Panel Interview of ONcology practices with Emergent Experience of teclistamab in the Real world: the TecPIONEER Study

Abstract

Objective

To understand clinicians’ current teclistamab step-up dosing (SUD) model and how they envision future administration models, as well as perceived barriers and facilitators to these models in day-to-day clinical practice.

Methods

Interviews of clinicians with RW experience administering teclistamab, with a subsequent roundtable discussion to discuss interview findings. Topics of interest included managing adverse events (AE), and handling logistics of SUD and transition of care (ToC).

Results

20 clinicians representing 19 practices participated. Of 14 practices administering inpatient teclistamab SUD, 12 (86%) utilized a single admission. A day 1-3-5 dosing schedule with a 7-day length of stay was planned in 10/14 (71%). The remaining 5 practices employed outpatient or hybrid SUD. SUD models depended on cellular therapy experience, patient volume, and monitoring capabilities. Clinicians desired to administer SUD outpatient for convenience and reduced healthcare resource use. 11% of practices reported using tocilizumab for cytokine release syndrome (CRS) prophylaxis, whilst it was uniformly used to treat grade 2+ CRS. Corticosteroids were the preferred treatment for neurotoxicity. Infection prophylaxis with intravenous immunoglobulin was reported by 89% of practices. Patient- and institution-level factors affected decision-making of transitioning patients back to referring sites after SUD.

Conclusion

The results consolidated practice-based experiences and indicated diverse RW SUD models and patient management strategies in practices with familiarity with teclistamab AE management and ToC protocols. Inpatient SUD is common, with expectations that approaches will evolve toward outpatient or community-based administration. Further research is needed to investigate outcomes of different care models and AE management strategies.

PLAIN LANGUAGE SUMMARY

Multiple myeloma is a blood cancer that forms in plasma cells. Teclistamab is a new treatment for patients with multiple myeloma who have received prior treatment but for whom their multiple myeloma has come back or stopped responding to treatment multiple times. Because teclistamab works differently than other existing multiple myeloma treatments, there is a need to understand how oncologists who have experience with teclistamab are managing their patients in order to inform best practices for use by more healthcare providers. We interviewed oncologists that treat patients with multiple myeloma to understand their experiences with teclistamab, including how they manage initial dosing (step-up dosing) processes, treat adverse events, and transition patients to outpatient or external clinics for continued care. Most practices were administering step-up dosing of teclistamab in an inpatient setting soon after teclistamab became a treatment option, with a high level of desire to move the initial dosing to an outpatient setting in the near future. Those that were already administering step-up dosing in an outpatient setting had models unique to their practice. Oncologists described numerous processes for monitoring and managing adverse events of the treatment, including treating patients with preventative medications and regularly monitoring vital signs throughout step-up dosing. Oncologists expected that their teclistamab administration processes will likely evolve over time as they gain more familiarity with the treatment, and will need to consider patient-level factors to administer step-up dosing in an outpatient setting.

Keywords:

• Relapsed and refractory multiple myeloma
• teclistamab
• BCMA
• bispecifics
• oncology

Introduction

Teclistamab is the first-in-class T-cell redirecting bispecific antibody approved for use in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least three (for European Medicines Agency) or four (for Food and Drug Administration) prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody^1,2. Teclistamab binds to both B-cell maturation antigen (BCMA) – widely expressed on the surface of myeloma cells, – and CD3 expressed on the surface of T-cells, leading to activation of T-cells and facilitating eradication of BCMA-expressing myeloma cells.

Regulatory approval for teclistamab (TECVAYLI, Janssen Pharmaceuticals) was granted in October 2022 in the United States (US) based on the results of the phase 1/2 MajesTEC-1 study, in which 165 patients with RRMM received once-weekly subcutaneous teclistamab 1.5 mg/kg. This resulted in a median progression-free survival (PFS) of 11.3 months; of the 63% of patients who registered a response to treatment, the median duration of response was 21.6 months and was longer in patients achieving ≥ complete response (CR; 26.7 months)³.

