FAQs on the Use of BCMA-Targeted Therapies for Relapsed or Refractory Multiple Myeloma

BCMA-targeted agents are an important novel treatment approach for our patients with relapsed/refractory (R/R) multiple myeloma (MM). BCMA is expressed on late memory B cells and cells committed to becoming plasma cells or mature plasma cells, and it plays an important role in the survival of long-lived plasma cells. However, BCMA also is expressed on MM tumor cells and is an important survival mechanism for these malignant plasma cells. Currently, 2 anti-BCMA–targeted therapies are approved by the FDA for the treatment of patients with R/R MM. Belantamab mafodotin is a BCMA-directed antibody–drug conjugate (ADC) approved for patients who have received at least 4 previous therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug (IMiD). Idecabtagene vicleucel is a BCMA-directed CAR T-cell therapy approved for patients who have received at least 4 previous lines of therapy, including an IMiD, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Many additional anti-BCMA–targeted therapies are under investigation for R/R MM.

In this commentary, Sagar Lonial, MD; Suzanne Lentzsch, MD, PhD; and Thomas G. Martin, MD, answer questions on the management of R/R MM with BCMA-targeted agents that were submitted by an audience of healthcare professionals during a recent live Clinical Care Options webinar.

BCMA Antibody–Drug Conjugates

Do you have any advice for using belantamab mafodotin?

Sagar Lonial, MD:
Belantamab mafodotin received accelerated FDA approval based on data from the phase II DREAMM-2 trial. In my clinical practice, I consider belantamab mafodotin for patients who are older or frailer, particularly those who may require immediate treatment and who cannot afford to wait 4-6 weeks for CAR T-cell production and administration. I also consider belantamab mafodotin for patients who do not want to be hospitalized or undergo the chemotherapy associated with CAR T-cell therapy.

Suzanne Lentzsch, MD, PhD:
Although belantamab mafodotin can be a good option for some of our patients, ocular toxicity can be a problem with this therapy. The ocular toxicity associated with belantamab mafodotin is typically not permanent, but it is something that should be followed closely and managed immediately to minimize long-term effects and ensure that it does not become debilitating for the patient.

Despite this risk of ocular toxicity, belantamab mafodotin is an effective therapy. For example, I had a patient who discontinued belantamab mafodotin after 2 or 3 cycles due to ocular toxicity, and we chose to restart their prior maintenance therapy to maintain the disease remission achieved with belantamab mafodotin. Over the next 6 months, the patient continued to respond. That means we are seeing ongoing responses for up to several months after discontinuing belantamab mafodotin in some patients. So, I would say do not give up too early and have a bit of patience when patients experience adverse events (AEs) with belantamab mafodotin.

Thomas G. Martin, MD:
I use belantamab mafodotin in patients who have experienced disease progression on anti-CD38 antibody therapy and have become triple class refractory. Although ocular toxicity can be problematic for some patients, I recommend that patients try at least 1 dose because the ocular toxicity associated with belantamab mafodotin typically occurs after the second or third dose. Therefore, we can give 1 dose to determine whether there is any anti-MM effects and if there is an initial response, I recommend continuing therapy with belantamab mafodotin. Some patients can have potent responses and we can see the level of light chains drop by 60% to 80% after 1 dose. Then, if ocular toxicity or other AEs do occur, we can dose reduce and/or lengthen the time between doses and patients can generally continue on belantamab therapy.

Sagar Lonial, MD:
That’s a good point—to not feel like you have to dose every 3 weeks. Some of my long term responders receiving belantamab mafodotin are patients who have had more than 1 grade 2 AE, and we have to periodically hold belantamab mafodotin doses until resolution to grade 1 but have had deep responses of more than 1 year in duration. For some patients with repeated AEs, we eventually decided on dosing every 6 weeks, and that has worked out well. In general, I tend to favor lower doses of some therapies over a longer period of time, with the idea that maybe patients will experience a longer response if you keep them on a better dose for a longer time.

Could belantamab mafodotin be used as a bridge to CAR T cell therapy?

