EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma.

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

Management of DOAC-related bleeding in cancer patients: a single center-case series.

Venous thromboembolism (VTE) and stroke carry significant mortality and morbidity in cancer patients. Direct oral anticoagulants (DOACs) have been demonstrated to be effective for the treatment of VTE and prevention of stroke in atrial fibrillation (AF). Bleeding rates are variable and are based on the cancer type and the patient's specific risk factors. There are approved specific antidotes for DOAC-associated bleeding. Other strategies are available for bleeding reversal, including the use of prothrombin complex concentrate (PCC). No randomized studies have compared head-to-head the efficacy and safety of reversal agents. We aim to examine the safety and effectiveness of hemostatic agents in cancer patients with DOAC-related major bleeding. A retrospective chart review study of patients at MD Anderson Cancer Center with DOAC-related major bleeding between 2014 and 2019. Bleeding severity and clinical hemostasis were described based on ISTH guidelines and the Sarode criteria, respectively. The rates of thrombotic complications and mortality at 30-day from the index bleeding event were described. We identified 23 patients with DOAC-related major bleeding; 14 patients received PCC and 9 patients received andexanet alfa. The most common sites of bleeding were the gastrointestinal tract and intracranial. Effective hemostasis and 30-day mortality were similar to reported results from other reports of outcomes of reversal agents for DOAC related-bleeding in non-cancer patients. One patient in each treatment group experienced a thrombotic event. Further larger scale studies are needed to confirm our findings in cancer patients.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

t(11;14) status is stable between diagnosis and relapse, and concordant between detection methodologies based on fluorescence in situ hybridization and next-generation sequencing in patients with multiple myeloma.

Multiple myeloma (MM) is associated with a wide variety of recurrent genomic alterations. The most common translocation in MM is t(11;14). In this retrospective, single-center, non-interventional study, patient bone marrow samples were examined at diagnosis and at relapse(s) following treatment with anti-myeloma regimens to determine whether t(11;14) status was stable over time. This Stability Cohort consisted of 272 patients, of whom 118 were t(11;14)-positive at diagnosis and 154 were negative. All patients in the Stability Cohort retained the same t(11;14) status at relapse that they had at diagnosis of MM. Sixteen patients who had t(11;14)-positive MM at diagnosis had multiple longitudinal FISH assessments at relapse events, which remained t(11;14)-positive across all time points. Patients who had t(11;14)-positive disease at diagnosis of monoclonal gammopathy of unknown significance (MGUS) or smoldering multiple myeloma (SMM) also retained t(11;14) positivity through MM diagnosis and relapse. The t(11;14) fusion patterns also remained constant for 90% of patients. For detection of t(11;14), results from fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) were compared to determine the rate of concordance between these 2 methods. This Concordance Cohort contained 130 patients, of whom 66 had t(11;14)-positive disease and 64 were t(11;14)-negative. In this sample set, the concordance between FISH and NGS-based detection of t(11;14) was 100%. These results strongly suggest that the t(11;14) rearrangement remains stable during the full disease course in patients with multiple myeloma and can be detected by FISH- and NGS-based methodologies.

Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

No pain, no gain: The military overtraining hypothesis of musculoskeletal stress and injury.

The purpose of this manuscript is to present a model of military overtraining and subsequent injury, discharge, and disability. Military training and combat operations are physically and physiologically demanding, placing great strain on the musculoskeletal system of warfighters. Non-battle musculoskeletal injuries (MSKI) are common and present a serious threat to operational readiness in today's military. MSKI risk stratification and prevention are an active area of research and is steeped in the background of sports science. Here, a model is proposed that incorporates the theory of General Adaptation Syndrome to describe how military training stressors may exceed that of training in traditional athletics and may induce sub-optimal training stressors. Positive feedback loops are discussed to explain how military overtraining (MOT) creates a system of ever-increasing stressors that can only be fully understood in the greater context of all environmental factors leading to overtraining. The Military Overtraining Hypothesis (MOTH) is proposed as a model that encapsulates the elevated MSKI risk in combat arms and other operational military personnel as an effort to broaden understanding of multifactorial military MSKI etiologies and as a tool for researchers and commanders to contextualize MSKI research and risk mitigation interventions.

Comparisons and Intercorrelations of Physical Performance Variables of Operational Preparedness in Special Operations Forces.