As part of teclistamab’s accelerated approval in the US, a Risk Evaluation and Mitigation Strategy (REMS) program was put in place given the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In MajesTEC-1, the rate of CRS was 72.1%, with a grade 3 or higher CRS rate of 0.6%⁴. Neurotoxicity was seen in 14.5% of patients, including a 3% (all grade 1-2) rate for ICANS⁴. As such, the FDA issued guidance in the package insert regarding initiation of therapy, “Patients should be hospitalized for 48 h after administration of all doses within the TECVAYLI step-up dosing schedule”⁵. The label recommended step-up dosing schedule is to administer the first (0.06 mg/kg) and second (0.3 mg/kg) step-up doses and the first treatment dose 2-4 days apart to allow for resolution of adverse reactions. The language in the label lends flexibility to various administration models, based on each practice’s institutional operations and requirements.

Infections were frequent in participants (n = 165) of the MajesTEC-1 study (76.4%), which was conducted from March 2020 to August 2021 during the height of the COVID-19 pandemic. Recruitment occurred before vaccines against COVID-19 were approved, and thus only 8% of patients received at least one dose of the vaccine⁴. Of participants who experienced infections, 44.8% experienced a grade 3 or 4 infection, with a COVID-19-related mortality rate of 7.2%⁴. Upon extended follow-up of 2 years, infections occurred in 80.0% of participants, with 55.2% experiencing a grade 3 or 4 infection and a mortality rate of 10.9% from COVID-19⁶.

The approval of teclistamab provided novel BCMA-directed immunotherapies for patients with RRMM. Given the novelty of bispecific antibody therapy, there are immediate needs for data based on real-world practices to inform operational processes and improve experiences while ensuring patient safety. In an effort to enhance care with teclistamab, we conducted a panel interview of oncology providers to consolidate real-world practices to help inform future teclistamab use.

Methods

Hematology/oncology clinicians with experience treating patients with teclistamab for RRMM in a real-world setting were recruited for a virtual 60-minute in-depth semi-structured interview between April to June 2023. Initially, a pool of 51 healthcare practices was identified based on claims of teclistamab ordering. As we sought to understand real-world practices for managing patients treated with teclistamab, teclistamab orders were used as a proxy for existing well-established processes that enabled continuous care with teclistamab. Individual clinicians, representing their practices, who were board certified in oncology or hematology, treated patients with RRMM, and had prescribed and treated patients with teclistamab in a RW setting were approached by email to participate. Convenience sampling was employed based on clinician interest and availability in participation, with oversampling of sites that were known to have unique care models in order to provide more diverse RW practices. Efforts were also made to ensure diverse geographic representation and heterogeneity of practice type. 58 clinicians across the 51 identified sites were invited to participate in an interview, among which 12 declined to participate, 5 were unable to contact, and 21 did not respond to the invitation. The remaining 20 clinicians participated in an interview, answering questions related to their standard practices at their current institutions. Interview discussions focused on overall processes and protocols and did not seek to collect data on individual patient outcomes. The interview topics included discussing how clinicians with early real-world experience with teclistamab (1) manage the step-up dosing and transition of care (ToC) to and from referring sites; (2) monitor, manage, and prevent adverse events (i.e. CRS, infections, and ICANS); and (3) foresee how future teclistamab step-up dosing administration models will evolve.

A subsequent 90-minute roundtable discussion with in-person and virtual attendees was held in June 2023 to validate interview findings and provide additional context on current clinical practices. The roundtable discussion participants included clinicians representing practices that were previously interviewed, in addition to clinicians who had not started administering commercial teclistamab due to challenges with teclistamab adoption at their practices. The purpose of expanding the inclusion criteria for the roundtable was to understand barriers to adoption of teclistamab and encourage discussion from experienced practices around recommendations for overcoming these barriers. Clinicians were compensated for their time participating in the interviews and/or roundtable discussion with a fair market value.