Thomas G. Martin, MD:
Many CAR T-cell studies exclude patients with prior BCMA therapy, and because belantamab mafodotin targets BCMA, we don’t really know how therapy with this agent would affect subsequent CAR T cell therapy. However, these 2 therapies work through different mechanisms of action: belantamab mafodotin is an ADC resulting in toxin-mediated cell death vs T-cell–mediated killing with CAR T-cell therapy. At my institution, we have cases where patients who have previously received belantamab mafodotin have then received CAR T-cell therapy, and they have had nice responses. With the approval of idecabtagene vicleucel, I have used belantamab mafodotin for 2-4 doses for some patients while awaiting a manufacturing slot for CAR T-cell therapy.

Suzanne Lentzsch, MD, PhD:
I agree. Most patients currently receive CAR T-cell therapies in clinical trials because of limited manufacturing slot assignments. Sometimes we have to give patients whichever treatment is available, but belantamab mafodotin would not be my first choice because I am concerned that this would hinder the efficacy of CAR T-cell treatment by exhausting the target BCMA. Currently, I avoid using belantamab mafodotin as a bridge for CAR T-cell therapy. It might make sense, but we do not yet have the data for this approach.

Sagar Lonial, MD:
We have used belantamab mafodotin as a bridge once or twice. For my patients, I feel that it is better to use whatever salvage therapy is available vs not being able to get a patient on CAR T-cell therapy because the perfect salvage therapy is not available. We had a similar question when other agents—such as pomalidomide or daratumumab—were first approved, but we did not have as many options. Overall, I agree with both of my colleagues: We do not have definitive data to guide us, but sometimes patients may not have other treatment choices, and treating with something is better than treating with nothing.

CAR T-Cell Therapy

Ciltacabtagene autoleucel and idecabtagene vicleucel both may be approved soon. How are you going to decide which to use?

Sagar Lonial, MD:
The BCMA-targeted CAR T-cell therapy idecabtagene vicleucel received approval on the basis of results from the phase II KarMMa trial, with impressive results for R/R MM. Currently, I consider idecabtagene vicleucel for treatment of patients who are younger, who are more fit, and who can wait for the manufacture of the CAR T‑cells, with or without bridging therapy. Cytokine-release syndrome (CRS) and neurotoxicity are the most significant AEs associated with idecabtagene vicleucel but are typically grade 1-2 and only rarely grade 4.

Ciltacabtagene autoleucel is not yet approved but currently under review for FDA approval based on the phase Ib/II CARTITUDE-1 study. The response rate was 98% in patients receiving ciltacabtagene autoleucel, but nearly all patients had some degree of CRS (94.8%), with almost all being low grade.

Thomas G. Martin, MD:
For me, once both CAR T-cell modalities are approved, the decision will mostly come down to timing of CRS and the management of AEs. If I have a patient who can receive fludarabine and cyclophosphamide as lymphodepleting chemotherapy and their CAR T cell therapeutic in an outpatient setting, I would consider ciltacabtagene autoleucel because it has a slightly longer median time to onset of CRS (approximately 7 days). I can keep them in the outpatient setting for the first 7-8 days before moving to a hospital setting for 1 week to monitor for and manage any potential CRS.

If a patient is coming from afar or has to be hospitalized during lymphodepletion chemotherapy with fludarabine and cyclophosphamide, I would recommend idecabtagene vicleucel because the median time to onset of CRS is shorter, usually occurring between Day 1 and 3 and a median duration of CRS of 5 days, so by Day 7-10, patients can typically be discharged from the hospital and followed in the outpatient setting. So, those are some of the strategies we’re going to follow for choosing 1 CAR T-cell therapy vs the other.

Is the manufacturing slot availability shortage to engineer CAR T-cells a short term problem? Will it continue if ciltacabtagene autoleucel also is approved?

