1.
The therapeutic landscape for multiple myeloma has changed drastically over recent years, leading to improvements in outcomes [1]. Bispecific T‐cell engager (BiTE) therapy is one such advancement that promotes T‐cell mediated cytotoxicity towards plasma cells by binding to both CD3 and plasma cell‐specific antigens [2]. Although these have shown promising results in the relapsed/refractory setting, adverse effects are well described and can be similar to those of CAR‐T therapy, including cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) [3]. Consequently, the initiation of BiTEs in centres without experience of managing these complications in the context of CAR‐T has been limited. In early‐phase BiTE studies however, Grade 3 or greater CRS or ICANS were rare, noted in < 1% of patients [4, 5, 6], much lower than the incidence with CAR‐T [7]. Therefore, with comprehensive management algorithms, the treatment could be considered deliverable in non‐tertiary centres. We hence describe our experience of delivering BiTE therapies to a cohort of 11 patients in a District General Hospital setting, with a focus on safety and feasibility.
Between January 2023 and September 2024, 11 patients received treatment with BiTEs including teclistamab (n = 3), talquetamab (n = 1) and elranatamab (n = 7) for triple‐class exposed relapsed/refractory multiple myeloma at Eastbourne District General Hospital. The cohort also included a heavily pre‐treated population, with a median of 5 prior lines of therapy, which were 100% triple‐class refractory and 64% penta‐refractory. 9 of the 11 patients (82%) had been treated with pomalidomide (Table 1). Individual patient characteristics are detailed in Table S1. All patients received dose escalations in line with the trial protocols of the Majes‐TEC1, MonumenTAL‐1 and MagnetisMM‐3 early‐phase trials for teclistamab, talquetamab, and elranatamab, respectively [4, 5, 6].
TABLE 1.
Baseline characteristics of patients receiving BiTE therapy at Eastbourne District General Hospital, as well as CRS rate and overall response.
| Patient characteristics | |
|---|---|
| Patient number | 11 |
| BCMA/GPRC5D target, n | 10/1 |
| Prior BCMA targeted therapy, n | 2 |
| Median prior lines of therapy (range) | 5 (3–11) |
| Median age | 76 (range 56–78) |
| Male, n (%) | 7 (64) |
| Race, n (%) | |
| White | 10 (91) |
| Black | 1 (9) |
| ECOG performance status n (%) | |
| 0 | 1 (9) |
| 1 | 8 (73) |
| 2 | 2 (18) |
| Type of myeloma n (%) | |
| IgG | 4 (36) |
| IgA | 4 (36) |
| Light chain | 2 (18) |
| Oligosecretory | 1 (9) |
| ISS (at diagnosis) n (%) | |
| I | 6 (55) |
| II | 1 (9) |
| III | 1 (9) |
| Unknown | 3 (27) |
| Cytogenetic risk (at diagnosis) n (%) | |
| Standard | 2 (18) |
| High* | 4 (36) |
| Not known/failed | 5 (45) |
| * t(4;14), t(14;16), del(17p), gain/amp(1q) | |
| Extramedullary disease n (%) | 5 (45) |
| Prior stem cell transplant n (%) | 5 (45) |
| Treatment refractory status n (%) | |
| Triple | 11 (100) |
| Penta | 7 (64) |
| Pomalidomide treated | 9 (82) |
| Response and CRS rate | |
|---|---|
| Best response n (%) | |
| CR | 1 (9) |
| VGPR | 3 (27) |
| PR | 1 (9) |
| SD | 0 |
| Refractory | 6 (55) |
| CRS | |
| No CRS | 7 (64) |
| Grade 1 | 4 (36) |
| Grade ≥ 2 | 0 |
Note: ISS is determined by International Myeloma Working Group Criteria [8]. Triple class refractory is defined as refractoriness to proteasome inhibitor, immunomodulatory drug (IMiD), and anti‐CD38 antibody. Penta‐refractory is defined as refractoriness to lenalidomide, pomalidomide, bortezomib, carfilzomib, and anti‐CD38 antibody.
