Citations

Purpose: Part II of this consensus aimed to provide recommendations for the prevention of meniscus injuries, nonoperative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures. Methods: This consensus followed the European Society of Knee Surgery, Sports Traumatology and Arthroscopy (ESSKA) formal consensus methodology. For this combined ESSKA—American Orthopedic Society for Sports Medicine (AOSSM)—American Academy of Sports Physical Therapy (AASPT) initiative, 67 experts from 14 countries, including orthopedic surgeons and physiotherapists, were involved. The 26 Steering Group members established guiding questions, screened the existing evidence, and proposed statements, and provided Grades of recommendations. The 41 Rating Group members assessed the statements according to a Likert scale (1–9). Final documents were assessed by an international peer review group for geographical adaptability. Results: Low to moderate scientific level of evidence was available, so that grades of recommendations were low (3 Grade A ratings, 4 Grade B, 3 Grade C and 13 Grade D), underlining the relevance of this consensus. One strong and 17 relative agreements with overall median of 8 (8–9) and a mean of 7.92 ± 0.37 were achieved for 23 statements on 18 questions. Prevention of meniscus injuries is possible with general knee injury reduction programs and through avoidance of certain activities. Non-operative treatment including physical therapy is the first line approach for degenerative meniscus lesions and may be an option for some acute tears. Return to sports after meniscus tear surgery should be both criterion-based and timebased. Patient reported outcomes in combination with performance-based measures are recommended to evaluate the rehabilitation process. Conclusion: This international EU–US consensus established recommendations for prevention strategies, describes rehabilitation of nonoperated patients and of patients after partial meniscectomy, meniscus repair and meniscus reconstruction, and establishes return to sport criteria. These updated and structured recommendations may be applied by surgeons and physiotherapists. Level of Evidence: Level I, consensus.

AbstractPurposePart two of this consensus aimed to provide recommendations for the prevention of meniscus injuries, non‐operative treatment of acute tears and degenerative lesions, return to sports and patient‐reported outcome measures.MethodsThis consensus followed the European Society of Knee Surgery, Sports Traumatology and Arthroscopy (ESSKA) formal consensus methodology. For this combined ESSKA—American Orthopedic Society for Sports Medicine (AOSSM)—American Academy of Sports Physical Therapy (AASPT) initiative, 67 experts from 14 countries, including orthopedic surgeons and physiotherapists, were involved. The 26 Steering Group members established guiding questions, screened the existing evidence, and proposed statements, and provided Grades of recommendations. The 41 Rating Group members assessed the statements according to a Likert scale (1–9). Final documents were assessed by an international peer review group for geographical adaptability.ResultsLow to moderate scientific level of evidence was available, so that grades of recommendations were low (three Grade A ratings, four Grade B, three Grade C and 13 Grade D), underlining the relevance of this consensus. One strong and 17 relative agreements with overall median of 8 (8–9) and a mean of 7.92 ± 0.37 were achieved for 23 statements on 18 questions. Prevention of meniscus injuries is possible with general knee injury reduction programmes and through avoidance of certain activities. Non‐operative treatment including physical therapy is the first line approach for degenerative meniscus lesions and may be an option for some acute tears. Return to sports after meniscus tear surgery should be both criterion‐based and time‐based. Patient reported outcomes in combination with performance‐based measures are recommended to evaluate the rehabilitation process.ConclusionThis international EU–US consensus established recommendations for prevention strategies, describes rehabilitation of non‐operated patients and of patients after partial meniscectomy, meniscus repair and meniscus reconstruction, and establishes return to sport criteria. These updated and structured recommendations may be applied by surgeons and physiotherapists.Level of EvidenceLevel I, consensus.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

PURPOSE To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166 ) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI). METHODS Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C trough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C trough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C trough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption. CONCLUSION IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3′ UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43–driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.

