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CRS in MM
Our Thoughts on Cytokine Release Syndrome With BCMA-Targeted Therapies for Relapsed/Refractory Multiple Myeloma

Released: June 19, 2023

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Key Takeaways
  • Great efficacy has been demonstrated with BCMA-targeted CAR T-cell therapies and bispecific antibodies in heavily pretreated patients with multiple myeloma.
  • Optimal approaches for monitoring and managing cytokine release syndrome with bispecific antibodies currently are being explored, with no single definitive strategy.

Efficacy of BCMA-Targeted Agents in Heavily Pretreated Multiple Myeloma

Donald C. Moore, PharmD, BCPS, BCOP, DPLA, FCCP:
BCMA is a protein that is expressed on late memory B-cells that are committed to plasma cell differentiation. It also is expressed on plasma cells and plays an important role in the survival of long-lived plasma cells. Because BCMA is ubiquitously expressed on myeloma cells rather than earlier, B-cell‒lineage stages, it has become an attractive therapeutic target in multiple myeloma. Agents targeting BCMA now include 2 CAR T-cell products—idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel)—and the bispecific antibody teclistamab. All of these agents are approved for patients with multiple myeloma after ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

Ide-cel was approved by the FDA based on results of the phase II KarMMa trial, which reported an overall response rate (ORR) of 73%, with most patients having a complete response or better. Median progression-free survival (PFS) and overall survival (OS) were 8.8 and 24.8 months, respectively. Cilta-cel was approved based on results of the phase Ib/II CARTITUDE-1 trial, which reported an ORR of 98%. After 33.4 months of follow-up, the final update of CARTITUDE-1 demonstrated a median PFS of 34.9 months and a 3-year OS of 62.9%. Teclistamab was evaluated in the phase I/II MajesTEC-1 trial, which led to its approval. The primary endpoint of ORR was achieved in 63% of patients, and most were deep responses, with 39% of patients having a complete response or better. After 23 months of follow-up, median PFS and OS were 11 and 22 months, respectively. Overall, with approved BCMA-targeted therapies, these are very high ORRs across the board. To provide context, other data have shown 26% to 30% ORRs with previous standard-of-care therapies in patients with triple-class exposed and refractory multiple myeloma.

Cytokine Release Syndrome With BCMA-Targeted Agents

Victoria Nachar, PharmD, BCOP:
As far as differences between these therapeutic options, CAR T-cell therapies involve a single infusion of a certain number of T-cells, whereas teclistamab is an SC injection. Teclistamab is given by step-up dosing on Day 1, 4, and 7, and then weekly thereafter indefinitely. The main toxicities of CAR T-cell therapies and teclistamab have some overlap, in that the 3 major toxicities are cytokine release syndrome (CRS), neurotoxicity, and risk of infection. The formulation of teclistamab as an SC product and the step-up dosing have been implemented in an attempt to mitigate CRS and neurotoxicity.

With ide-cel in KarMMa, 84% of patients experienced CRS, which was mostly low grade, with grade ≥3 CRS in 5% of patients. The median time to onset for CRS with ide-cel was approximately 1 day. With cilta-cel in CARTITUDE-1, 95% of patients experienced CRS, also with grade ≥3 CRS in 5% of patients, with a median time to onset of 7 days. The delay is important to keep in mind. When looking at teclistamab, the incidence of CRS is 72.1%, but it is mostly low grade, with grade ≥3 CRS in <1% of patients. The median time to onset is approximately 2 days. Approximately 30% of patients had a recurrent CRS event, which may be related to the step-up dosing. For CAR T-cell therapy, management of CRS is standardized, with supportive care for grade 1, and then there is reliance on tocilizumab for grade ≥2 CRS. Tocilizumab can be considered for grade 1 CRS in a patient who is frail or who may not tolerate higher grade CRS very well. It is worth noting that the management of CRS has never been prospectively studied or validated in a clinical trial and is based on expert opinion. With bispecific antibodies, the optimal CRS management approach is even less established. The 2 treatment modalities do not work the same way, and both appear to cause cytokine release into the bloodstream. The approach for CRS management with bispecific antibodies at our institution was derived from our experience with blinatumomab. Our approach relies mostly on corticosteroids vs tocilizumab for grade 2 CRS. Logistically, it is easier to administer corticosteroids initially. It is important that we, as pharmacists, really emphasize standardizing the approach at our institutions. With different management strategies depending on the product, there could be confusion. Ultimately, the confusion becomes a safety concern.

Administration Considerations With Bispecific Antibodies

Victoria Nachar, PharmD, BCOP:
When choosing a BCMA-targeted therapy for a patient, access and other logistics are part of treatment planning. Administration of CAR T-cell therapies is more labor-intensive up front, and there is a Risk Evaluation and Mitigation Strategy (REMS) program that addresses the education and monitoring regarding CRS. Bispecific antibodies may provide an opportunity to improve access. A logistical challenge is not only the initial period of CRS risk when most centers are not used to monitoring and managing CRS, but also the ongoing therapy. Teclistamab has a REMS program directed toward healthcare professional training and a patient wallet card. The manufacturer recommends inpatient hospitalization for step-up dosing, but it is not a requirement of the REMS. Institutions need the infrastructure and support for monitoring and managing patients if teclistamab is administered on an outpatient basis.

Donald C. Moore, PharmD, BCPS, BCOP, DPLA, FCCP:
We administer the initial step-up doses of teclistamab on an outpatient basis and then admit the patient under observation status to one of our hematology services, specifically one that is used to managing cellular therapies. We are considering an adaptive approach of perhaps moving the third step-up dose to the outpatient setting if the first two were uneventful. If the patient is motivated and provided with specific directions on when to take acetaminophen and when to call the triage line, the model may be successful. As far as access, community-based centers are spread around our metropolitan area and outskirts. We try to administer the step-up doses at the main hub, but once the initial CRS risk has passed, we can shift the patients back to a local provider or center within our network to receive their weekly SC doses closer to home.

Victoria Nachar, PharmD, BCOP:
We started out by doing all inpatient administration. It was logistically simpler, with our infusion centers at maximum capacity and then having to see if inpatient beds were ready if the patient needed to be admitted. Our CRS rates have been low. We are starting to evaluate the outpatient observation approach you described. Our protocol is attempting to address which specific patient criteria or clinical features necessitate inpatient admission, in addition to the specific home situation and the comfort level of their caregivers with managing potential CRS. Right now, it is mostly inpatient, but we are working toward making it outpatient, and patients are looking forward to this.

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How does your practice manage CRS with the different available BCMA-targeted therapies? Join the conversation by adding a comment in the discussion section.

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