Due to the risk of immune‐effector syndromes (IESs), a standard operating procedure (SOP) document was prepared prior to commencing therapy. The SOP included methods of administration, monitoring guidance, summary of the symptoms and grading of CRS and ICANS according to ASTCT consensus [9], treatment algorithms and clear indications for escalation to intensive care. Tocilizumab was also made available on the ward prior to administration and additional supply could be dispensed at short notice from pharmacy. The attending consultant was informed of treatment initiation and reviewed patients prior to the first dose. They were also informed if CRS or ICANS of any grade developed, including out of hours. At our centre, patients were monitored as inpatients for a minimum of 48 h following each dose escalation. Due to the dose escalations on days 1, 4, and 7, patients remained inpatients for an average of 9 days. At discharge, patients were counselled on symptoms to be aware of, as well as given a thermometer, emergency contacts, alert card, and educational materials.
All 11 patients completed the dose‐escalation phase and at least one full cycle of therapy. Grade 1 CRS with a temperature of ≥ 38°C was seen in four (35%) patients and no patients developed CRS of Grade 2 or above (Figure 1A). These patients were also managed according to local guidelines for fever in immunocompromised patients, including the use of antibiotics, and all patients were escalated to the attending Consultant in line with our SOP. No patients required tocilizumab but it was available if fever persisted or progression to CRS Grade 2 or above was noted. All patients were managed on the ward, with no input by the intensive care team required, and we did not see evidence of ICANS in any patient.
FIGURE 1.
Outcomes of BiTE therapy in patients receiving either teclistamab, talquetamab or elranatamab at Eastbourne District General Hospital. (A) Incidence and grade of CRS whilst receiving BiTE therapy. (B) Best response rate according to the International Uniform Response Criteria [10]. Three patients are receiving ongoing therapy. CR; complete response, CRS; cytokine release syndrome, PD; progressive disease, PR; partial response, SD; stable disease, VGPR; very good partial response.
Although incidence of IESs of Grade 3 and above was rare in early‐phase BiTE trials, CRS overall was common, seen in up to 80% of patients [4, 5, 6]. A total of 22.7% of patients also received tocilizumab for CRS or ICANS whilst receiving elranatamab [6]. The findings within our cohort therefore contrast with the trial findings, highlighting the importance of implementing comprehensive SOPs prior to administering these therapies, even if the complications are not seen. Step‐up dosing was also used, which has been shown to reduce the duration and intensity of CRS if it occurs [11] and may account for some of the differences.
Aside from IESs, infections were also common, including one Grade 5 infection, illustrating the potential immune compromise that can occur in patients receiving BiTE therapies, particularly in heavily pre‐treated individuals. The effect of long‐term administration on immune function should therefore also be considered, a phenomenon which is well‐described [12] and more long‐term data is required. We did note that the non‐involved light chain level was below the limit of detection in 10 (91%) of the 11 patients, suggesting marked compromise of the non‐malignant plasma cell reservoir. In our experience intravenous immunoglobulin has also been used in this context, although it was not required in our patient cohort. Otherwise, six other patients died during the period reported due to progressive/refractory disease, and no patient died as a direct result of the treatment. Other complications are outlined in Table S2.
Our objective response rate (ORR), as determined by achieving a partial response (PR) or better, was noted in five patients (45%) with six patients being refractory to BiTE therapy (Figure 1B). This is less than that reported in the trials, but despite the responses being inferior the ORR is favourable when compared to other options used in the later stages of disease, including pomalidomide [13, 14, 15].
We therefore suggest that administration of BiTEs for relapsed/refractory myeloma may be undertaken in non‐tertiary centres as long as robust SOPs and management protocols are created and adhered to, and widespread education about recognition and management of complications is carried out. This is important as the use of BiTEs and other immune‐effector strategies is likely to become universal across multiple cancer types, meaning that this non‐tertiary experience will be required. In our cohort, patients received a median of five prior lines of therapy. We would emphasise that additional caution is required if BiTEs are used earlier in the treatment algorithm, when the T‐cell repertoire is likely to be fully functional and the disease burden high. In this population of patients, CRS and ICANS may theoretically be more marked and new data and experience must be collated in this regard.
Author Contributions
B.L., J.J. and S.G. collected and analysed the data, generated the figures and tables, and co‐wrote the manuscript. P.H., R.G., A.L. and J.J. devised the treatment pathway and BiTE standard operating procedure. All authors were involved in patient care, discussed the results, and commented on the final manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supplementary Table 1. Characteristics of individual patients receiving BiTE therapy at Eastbourne District General Hospital, including demographics and prior lines of treatment. Supplementary Table 2. Adverse events noted in >50% of patients.
