Problem gambling in psychotic disorders: A systematic review and meta-analysis of prevalence.

INTRODUCTION: Problem gambling (PBG) is more common in people with mental health disorders, including substance use, bipolar, and personality disorders, than in the general population. Although individuals with psychotic disorders might be expected to be more vulnerable to PBG, fewer studies have focused on this comorbidity. The aim of this review was to estimate the prevalence of PBG in people with psychotic disorders. METHODS: Medline (Ovid), EMBASE, PsycINFO (Ovid), CINAHL, CENTRAL, Web of science, and ProQuest were searched on November 1, 2023, without language restrictions. Observational and experimental studies including individuals with psychotic disorders and reporting the prevalence of PBG were included. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal for systematic reviews of prevalence data. The pooled prevalence of PBG was calculated using a fixed effects generalized linear mixed model and presented through forest plots. RESULTS: Of 1271 records screened, 12 studies (n = 3443) were included. The overall prevalence of PBG was 8.7% (95% CI = 7.8%-9.7%, I2 = 69%). A lower prevalence was found in studies with a low risk of bias (5.6%; 95% CI = 4.4%-7.0%) compared with studies with a moderate risk of bias (10.4%; 95% CI = 9.2%-11.7%). Different methods used to assess PBG also contributed to the heterogeneity found. CONCLUSION: This meta-analysis found substantial heterogeneity, partly due to the risk of bias of the included studies and a lack of uniformity in PBG assessment. Although more research is needed to identify those at increased risk for PBG, its relatively high prevalence warrants routine screening for gambling in clinical practice.

Problem gambling among people with first-episode psychosis: protocol for a prospective multicenter cohort study.

BACKGROUND: The limited available data suggest that the prevalence of problem gambling is increased among young adults with first-episode psychosis, possibly due in part to several risk factors for problem gambling that are common in this population. Aripiprazole, a widely used antipsychotic drug, has also been linked to cases of problem gambling, but causality remains uncertain. Although the consequences of problem gambling further hinder the recovery of people with first-episode psychosis, there is a paucity of research about this comorbidity and its risk factors. Additionally, to our knowledge, no screening instrument for problem gambling tailored to these individuals exists, contributing to its under-recognition. Further, treatment approaches for problem gambling adapted to this population are at an embryonic stage, while existing treatments effectiveness remains to be documented. Using an innovative screening and assessment procedure for problem gambling, this study aims to identify risk factors for problem gambling among people with first-episode psychosis and to document the effectiveness of standard treatment approaches. METHODS: This is a multicenter prospective cohort study conducted in two first-episode psychosis clinics, including all patients admitted between November 1st, 2019, and November 1st, 2023, followed for up to 3 years until May 1st, 2024. These 2 clinics admit approximately 200 patients annually, for an expected sample size of 800 individuals. The primary outcome is the occurrence of a DSM-5 diagnosis of gambling disorder. All patients are screened and evaluated for problem gambling using a systematic procedure at admission, and every 6 months thereafter. Socio-demographic and clinical variables are prospectively extracted from the patients' medical records. The nature and effectiveness of treatments for problem gambling offered to affected individuals are also documented from medical records. Survival analyses with Cox regression models will be used to identify potential risk factors for problem gambling. Descriptive statistics will document the effectiveness of treatments for problem gambling in this population. DISCUSSION: A better understanding of potential risk factors for problem gambling among people with first-episode psychosis will allow for better prevention and detection of this neglected comorbidity. Results of this study will also hopefully raise clinicians' and researchers' awareness and serve as the basis to adapted treatments that will better support recovery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05686772. Retrospectively registered, 9 January 2023.

Neuropathic Pain After Dental Implant Surgery: Literature Review and Proposed Algorithm for Medicosurgical Treatment.