Results

During the interview phase, 20 clinicians were interviewed representing 19 practices from 13 states across the US. Demographic data are described in Table 1. The majority (11/20, 55%) of clinicians reported treating patients with MM for 6-10 years. Most interviewed practices represented academic medical centers (17/19, 90%), with the remaining being non-teaching hospitals. Most (12/19, 63%) reported treating over 100 patients with MM per month. 13 (68%) had treated more than 10 patients with commercial teclistamab by the time of their interview. During the roundtable discussion, 10 of the 20 interviewed clinicians were joined by 3 oncologists representing practices without prior real-world teclistamab experience; all 3 were from community practices for a total of 13 practices represented at the roundtable discussion.

Table 1. Interview practice demographics (n = 19).

Characteristic	N (%)
Principal practice setting
University/Academic Medical Center	17 (89.5)
Hospital-Based Practice (Non-Teaching Hospital) or Integrated Delivery Network (IDN)	2 (10.5)
Number of patients treated for MM each month
1-10	1 (5.3)
11-50	2 (10.5)
51-100	4 (21.1)
Over 100	12 (63.2)
Total number of MM patients treated with teclistamab
1-4	3 (15.8)
5-10	3 (15.8)
11-50	12 (63.2)
51-100	1 (5.3)
Practice’s census region
South	8 (42.1)
Northeast	5 (26.3)
Midwest	3 (15.8)
West	3 (15.8)

Step-Up dosing administration

Among the 19 practices, 14 (74%) reported administering the step-up dosing exclusively in an inpatient setting, typically in a specialized hematology/oncology or cellular therapy unit. Among these, 12/14 (86%) had been giving the entire step-up dosing in one continuous hospital admission, primarily (10/14, 71%) with 2-day intervals between step-up doses (i.e. days 1, 3, and 5 dosing schedule), leading to a planned length of inpatient stay of 7 days.

Outpatient or hybrid administration models were employed by 5 (26%) practices and were heterogeneous in model implementation (Table 2). The majority leveraged models previously established for outpatient cell therapy. Three of these sites administered step-up dosing fully in an outpatient setting with daily visits; of those three sites, one site used continuous remote monitoring, another used home monitoring of vital signs with nightly clinician phone calls, and the third had patients attend clinic appointments on days not receiving step-up dosing. Criteria for inpatient admission under an outpatient model included onset of any grade CRS or ICANS, except one center that could administer tocilizumab in an outpatient setting and admitted only for grade 2 or higher CRS or CRS with no response to tocilizumab. The remaining two sites employed a hybrid model where some step-up doses were administered in the outpatient setting followed by an observation period in the hospital.

Table 2. Outpatient and hybrid administration models.

Site	Dosing Schedule for Step-Up Doses	Monitoring Processes
1	Days 1, 3, 5	Patient selection for outpatient administration based on comorbidities, disease burden and caregiver support Outpatient dosing on days 1, 3, 5, observed for 1 hour Clinic appointments on days 2, 4, and 6 for monitoring Admit if Grade 2 or higher CRS and patient does not respond to tocilizumab or for any Grade ICANS
2*	Every 3-4 days	For all step-up doses, patients are admitted under an “observation status”, monitored for 48 hours in an outpatient bed following each dose Dosing every 3-4 days, spaced out to allow breaks between monitoring periods Admit patient if they have any grade CRS,
3*	Days 1, 3, 5	First dose in outpatient setting All patients admitted 24 hours later for monitoring and subsequent doses Discharge after 9 days Admit within the first 24 hours if patient has fever, dizziness, hypotension, or shortness of breath
4	Every 48-72 hours	Fully outpatient model evolved from existing cellular and CAR T-cell therapy models Continuous remote patient monitoring practice allows for timely admission processes if necessary
5	Days 1, 3, 8	Home monitoring of vital signs with nightly clinician phone calls Daily clinic appointments

*Hybrid administration: These sites contained some elements of outpatient SUD administration, as described, but were not administering SUD exclusively in outpatient settings.

