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Aim: Chronic postsurgical pain (CPSP) is a common complication of surgery. This study was conducted to evaluate the efficacy and safety of paresthesia-free, 10-kHz spinal cord stimulation (SCS) as a treatment for CPSP. Patients & methods: Subjects in this prospective, single-arm study had an average pain intensity of ≥5 cm on a 10-cm visual analog scale. The subjects who had pain relief of ≥50% (response) with temporary trial stimulation were permanently implanted with 10-kHz SCS and assessed for 1 year. Results: At 12 months, 94% of subjects were responders to 10-kHz SCS, and 88% had pain remission (visual analog scale ≤2.5 cm). Conclusion: The pain relief was durable in CPSP subjects and the safety profile of 10-kHz SCS was as expected. Clinical Trial registration number: VT005076953 (Privacy Commission of Belgium)

BACKGROUND Refractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM. MATERIALS AND METHODS Twenty adults with rCM (mean numbers of preventive treatments failed: 12.2 ± 3.1) were enrolled in this single-center, open-label, prospective study and implanted with a 10 kHz SCS system (Senza™ system, Nevro Corp.), with the distal tip of the lead(s) positioned epidurally at the C2 vertebral level. Safety and effectiveness outcomes, such as adverse events, headache and migraine reductions, responder rates, Migraine Disability Assessment (MIDAS), Headache Impact Test-6 (HIT-6), and Migraine-Specific Quality-of-Life (MSQ), were captured up to 52 weeks after implantation. RESULTS Compared to baseline, at 52 weeks postimplantation, there was a significant reduction of mean monthly migraine days (MMD) by 9.3 days (p

Aim: It is argued that chronic pain patients who reduce/eliminate their opioids may have compromised pain relief. This study therefore aimed to analyze if reduced opioid consumption associated with 10-kHz spinal cord stimulation adversely affected pain relief. Methods: Post hoc analysis was performed on data from two prospective studies in subjects with upper limbs and neck pain conducted in USA. Results & conclusion: A 10-kHz spinal cord stimulation treatment was associated with reduction in mean visual analog scale scores for upper limbs and neck pain and mean daily opioid consumption. Pain scores decreased in subjects who decreased opioid use and in those who maintained/increased use. Opioid reduction and pain relief was also achieved in subjects taking >90 mg morphine equivalents of opioids at baseline.

Background. Spinal cord stimulation (SCS) has been used over decades for pain management, but migration of percutaneous leads has been the most common complication. Better surgical techniques and newer SCS technologies likely reduced the incidence of lead migration requiring surgical revision, although data are sparse. This study aimed to retrospectively evaluate the incidence of clinically significant percutaneous lead migration in patients permanently implanted with a 10 kHz SCS system. Methods. Consecutive patients with chronic trunk and/or limb pain, permanently implanted between January 2016 and June 2019, were included in the analysis. Data were collected from the hospital’s electronic medical records and the manufacturer’s database. Clinically significant lead migration, defined as diminished pain relief followed by surgery to correct lead location, was assessed at the 6-month follow-up. Results. At the 6-month follow-up, there were no cases of clinically significant lead migration, average pain relief was 65.2%, 82% of patients had response (≥50% pain relief), improvement of function was noted in 72% of patients, and decrease of medication was observed in 42% of patients. Therapy efficacy was sustained in patients with >12 months follow-up; the average pain relief was 58.5%, and the response rate was 82%. Conclusions. The surgical techniques in use today are designed to minimise the risk of percutaneous lead migration and may have reduced its incidence. In addition, new SCS systems may give greater opportunity to mitigate cases of minor lead movement using alternative stimulation programs.

Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8(+) and CD4(+) T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.