The objective of this study is to establish an algorithm for the medicosurgical treatment of dental implant-induced neuropathic pain. The methodology was based on the good practice guidelines from the French National Authority for Health: the data were searched on the Medline database. A working group has drawn up a first draft of professional recommendations corresponding to a set of qualitative summaries. Consecutive drafts were amended by the members of an interdisciplinary reading committee. A total of 91 publications were screened, of which 26 were selected to establish the recommendations: 1 randomized clinical trial, 3 controlled cohort studies, 13 case series, and 9 case reports. In the event of the occurrence of post-implant neuropathic pain, a thorough radiological assessment by at least a panoramic radiograph (orthopantomogram) or especially a cone-beam computerized tomography scan is recommended to ensure that the tip of the implant is placed more than 4 mm from the anterior loop of the mental nerve for an anterior implant and 2 mm from the inferior alveolar nerve for a posterior implant. Very early administration of high-dose steroids, possibly associated with partial unscrewing or full removal of the implant preferably within the first 36-48 hours after placement, is recommended. A combined pharmacological therapy (anticonvulsants, antidepressants) could minimize the risk of pain chronicization. If a nerve lesion occurs in the context of dental implant surgery, treatment should be initiated within the first 36-48 hours after implant placement, including partial or full removal of the implant and early pharmacological treatment.

Problem Gambling Associated with Aripiprazole: A Nested Case-Control Study in a First-Episode Psychosis Program.

BACKGROUND: Aripiprazole has been linked to cases of problem gambling (PBG), but evidence supporting this association remains preliminary. Additionally, data specific to PBG in individuals with first-episode psychosis (FEP) receiving aripiprazole are limited to a few case reports, even though aripiprazole is widely used among this population that might be especially vulnerable to PBG. METHODS: To examine this association, a nested case-control study was conducted in a cohort of 219 patients followed at a FEP program located in the Quebec City, Quebec, Canada, metropolitan area. Fourteen cases meeting the PBG criteria according to the Problem Gambling Severity Index were identified and matched for gender and index date to 56 control subjects. RESULTS: In the univariable conditional logistic regression analysis, the use of aripiprazole was associated with an increased risk of PBG (odds ratio [OR] 15.2; 95% confidence interval [CI] 2.1-670.5). Cases were more likely to have a prior gambling history (either recreational or problematic) than controls at admittance in the program; they were also more frequently in a relationship and employed. After adjustment for age, relationship status, employment and Cluster B personality disorders, the use of aripiprazole remained associated with an increased risk of PBG (OR 8.6 [95% CI 1.5-227.2]). CONCLUSIONS: Findings from this study suggest that FEP patients with a gambling history, problematic or not, may be at increased risk of developing PBG when receiving aripiprazole. They also highlight the importance of systematically screening for PBG all individuals with psychotic disorders, as this comorbidity hinders recovery. While the results also add credence to a causal association between aripiprazole and PBG, further prospective studies are needed to address some of the limitations of this present study.

Problem Gambling Associated With Aripiprazole in First-Episode Psychosis Patients: A Series of 6 Case Reports.

BACKGROUND: Aripiprazole (ARI), an antipsychotic drug used to treat various mental health disorders, has recently been associated with the emergence of problem gambling (PBG). However, few cases have been reported in the schizophrenia-related psychotic disorders population, and even fewer provided sufficient details to systematically assess the causality of the association. METHODS: This article describes 6 cases with first-episode psychosis in whom PBG emerged while on ARI. Detailed information was gathered from clinical staff and patients' families to systematically assess the causal link between ARI and the emergence of PBG using the Naranjo and Liverpool Adverse Drug Reaction scales. FINDINGS: Five of these cases were previously diagnosed with a substance use disorder and/or cluster B personality traits. Five had received a more potent dopaminergic antagonist treatment before being switched to ARI. Two of them had presented PBG before being diagnosed with a psychotic disorder. The level of certainty about the causal role of ARI varied from possible to certain, and in 4 cases, the 2 scales yielded different ratings. IMPLICATIONS: Although these cases suggest that ARI may be associated with the emergence of PBG in the early course of schizophrenia-related psychotic disorders, they cannot prove the causality or the strength of this association. They provide the impetus to perform adequately powered and well-controlled prospective studies to draw more definite conclusion about the causality of this association and, in the meantime, further emphasize the need to carefully assess PBG in this population.

