Treatment Approaches to Relapsed/Refractory Multiple Myeloma

Yi (Lisa) Hwa

Amie, thanks for joining me to discuss treatment approaches in relapsed/refractory multiple myeloma in the era of treatment advancement using CAR T-cell and bispecific antibody therapy.

CAR-T and bispecific antibodies have emerged as promising novel therapies for heavily treated patients with relapsed/refractory disease. Currently, there are few CAR-T products and three bispecific antibodies that have been granted approval by the FDA. There are also ongoing clinical trials and new bispecific antibodies being developed. In your clinical practice as an advanced practitioner, how do you counsel your patients to determine whether to do CAR-T or bispecifics? Can you share an example of how you help your patients decide on the best therapy for them?

Amie Fonder

Lisa, that’s an excellent question. It's definitely an interesting time to be treating patients with multiple myeloma because we have so many treatment options and now that we have both CAR-T and bispecific antibodies available, it can be more difficult to decide which approach is best for which patient.

I have a case to start to share. I had a 70-year-old male patient with no major comorbidities to speak of. He has a history of lambda light chain-restricted multiple myeloma, and over the course of one month, his lambda light chain increased from 4.98 mg/dL to 42.6 mg/dL. That’s quite a large jump in the disease measurement parameters in the course of just one month.

This patient has had six prior lines of therapy, including treatment with proteasome inhibitors, immune modulators, anti-CD38 antibodies, SLAMF7 inhibitors, as well as an autologous stem cell transplant. Overall, the complete blood count and chemistry labs have been stable. The patient has a history of mild renal insufficiency, which is stable. Given that we are in a state of rapid relapse, we need to make a decision for what might be the best next step for him.

Yi (Lisa) Hwa

This is a really great example. What I'm hearing is that the patients is refractory to most FDA-approved classes of medications. NCCN guidelines recommend to always consider patients for clinical trials regardless of where they are in their treatment course. So, for this patient, we first need to talk about clinical trials. However, the options, availability and eligibility requirements of clinical trials in each institution may vary.

Today we will focus on how to help the patients in choosing commercially available CAR-T vs bispecific antibody therapies. Let’s say there are no available clinical trials for this patient at his relapse and he is interested in both CAR T-cell therapy and bispecifics and he's a candidate for both therapies. How do you help this patient evaluate which therapy is the best option for him in consideration of the treatment efficacy, adverse events, and his disease status?

Amie Fonder

There's a lot to consider in choosing between CAR-T and bispecific antibodies. The first thing that I like to look at with patients are the response rates of individual therapies. The response rates and duration of response for CAR-T are a bit better than those for bispecific antibodies. There are two FDA-approved CAR T-cell therapies like you mentioned. For the Abecma product (ide-cel CAR-T), progression-free survival is about 12.2 months for all responders, which increases to 20.2 months for patients who achieve complete response or stringent complete response.

For the Carvykti product (cilta-cell CAR-T), the median progression-free survival is 34.9 months. Teclistamab and elranatamab, both anti-BCMAxCD3 bispecific antibodies, haven't been around as long so we don't have as much long-term data.

Teclistamab has data from the MajesTEC-1 trial that shows that 90.6% of patients continued to respond at 6 months and 66.5% continued to respond at 9 months. Elranatamab, with the same target as teclistamab, in a BCMA-naive cohort, had an overall response rate of 57.7% with 82.3% of those patients responding at 9 months. These data were lower if patients had received prior BCMA-directed therapy. It’s helpful that we have the data for patients who've had prior BCMA exposure. Understanding how they respond after BCMA exposure is important. And in that population there was a 33.3% overall response rate with 84.3% still responding at 9 months.

Talquetamab is an anti-GPRC5DxCD3 bispecific, which has weekly and every-other-week dosing options. The overall response rates were similar at 73% for weekly dosing and 73.6% for every-other-week dosing. The median duration of response was about 9.5 months with weekly dosing and hasn't been achieved yet with the every-other-week dosing. Response rates are important but are certainly not the only thing that would be considered when deciding between CAR-T or bispecific antibodies treatment.

Yi (Lisa) Hwa

Yes, I totally agree. The response rate, duration of response, and patient disease status are very important factors to consider when we're choosing next-line therapy. You mentioned prior BCMA exposure. This is a very important point as well. As the AP clinicians, we should always have a good understanding of a patient's treatment history because this may affect the efficacy of the next-line treatment.