Introduction Persistent back/and or leg pain is a common outcome after spinal surgery (otherwise known as failed back surgery syndrome [FBSS]). Studies have shown that spinal cord stimulation (SCS) at 10 kHz provides effective analgesia in FBSS patients with both back and leg pain symptoms and in those with predominant back pain. This study is the first to evaluate the therapy in FBSS patients with predominant leg pain. Methods The safety and efficacy of 10 kHz SCS was evaluated in an uncontrolled, open‐label, prospective study of FBSS patients with predominant leg pain in the Netherlands. Follow‐ups were performed at 1, 3, 6, and 12 months post implantation. Results Sixty out of 68 patients (88%) experienced sufficient pain relief during a stimulation trial. Of these, 58 proceeded to permanent implantation of a 10 kHz SCS system. After 12 months of treatment, 80% of patients experienced ≥ 50% reduction in baseline leg pain, and a similar proportion (76%) experienced ≥ 50% reduction in baseline back pain. At least two‐thirds of patients were also leg pain and back pain remitters (visual analog scale [VAS] ≤ 2.5 cm). The therapy was also associated with a general improvement in patients’ quality of life, as measured by secondary outcomes including disability, perception of health improvement, mental well‐being, and satisfaction. A positive impact on opioid consumption was also observed. Conclusions Consistent with previous findings, 10 kHz SCS for the treatment of FBSS patients with predominant radicular symptoms is safe and effective and is associated with improved quality of life.

Background Chronic upper extremity pain (UEP) has complex etiologies and is often disabling. It has been shown that 10 kHz SCS can provide paresthesia-free and durable pain relief in multiple pain types and improve the quality of life of patients. Objective To gain additional evidence on the safety and effectiveness of 10 kHz SCS for the treatment of chronic UEP. Study design It was a prospective, multicenter, and observational study. The study was registered on ClinicalTrials.gov prospectively (clinical trial identifier: NCT02703818). Setting Multicenter. Patients intervention and main outcomes A total of 43 subjects with chronic UEP of ≥5 cm (on a 0-10 cm visual analog scale; VAS) underwent a trial of 10 kHz SCS, and subjects with ≥40% pain relief received a permanent implant. All subjects had upper limb pain at baseline, while some had concomitant shoulder or neck pain. Subject outcomes were assessed for 12 months, and the primary outcome was the responder rate (percentage of subjects experiencing ≥50% pain relief from baseline) at three months. Results Thirty-eight subjects successfully completed the trial (88.3% success rate), 33 received permanent implants (five withdrew consent), and 32 had device activation (per protocol population). There were no paresthesias or uncomfortable changes in stimulation related to changes in posture during the study and there were no neurological deficits. Responder rates at 12 months for upper limb, shoulder, and neck pain in per protocol population (N=32) were 78.1%, 85.2%, and 75.0%, respectively. At 12 months, 84.4% of subjects were satisfied or very satisfied with 10 kHz SCS, and 38.7% either reduced or eliminated opioid usage. Conclusion This study further supports the effectiveness of 10 kHz SCS for chronic UEP treatment and documents the safety profile of the therapy. Clinical trial identifier NCT02703818.

Aim: Previous studies of 10 kHz spinal cord stimulation demonstrated its safety and efficacy for treatment of neuropathic pain of the trunk and/or limbs. This study analyzed data from a subset of subjects with painful diabetic neuropathy enrolled in a prospective, multicenter study of peripheral polyneuropathy with various etiologies. Materials & methods: Of the eight subjects that had permanent devices, seven attended the 12-month follow-up assessment. Results & conclusion: At 12 months, 6/7 subjects were treatment responders (≥50% pain relief) and had pain remission (visual analog scale ≤ 3.0 cm). Worsening of neurologic deficits was not reported in any subject. Instead, 5/7 subjects showed improvements in sensory testing and/or reflexes. These results support further investigation of 10 kHz spinal cord stimulation as a safe and effective treatment for intractable painful diabetic neuropathy.

Background Chronic pelvic pain (CPP) is a debilitating condition that often leads to disability and does not respond to conventional treatments. This study was conducted to evaluate the effects of paresthesia‐independent 10‐kHz spinal cord stimulation (SCS) in subjects with CPP. Methods This prospective, single‐arm pilot study enrolled subjects with clinical diagnoses of CPP and mean pain scores of ≥ 5.0 cm on a 10‐cm VAS. Subjects underwent trial stimulations with 10‐kHz SCS, and those who had successful trial stimulations (≥40% pain relief) received permanently implanted devices and were followed for 12 months. Results Of the 21 subjects who underwent the 10‐kHz SCS trial, 17 were successful and 14 subjects received permanent implants. No neurological deficits were observed in any subjects and all adverse events (AEs) were resolved without sequelae during the study period. Over 12 months, mean VAS scores decreased by 72% from baseline, and 10 of 13 subjects (77%) were responders (≥50% pain relief). Pain remission (VAS score ≤ 3.0 cm) was reported by 8 of 13 subjects (62%), and mean pain scores on the short‐form McGill Pain Questionnaire 2 decreased as well. Pain Disability Index scores declined by 29 points, and 85% of the subjects reported satisfaction. Conclusions Paresthesia‐independent stimulation with 10‐kHz SCS reduced pelvic pain in subjects with CPP and was not associated with any unexpected AEs. While larger, controlled studies are needed, results of this study suggest that this therapeutic modality could potentially treat patients with CPP while improving their quality of life.

