Key Principles in Safely Prescribing Bispecific Antibodies in Heavily Pretreated Patients With Multiple Myeloma (Part 1)
Welcome to this Clinical Case Series learning module!
Here's how it works:
- Read these 3 case studies on the AP role in managing patients heavily pretreated for multiple myeloma as they receive bispecific antibody therapy. But don't miss the 3 other cases that make up part 2 of this module.
- Answer the poll next to each case to see how your colleagues are managing these patients. You'll see results in real time.
- Continue your learning by watching a recording of a webinar presented by Josh Epworth, MSN, ARNP
Novel Treatment Option for Heavily Pretreated Multiple Myeloma
Clinical Pearl: New therapies with effective mechanisms of action exist for heavily pretreated patients with multiple myeloma
Mr. S is 64-year-old male who was diagnosed with standard-risk IgG kappa multiple myeloma (MM) in March 2019. The results of his laboratory tests—including calcium, creatinine, hemoglobin, beta-2 microglobulin, albumin, and lactate dehydrogenase (LDH)—are shown in the table below. His PET-CT scan showed an absence of abnormal FDG uptake; no lytic lesions were observed. SPEP showed a 3.63 g/dL monoclonal protein, which was identified by immunofixation as an IgG kappa monoclonal protein. The bone marrow biopsy performed on March 15, 2019, showed 32% involvement by a plasma cell neoplasm with no high-risk cytogenetics present. Mr. S was diagnosed with Revised International Staging System (R-ISS) stage I disease.
Table. Laboratory Values at MM Diagnosis
| Parameter | Value at Diagnosis |
|---|---|
| Calcium | 9.0 mg/dL |
| Creatinine | 0.98 mg/dL |
| Hemoglobin | 13.8 g/dL |
| Beta-2 microglobulin | 2.57 μg/mL |
| Albumin | 4.0 g/dL |
| LDH | 156 U/L |
| Serum free light chains | |
| Kappa | 8.3 mg/dL |
| Lambda | 0.76 mg/dL |
| Kappa:lambda | 10.92 |
Since his diagnosis, Mr. S has received 5 lines of therapy. He achieved a complete response (CR) to his first line of therapy with 4 cycles of lenalidomide, bortezomib, and dexamethasone. He then underwent an autologous hematopoietic stem cell transplant followed by lenalidomide maintenance. He developed biochemical progression of disease after 7 months of maintenance therapy, in which the SPEP increased to 0.5 g/dL and the plasma cells were 15%-20% in the bone marrow. Mr. S then received 2 cycles of cyclophosphamide, bortezomib, and dexamethasone with progressive disease, followed by daratumumab, pomalidomide, and dexamethasone with a very good partial response (VGPR). Following 8 months on this regimen, Mr. S again exhibited disease progression. He received 10 cycles of daratumumab, carfilzomib, and dexamethasone, and achieved a VGPR. He again developed disease progression. He received two cycles of elotuzumab, pomalidomide, and dexamethasone, yet experienced continued disease progression.
As illustrated by Mr. S’s treatment journey, finding effective regimens for heavily pretreated patients with MM can be challenging. Teclistamab is a bispecific antibody that targets CD3 expressed by T cells and BCMA expressed by myeloma cells. It was approved by the U.S. Food and Drug Administration (FDA) in October 2022 for the treatment of patients with relapsed or refractory MM who have received at least 4 prior lines of therapy (including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody) based on the findings of the MajesTEC-1 trial.1 In the phase 1/2 portion of the trial, with 165 patients with heavily pre-treated disease, there was an overall response rate of 63% with a median duration of response of 18.4 months.2
Mr. S began treatment with teclistamab in the inpatient setting, which allowed for consistent monitoring for the potential adverse events of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the MajesTEC-1 trial, CRS occurred in 72.1% of patients, 0.6% of which were grade 3 and 0% were grade 4, and ICANS occurred in 3% of patients, all of which were grade 1 or 2.2 After discharge, Mr. S continued teclistamab therapy in the outpatient setting. Following 8 weeks of therapy, his free light chains had returned to the normal range and results of the serum protein electrophoresis had declined by 55%. As Mr. S tolerated teclistamab therapy well, he planned to stay on treatment until disease progression.
References
- U.S. Food and Drug Administration. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. Press release. October 25, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma. Accessed May 10, 2023.
- Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495-505.
Monitoring for Teclistamab-Associated Cytokine Release Syndrome
Clinical Pearl: If it occurs, cytokine release syndrome typically develops within a specific period of time following the initial doses of teclistamab
Mrs. L is a 53-year-old woman who presented to her local emergency department reporting lightheadedness and fatigue. The results of a complete blood count (CBC) are shown in the table below. Her treatment team initiated hemodialysis. A CT C/A/P scan exhibited multiple skeletal lesions concerning for multiple myeloma (MM). An SPEP was performed, showing 2.9 g/dL of IgG lambda with kappa free light chain of 0.37 mg/dL and lambda free light chain of 201 mg/dL. A bone marrow biopsy exhibited 75% lambda restricted plasma cells with standard-risk cytogenetics and t(11;14). Mrs. L was diagnosed with Revised International Staging System (R-ISS) stage II disease.
Table. Laboratory Values at MM Diagnosis
| Parameter | Value at Diagnosis |
|---|---|
| Creatinine | 20.7 mg/dL |
| Hemoglobin | 2.2 g/dL |
| Hematocrit | 6.7% |
| Platelets | 101,000 U/L |
| Beta-2 microglobulin | 5.4 mg/L |
| Albumin | 3.8 g/dL |
| LDH | 222 U/L |
Treatment was started with cyclophosphamide, bortezomib, and dexamethasone for 3 cycles, which stabilized Mrs. L’s disease. However, she had difficulty tolerating treatment. Her therapy was changed to carfilzomib with dexamethasone for 1 cycle; she was found to have progressive disease (SPEP increased to 6.1 g/dL). The third line of therapy was RVd-PACE for 4 cycles, to which her disease responded with a reduction of SPEP to 1.4 g/dL. At this time, stem cells were collected. Mrs. L was transitioned to daratumumab, pomalidomide, plus dexamethasone for 5 cycles, resulting in stable disease. She received 3 cycles of hyper-CVAD with very good partial response and went on to an autologous hematopoietic stem cell transplant (HSCT) but experienced a rapid relapse of her disease within 3 months. Mrs. L underwent venetoclax, bortezomib, and dexamethasone for 10 cycles before she experienced disease progression.
At this time, Mrs. L began teclistamab, which resulted in improvement of kappa free light chain to 1.3 mg/dL, lambda free light chain to 32.9 mg/dL, and SPEP to 2.7 g/dL. She received teclistamab in the hospital so she could be monitored for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). She was given the standard dose of 0.06 mg/kg on day 1, 0.3 mg/kg on day 4, and 1.5 mg/kg on day 7.
Cytokine release syndrome is a common adverse event associated with teclistamab administration. This medication targets tumor cells and elicits release of the cytokines IFN-γ or TNF-α, which leads to the activation of bystander immune and non-immune cells, including monocytes/macrophages, dendritic cells, natural kill cells, T cells, and endothelial cells. This activity induces a release of proinflammatory cytokines that trigger a cascade reaction. Macrophages and endothelial cells produce large amounts of IL-6, which in turn activates T cells and other immune cells, leading to a cytokine storm of variable severity. In the MajesTEC study, the median time to CRS onset was 2 days (range, 1–6) and the median duration of CRS was 2 days (range, 1–9). Overall, 72.1% of patients developed any-grade CRS; however, only 1 patient (0.6%) developed grade 3 CRS. There were no episodes of grade 4 CRS.1
On day 2 of her hospital observation period, Mrs. L exhibited a single episode of a fever of 38.0o C but no other symptoms. Her temperature reduced to 36.9o C within 1 hour without intervention. Blood cultures and chest x-ray exhibited no growth or abnormalities, respectively. Since she was monitored carefully as an inpatient for the first 3 doses and experienced no additional CRS or ICANS, it was deemed safe for her to receive the rest of her doses in the outpatient setting. Mrs. L has exhibited no further episodes of reaction to the teclistamab in either the inpatient or outpatient setting. After nearly 3 cycles, her free light chains have normalized and her SPEP is “too small to quantify.” Mrs. L is tolerating treatment without difficulty.
References
- Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495-505.