1001 Background: Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who had disease progression on or after aromatase inhibitor-based therapy, showed significant progression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrant or exemestane) in pts with ESR1 mutations ( ESR1 m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1 m. Exploratory PRO analyses are presented here. Methods: EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and ≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting 0 (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE. Results: In pts with ESR1 m, imlu monotherapy was associated with many improved or maintained EORTC QLQ-C30 scores, whereas scores with SOC were declined or maintained. Specifically, pts with ESR1 m on imlu had improved global health status (GHS)/quality of life (QOL) and physical function (PF) scores, while scores with SOC declined (mean change differences between treatments: 9.9 [0.1, 19.7] and 6.2 [-0.8, 13.1], respectively). These PRO findings mirror the PFS findings in this group. In the overall population, GHS/QOL scores declined similarly with imlu vs SOC (mean change differences: 0.5 [-4.7, 5.7]), while PF scores were maintained with imlu vs a slight decline with SOC (mean change difference: 2.5 [-1.1, 6.1]). Most fulvestrant recipients (72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2], respectively). Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%). Conclusions: PROs from EMBER-3 demonstrated that patients with ESR1 m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC. Clinical trial information: NCT04975308 .

7506 Background: IV Isa-Pd is approved to treat RRMM patients (pts) based on the ICARIA-MM study. A Phase 1b study showed safety and efficacy of Isa SC via an OBDS, an investigational wearable bolus injector, plus Pd, in RRMM pts. Isa SC offers shorter duration, fixed dose and smaller administration volume. Here, we report results of the IRAKLIA trial (NCT05405166); Isa SC vs IV + Pd in RRMM pts, the first Phase 3 myeloma trial reporting the use of an OBDS. Methods: This multicenter, open-label study enrolled pts aged ≥18 years with ≥1 prior line of therapy (LOT). Pts were randomized 1:1 to Isa SC (1400 mg) or Isa IV (10 mg/kg) weekly in Cycle (C)1, then every 2 weeks + P (4 mg/day, Day [D]1–21) + d (40 mg [20 mg if age ≥75 years] weekly). Pts had 4-week cycles until progression, unacceptable toxicity or patient request. Co-primary endpoints were overall response rate (ORR; non-inferiority [NI] margin of 0.839) and Isa trough level (C trough ) at steady state (predose at C6D1; NI if lower limit of 90% CI of geometric mean ratio ≥0.8). Results: 531 pts (SC n=263; IV n=268 [4 not treated]) were randomized. Baseline characteristics were balanced (median age 66 years; median 2 prior LOT). After median 12 months follow-up, ORR was 71% (SC arm) and 71% (IV arm; relative risk [95% CI] = 1.008 [0.903–1.126]; lower CI > NI margin). Mean (SD) C trough at C6D1 was 499 (259) μg/mL for SC and 340 (169) μg/mL for IV. C trough geometric mean ratio (90% CI) was 1.532 (1.316–1.784); lower CI > NI margin. Co-primary and all 4 key secondary endpoints including pt experience are in the Table. Grade ≥3 treatment-emergent adverse events occurred in 82% (SC) and 76% (IV) of pts; with treatment discontinuation rates of 8% and 9%. Injection site reactions (ISRs) occurred in 4% (11/263) of the SC arm and in 19 (0.4%) of 5145 SC injections (all Grade 1–2). 99.9% of OBDS injections were completed without interruption. Conclusions: IRAKLIA met its co-primary endpoints, showing efficacy and pharmacokinetic NI between Isa SC vs IV + Pd. No new safety signal besides a low ISR incidence was observed, showing excellent Isa SC tolerability. Far fewer infusion reactions and higher pt satisfaction were also noted for SC vs IV. Efficacy and safety are comparable to Isa IV in ICARIA-MM. These results support potential use of Isa SC delivered via the OBDS, designed to improve pt experience and practice efficiency. Clinical trial information: NCT05405166 . Isa SC + Pd Isa IV + Pd Efficacy, % N=263 N=268 ORR 71 71 ≥VGPR 46 46 PK*, µg/mL N=131/121 N=126/121 Geometric mean Isa C trough at C2D1 / C6D1 360/426 277/278 Safety, % N=263 N=264 All grade IR 2 25 Pt satisfaction with injection method at C5D15, % 70 53 *PK was analyzed at C6D1 with PP PK population and at C2D1 with PP CT4W population. CT4W, C trough at 4 weeks; IR, infusion reaction; PK, pharmacokinetics; PP, per protocol; VGPR, very good partial response.