INTRODUCTION: Marine Forces Special Operations Command (MARSOC) deploys teams of operators (OP) and enablers (EN) to accomplish special operations missions. OP and EN are required to train and deploy together to accomplish these missions; however, they have different training and selection pipelines. Advanced strength and conditioning training strategies are applied to both OP and EN to enhance physical preparedness; however, it is unclear how the selection pipeline of these two personnel types affects overall physical preparedness and the relationships between performance variables. The purpose of this study is to gain a greater understanding of the relationships of a wide array of physical preparedness variables in OP and EN in an effort to streamline testing and training strategies. MATERIALS AND METHODS: For this study, 155 male (82 OP, 73 EN) MARSOC personnel (age: 29.5 ± 4.9 years, mass: 87.9 ± 11.1 kg, height: 1.79 ± 0.07 m) completed a physical preparedness assessment that included a DEXA assessment of body composition (BF%), 27.4 m sprint (30 yd), countermovement jump (VJ), 5-10-5 pro-agility (Agility), medicine ball toss (UBP), isometric mid-thigh pull (IMTP), and a 30 second (AnC) and 5 minute (AC) non-motorized treadmill run. Independent samples t tests, Mann-Whitney U tests, and Spearman's Rank correlations were used to compare variables between OP and EN. RESULTS: OP demonstrated greater VJ, UBP, IMTP, AnC, and AC (P < 0.05); and significantly lower BF% and agility time (P < 0.05). Measurements of mass, height, body mass index, and 30 yd were not significantly different (P > 0.05). Weak to moderate correlations were seen between anthropometric and performance variables. OP and EN demonstrated similar correlations for most performance and anthropometric variables. CONCLUSIONS: These results suggest that MARSOC OP demonstrate better physical preparedness over EN, while similar trends are observed between performance variables. Tests with moderate to high correlations may be removed from the protocol to account for testing time constraints. Height, weight, and BF% variables are poorly correlated with performance, particularly in OP, questioning their value in physical performance assessments in this population.

Return to Sports After Total Hip Arthroplasty: An Umbrella Review for Consensus Guidelines.

BACKGROUND: Current recommendations on safe return to sports (RTS) after total hip arthroplasty (THA) are subjective and based on studies of varying quality. PURPOSE: The aim of this study was to synthesize systematic reviews and meta-analyses on post-THA RTS to propose practice guidelines identifying which sports can be resumed, when they can be resumed, and what risks are present. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: This umbrella review followed the Joanna Briggs Institute (JBI) protocol and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The Embase, Medline, and Cochrane databases were searched. Included studies were either systematic reviews or meta-analyses addressing primary or secondary outcomes. Outcomes of interest included safe sports after THA, time to RTS, prognostic indicators of RTS, reasons patients do not RTS, percentage of patients who RTS, implant complications, and objective classification of sports by impact level. Included reviews had data extracted and were assessed for methodological quality using the JBI protocol. The authors defined RTS as "returning to a sport the patient participated in at any point preoperatively." RESULTS: Patients demonstrated a trend toward lower-impact sports postoperatively. Sports were classified as low (eg, walking), moderate (eg, downhill skiing), or high impact (eg, soccer). A total of 82% (range, 55%-104%) of patients were able to RTS at a mean time of 6 months (range, 4-7 months). The best prognostic indicator for RTS was previous experience in that sport. The main reason patients did not RTS was surgeon recommendation. Aseptic loosening was the most cited complication after RTS. CONCLUSION: Most patients are able to return to preoperative levels of low- (eg, walking) and moderate-impact (eg, hiking) sports between 7 and 12 months after THA. Patients planning a return to high-impact (eg, singles tennis) sports should be counseled on the possible risks of traumatic injuries and aseptic loosening and monitored closely.

"Nailable" Does Not Always Mean Reducible in Distal Femur Fractures: Arthroplasty Component and Nail Design Matter.

Distal femur fractures above a total knee arthroplasty (TKA) are challenging. These fractures can be fixed with a retrograde intramedullary nail (rIMN), but the design of the femoral component of the TKA influences the starting point for an rIMN. We performed a biomechanical study to evaluate how different TKA components influence the starting point for an rIMN and how that can lead to a deformity in the sagittal plane. We simulated a distal femur fracture with three different arthroplasty components. We used three different implants to simulate fracture reduction and measured the resultant sagittal plane deformity. Low and moderate femoral component ratio (FCR) design components were able to maintain fracture alignment within 5° of anatomic. High FCR component (more posterior starting point) sagittal plane deformities of up to 15° were observed with both the straight and medium Herzog bend nails, which was statistically significant (P<.001). Use of a high Herzog bend nail decreased the deformity by an average of 6°, which was statistically significant (P<.001). There is variability in how the TKA design affects the starting point and thus the sagittal plane alignment after fixation. This study helps quantify the effect of arthroplasty component design on fracture alignment. [Orthopedics. 2023;46(1):35-38.].

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Total Knee Arthroplasty Complicated by Posterior Dislocation of a Polyethylene Insert and Neurovascular Compromise.

Dislocation of the polyethylene insert is a rare complication of total knee arthroplasty (TKA), which has only been described in a handful of case reports. Here, we describe a report of a 55-year-old woman presenting 13 months after the primary TKA with signs of neurovascular compromise. A magnetic resonance image showed posterior extrusion of her polyethylene insert causing a mass effect on the gastrocnemius muscle and the popliteal neurovascular bundle. A multidisciplinary team including a joint reconstruction surgeon, vascular surgeon, and nerve specialist performed a revision TKA with peroneal nerve decompression. The polyethylene insert was noted to be dislocated, rotated 90 degrees, and incarcerated in the posterior knee.