Funding: The authors received no specific funding for this work.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
Data Availability Statement
Due to patient confidentiality, the datasets used in this report have not been made publicly available. However, upon reasonable request, certain subsets of anonymised data may be made accessible.
References
- 1. Shah U. A. and Mailankody S., “Emerging Immunotherapies in Multiple Myeloma,” Bmj 370 (2020): m3176. [DOI] [PubMed] [Google Scholar]
- 2. Tian Z., Liu M., Zhang Y., and Wang X., “Bispecific T Cell Engagers: An Emerging Therapy for Management of Hematologic Malignancies,” Journal of Hematology & Oncology 14, no. 1 (2021): 75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Moreau P. and Touzeau C., “T‐Cell Redirecting Bispecific Antibodies in Multiple Myeloma: A Revolution?” Blood 139, no. 26 (2022): 3681–3687. [DOI] [PubMed] [Google Scholar]
- 4. Chari A., Minnema M. C., Berdeja J. G., et al., “Talquetamab, a T‐Cell‐Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma,” New England Journal of Medicine 387, no. 24 (2022): 2232–2244. [DOI] [PubMed] [Google Scholar]
- 5. Moreau P., Garfall A. L., van de Donk N., et al., “Teclistamab in Relapsed or Refractory Multiple Myeloma,” New England Journal of Medicine 387, no. 6 (2022): 495–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Lesokhin A. M., Tomasson M. H., Arnulf B., et al., “Elranatamab in Relapsed or Refractory Multiple Myeloma: Phase 2 MagnetisMM‐3 Trial Results,” Nature Medicine 29, no. 9 (2023): 2259–2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Omer M. H., Shafqat A., Ahmad O., Alkattan K., Yaqinuddin A., and Damlaj M., “Bispecific Antibodies in Hematological Malignancies: A Scoping Review,” Cancers 15, no. 18 (2023): 4550. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Palumbo A., Avet‐Loiseau H., Oliva S., et al., “Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group,” Journal of Clinical Oncology 33, no. 26 (2015): 2863–2869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Lee D. W., Santomasso B. D., Locke F. L., et al., “ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells,” Biology of Blood and Marrow Transplantation 25, no. 4 (2019): 625–638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Durie B. G. M., Harousseau J.‐L., Miguel J. S., et al., “International Uniform Response Criteria for Multiple Myeloma,” Leukemia 20, no. 9 (2006): 1467–1473. [DOI] [PubMed] [Google Scholar]
- 11. Ball K., Dovedi S. J., Vajjah P., and Phipps A., “Strategies for Clinical Dose Optimization of T Cell‐Engaging Therapies in Oncology,” MAbs 15, no. 1 (2023): 2181016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Zieger N., Kazerani M., Nicholls A., et al., “T‐Cell Exhaustion Induced by Continuous Bispecific Molecule Exposure Is Ameliorated by Treatment‐Free Intervals,” Blood 140, no. 10 (2022): 1104–1118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Kumar S. K., Lee J. H., Lahuerta J. J., et al., “Risk of Progression and Survival in Multiple Myeloma Relapsing After Therapy With IMiDs and Bortezomib: A Multicenter International Myeloma Working Group Study,” Leukemia 26, no. 1 (2011): 149–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Richardson P. G., Siegel D. S., Vij R., et al., “Pomalidomide Alone or in Combination With Low‐Dose Dexamethasone in Relapsed and Refractory Multiple Myeloma: A Randomized Phase 2 Study,” Blood 123, no. 12 (2014): 1826–1832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Richardson P. G., Hungria M., Yoon S. S., et al., “Panobinostat Plus Bortezomib and Dexamethasone in Previously Treated Multiple Myeloma: Outcomes by Prior Treatment,” Blood 127, no. 6 (2015): 713–721. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Characteristics of individual patients receiving BiTE therapy at Eastbourne District General Hospital, including demographics and prior lines of treatment. Supplementary Table 2. Adverse events noted in >50% of patients.
Data Availability Statement
Due to patient confidentiality, the datasets used in this report have not been made publicly available. However, upon reasonable request, certain subsets of anonymised data may be made accessible.