of Hematology annual meeting, we saw results of a trial combining CAR T-cell therapy with the GSI JSMD194 given 5 days prior to CAR T-cell infusion and then 3 times a week for 3 weeks in combination with CAR T-cells. The GSI treatment caused an increased BCMA surface density on plasma cells. Such a dosing strategy may help manage the toxicity associated with GSI administration.

If you have a patient with R/R MM with whom 3 drugs have failed, should you move to quadruplet therapy? 

Natalie S. Callander, MD:
To answer this, we would need to know exactly what is happening with the patient. Is the patient really sick from MM, and is the provider really worried? Jumping to quadruplet therapy may not be the solution in all situations. It is difficult to make blanket statements about the best thing to do. If the patient hasn’t had an autologous stem cell transplant, I would suggest that as salvage therapy, particularly for early relapse.

Why is less neurotoxicity seen with the combination of selinexor and bortezomib compared with bortezomib alone?

Natalie S. Callander, MD:
The phase III BOSTON study (NCT03110562) compared the safety and efficacy of selinexor plus bortezomib and low-dose dexamethasone (weekly) vs bortezomib plus low-dose dexamethasone (twice weekly) in adult patients with R/R MM. Patients receiving selinexor plus bortezomib/dexamethasone weekly had a significantly reduced risk of peripheral neuropathy than those receiving bortezomib/dexamethasone twice weekly (any grade: 32.3% vs. 47.1%; grade 3/4: 4.6% vs. 8.8%).

It is believed that a decrease in dosing frequency, particularly for bortezomib, may be responsible for the decrease in neuropathy, although it is unknown whether selinexor is really delivering a protective effect. Most of the focus has been on the toxicity that selinexor brings, but we don’t know if it can modulate the effects of other drugs. This will become clearer as we test combination regimens. What we do know is that selinexor has many effects at the cellular level.

Paul G. Richardson, MD:
It is very interesting because we know selinexor has anti-inflammatory effects, and we do know that a proportion of the neurotoxicity associated with bortezomib is inflammatory. It may be that some modulation of the inflammatory cascade is playing a role.

Beyond cell therapy and bispecifics, is there still a role for targeted small molecules?

Noopur Raje, MD:
I don’t think they’re mutually exclusive. I will tell you that some of our patients who have received CAR T-cell therapies are relapsing, and we are performing studies with the cereblon E3 ligase modulators iberdomide and CC-92480. The advantage of the cereblon E3 ligase modulators is that these drugs are easy to combine with other agents. They already are being combined with the usual proteasome inhibitors and with monoclonal antibodies. There is a lot of potential for their use in combination with cell therapies as opposed to thinking about them as only for use as single agents.

Natalie S. Callander, MD:
I agree that we will see more combinations with small molecules. I think we’ve just scratched the surface with venetoclax in patients with MM and translocation t(11;14). There were some great data from a phase II trial (NCT02899052) looking at safety and efficacy of venetoclax plus carfilzomib/dexamethasone in patients (N = 49) with R/R MM, including 13 with translocation t(11;14). The overall response rate was 80%, and median progression-free survival was 22.8 months. Treatment-emergent adverse events included diarrhea (65%), nausea (47%), fatigue (47%), and lymphopenia (35%). 

Paul G. Richardson, MD:s?
I’ve always felt it is important to take advantage of all our useful therapeutic tools. Small molecules are especially important, as is fully recognizing the potential of immunotherapy and cellular approaches. In my experience, venetoclax has been a game changer in the right setting. It’s not yet FDA approved in the R/R MM setting, but there has been success with its off-label use to treat patients with translocation t(11;14), as well as in the setting of clinical trials.

How can we get better at predicting and/or managing toxicity with novel therapies?

Natalie S. Callander, MD:
As newer agents come in, we get a whole new round of toxicities that we perhaps didn’t imagine. It is the same when trying new combinations of existing drugs; sometimes, you’re pleasantly surprised when there seems to be less toxicity (eg, selinexor plus bortezomib).