Management of Teclistamab-Associated Cytokine Release Syndrome
Clinical Pearl: Successful management of cytokine release syndrome associated with teclistamab requires consistent observation and implementation of progressive clinical interventions
Mr. O is a 64-year-old male who presented to his primary care provider in 2019 complaining of persistent back pain. His laboratory results are shown in the table below. Serum kappa free light chain was 8.7 mg/dL, lambda free light chain was 0.83 mg/dL, and SPEP was 4.11 g/dL IgG kappa. The PET-CT showed absence of abnormal FDG uptake; there were no lytic lesions seen. The bone marrow biopsy showed 65% to 70% plasma cells without high-risk cytogenetics.
Table. Laboratory Values at MM Diagnosis
| Parameter | Value at Diagnosis |
|---|---|
| Calcium | 9 mg/dL |
| Creatinine | 0.98 mg/dL |
| Hemoglobin | 13.8 mg/dL |
| Total protein | 10 g/dL |
| Beta-2 microglobulin | 2.57 mg/L |
| Albumin | 3 g/dL |
| LDH | 200 U/L |
Initial treatment included 4 cycles of lenalidomide, bortezomib, and dexamethasone, which resulted in a stringent complete response (sCR) as indicated by normalization of free light chains, non-detectable SPEP, and absence of disease by flow cytometry. Mr. O went on to an autologous hematopoietic stem cell transplant followed by lenalidomide maintenance. A biochemical relapse occurred after 26 months of maintenance therapy, in which the SPEP increased to 0.5 g/dL and there were 15% to 20% plasma cells in the bone marrow. He was treated with 2 cycles of cyclophosphamide, bortezomib, and dexamethasone with continued progressive disease.
Mr. O’s treatment team switched him to daratumumab, pomalidomide, and dexamethasone, which resulted in a sCR. After 11 months, Mr. O developed progressive disease and changed therapy to daratumumab, carfilzomib, and dexamethasone resulting in stable disease for 5 months. Upon disease progression, he received 4 cycles of elotuzumab, pomalidomide, and dexamethasone. He again developed progressive disease. At this time, teclistamab was initiated in the inpatient setting.
With the introduction of T-cell driven therapy and the occurrence of cytokine release syndrome (CRS), a host of protocols were developed to classify the severity of CRS. In addition to using signs and symptoms to classify the seriousness of this reaction, these protocols also developed progressive and more intensive responses based on the number of signs and symptoms. The American Society for Transplant and Cellular Therapy’s CRS grading system uses the criteria of fever, hypotension, and hypoxia to categorize the severity of CRS into 4 tiers.1 The goal of this grading system is to effectively manage CRS such that teclistamab can be safely continued.
Six hours following his day 4 dose of teclistamab (0.3 mg/kg), Mr. O developed a fever of 39o C, exhibited a blood pressure of 89/54 mmHg with tachycardia of 106 bpm, and oxygen saturation of 99% on room air. A fluid bolus was given, with no significant improvement. Blood cultures and a chest x-ray were performed. Mr. O was given 650 mg of acetaminophen along with IV antibiotics. A second fluid bolus was introduced, and 8 mg/kg of IV tocilizumab was started. Shortly afterward, his blood pressure improved to 110/66 mmHg, his pulse reduced to 82 bpm, and his temperature decreased to 36.8o C. The chest x-ray and blood cultures were unremarkable. According to the ASTCT grading system, Mr. O had developed grade 2 CRS. No further episodes of CRS were exhibited during hospitalization, and he received his day 7 dose of teclistamab without difficulty. Following discharge, Mr. O has tolerated teclistamab without difficulty for 4 months and has achieved a very good partial response (VGPR).
References
- Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625-638.
Meet the Faculty
Josh Epworth
MSN, ARNP
Nurse Practitioner, Hematology Oncology
Fred Hutchinson Cancer Center
Josh Epworth is a nurse practitioner at the Fred Hutchinson Cancer Center, where he has treated plasma cell malignancies for nearly a decade. In addition to working with patients on active treatment, Josh manages the Multiple Myeloma Maintenance and Monitoring Clinic (M4 Clinic). This is an APP staffed clinic for patients whose multiple myeloma is under control with maintenance or monitoring alone. The purpose of this clinic is to watch for indications of progression of disease, manage maintenance-related side effects, and improve access to active care teams for patients with new and relapsing multiple myeloma.
Let us know what you'd like to learn more about at jadpro-editor@broadcastmed.com