In our practice we see a lot of heavily treated patients who have already received BCMA-directed therapy. Like what you have shared about the PFS data in CARTITUDE-1 trial, the median PFS is 34.9 months. However, in the data from the CARVYKTI-2 trial, a median PFS is only 5.3 months and 9.5 months respectively for those patients who had were previously treated with a BCMA-directed bispecific antibody or antibody-drug conjugate. In those patients who had prior BCMA treatment, talquetamab may be a better option rather than choosing another BCMA-directed therapy as the immediate next line of treatment.

The other important factor to consider is the safety profile. Adverse events are one of the major components we need to discuss with the patient when choosing the next line of therapy. Can you talk about what kind of safety profile data you share with your patients?

Amie Fonder

You're absolutely right. The safety profile of these types of therapies are actually quite different than the safety profiles from the older types of therapies like the proteasome inhibitors, the monoclonal antibodies, and the immune modulators.

There's a phenomenon called cytokine release syndrome where the cytokines, which are part of the body’s natural immune response to infections, can be produced in such a rapid and high quantity that fevers, rigors, or fluctuating blood pressure occurs.

There are a lot of potential physiologic manifestations of cytokine release syndrome. This is a probable outcome with either treatment modality, whether we're looking at CAR-T or whether we're looking at bispecific antibodies. There is a higher rate of cytokine release syndrome, or CRS as we refer to it, in the CAR-T protocols compared with the bispecific antibodies.

The Abecma product is 85% all-grade toxicity for CRS. There was one patient death reported in the clinical trials. The Carvykti product showed 95% of patients had some grade of cytokine release syndrome, 4% of which were grade 3/4. Again, one patient death was reported. Compared with the bispecific antibodies, teclistamab was 72% all-grade with 0.6% of those being grade 3, talquetamab was 76% all-grade with 1.5% grade 3, and elranatamab was 58% all-grade with 0.5% grade 3.

So, there's definitely a higher risk of CRS with these treatments. If you have patients you think might be more susceptible to complications from CRS, a bispecific antibody may need to be strongly considered as being safer than a CAR-T therapy. Along with cytokine release syndrome, neurological toxicity can be an issue. One neurological toxicity is ICANS, which stands for Immune Effector Cell-Associated Neurotoxicity Syndrome. ICANS is a clinical and neuropsychiatric syndrome that can occur in the days or even weeks following the administration of certain types of immunotherapies, which includes CAR-T and bispecific antibodies.

The data for CAR-T includes the all-grade neurological toxicity and ICANS separately, whereas these are reported as combined toxicity with the bispecifics. Comparing the data between CAR-T and what we have for the bispecifics is a little bit more difficult, but for example, neurological toxicity for Abecma and Carvykti were 28% and 26% all-grade respectively. ICANS, which has a specific grading system, was 23% all-grade for Carvykti, but not reported in Abecma.

The numbers that are distributed for the bispecific antibodies include ICANS within basic neurological toxicity. The numbers are similar across the three products. Teclistamab was 57% all-grade, talquetamab 55% all-grade, and elranatamab 59% all-grade for neurological toxicity. Neurological toxicity can include anything from seizures to confusion, or even affect a patient’s handwriting.

In some cases, we have to look at what neuropsychiatric history a patient has and determine if they're going to be at higher risk for a particular type of neurotoxicity from one of these types of therapies. But there are other considerations beyond neurological toxicity and cytokine release syndrome. Can you share a little bit more about what things you discussed with your patients beyond CRS and neurotoxicity?

Yi (Lisa) Hwa

Yes, of course. It’s important to make patients aware of the risk of infection, cytopenias, and other particular safety profiles. For example, patients being treated with talquetamab tend to report more AEs that are related to the skin, nail, and taste changes. This is different from BCMA-directed therapy.

Another important factor to consider is the drug administration process. In the setting of CAR-T cell therapy, patients need to be off of anti-myeloma therapy for 2 weeks prior to their T-cell collections and again off for 2 weeks prior to the leukoreduction chemotherapy (typically cyclophosphamide and fludarabine). The T cells may take 4-6 weeks to manufacture in the labs and then there's a 1-year shelf life from the manufactured date. Most patients require bridging therapy to keep their disease under control while waiting for the CAR T-cells being manufactured in the lab. Since most of these patients have been heavily pretreated, the options for bridging therapy can be limited. Therefore, for those patients who present with a rapid progression, bispecific antibodies may be a better option than CAR-T, especially if there are limited options for bridging therapy that can effectively control disease progression during the waiting period.

On the other hand, there's no maintenance therapy after CAR-T cells infused and patients may enjoy a “drug holiday” which can be an advantage for some patients. Following CAR T-cell infusion, the patient needs to be closely monitored for toxicities, as either an inpatient or in a hospital-based outpatient setting.