Respondents were also queried on decision factors leading to an inpatient versus an outpatient model. These decision factors can be divided into institution-level factors and patient-level factors. Institution-level factors included bed availability, costs and reimbursement consideration, interpretation of the teclistamab package insert as to the requirement vs. recommendation for inpatient monitoring and whether there were dedicated staff for remote monitoring. Patient-level factors included individual comorbidities, disease burden, insurance copays, distance to care setting, and availability of a caregiver. Across all the respondents, outpatient step-up dosing models were desirable and viewed as beneficial especially for large-volume practices where the processes may be adopted from or applied to other therapies. Several practices indicated a plan to explore outpatient administration models in the near future.

Transitions of care

Nearly all (18/19, 95%) practices reported receiving referrals from other sites for teclistamab step-up dosing; however, only 59% of the 17 practices that discussed their ToC patterns reported transferring patients back to referring sites following step-up dosing. Reasons for not transferring patients back to their referring providers ranged from patient-specific factors (patient preference, comorbidities, adverse events from step-up dosing) to local provider-specific factors (need for REMS certification, lack of adverse event management protocols, comfort with administration, financial and reimbursement considerations). Delay in reimbursement for continuation of teclistamab in community hospitals was one of the major reasons limiting referring clinicians in their ability to resume care of their patients after they completed step-up dosing in an academic center.

Among clinicians who were able to transfer patients back to referring sites, the typical timeframe ranged from 2 weeks to 2 months (∼8 doses) following completion of step-up dosing. This timeframe was felt to be optimal to ensure that the patient was responding to and tolerating teclistamab. It was noted that transitions have begun to happen earlier as community providers became more comfor with teclistamab. Care coordinators were often involved in navigating the transition back to referring sites, and written materials with adverse event monitoring instructions were shared. Respondents reported following discharged patients anywhere from once a month to once every 6 months, and in some cases no further follow-up was mandated. The insurance approval for teclistamab was reported to take anywhere from 3 days to 2 weeks.

Adverse event management

Clinicians shared that teclistamab monitoring practices were similar to those they had employed for chimeric antigen receptor (CAR) T-cell therapies or other bispecific antibodies. The REMS program was reported to have minimal impact on standard operating procedures and clinical practice. Vital signs – including temperature, blood pressure, heart rate, and oxygen saturation – were typically monitored every 4 h. Daily laboratory testing was performed for complete blood count, comprehensive metabolic panel, C-reactive protein, and ferritin levels.

Few (2/19; 11%) practices reported using tocilizumab as primary prophylaxis for CRS. Reasons for not using prophylactic tocilizumab included cost consideration, availability, ability to intervene and manage low-grade CRS without it, and the lack of an indication for CRS prophylaxis leading to reimbursement issues. Pretreatment medications were used as per teclistamab package insert, which recommends use of corticosteroids (oral or intravenous dexamethasone 16 mg), histamine-1 (H1) receptor antagonist (oral or intravenous diphenhydramine 50 mg or equivalent) and antipyretics (oral or intravenous acetaminophen 650 mg to 1,000 mg or equivalent).

Management of first incidence of grade 1 CRS varied. While some participants used acetaminophen alone, the majority agreed that tocilizumab should be used early in the onset of CRS to shorten symptoms and prevent subsequent CRS during teclistamab treatment. Management of persistent grade 1 CRS was consistent across respondents, with all using tocilizumab in this setting. There was also a high concordance for the use of tocilizumab and dexamethasone for progressing or grade 2+ CRS. While interviewed clinicians found grade 1-2 CRS to be a common occurrence during the step-up dosing period, none had experienced any occurrences of severe (grade 3+) CRS. All respondents stated that they followed package insert guidelines regarding pausing step-up dosing when CRS occurred and resumed once CRS has resolved. Practices administering teclistamab as an outpatient typically admitted their patients with CRS.