Sleep or Play Online Poker?: Gambling Behaviors and Tilt Symptoms While Sleep Deprived.

Online poker has the convenience of being accessible 24/7 allowing a large proportion of players to gamble at night. Although some studies postulate a bi-directional relationship between excessive online poker playing and sleep disturbances, sleep has yet to be studied as a primary outcome variable in online poker studies. Sleep deprivation has been linked to alterations in emotional regulation, decision-making, and risk-taking behaviors. All of which are known to induce episodes of tilt. Conversely, online poker playing during regular sleep hours may interfere with sleep quality. The objectives of the present study are (a) to explore the effects of sleep deprivation on tilt symptoms and gambling behaviors and (b) to assess whether playing an online poker session shortly before bedtime (120 min) influences the player's sleep quality. Sleeping habits, tilt symptoms, and online poker behaviors of 23 regular online poker players (22 men, 1 woman) were monitored daily for 28 days using questionnaires and hand histories. Tilt and gambling behaviors during online poker sessions (n = 588) played while the player was sleep-deprived were compared to sessions played while not sleep-deprived. Different sleep variables were also compared for sessions (n = 897) played 2 h before bedtime to no sessions played before sleep. Sleep-deprived poker sessions revealed higher emotional and behavioral tilt, a higher number of hands played and unfavorable financial results than at-rest sessions. Also, emotional and behavioral tilt was higher when alcohol was consumed. Sessions played 2 h before bedtime revealed a shorter sleep onset latency than when no sessions were played before bedtime. Post-hoc mixed regression analyses revealed that emotional and behavioral tilt is associated with shorter total sleep time and shorter sleep onset latency, while cognitive tilt is associated with a decrease in sleep efficiency. This study is the first to specifically explore sleep variables with online poker players within an ecological study design. The findings shed light on the daily impacts of nighttime online gambling practices. Future studies are needed to further explore the interaction between subjective and objective sleep variables and online gambling habits as well as investigate players' motives for playing while sleep deprived.

Three-phase Bone Scintigraphy Can Predict the Analgesic Efficacy of Ketamine Therapy in CRPS.

OBJECTIVES: The efficacy of ketamine in relieving complex regional pain syndrome (CRPS) lacks predictive factors. The value of three-phase bone scintigraphy (TPBS) was assessed for this purpose. MATERIALS AND METHODS: TPBS was performed in 105 patients with unilateral, focal CRPS of type 1 before 5 days of ketamine infusions. Tracer uptake was measured in the region of interest concerned by CRPS and the contralateral homologous region. For the 3 scintigraphic phases (vascular, tissular, and bone phases), an asymmetry ratio of fixation was calculated between the affected and the unaffected sides (vascular phase [VPr], tissular phase [TPr], and bone phase [BPr]). Ketamine efficacy was assessed on pain intensity scores. RESULTS: Ketamine-induced pain relief did not correlate with VPr, TPr, and BPr, but with the ratios of these ratios: BPr/TPr (r=0.32, P=0.009), BPr/VPr (r=0.34, P=0.005), and TPr/VPr (r=0.23, P=0.02). The optimum cut-off value for predicting the response to ketamine therapy was >1.125 for BPr/TPr, >1.075 for BPr/VPr, and >0.935 for TPr/VPr. The combination of increased values of BPr/TPr, BPr/VPr, and TPr/VPr was highly significantly associated with ketamine therapy outcome. CONCLUSIONS: The relative hyperfixation of the radioactive tracer in the limb region concerned by CRPS in phases 2 and 3 versus phase 1 of TPBS correlated positively to the analgesic efficacy of ketamine. This study shows for the first time the potential predictive value of TPBS regarding ketamine therapy outcome. In addition, these results suggest that the analgesic action of ketamine is not restricted to "central" mechanisms, but may also involve "peripheral" mechanisms related to tissue inflammation and bone remodeling.