Background Patients living with chronic upper limb and neck (ULN) pain are reliant on often ineffective therapies as they face limited options for effective long-term treatment. Objective Prospective clinical studies have demonstrated that high-frequency spinal cord stimulation at 10 kHz (10 kHz SCS) is effective in treating chronic pain in multiple etiologies including ULN pain. This study aimed at validating the findings from clinical studies on ULN in a real-world cohort. Study design A retrospective, observational review. Setting A multicenter review between April 2016 and August 2019. Patients and methods Anonymized data were extracted from a real-world database of 47 consecutive patients aged ≥18 years of age with chronic upper limb and/or neck pain who were trialed and permanently implanted with 10 kHz SCS. Patient-reported pain relief, quality of life, function, sleep and medication use were extracted from anonymised patient records where available. Responder rates, defined as the proportion of patients with at least 50% pain relief at the end of trial and the last visit after implantation, were calculated. Results All patients reported successful response (≥50% pain relief) at the end of trial and >75% patients continued to respond to the therapy at the last follow-up period. Majority (72%) of patients reported improvement in function, about half of the patients (53%) reported improvement in sleep and one-third of the patients (36%) reported reducing their medication at last follow-up. Conclusion 10 kHz SCS provides durable pain relief to patients with chronic upper limb and neck pain.

Inhibitor of growth family member 3 (ING3), a tumor suppressor, plays crucial roles in cell cycle regulation, apoptosis and transcription. Previous studies suggest important roles of nuclear ING3, however, the nuclear localization sequence (NLS) of ING3 is not defined and its biological functions remain to be elucidated. In this study, various ING3 mutants were generated to identify its NLS. The NLS of ING3 was determined as KKFK between 164 and 167 amino acids. More intriguingly, replacement of Lysine 164 residue of ING3 with alanine (K164A) resulted in retention of ING3 in the cytoplasm. Overexpression of ING3 led to inhibition of melanoma cell migration, invasion, and angiogenesis respectively, however, this inhibition was abrogated in cells with overexpression of ING3-K164A mutant. In conclusion, this study identified the NLS of ING3 and demonstrated the significance of ING3 nuclear localization for tumor suppressive functions of ING3, and future studies await to elucidate the role of ING3 (K164) post-modificaton in its nuclear transportation and cancer development.

Summary Spinal cord stimulation at 10 kHz is a promising therapy for non‐surgical refractory back pain; however, published data are currently limited. We present a subanalysis of prospectively collected clinical outcome data for non‐surgical refractory back pain patients treated with 10 kHz spinal cord stimulation, from the independent cohorts of two previous studies (SENZA‐RCT and SENZA‐EU). Clinical outcomes were evaluated at pre‐implantation (baseline), 3 months, 6 months and 12 months following 10 kHz spinal cord stimulator implantation. These included: pain relief; responder rate (≥ 50% pain relief from baseline); remission rate (VAS ≤ 3.0 cm); disability (Oswestry Disability Index(ODI)); and opioid use. At 3 months, average back pain decreased by 70% in the combined cohort (60% in the SENZA‐RCT and 78% in the SENZA‐EU cohorts). This was sustained at 12 months, with a 73% back pain responder rate and 68% remission rate in the combined cohort. Leg pain relief results were generally comparable to those for back pain relief. At 12 months, the combined cohort had an average decrease in ODI scores of 15.7% points from baseline and opioid use more than halved. In conclusion, 10 kHz spinal cord stimulation reduced pain, disability and opioid consumption in non‐surgical refractory back pain subjects. Application of this therapy may improve the care of non‐surgical refractory back pain patients and reduce their opioid consumption.

