Acknowledging Infection Risk in Bispecific Antibody Trials in the Treatment of Multiple Myeloma

Cliff, Edward R Scheffer; Reynolds, Gemma; Popat, Rakesh; Teh, Benjamin W; Kesselheim, Aaron S.; Mohyuddin, Ghulam Rehman

doi:10.1200/jco.22.02197

Cited by 16 publications

(14 citation statements)

References 19 publications

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“…1,5,6,[8][9][10][11][12] Novel therapies targeting B-cell maturation antigen (BCMA) may increase the risk of infection through on-target, off-tumor toxicity, including neutropenia (partly because of cytokine-mediated impairment of hematopoiesis); elimination of normal (non-MM) BCMA-expressing plasma cells resulting in hypogammaglobulinemia; persistent B-cell aplasia; and disruption of BCMA signaling, which impacts plasma cell survival and proliferation. 1,5,6,11,[13][14][15] BCMA-bispecific antibodies have been associated with high rates of all-grade and grade ≥3 infection relative to other MM therapies, including non-BCMA-bispecific antibodies. 4,6,11,13,[16][17][18][19] Although these differences in infection risk remain to be fully characterized from a mechanistic perspective, key drivers may include the corresponding decrease in normal plasma cells during BCMA-targeted therapy, which in turn impacts the ability to maintain humoral immunity, 14,20 and T-cell exhaustion, which has been observed following bispecific antibody therapy.…”

Section: Introductionmentioning

confidence: 99%

“…1,5,6,11,[13][14][15] BCMA-bispecific antibodies have been associated with high rates of all-grade and grade ≥3 infection relative to other MM therapies, including non-BCMA-bispecific antibodies. 4,6,11,13,[16][17][18][19] Although these differences in infection risk remain to be fully characterized from a mechanistic perspective, key drivers may include the corresponding decrease in normal plasma cells during BCMA-targeted therapy, which in turn impacts the ability to maintain humoral immunity, 14,20 and T-cell exhaustion, which has been observed following bispecific antibody therapy. 21,22 Time on therapy may potentially also play a role, based on recent data suggesting that the rate of infection may be higher with BCMA-bispecific antibodies than BCMA chimeric antigen receptor T-cell therapy, which is likely related to their prolonged dosing duration given they have the same target.…”

Section: Introductionmentioning

confidence: 99%

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Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC‐1 study

Nooka,

Rodriguez,

Mateos

et al. 2023

Cancer

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BackgroundPatients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B‐cell maturation antigen‐directed bispecific antibody approved for triple‐class–exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC‐1 study.MethodsPatients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step‐up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2–4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines.ResultsAt a median follow‐up of 22.8 months (range, 0.3–33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID‐19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty‐one patients died from infections (18 from COVID‐19). Median time to first onset of any‐grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2–19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0–18.1]).ConclusionBased on the infection profile of B‐cell maturation antigen–targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important.Clinical trial registrationNCT03145181/NCT04557098 (ClinicalTrials.gov)Plain Language Summary Before starting teclistamab, patients should be up to date with vaccinations (including COVID‐19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3–6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC‐1 study

Nooka,

Rodriguez,

Mateos

et al. 2023

Cancer

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“…We are grateful for the thoughtful comments by Cliff et al 1 in reference to our article. 2 We share their enthusiasm for the response rates seen with ABBV383 in patients with relapsed and/or refractory multiple myeloma (MM), to our knowledge, in this first-in-human phase I trial designed to find the optimal dose of ABBV383 for further development.…”

mentioning

confidence: 79%

Reply to E.R.S. Cliff et al

D’Souza

Kumar

2023

JCO

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“…There was no evaluation of use of other terms to describe toxic effects, and articles that used minimizing terms may also concurrently use other terms to describe such effects. The attribution of toxic effects (and death) to an intervention is inherently subjective and imperfect . Our review may not have included all separate publications that contained PROs.…”

Section: Discussionmentioning

confidence: 99%

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma

Najjar,

McCarron,

Cliff

et al. 2023

JAMA Netw Open

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ImportanceCancer treatment can result in burdensome toxic effects that profoundly affect patient quality of life. In seeking to emphasize the efficacy of tested treatments, clinical trial reports may use subjective or minimizing terms to describe adverse events (AEs).ObjectiveTo evaluate patterns of AE reporting in multiple myeloma (MM) randomized clinical trials (RCTs) published between 2015 and early 2023.Design, Setting, and ParticipantsFor this cohort study, the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to assess the prevalence of minimizing terms in MM RCTs published between January 1, 2015, and March 1, 2023. Minimizing terms were defined as subjective terms used to favorably describe the safety profile of the intervention. The terms searched included convenient, manageable, acceptable, expected, well-tolerated, tolerable, favorable, and safe. Final data analysis was performed on July 21, 2023.Main Outcomes and MeasuresThe primary outcome was the occurrence of at least 1 minimizing term in an article. Univariate logistic regression analyses were performed to evaluate the association between the presence of at least 1 minimizing term and the actual incidence of grade 3 or 4 AEs, serious AEs, or grade 5 AEs.ResultsOf the 65 RCTs included, 56 (86%) used minimizing terms when describing treatment-emergent AEs. The most frequently used minimizing terms were well-tolerated or tolerable in 29 trials (45%), manageable in 18 (28%), and acceptable in 16 (25%). Grade 3 or 4 AE rate in the examined RCTs ranged from 23% to 94%, with a median of 75% (IQR, 59%-82%). A univariate regression analysis demonstrated no association between the use of minimizing terms and grade 3 or 4 AE rates (odds ratio [OR], 1.35 [95% CI, 0.88-2.10] per 10% AE rate increase; P = .17) or grade 5 AE rates (OR, 3.16 [95% CI, 0.27-12.7] per 10% AE rate increase; P = .45).Conclusions and RelevanceThese findings suggest that trial investigators and sponsors regularly use minimizing terms to describe toxic effects in MM trials, and use of this terminology may not reflect actual AE rates in these studies. Instead of using these terms, trial investigators should highlight event rates and patient-reported outcomes, to allow clinicians and patients to better evaluate the true tolerability of AEs.

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Acknowledging Infection Risk in Bispecific Antibody Trials in the Treatment of Multiple Myeloma

Cited by 16 publications

References 19 publications

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC‐1 study

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC‐1 study

Reply to E.R.S. Cliff et al

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma

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