Thomas G. Martin, MD:
Limited slot availability has been problematic, and many patients are awaiting this important therapy across the country. We're hoping that as more CAR T-cell products become available and as these CAR T-cell products get further from their initial approval, manufacturing slots and access will improve. I think that there will likely be some initial slot limitations with ciltacabtagene autoleucel, similar to what is currently happening with idecabtagene vicleucel, due to FDA mandates. Once we know that the commercial manufacturing and product performance is as expected, I hope that additional slots will open quickly. We certainly have plenty of patients waiting for this therapy, and we need better throughput for sure.

Anti-BCMA Bispecific T-Cell Engagers and Bispecific Monoclonal Antibodies

How do the BCMA-targeted bispecific antibodies compare with one another?

Sagar Lonial, MD:
Bispecific antibodies are engineered antibodies that can target anti-CD3 on T-cells and, in the case of MM, BCMA on the MM cell. The effect is to bring the MM cell in proximity with T-cells and to activate the T-cells for an anti-MM response. Multiple anti-BCMA bispecific antibodies currently are under investigation in R/R MM, and I don’t think we have enough data to make a comparison.

Suzanne Lentzsch, MD, PhD:
I also think it is too early to compare these agents. It is a competitive landscape, and I shy away from comparing bispecific antibodies, especially with phase I data only. But, I think subcutaneous dosing with teclistamab, elranatamab, and talquetamab is advantageous for patients while some agents require administration every 2 weeks instead of weekly, for instance. As we learn more about these agents, we will begin to understand if differences in manufacturing or the structure of each bispecific antibody results in differences in efficacy and/or safety.

How do the anti-BMCA bispecific antibodies compare with anti-BCMA CAR T-cell therapy? Which do you think will have a larger impact on the treatment of MM?

Suzanne Lentzsch, MD, PhD:
Once anti-BCMA bispecific antibodies are approved, I would likely use them for frailer patients. For younger, fitter patients, I would likely still use a CAR T-cell therapy. The CAR T cells are exciting in that they are administered only once with the hope of inducing a long term remission, whereas the current trials with bispecific antibodies use a continuous treatment modality until disease progression.

Thomas G. Martin, MD:
Once approved, I think the throughput and access to the bispecific antibodies will be better than for CAR T-cell therapy and bispecific antibodies can and will be used by local doctors before a patient is referred to a CAR T cell center. Many more patients may be able to get bispecific antibody therapy vs CAR T-cell therapy in general, especially if we continue to have a shortage of manufacturing slots.

However, I do think that we may eventually have a patient undergo CAR T-cell therapy and then use bispecific antibody therapy as maintenance to eliminate measurable residual disease after CAR T-cell therapy, especially if the patient has not achieved a stringent complete response after the CAR T-cell therapy. I think this would be a perfect time to use a bispecific antibody aimed at a different cell surface target. Overall, I think we will be using all of these anti-BCMA modalities in concert for many of our patients with MM, hopefully with improved success.

In a community-based setting, how likely are we to be able to give a bispecific antibody in our office with the variable history or timing for CRS and neurotoxicity?

Suzanne Lentzsch, MD, PhD:
I have experience with bispecific antibodies in clinical trials, and many patients have no CRS, but I did experience a few patients who developed CRS that was severe enough to require tocilizumab.

Based on my current experiences, I would favor giving the first and second dose of a bispecific antibody in an inpatient setting or giving the agents in the morning and having the patient at the clinic for observation during the day. Remember, many of our patients with MM are frail, and we might recommend a bispecific antibody because the patient is too frail for CAR T-cell therapy, so observation after administration of a bispecific antibody is an important aspect of care.

There also will be a learning curve, as with any new class of agents. In the beginning, we might be more likely to admit a patient for potential CRS and neurotoxicity after a bispecific antibody, especially if they are older and frail, until we know more about how to best manage these AEs. With more experience we might be able to administer these bispecific antibodies in all patients in an office setting.

Thomas G. Martin, MD:
I agree. Bispecific antibodies also are being tested in breast cancer and prostate cancer. Once these agents are approved in multiple cancers, every oncologist will want to use them and have that same type of learning curve because more patients are going to need them.