Psychological Vulnerability and Problem Gambling: The Mediational Role of Cognitive Distortions.

Despite numerous studies demonstrating the influence of cognitive distortions on gambling problem severity, empirical data regarding the role of psychological vulnerability on the latter is limited. Hence, this study assesses the mediating effect of cognitive distortions between psychological vulnerability (personality and mood), and gambling problem severity. It also verifies whether the relationships between these variables differs according to the preferred gambling activity. The sample is composed of 272 male gamblers [191 poker players; 81 video lottery terminal (VLT) players] aged between 18 and 82 years (M = 35.2). Bootstrap analysis results revealed that cognitive distortions mediate the effect of narcissism on gambling problem severity for both groups. The level of depression for VLT players significantly predicted gambling problem severity, both directly and indirectly via the mediating effect of cognitive distortions. Mediation analyses also indicated that narcissism had an indirect impact on problem gambling through cognitive distortions for both groups. These findings suggest that certain vulnerabilities related to personality and mood may influence cognitive distortion intensity and gambling problem severity. In addition, psychological vulnerabilities could differ based on preferred gambling activity. These results may be useful for prevention policies, identifying high risk gamblers and planning psychological interventions.

Efficacy of a Self-Help Treatment for At-Risk and Pathological Gamblers.

Available evidence suggests that self-help treatments may reduce problem gambling severity but inconsistencies of results across clinical trials leave the extent of their benefits unclear. Moreover, no self-help treatment has yet been validated within a French Canadian setting. The current study therefore assesses the efficacy of a French language self-help treatment including three motivational telephone interviews spread over an 11-week period and a cognitive-behavioral self-help workbook. At-risk and pathological gamblers were randomly assigned to the treatment group (n = 31) or the waiting list (n = 31). Relative to the waiting list, the treatment group showed a statistically significant reduction in the number of DSM-5 gambling disorder criteria met, gambling habits, and gambling consequences at Week 11. Perceived self-efficacy and life satisfaction also significantly improved after 11 weeks for the treatment group, but not for the waiting list group. At Week 11, 13% of participants had dropped out of the study. All significant changes reported for the treatment group were maintained throughout 1, 6 and 12-month follow-ups. Results support the efficacy of the self-help treatment to reduce problem gambling severity, gambling behaviour and to improve overall functioning among a sample of French Canadian problem gamblers over short, medium and long term. Findings from this study lend support to the appropriateness of self-help treatments for problem gamblers and help clarify inconsistencies found in the literature. The low dropout rate is discussed with respect to the advantages of the self-help format. Clinical and methodological implications of the results are put forth.

Cognitive Characteristics of Strategic and Non-strategic Gamblers.

Participation in strategic and non-strategic games is mostly explained in the literature by gender: men gamble on strategic games, while women gamble on non-strategic games. However, little is known about the underlying cognitive factors that could also distinguish strategic and non-strategic gamblers. We suggest that cognitive style and need for cognition also explain participation in gambling subtypes. From a dual-process perspective, cognitive style is the tendency to reject or accept the fast, automatic answer that comes immediately in response to a problem. Individuals that preferentially reject the automatic response use an analytic style, which suggest processing information in a slow way, with deep treatment. The intuitive style supposes a reliance on fast, automatic answers. The need for cognition provides a motivation to engage in effortful activities. One hundred and forty-nine gamblers (53 strategic and 96 non-strategic) answered the Cognitive Reflection Test, Need For Cognition Scale, and socio-demographic questions. A logistic regression was conducted to evaluate the influence of gender, cognitive style and need for cognition on participation in strategic and non-strategic games. Our results show that a model with both gender and cognitive variables is more accurate than a model with gender alone. Analytic (vs. intuitive) style, high (vs. low) need for cognition and being male (vs. female) are characteristics of strategic gamblers (vs. non-strategic gamblers). This study highlights the importance of considering the cognitive characteristics of strategic and non-strategic gamblers in order to develop preventive campaigns and treatments that fit the best profiles for gamblers.

