Teclistamab in Relapsed or Refractory Multiple Myeloma

In the paper

“CAR-T therapy requires that patients have access to specialized care centers and can wait the minimum 4-week period for production, which can result in attrition rates of approximately 10 to 15%,6-8”

What the sources say

• Partly supported

  The Patients section (page not available) reports that 12 of 140 enrolled patients discontinued before ide-cel infusion, an attrition rate of about 8.6%, and that some patients received bridging therapy during manufacturing. It does not establish a minimum four-week production period, a requirement for access to specialized care centers, or that waiting caused the discontinuations. (LLM, conf=0.85)

  cites [6] sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion and future perspectives section (page unavailable) says CAR T-cell treatment involves a specialized center and that manufacturing takes several days to weeks, during which disease may progress. It does not establish a minimum four-week production period or an attrition rate of approximately 10–15%. (LLM, conf=0.88)

  cites [7] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [8] source

In the paper

“Such absence of minimal residual disease has been associated with improved overall survival and progression-free survival in patients with myeloma.14-16”

What the sources say

• ?Not checked — no full text of the sourcecites [14] source
• Supported

  The Introduction states that MRD-negative status is associated with improved progression-free survival (PFS) and overall survival (OS). The Discussion likewise reports prior multiple-myeloma findings for both outcomes; the paper's own OS data were immature, but the claim does not attribute an OS result to this study's analysis. (LLM, conf=0.94)

  cites [15] source
• Supported

  The Discussion states that MRD negativity is associated with improved survival in both newly diagnosed and relapsed/refractory myeloma. The Introduction links MRD negativity with prolonged progression-free and overall survival, supporting both endpoints in the claim. (LLM, conf=0.90)

  cites [16] source

In the paper

“Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03), except for cytokine release syndrome (Table S2) and immune effector cell–associated neurotoxicity syndrome, which were graded according to the criteria of the American Society for Transplantation and Cellular Therapy.12”

What the sources say

• Supported

  The citation supports the exception for CRS and ICANS: the paper sets out consensus grading criteria for both in its ‘Consensus on CRS Grading (Table 2)’ and ‘Consensus on ICANS Grading for Adults’ sections (page not available). The citing study’s choice to grade its other adverse events using CTCAE v4.03 is not attributed to this source. (LLM, conf=0.93)

  cites [12] source

In the paper

“The primary end point of the phase 2 study was the overall response rate, which was defined as a partial response or better according to the criteria of the International Myeloma Working Group, as assessed by an independent review committee”

What the sources say

• Partly supported

  The Response criteria section recommends IMWG criteria for clinical trials and endorses the IMWG definition of partial response; the Minimal response section also distinguishes partial response or better from minimal response. The paper does not establish that overall response rate was the primary endpoint of the particular phase 2 study or that an independent review committee assessed it (pages not provided). (LLM, conf=0.87)

  cites [10] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [11] source

In the paper

“Of the 19 deaths due to adverse events in our study, 12 were attributed to Covid-19, which was consistent with the higher mortality observed from Covid-19 in patients with hematologic cancers during this time frame.24”

What the sources say

• Supported

  The citation supports the background comparison, not the citing authors’ own count of 12 COVID-19 deaths among 19 adverse-event deaths. The Discussion reports high COVID-19 mortality in patients with hematologic malignancies and says it was substantially higher than in the general population, while cautioning that the estimate may be elevated by the large proportion of hospitalized patients. (LLM, conf=0.92)

  cites [24] source

In the paper

“median, five previous therapy lines”

• Also stated in: § PATIENTS · plain

  “Patients had received a median of 5 previous lines of therapy (range, 2 to 14)”

In the paper

“Teclistamab exposure was sustained over the predetermined target level (6 μg per milliliter, based on the upper boundary of an experimentally determined range of the 90% maximal effective concentration) with a low peak-to-trough ratio (Fig. S3).”

In the paper

“Cytokine release syndrome occurred in 119 patients (72.1%). Most events occurred after step-up and cycle 1 doses, with 6 patients (3.6%) having cytokine release syndrome in cycle 2 or later. Most events of cytokine release syndrome were grade 1 or 2 in severity and fully resolved, except for one grade 3 event”

• Also stated in: § RESULTS · plain

  “cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4)”

In the paper

“Response rates were lower in patients with extramedullary disease, stage III disease, and at least 60% marrow replacement by plasma cells and were higher in those who had received no more than three previous lines of therapy.”

In the paper

“thrombocytopenia (in 66 [40.0%])”

• Also stated in: § RESULTS · plain

  “thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%)”

In the paper

“A total of 68 patients (41.2%) died, with most deaths (41) attributed to progressive disease (Table S9). Nineteen patients died from adverse events, including 12 deaths from coronavirus disease 2019 (Covid-19). Five deaths were considered by investigators to be related to teclistamab”

In the paper

“In addition, reductions in soluble BCMA levels occurred during the first 4 cycles of treatment in 63 of 72 evaluable patients (88%) who had a partial response or better, whereas all the evaluable patients who did not have a response (9 of 9 patients) had increased levels of soluble BCMA.”