In addition to monitoring for CRS, respondents reported using the 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score every 8-12 h and following existing CAR T-cell therapy protocols and the teclistamab package insert for neurologic monitoring with teclistamab initiation. Only 3/20 (15%) providers reported using prophylactic levetiracetam (for patients with a history of seizures) or dexamethasone in their practices. Neurotoxicity was noted to be rare and low grade; treatment protocols consisted of corticosteroids and levetiracetam for secondary prevention of seizures, while for severe cases of ICANS, clinicians stated they would consider anakinra and intrathecal corticosteroids and/or chemotherapy.

Infection mitigation strategies included monitoring for cytomegalovirus and screening for hepatitis B and C infections by PCR, and clinical monitoring for shingles and respiratory infections. Prophylaxis was primarily against VZV (acyclovir or valacyclovir) throughout the treatment and PJP (TMP-SMX, dapsone, or inhaled pentamidine) until the CD4 count recovered above 200 cells/mm3. Some providers also recommended antibiotic prophylaxis with a fluoroquinolone or third-generation cephalosporin, and some recommended an antifungal in the setting of neutropenia. Granulocyte colony stimulating factor (G-CSF) was administered for neutropenia. Intravenous immunoglobulins (IVIG) 0.4 g/kg every 4-8 weeks was widely used, with 17/20 (85%) of clinicians using it prophylactically for IgG levels below 400 mg/dL regardless of infection history. Vaccination against COVID-19 was encouraged by participants.

Perspectives on future administration models

All providers who reported administering step-up dosing in the inpatient setting described a desire to shift to administering step-up dosing in an outpatient setting, particularly for patients deemed by the treating physician to have low disease burden and fewer comorbidities, lower risk of adverse events, and with good caregiver support. Tocilizumab use for CRS prophylaxis was thought to have a role in outpatient SUD to mitigate the need for inpatient admission. Remote patient monitoring was deemed a potential solution to enhance the outpatient step-up dosing administration. Several identified barriers would need to be addressed for outpatient administration: lack of clarity on FDA label regarding need vs. recommendation for hospitalization, lack of remote monitoring and ability to administer outpatient tocilizumab, and shortage of healthcare resources and staffing to allow for 24/7 urgent care or prompt availability of inpatient beds. Participants acknowledged that for patients with higher disease burden, more comorbidities, and lack of caregiver support, they may prefer inpatient SUD even when the outpatient option is available.

Discussion

The addition of teclistamab into the armamentarium of multiple myeloma therapeutics brings both enthusiasm due to efficacy outcomes and new knowledge gaps about the optimal care model and toxicity management. The results of this panel interview of oncology clinicians to aggregate early real-world experiences with teclistamab in primarily academic institutions identified several key commonalities in teclistamab administration and provides substance for future investigations. Many clinicians reported looking for the proper infrastructure to deliver outpatient SUD for teclistamab and are currently opting for inpatient initiation on days 1, 3 and 5 with a target hospitalization of 7 days to minimize inpatient stay. Our study shows this schedule is feasible in daily practice if CRS is managed early and resolves before the subsequent dose is administered.

Our research also suggests that outpatient SUD for teclistamab has been implemented by institutions with promising outcomes, though providers must be attuned to and comfortable with addressing the unique side effect profile^7,8. Centers that have been able to successfully implement a fully outpatient model had leveraged institution-wide initiatives to facilitate remote monitoring and 24/7 urgent care access with robust drug delivery capabilities. As understanding of adverse event mitigation strategies unfold, complete outpatient administration of teclistamab may become a reality for a broad range of practices.