Bispecific antibodies require step-up dosing initially followed by either weekly or every other week dosing schedule depending on the selected agent. The patient will continue with the therapy indefinitely until disease progression or until they develop a severe intolerance to treatment-related AEs. However, an advantage of bispecific antibodies is to allow a temporary treatment hold if patients do develop acute AEs.

Financial concerns and caregiver availability also need to be considered for each patient when discussing treatment options. The patient must stay near the tertiary care center where they receive CAR-T or bispecific antibody therapy. For CAR-T, they need to be admitted to inpatient or stay at the hospital-based outpatient setting for 6 weeks during the T-cell collection and infusion of the CAR-T cells. For bispecific therapy, the time away from home is usually much shorter, typically about 2 weeks. At the Mayo Clinic, many patients start their step-up dosing at our center then transition to their local clinic to continue their therapy with bispecific antibody. Patients are often required to have a caregiver when they are treated in the outpatient setting while away from home. On top of losing their income from not being able to work, the patient also has to deal with additional expenses for housing, meals, and transportation. It’s important to consider financial factors as part of the quality of life when choosing CAR-T or bispecific antibody therapies.

For example, HealthWell Foundation and Leukemia Lymphoma Society grants can help cover the insurance copays and premiums. Some grants cover up to $5,000 a year. There are several small grants of $500 available for urgent need cases. AP clinicians should collaborate with the social service team to help the patient and family identify potential funding resources.

Amie Fonder

That's a great point, Lisa. I'm really glad that you brought up the financial and logistical processes that we need to think about because toxicity for patients is not just physical, but there's also emotional toxicity and there's financial toxicity. That's important to consider for each patient when we are talking about therapies. It's easy to get caught up in data and what might be most effective, but it's imperative to have a conversation that includes the patient and determine what is truly best for them as an individual, taking into consideration all of those factors.

Going back to my patient, to recap, he is a 70-year-old male with no major comorbidities. From that standpoint, he would be a good candidate for either CAR-Tor bispecific therapy. He is lambda light chain restricted myeloma and over a month the rate of increase was pretty concerning as the lambda free light chain went from around 5 mg/dL to just over 40 mg/dL.

While CAR-T has better long-term efficacy data, there is concern for whether this patient's disease is indolent enough for CAR-T. Can we safely hold his treatment for 2 weeks to accommodate the pause needed before collection and before administration of the T cells? He does have the appropriate number of prior lines of therapy. Both the CAR-T and bispecific antibodies are approved in the U.S. for patients with 4 prior lines of therapy, which must include a proteasome inhibitor, an immune modulator, and an anti-CD38 monoclonal antibody.

He would meet the treatment requirements from the FDA for approval for either type of therapy. If CAR-T were to be selected, we also would need to consider what we could use for bridging therapy since we've used almost all other FDA-approved therapies.

Really, the last option for bridging for this patient would be a bispecific antibody and there are a few clinicians in our practice who have done this. But there's really not much data on CAR-T outcomes in this scenario for multiple myeloma. I think we'll see more data coming out in the future as we have more patients go through this scenario of wanting to do CAR-T but not having anything else accessible for bridging therapy except for bispecifics.

Overall, the rest of his labs were quite good, with the exception of some mild renal insufficiency. Both CAR-T and bispecific antibodies can be safely given to patients with mild renal insufficiency. For this patient, we decided to use teclistamab given the toxicity profile and the duration of response profiles. He achieved a very good partial response–a 90% reduction in the monoclonal proteins after 2 cycles. We were pleased with that response and the patient tolerated the treatment quite well.

Yi (Lisa) Hwa

You brought up an excellent point about using bispecific antibodies as bridging therapy for the CAR-T in those heavily treated patients. As you have mentioned, there are limited data on the treatment efficacy and outcome using bispecific antibody as bridging therapy for CAR-T. It may also raise a clinical dilemma regarding when to discontinue bispecific antibody when being used for the purpose of bridging purpose. Last week I saw a patient who started bispecific antibody for bridging therapy as the initial plan. The patient responded to and tolerated the treatment very well. Now it comes to the clinical dilemma of whether to continue with the bispecific therapy or move on to CAR-T therapy. The patient is very satisfied with his current bispecific treatment while maintaining a good quality of life. He would like to continue with bispecific antibody therapy for now, as the shelf life of CAR-T cells is 1 year from the manufactured date.

Amie, thank you for sharing your clinical expertise. The case you chose and discussed today is a great example to demonstrate how you apply clinical guidelines in individualized care to best meet the needs for your patients. Thank you.

Amie Fonder

Yes, thank you for meeting with me as well and I hope that this helps others have a better, more well-rounded conversation with their patients about which therapy might be most useful for them in the age of both bispecific antibodies and CAR-T cell therapies.