Objective Chronic pain is a prevalent condition which has a significant effect on the lives of those it impacts. High‐frequency 10 kHz spinal cord stimulation (10 kHz SCS) has been shown to provide paresthesia‐free pain relief for a wide variety of pain indications. This article summarizes the current and emerging data as they relate to the clinical use of the therapy in various pain syndromes. Methods A literature search was conducted using the PubMed electronic database using keywords related to 10 kHz SCS. The database was queried from 2013 to May 2019. Articles reporting clinical studies that included human subjects permanently treated with 10 kHz SCS (Senza® system) were included in the review. Recent and relevant conference proceedings known to the authors were also included. Results The selected literature demonstrated significant evidence for the efficacy of 10 kHz SCS in treating chronic back and leg pain (CBLP), including a randomized, controlled trial as well as prospective and retrospective studies. One‐year follow‐up responder rates (pain relief ≥50%) ranged from 60% to 80%. Other studies and case series showed promising outcomes in specific conditions, including nonsurgical refractory back pain, neuropathic limb pain, complex regional pain syndrome, chronic widespread pain, chronic pelvic pain, and intractable headache. Subgroup analyses also pointed toward the potential of 10 kHz SCS being successful when low‐frequency SCS has failed. The vast majority of these studies reported improved quality of life (QOL) metrics and/or reduced opioid consumption. Conclusions Level I evidence already exists for the efficacy of 10 kHz SCS in treating CBLP, supported by real‐world clinical experience. Other studies demonstrate the potential of the therapy across a range of chronic pain etiologies, although larger confirmatory studies are recommended. Overall, the literature suggests that the therapy is associated with improved QOL as well as reduced opioid consumption.

The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age 1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50–100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.

The success of antibodies targeting Programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in cancer treatment and the need for improving response rates has led to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone. As more and more drugs with translational potential are identified, the number of clinical trials evaluating combinations has increased considerably and the demand to prioritize combinations having potential for success over the ones that are unlikely to be successful is rising. This review aims to address the unmet need to prioritize cancer immunotherapy combinations through comprehensive search of potential drugs and ranking them based on their mechanism of action, clinical efficacy and safety. As lung cancer is one of the most frequently studied cancer types, combinations that showed potential for the treatment of lung cancer were prioritized. A literature search was performed to identify drugs with potential in combination with PD-1/PD-L1 blockers and the drugs were ranked based on their mechanism of action and known clinical efficacy. Nineteen drugs or drug classes were identified from an internal list of lead molecules and were scored for their clinical potential. Efficacy and safety data from pivotal studies was summarized for the selected drugs. Further, overlap of mechanisms of action and adverse events was visualized using a heat map illustration to help screen drugs for combinations. The quantitative scoring methodology provided in this review could serve as a template for preliminary ranking of novel combinations. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02111-5.

Immune checkpoint blockers have dramatically improved the chances of survival in patients with metastatic cancer, but only a subset of the patients respond to treatment. Search for novel targets that can improve the responder rates and overcome the limitations of adverse events commonly seen with combination therapies, like PD-1 plus CTLA-4 blockade and PD-1/PD-L1 plus chemotherapy, led to the development of monoclonal antibodies blocking T-cell immunoglobulin and ITIM domain (TIGIT), a inhibitory checkpoint receptor expressed on activated T cells and NK cells. The strategy showed potential in pre-clinical and early clinical studies, and 5 molecules are now in advanced stages of evaluation (phase II and above). This review aims to provide an overview of clinical development of anti-TIGIT antibodies and describes the factors considered and thought process during early clinical development. Critical aspects that can decide the fate of clinical programs, such as origin of the antibody, Ig isotype, FCγR binding, and the dose as well as dosing schedule, are discussed along with the summary of available efficacy and safety data from clinical studies and the challenges in the development of anti-TIGIT antibodies, such as identifying patients who can benefit from therapy and getting payer coverage.