Training Strategies Maintain Performance Characteristics in Marines Selected for Marine Forces Special Operations Individualized Training Course.

INTRODUCTION: Marines must complete an intensive Assessment and Selection (A&S) course before becoming a U.S. Marine Forces Special Operations Command (MARSOC) Raider. Following selection, marines are given training recommendations designed to maintain performance characteristics deemed relevant to successfully complete a rigorous 9-month Individualized Training Course (ITC). However, training strategies are individually implemented by the marine, and the time between the two courses is highly irregular, ranging between 2 months and 24 months based on operational factors related to military occupational specialty (MOS). The purpose of this study was to evaluate changes in performance between the completion of A&S and the start of ITC and to examine if the duration between courses and previous MOS influenced changes in performance. MATERIALS AND METHODS: Body fat percentage (BF%), anaerobic power (AP), anaerobic capacity (AC), aerobic capacity (VO2max), knee flexion (KF), knee extension (KE), trunk extension (TE), and trunk flexion (TF) isokinetic strength were collected on 38 marines (age: 25.1 ± 2.7 years, height: 1.77 ± 0.05 m, mass: 83.2 ± 7.7 kg, Post-A&S to ITC start: 204.1 ± 68.4 days) following A&S and directly before ITC. RESULTS: Pre-ITC students had significantly greater mass (P = .002), BF% (P = .000), and AP (P = .039). There were no significant changes in AC (P = .170), VO2max (P = .259), KF (P = .400), KE (P = .320), TE (P = .178), and TF (P = .643). There was no significant relationship between performance outcomes and time between courses and previous MOS. CONCLUSION: Current training strategies appear effective at addressing performance deficits that occur as a result of A&S, while maintaining high levels of KF, KE, TE, TF, AC, and VO2max. However, pre-ITC students still exhibited AP deficits compared to active marine raiders, so forthcoming programming may benefit from an increased emphasis on AP. Assessment of additional selectees at these timepoints, as well as students before A&S may provide valuable information to MARSOC human performance specialists to develop programing, ultimately leading to a higher ITC graduation rate, increased force readiness, and decreased financial burden forcewide.

Asymmetrical Loading Patterns in Military Personnel With a History of Self-Reported Low Back Pain.

BACKGROUND: Servicemembers are required to operate at high levels despite experiencing common injuries such as chronic low back pain. Continuing high levels of activity while compensating for pain may increase the risk of musculoskeletal injuries. As such, the purpose of this project was to determine if servicemembers with chronic low back pain have reduced lower extremity performance, and if they use alternate strategies to complete a functional performance task as compared to healthy servicemembers. METHODS: Of a total of 46 male United States Marine Corps Forces Special Operations Command (MARSOC) personnel, 23 individuals who suffered from chronic low back pain (age = 28.6 ± 4.4 years, weight = 84.2 ± 6.8 kg) and 23 healthy controls (age = 27.9 ± 3.8 years, weight = 83.8 ± 7.7 kg) completed a stop jump task. In this task, three-dimensional biomechanics were measured, and lower extremity and trunk strength were assessed. RESULTS: The low back pain group exhibited higher vertical ground reaction force impulse on the dominant limb (0.26% body weight [BW]/s), compared to the nondominant limb (0.25% BW/s, p = .036). The control group demonstrated relationships between jump height and strength in both limbs (dominant: r = 0.436, p = .043; nondominant: r = 0.571, p = .006), whereas the low back pain group demonstrated relationships between jump height and dominant limb knee work (r = 0.470, p = .027) and ankle work (r = 0.447, p = .037). CONCLUSIONS: This study demonstrates that active-duty MARSOC personnel with a history of low back pain reach similar levels of jump height during a counter movement jump, as compared to those without a history of low back pain. However, the asymmetries displayed by the low back pain group suggest an alternate strategy to reaching similar jump heights as compared to healthy individuals.

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Venetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM. PATIENTS AND METHODS: This phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy. RESULTS: Eight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months. CONCLUSIONS: Given the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14).

PURPOSE: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.

Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies.

INTRODUCTION: Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs. METHODS: We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used. RESULTS: Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity. CONCLUSION: Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs. IMPLICATIONS FOR PRACTICE: As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.

Radiographic False Evidence of a Tibial Baseplate Fracture After Total Knee Arthroplasty.

Fracture of the tibial baseplate is a rare but dramatic cause of typically late fatigue failure in the setting of loosening after total knee arthroplasty. A 58-year-old female presented 4 months after total knee arthroplasty for evaluation of contralateral knee pain. Plain radiographs of the left knee incidentally suggested the possibility of tibial baseplate fracture despite minimal, expected postoperative symptoms. Subsequent computed tomography imaging demonstrated no confirmatory evidence of component failure or fracture. Malalignment and fatigue fracture are proposed etiologies of baseplate fractures. The presented case illustrates the importance of computed tomography imaging and clinical correlation when a diagnosis of baseplate fracture is suspected to avoid an unnecessary revision surgery.