3116 Background: Pralsetinib is an oral tyrosine kinase inhibitor that selectively and potently targets oncogenic RET fusion and mutation proteins. RET fusions or mutations are present in various tumor types. We report the final results from the phase 2 portion of ARROW, a phase 1/2, open-label, multi-cohort, dose-expansion study evaluating the efficacy and safety of pralsetinib (NCT03037385) in patients with RET fusion-positive solid tumors other than non-small-cell lung cancer (NSCLC) and thyroid cancer. Methods: Eligible pts were ≥18 years of age with a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, had previously received standard of care appropriate for their tumor type, and were not eligible for any other study groups. Overall response rate (ORR) and safety were primary endpoints of the study. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The final database lock was May 20, 2024. Results: Twenty-nine patients were enrolled with 11 different solid tumor histologies. Twenty-six (90%) received prior systemic therapy. Median age was 58 years (range 25-75); 59% were female. Twenty-eight patients were included in the efficacy analysis. ORR (by RECIST) was 46.4% (13/28); 10.7% (3/28) achieved complete response (pancreatic cancer, n=2; cancer of unknown primary, n=1) and 35.7% (10/28) achieved partial response. Median PFS was 7 months (95% CI: 3.9, 12.8). Median DOR was 11.1 months (95% CI: 5.5, 25.1). Median OS was 10.3 months (95% CI: 6.8, 25.2). Twenty-five (86%) patients experienced treatment-related adverse events (TRAEs); 19/29 (66%) reported TRAEs ≥grade 3. The most common TRAEs included increased aspartate aminotransferase (11/29; 38%), increased alanine aminotransferase (10/29; 35%), and anemia (9/29; 31%). Four (13.8%) patients experienced hypertension, and 1 (3.4%) patient had ≥grade 3 hypertension. No new safety risks were identified; AEs remained manageable with supportive care and/or dose modifications. Conclusions: In the phase 2 portion of this trial, responses were observed in many tumor types (Table). Pralsetinib demonstrated robust and durable anti-tumor activity with an ORR of 46.4%. These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition and activity beyond NSCLC and thyroid cancer, further supporting the promising potential of pralsetinib to address the unmet medical need in these patients. Clinical trial information: NCT03037385 . Overall response rate by tumor type. Cancer Type (patient n) ORRn (%) Pancreatic (5) 5 (100) Cancer of unknown primary (1) 1 (100) Neuroendocrine (3) 2 (67) Sarcoma (3) 2 (67) Head and neck (2) 1 (50) Small cell lung (2) 1 (50) Hepatobiliary (4) 1 (25) Colorectal (5), gastric (1), ovarian (1), thymic (1) 0

Purpose The aim of part-one of this EU-US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programs, non-operative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures (PROMS) will be presented in a part-II article. Methods This consensus followed ESSKA “formal consensus” methodology. For this combined ESSKA (European Society for Sports Traumatology and Arthroscopy), AOSSM (American Orthopedic Society for Sports Medicine), ASSPT (American Academy of Sports Physical Therapy) initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (USA and 13 European countries) including orthopedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature, proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations reaching final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to adress the geographical adaptability. Results The overall level of evidence of the literature was low. Of the 19 questions (leading to 29 statements), one received a grade A of recommendation, two a grade B, nine a grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1-9) and the global mean rating was 8.4+/-0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion-based rehabilitation protocol, based on milestones rather than a time-based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion-based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated, and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence I, Consensus.

Abstract Purpose The aim of part one of this EU‐US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programmes, non‐operative treatment of acute tears and degenerative lesions, return to sports and patient‐reported outcome measures will be presented in a part II article. Methods This consensus followed the European Society for Sports Traumatology and Arthroscopy (ESSKA)'s ‘formal consensus’ methodology. For this combined ESSKA, American Orthopedic Society for Sports Medicine and American Academy of Sports Physical Therapy initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (US and 13 European countries), including orthopaedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature and proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations, reaching a final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to address the geographical adaptability. Results The overall level of evidence in the literature was low. Of the 19 questions (leading to 29 statements), 1 received a Grade A of recommendation, 2 a Grade B, 9 a Grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1–9). The global mean rating was 8.4 ± 0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion‐based rehabilitation protocol, based on milestones rather than a time‐based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion‐based milestones. Conclusion Rehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery. Level of Evidence Level I, consensus.