Honghui Feng,1 Patrick Doherty,1 Anand Rotte2 1Lawrence and Memorial Hospital, Yale New Haven Healthcare, New London, CT, USA; 2Nevro Corp., Redwood City, CA, USACorrespondence: Honghui Feng Email fenghonghui@yahoo.comBackground: Chronic pain is frequently treated with opioid analgesics, but there is limited evidence for efficacy for chronic use of opioids and the drugs pose significant risks to patients’ physical and mental health. Spinal cord stimulation delivered at a frequency of 10,000 Hertz (10 kHz SCS) is a minimally invasive therapy with demonstrated efficacy and safety in treating chronic pain that has also been associated with decreased opioid use.Objective: To evaluate opioid reduction and pain relief in real-world cohort.Study Design: Retrospective review.Setting: Single center.Patients and Methods: Consecutive patients who were implanted with 10 kHz SCS devices from December 1, 2015, to June 30, 2020 for the treatment of chronic pain in the trunk or lower limbs were included. Changes in opioid use following 10 kHz SCS treatment were extracted from electronic medical records, and patient-reported pain relief, improvement in function and sleep were extracted from manufacturer’s database. Responder rate was defined as the proportion of patients with at least 50% pain relief. Anonymised results from descriptive analysis of the data are reported.Results: At last follow-up (median 21.4 months), mean daily opioid dose fell by 48.4 morphine milligram equivalents (MME), and fewer patients used opioids. Mean pain relief in these patients was 57% ± 4%, and responder rate was 68% at last recorded follow-up. Interestingly, pain relief (66%) and responder rate (86%) were higher in patients with 1 year or more. Finally, 50% of patients reported improved sleep, and 73% reported improvement in function at last recorded follow-up after treatment with 10 kHz SCS.Conclusion: These results support 10 kHz SCS as a safe and effective treatment of chronic pain in real-world patients with secondary benefits to opioid consumption and measures of patients’ quality of life.Keywords: spinal cord stimulation, chronic pain, opioid analgesics, failed back surgery syndrome

Introduction Spinal cord stimulation (SCS) with lower thoracic leads has been studied extensively. However, the evidence base for cervical SCS is less well developed, and reports of multiarea SCS lead placement are uncommon. Therefore, this single-center retrospective study evaluated outcomes from 10-kHz SCS with cervical or combined cervical and thoracic lead placement. Method All patients that underwent a 10-kHz SCS trial with either cervical or combined cervical and thoracic lead placement between 2015 and 2020 were included in our study. We reviewed patient’s charts for demographic information, lead placement, and pain scores up to 48 months after implantation. Results Of the 105 patients that underwent a 10-kHz SCS trial during the review period, 92 (88%) had back/neck or extremity pain that responded to therapy (≥ 50% pain relief from baseline) and received a permanent system. Sixty-two of these patients (67%) were implanted with combined cervical and thoracic leads, while 30 (33%) received cervical-only leads. Pain relief in both regions exceeded 60% at most visits throughout the 48-month study period. Throughout follow-up, the responder rate in both pain areas was consistently ≥ 70%. No unexpected adverse events occurred. Conclusion The 10-kHz SCS provided effective and durable pain relief with either cervical or combined cervical and thoracic leads. The efficacy and safety profile of both applications appears to be comparable to lower thoracic SCS. Our results suggest that 10-kHz SCS is a useful paresthesia-free therapeutic option for chronic neuropathic pain originating in the cervical area, as well as more complex multiarea pain presentations.

Chronic pain is a common condition that affects the physical, emotional, and mental well‐being of patients and can significantly diminish their quality of life. Due to growing concerns about the substantial risks of long‐term opioid use, both governmental agencies and professional societies have recommended prioritizing the use of nonpharmacologic treatments, when suitable, in order to reduce or eliminate the need for opioid use. The use of 10 kHz spinal cord stimulation (10 kHz SCS) is one such nonpharmacologic alternative for the treatment of chronic, intractable pain of the trunk and limbs. This review examines published clinical data regarding the efficacy of 10 kHz SCS for decreasing chronic pain in patients and its potential to reduce or eliminate opioid usage. Multiple prospective and retrospective studies in patients with intractable pain demonstrated that 10 kHz SCS treatment provided ≥50% pain relief in >70% patients after at least 1 year of treatment. Pain relief with 10 kHz SCS therapy ranged from 54% to 87% in the studies. More importantly, the mean daily dose of opioids required by patients in these studies was reduced after 10 kHz SCS treatment, and on average over 60% patients in studies either reduced or eliminated opioids at the last follow‐up., The use of 10 kHz spinal cord stimulation (10 kHz SCS) is a nonpharmacologic alternative for the treatment of chronic, intractable pain of the trunk and limbs. This review examines published clinical data regarding the efficacy of 10 kHz SCS for decreasing chronic pain in patients and its potential to reduce or eliminate opioid usage.