The European Myeloma Network published guidelines for prevention and management of toxicities during treatment with bispecific antibodies and CAR T-cells in MM^9,10. Such guidelines provide helpful strategies for the practicing clinician, though they are product agnostic and do not address issues specific to administration of teclistamab in the US. One of the key differences in adverse event prevention between practices capable of doing outpatient step-up dosing compared to those restricted to inpatient administration is the use of prophylactic tocilizumab, with outpatient centers preferring prophylactic tocilizumab to prevent hospitalization. While the present study is not the best setting and design to collect data on patient outcomes, including frequency and severity of adverse events, such information can provide valuable insights to help inform future patient management. Ongoing studies are assessing treatment outcomes and consolidating findings. In an exploratory cohort in MajesTEC-1, 23 patients received a single dose of prophylactic tocilizumab 8 mg/kg within 4 h of the first teclistamab step-up dose; CRS occurred in 6/23 (26%) with two grade 1 and four grade 2 events¹¹. This rate of CRS was lower than the reported results of the main MajesTEC-1 cohort (72%), though the rate of grade 2 or higher CRS was similar (21% vs. 22% with an n = 165). This raises the question of the utility of CRS prophylaxis in the inpatient setting, where patients undergo closer monitoring and have rapid access to CRS ameliorating agents such as tocilizumab. With respect to first-instance grade 1 CRS management, clinicians who advocated for use of tocilizumab at a first occurrence of CRS cited potential for less severe/recurrent CRS¹², leading to a shorter length of stay and reduced healthcare resource utilization¹², while clinicians who preferred to reserve tocilizumab for treatment of persistent grade 1 or grade 2 and higher CRS reasoned that evidence was insufficient for early use.

Infection mitigation strategies presented another area of uncertainty for clinicians. While administration of IVIG for IgG < 400 mg/dL was widely reported, the use of other prophylactic antimicrobials was less uniform¹³. Some practices reported only using antibiotic and antifungal prophylaxis in the setting of neutropenia, while PJP prophylaxis was recommended until the CD4+ T-cell counts recovered. Additionally, alterations of dosing frequency or duration to reduce incidence of adverse events were not discussed in the present study, though durability of responses with biweekly dosing of teclistamab has been studied in the clinical trial setting¹⁴. RW practice of this or other alternative dosing schedules should be further explored in future research.

Lastly, we noted that delay in reimbursement for teclistamab in community hospitals was one of the major factors limiting ToC after completing step-up dosing. At the time of our study, implementation of teclistamab in community oncology practices, including transition of care to the referring sites, was somewhat limited due to the pending status of teclistamab’s HCPCS Level II J-Code designation. This designation allows practitioners to be reimbursed by insurers for non-oral medications they administer. A permanent J-Code was since assigned to teclistamab in July 2023.

Limitations of this study center around the qualitative research design, which may limit external validity as results may not represent all providers. Qualitative research is not designed to be representative of the broader oncologist population. Rather, the participants were those who treated patients using a novel product, with the purpose of this study to inform others on how they are treating patients with teclistamab. Strengths of the study design include the use of qualitative data collection techniques that enable the capturing of perspectives and opinions of clinicians across a broad spectrum of topics; this methodology allows an in-depth exploration of complex concepts, which is not possible in quantitative research.

Conclusion

Our study represents the first qualitative study of real-world practices surrounding treatment with teclistamab following FDA approval. The results indicated diverse real-world SUD administration models and patient management strategies in practices with early familiarity with teclistamab. The consolidated practice-based experiences are not intended as clinical advice, but rather are expected to inform broader practices employing this novel therapy. As care models evolve, outpatient or community-based SUD may soon become more common. Continued evidence generation on real-world treatment outcomes and care quality improvements emerging from evolving SUD models and adverse event management strategies is warranted.

Transparency

Declaration of funding

This work was supported by Janssen Scientific Affairs, LLC.

Declaration of financial/other relationships

B.A.D. declares consultancy for COTA Inc, GLG Consulting, Guidepoint, Janssen, and PRECISIONheor; honoraria from American Physician Institute, Multiple Myeloma Research Foundation, and Plexus Communications; independent clinical trial reviewer for BMS. M.R., R.M, N.P., and A.J. declare employment by PRECISIONheor. D.L., B.W., N.K., M.D., J.F., am, and A.P-S declare employment by Janssen. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no other relevant financial relationships to disclose.

Author contributions

Conception and design: All authors; Financial support: Janssen Scientific Affairs, LLC; Collection and assembly of data: All authors; Data analysis and interpretation: All authors; Initial manuscript draft: B.A.D.; Manuscript editing and final approval: All authors; Accountable for all aspects of the work: All authors.