Sagar Lonial, MD:
The advantages of the bispecific antibodies are that they can be used off the shelf, they are highly effective, and they can eventually be given in the outpatient setting. But one of the challenges we’ve seen both with CAR T-cell therapies and bispecific antibodies is profound immunosuppression from blocking BCMA. This immunosuppression, which may or may not be related to patients having numerous prior lines of therapy, leads to unusual infections, viral and otherwise.

Thomas G. Martin, MD:
Yes, I think healthcare professionals who treat patients with these agents should get comfortable working closely with their infectious disease colleagues. If patients develop infections, fevers, or other signs of unusual infections, consults with infectious disease colleagues are appropriate and infectious disease specialists can help provide guidance on managing these infections in our immunosuppressed patients.

Do you believe a second BCMA-targeting agent could be effective after relapse on another BCMA-targeted agent?

Suzanne Lentzsch, MD, PhD:
We do not have enough data to answer that question because most of the treatments, including CAR T-cells and bispecific antibodies, excluded prior BCMA-targeted treatment. However, there are some anecdotal data for a few bispecific antibodies showing responses, including complete responses and very good partial responses, in patients with prior BCMA therapy.

Thomas G. Martin, MD:
One important caveat of this question is whether BCMA is still present on the patient’s plasma cells after relapse. Complete loss of BCMA expression is unusual. There are anecdotal reports of patients receiving CAR T-cell therapy and then responding to a bispecific antibody.

In addition, because ADCs have a different mechanism of action and do not work specifically through T cell activation, giving belantamab mafodotin before or after a CAR T-cell therapy or a bispecific antibody may be reasonable, but we need additional data to prove these principles.

Sagar Lonial, MD:
I agree. Small datasets suggest that loss of BCMA occurs less than 10% of the time. At my institution, when we are retreating with a different BCMA directed therapy, we check for BCMA expression on a bone marrow biopsy before we start treatment. The test is hard to get, but it offers the comfort of knowing that the target is expressed. This is different from CD19, where loss of CD19 is a major mechanism of drug resistance.

Do you believe that talquetamab and cevostamab, having novel mechanisms of action and targets, will have the advantage of being more versatile agents?

Suzanne Lentzsch, MD, PhD:
Talquetamab and cevostamab are bispecific antibodies that target GPRC5D and FcRH5, respectively, and the hope is that they can be used for patients with resistance to anti-BCMA therapy.

My concern is that patients might not have enough active T-cells to engage in the antitumor effect after multiple lines of therapy that harness T-cells for activity. I may not go from one bispecific antibody to another right away but would switch treatment—for example, using an IMiD to activate the T-cells—before going back to another bispecific antibody.

Sagar Lonial, MD:
I agree. I think IMiDs do have the ability to potentially overcome some the T-cell exhaustion that may be a mechanism of resistance to an anti-BCMA bispecific antibody therapy or CAR T-cell therapy. In addition, the CELMoD iberdomide is a more potent immune activator and might be a good potential option in the case of T-cell exhaustion.

How are you dealing with the tocilizumab shortage?

Thomas G. Martin, MD:
The shortage of tocilizumab is a real issue. I hope there will be some ways to increase the rate of manufacturing of tocilizumab in the near future. In the meantime, at my institution, we are trying to give a single dose of tocilizumab early on for grade 1 CRS to try to mitigate symptoms right away. Then, if the patient has persistent fevers, we put them on steroids rather than giving additional doses of tocilizumab. In practice, I actually have not seen much of a difference, because 1 dose of tocilizumab has been our median number in patients with MM even before the shortage.

Sagar Lonial, MD:
Siltuximab is another option to help manage CRS for patients. It binds to interleukin-6 itself, instead of the interleukin-6 receptor, so it may be able to be used in place of tocilizumab or for patients who are refractory to tocilizumab.

Suzanne Lentzsch, MD, PhD:
Yes, we discuss it with our pharmacy, because we have run into that problem with the shortage of tocilizumab even for clinical trials. So, we agreed that siltuximab would be an approved alternative.

Your Thoughts?
What questions do you have about managing R/R MM with BCMA-targeted agents in your clinical practice? Please answer the poll and post your thoughts and questions in the discussion box below.