Objective: In the treatment of chronic diseases, remission is commonly used as a meaningful treatment goal, synonymous with the absence of significant clinical signs and symptoms of a disease, but not representing a cure. The objective of this paper is to propose a definition for remission for use as an outcome to evaluate the long-term efficacy of therapies for chronic pain. Methods: Data from a randomized clinical trial (NCT01609972) testing the efficacy of spinal cord stimulation in low back and leg pain subjects was used to evaluate the association between pain and functional outcomes and identify the cut-off value to predict remission. Available data over 24-month assessment period included visual analog score (VAS), disability (Oswestry Disability Index [ODI]), patient and clinician global impression of change (PGIC and CGIC), and patient satisfaction. Cluster analysis, Pearson's correlation coefficients, sensitivity, and specificity analyses were used to evaluate its utility in predicting higher patient functionality and satisfaction. Results: Though the term remission has been used in the chronic pain field, a consistent definition has not been previously established. Based on the analysis of the clinical data, we propose that a sustained (≥6 months) pain score of ≤3.0 cm out of 10 cm on VAS be defined as remission. Applying this definition to the clinical trial data: subjects in remission at 24 months versus non-remitters were significantly more likely to be in the highest functional category of minimally disabled according to the ODI (31.5 vs. 8.2%, respectively, p = 0.001), and be 'very satisfied' (75.7 vs 22.6%, respectively, p < 0.001). Conclusions: The validity of the proposed definition of remission is supported by the persistence of remission in this study group, and its correspondence with patient satisfaction, and reduced disability. Further evaluation of the definition using clinical data from other long-term studies is needed.

Objectives High‐frequency spinal cord stimulation (HF‐SCS) at 10 kHz has proven to be efficacious in the treatment of chronic back and leg pain in a randomized, controlled, trial (SENZA‐RCT). However, large observational studies have yet to be published. Therefore, we performed a real‐world, multicenter, retrospective, review of therapy efficacy in 1660 patients with chronic trunk and/or limb pain. Methods Data were collected in a real‐world environment and retrospectively sourced from a global database. Included patients were trialed and/or permanently implanted with HF‐SCS at 10 kHz between April 2014 and January 2018. We evaluated responder rates at 3, 6, and 12 months post‐implantation. Response was defined as ≥50% pain relief from baseline. A last visit analysis included responder rate along with overall change in function, sleep, quality of life, and medication intake versus baseline. Results Eighty‐four percent of our HF‐SCS‐treated patients had both chronic back and leg pain. At least 70% of patients reported response to therapy throughout 12 months of follow‐up. This sustained responder rate was corroborated by the last visit value (74.1%). Most patients reported concomitant improvements in function (72.3%), sleep (68.0%), and quality of life (90.3%) at their last visit versus baseline. Thirty‐two percent of patients reported decreased medication intake at their last visit. Interpretation Sustained and effective pain relief was experienced by >70% of our HF‐SCS‐treated patients, consistent with the findings of a previously published randomized, controlled, trial. Our review provides complementary evidence to support the treatment of chronic back and leg pain with this therapy.