In the paper

“A total of 98 patients (59.4%) received at least 6 months of teclistamab treatment, and 79 patients (47.9%) received at least 9 months of treatment.”

In the paper

“All 165 patients reported having an adverse event (Table 2 and Table S5), which were grade 3 or 4 in 156 patients (94.5%).”

In the paper

“Five patients had a total of 9 events of immune effector cell–associated neurotoxicity syndrome, all either grade 1 or 2. Of these 9 events, 7 were concurrent with cytokine release syndrome, and all 9 events resolved without discontinuation or dose reduction.”

In the paper

“neutropenia (in 117 patients [70.9%])”

• Also stated in: § RESULTS · plain

  “neutropenia (in 70.9%; grade 3 or 4, 64.2%)”

In the paper

“Injection-site reactions were reported in 60 patients (36.4%); all such events were grade 1 or 2.”

In the paper

“The median time until the onset of cytokine release syndrome was 2 days (range, 1 to 6) after the most recent dose, and the median duration was 2 days (range, 1 to 9).”

In the paper

“Investigator-assessed neurotoxic events, including immune effector cell–associated neurotoxicity syndrome, were reported in 24 patients (14.5%).”

• Also stated in: § RESULTS · plain

  “Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).”

In the paper

“anemia (in 86 [52.1%])”

• Also stated in: § RESULTS · plain

  “anemia (in 52.1%; grade 3 or 4, 37.0%)”

In the paper

“The median time until the first response was 1.2 months (range, 0.2 to 5.5), and the median time until a best response was 3.8 months (range, 1.1 to 16.8).”

In the paper

“One patient had a dose reduction during cycle 21 because of recurrent neutropenia, and 104 patients (63.0%) skipped a dose because of adverse events. Two patients discontinued teclistamab because of adverse events (grade 3 adenoviral pneumonia and grade 4 progressive multifocal leukoencephalopathy).”

In the paper

“As of March 16, 2022, 70 patients (42.4%) were continuing to receive treatment (Fig. S1), with a median treatment duration of 8.5 months (range, 0.2 to 24.4).”

In the paper

“Infections occurred in 126 patients (76.4%); 74 patients (44.8%) had grade 3 or 4 infections.”

• Also stated in: § RESULTS · plain

  “Infections were frequent (in 76.4%; grade 3 or 4, 44.8%).”

In the paper

“The overall depth of response was highlighted by the observation that 26.7% of the patients were found to have no minimal residual disease at a sensitivity level of 10−5; these patients made up 82% of those in whom minimal residual disease could be evaluated.”

In the paper

“Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2.”

• Also stated in: § DISCUSSION · plain

  “Toxic effects were also common but were mainly of low grade and reversible.”

In the paper

“The sponsor established a safety evaluation team to monitor patient safety throughout the phase 1 study. In phase 2, safety was monitored through continuous review by the sponsor.”

In the paper

“In addition, subgroup analyses suggest that patients who have received no more than three previous therapy lines may have a better response rate than those who have received more than three therapies, a finding that supports the use of teclistamab in earlier therapy lines (although the confidence intervals for this finding are wide).”

In the paper

“Teclistamab redirects CD3+ T cells to BCMA+ myeloma cells, resulting in T-cell activation and subsequent lysis and death of BCMA+ cells.18”

What the sources say

• ?Not checked — no full text of the sourcecites [18] source

In the paper

“The study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation.”

In the paper

“Toxic effects were also common but were mainly of low grade and reversible.”

In the paper

“The median relative dose intensity was high, and dose reductions and discontinuations owing to adverse events were infrequent.”

In the paper

“The safety and efficacy populations for this analysis included all the patients who had received at least one dose of teclistamab at the recommended phase 2 dose in phase 1 or phase 2 as of September 7, 2021.”

In the paper

“Response rates were also compared across various prespecified subgroups, including those defined according to cytogenetic risk, refractory status, and number of previous lines of therapy.”

In the paper

“For phase 2, we determined that a sample size of 100 patients would provide a power of at least 85% to establish an overall response rate of more than 30% at a one-sided significance level of 0.025, assuming an overall response rate of at least 45%.”

In the paper

“Adverse events in this phase 1–2 trial were common and included low-grade cytokine release syndrome and grade 3 or 4 cytopenia and infection in a patient population that has an increased susceptibility to infection due to the immunodeficiency associated with myeloma and immunosuppressive effects of previous myeloma therapies.23”

What the sources say

• ?Not checked — no full text of the sourcecites [23] source

In the paper

“Negativity for minimal residual disease was assessed by next-generation sequencing of DNA obtained from bone marrow aspirate (clonoSEQ assay, version 2.0 [Adaptive Biotechnologies]) with a threshold of 10−5 cells.”

In the paper

“The study protocol, amendments, and relevant documents were approved by the local independent ethics committee or institutional review board at each study site. All the patients provided written informed consent.”

In the paper

“All the authors affirm that the trial was conducted in accordance with the study protocol and vouch for the accuracy and completeness of the data.”