I would say that perhaps we underestimate toxicity. What patients complain about most in studies isn’t nausea and vomiting; rather it is fatigue. I have no solution to that, except for perhaps exercise or diet, but there is a real unmet need to address toxicity from a patient perspective.

Paul G. Richardson, MD:
To be fair, I also think the challenge is that we are driven to maximize dose to generate single-agent activity. We’re almost starting from the wrong end of the spectrum. Perhaps, as we think about innovative trial designs and work with our regulatory partners, we can consider starting low and increasing the dosage without necessarily reaching the levels of toxicity that we may otherwise encounter. However, we obviously need to achieve efficacy. That being said, it is often true that less is more, especially when agents are being used in combination.

Natalie S. Callander, MD:
I’m very excited about studies, like the MASTER trial (NCT03224507), that are underway that are going to try to limit therapy. In the MASTER trial, the duration of therapy is measurable residual disease (MRD) response adapted, and patients who achieve MRD-negative status will discontinue therapy and have no maintenance therapy. In turn, they will be monitored for MRD and relapse. I think that is what patients would like, and although it won’t be the answer for every patient, there may be some that we can take off treatment and do it rationally.

We may get to the point where we can monitor circulating tumor DNA and realistically take a patient off treatment for 2 or 3 years. We are hoping that this could be a strategy we can use at least in a subset of patients.

What responses to COVID vaccination and antiviral therapy are you seeing by patients with R/R MM?

Noopur Raje, MD:
It is very important that our patients get vaccinated against SARS-CoV-2. There is no downside to vaccination, even when we don’t know how much of an antibody response our patients will mount.

We have learned that the greatest predictor of how well patients with R/R MM did post COVID-19 was how well controlled their MM was. After immunizing patients with MM for SARS-CoV-2, we then use other supportive strategies if they do not mount an immune response. We found that more than 60% of patients with MM do mount an immune response to COVID-19 vaccination, specifically those who are in a complete response on an immunomodulatory drug. Patients treated with drugs like daratumumab or some of the BCMA-targeting strategies don’t necessarily mount a robust response.

Natalie S. Callander, MD:
Patients who have received daratumumab are some to be a bit more worried about in terms of COVID-19. For this reason, we do try to get them tixagevimab plus cilgavimab to prevent SARS-CoV-2 infection, and we are very aggressive with their dosing of nirmatrelvir plus ritonavir if they do get infected.

Paul G. Richardson, MD:
I would add that in my experience with nirmatrelvir plus ritonavir, I’ve found the need to repeat courses because sometimes the 5-day course isn’t enough for certain patients, depending on what else they are being treated with. We occasionally need 10 days with nirmatrelvir plus ritonavir to fully suppress the virus.

What is your take on the targeting of BCMA and the associated lack of antibody response to COVID-19 vaccines?

Noopur Raje, MD:
Most of what we are doing with bispecific antibodies and CAR T-cell therapy is targeting BCMA. By manipulating the immune system in this way, not only are we getting rid of MM cells, but we also are getting rid of normal plasma cells. Unfortunately, these patients essentially end up with B-cell aplasia, and they tend not to develop antibodies to the COVID-19 vaccine.

With both bispecific antibodies and CAR T-cell therapy directed against BCMA, what we have been using all along is intravenous immunoglobulin replacement. I think the judicious use of tixagevimab plus cilgavimab in patients who do not mount an antibody response to the COVID-19 vaccine is quite critical. Some of the early COVID-19 deaths that we saw in patients receiving bispecific antibodies came during the surge at the beginning of the pandemic when we didn’t have other tools available.

The use of drugs like nirmatrelvir plus ritonavir and tixagevimab plus cilgavimab hopefully will minimize issues, but because we are targeting plasma cells, the problem of not mounting an antibody response is real.

Your Thoughts?
What challenges do you experience when treating patients with novel therapies for R/R MM? Answer the polling question and join the conversation in the discussion box below.

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Supported by educational grants from
AbbVie Inc.
Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC
Karyopharm Therapeutics
Regeneron Pharmaceuticals, Inc.

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