8003 Background: Chimeric Antigen Receptor (CAR) T cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated benefit in patients (pts) with relapsed and/or refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy that utilizes a novel, synthetic binding domain, called a D-Domain, instead of a typical scFv binder. The objective of this first-in-human trial is to assess the safety and efficacy of CART-ddBCMA. Methods: This is a Phase 1, multi-center, open label, dose escalation trial for pts with RRMM who have received ≥3 prior regimens or are triple-refractory. After apheresis, bridging therapy is allowed during manufacturing. Pts receive fludarabine and cyclophosphamide (30/300 mg/m2/day) days -5 to -3 and CART-ddBCMA infusion on day 0. Dose escalation was performed at 100 (DL1) and 300 (DL2) x 106 (± 20%) CAR+T cells, followed by expansion of DL1. The primary endpoint is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional endpoints are depth and duration of response (IMWG Criteria), minimal residual disease (MRD, clonoSEQ), progression-free (PFS) and overall survival (OS). Pts with 1- and 3-months follow-up were eligible for safety and efficacy analysis, respectively. Results: As of January 25, 2022, 25 pts received CART-ddBCMA, with median age 66 (range: 44-76), after a median of 5 prior lines of therapy (3-16), including 10 (40%) with extramedullary disease (EMD). Median follow-up was 9.8 (2-23.7) months. Overall, 25 pts (19 DL1; 6 DL2) were evaluable for safety and 24 (18 DL1; 6 DL2) for efficacy analysis. All pts experienced CRS, but only 1 pt (in DL2) had grade (gr) 3 CRS. All other CRS cases were gr ≤2, with no cases of gr ≥3 CRS in DL1. Four pts experienced ICANS (2, gr ≤2; 2, gr 3), with 1 gr 3 case in each of DL1 (5%) and DL2 (17%). Standard management resulted in resolution of CRS/ICANS within 30 days in all cases without sequelae. The ORR = 100%, sCR/CR rate = 67%, and ≥VGPR rate = 88%. Conversion to CR/sCR has occurred with longer follow-up, as late as month 9 in this trial. At time of data-cut 5 pts in DL1 with PR/VGPR have < 9 months follow-up, with 4 (of 4 evaluable) negative at ≥10-5 for MRD. Overall, 17 of 20 (85%) evaluable pts have achieved best MRD response of ≥10-5. In the dose escalation pts (i.e., those with longest follow-up, n = 12), the ORR and CR/sCR rate was 100% and 75%, respectively, despite 58% (7/12) EMD in this group. Of the first 6 pts dosed in DL1, 4 (67%) continue in ongoing sCR beyond 18 months, including 3 with EMD. Median duration of response, PFS and OS were not evaluable at the time of data-cut because 19 of 24 evaluable pts (79%) remain in ongoing response. Conclusions: CART-ddBCMA administration, to date, has demonstrated clinical activity, including 100% ORR with rates of CR/sCR and ≥VGPR of 67% and 88%, respectively. Durable responses beyond 18 months have been observed, including in pts with EMD. Clinical trial information: NCT04155749.

Background Chronic upper extremity pain (UEP) has complex etiologies and is often disabling. It has been shown that 10 kHz SCS can provide paresthesia-free and durable pain relief in multiple pain types and improve the quality of life of patients. Objective To gain additional evidence on the safety and effectiveness of 10 kHz SCS for the treatment of chronic UEP. Study Design It was a prospective, multicenter, and observational study. The study was registered on ClinicalTrials.gov prospectively (clinical trial identifier: NCT02703818). Setting Multicenter. Patients, Intervention and Main Outcomes A total of 43 subjects with chronic UEP of ≥5 cm (on a 0–10 cm visual analog scale; VAS) underwent a trial of 10 kHz SCS, and subjects with ≥40% pain relief received a permanent implant. All subjects had upper limb pain at baseline, while some had concomitant shoulder or neck pain. Subject outcomes were assessed for 12 months, and the primary outcome was the responder rate (percentage of subjects experiencing ≥50% pain relief from baseline) at three months. Results Thirty-eight subjects successfully completed the trial (88.3% success rate), 33 received permanent implants (five withdrew consent), and 32 had device activation (per protocol population). There were no paresthesias or uncomfortable changes in stimulation related to changes in posture during the study and there were no neurological deficits. Responder rates at 12 months for upper limb, shoulder, and neck pain in per protocol population (N=32) were 78.1%, 85.2%, and 75.0%, respectively. At 12 months, 84.4% of subjects were satisfied or very satisfied with 10 kHz SCS, and 38.7% either reduced or eliminated opioid usage. Conclusion This study further supports the effectiveness of 10 kHz SCS for chronic UEP treatment and documents the safety profile of the therapy. Clinical Trial Identifier NCT02703818.