Cognitive restructuring of gambling-related thoughts: A systematic review.

Gamblers' thoughts have a fundamental influence on their gambling problem. Cognitive restructuring is the intervention of choice to correct those thoughts. However, certain difficulties are noted in the application of cognitive restructuring techniques and the comprehension of their guidelines. Furthermore, the increase of skill game players (e.g. poker) entering treatment creates a challenge for therapists, as these gamblers present with different thoughts than those of the gamblers usually encountered in treatment (e.g. chance-only games like electronic gambling machines). This systematic review aims to describe how cognitive restructuring is carried out with gamblers based on the evidence available in empirical studies that include cognitive interventions for gambling. Of the 2607 studies collected, 39 were retained. The results highlight exposure as the most frequently used technique to facilitate identification of gambling-related thoughts (imaginal=28.2%; in vivo=10.3%). More than half of the studies (69.2%) clearly reported therapeutic techniques aimed to correct gamblers' thoughts, of which 37% involved visual support to challenge those thoughts (e.g. ABC log). Of the 39 studies retained, 48.7% included skill game players (i.e., poker, blackjack, sports betting) in their sample. However, none of these studies mentioned whether cognitive restructuring had been adapted for these gamblers. Several terms referring to gamblers' thoughts were used interchangeably (e.g. erroneous, dysfunctional or inadequate thoughts), although each of these terms could refer to specific content. Clinical implications of the results are discussed with regard to the needs of therapists. This review also suggests recommendations for future research.

Gambling-Related Cognition Scale (GRCS): Are skills-based games at a disadvantage?

The Gambling-Related Cognition Scale (GRCS; Raylu & Oei, 2004) was developed to evaluate gambling-related cognitive distortions for all types of gamblers, regardless of their gambling activities (poker, slot machine, etc.). It is therefore imperative to ascertain the validity of its interpretation across different types of gamblers; however, some skills-related items endorsed by players could be interpreted as a cognitive distortion despite the fact that they play skills-related games. Using an intergroup (168 poker players and 73 video lottery terminal [VLT] players) differential item functioning (DIF) analysis, this study examined the possible manifestation of item biases associated with the GRCS. DIF was analyzed with ordinal logistic regressions (OLRs) and Ramsay's (1991) nonparametric kernel smoothing approach with TestGraf. Results show that half of the items display at least moderate DIF between groups and, depending on the type of analysis used, 3 to 7 items displayed large DIF. The 5 items with the most DIF were more significantly endorsed by poker players (uniform DIF) and were all related to skills, knowledge, learning, or probabilities. Poker players' interpretations of some skills-related items may lead to an overestimation of their cognitive distortions due to their total score increased by measurement artifact. Findings indicate that the current structure of the GRCS contains potential biases to be considered when poker players are surveyed. The present study conveys new and important information on bias issues to ponder carefully before using and interpreting the GRCS and other similar wide-range instruments with poker players. (PsycINFO Database Record

Online and Mobile Interventions for Problem Gambling, Alcohol, and Drugs: A Systematic Review.

Online interventions for gambling, alcohol, and illegal drug related problems have been developing at a fast pace over the past decade. Yet, little is known about the content and efficacy of interventions provided entirely online for reducing drug/alcohol use and gambling, or about the characteristics of those who use these interventions. This systematic review aims to describe the characteristics of online interventions, their efficacy, and the profile of their clientele. Documentation was mainly obtained through four scientific databases in psychology, technology, and medical research (PsychINFO, MedLine, Francis, and INSPEC) using three keywords (substances or gambling, intervention, Internet). Of the 4,708 documents initially identified, 18 studies meeting admissibility criteria were retained and analyzed after exclusion of duplicates and non-relevant documents. No study in the review related to problem gambling. The majority of interventions were based upon motivational or cognitive-behavioral theoretical approaches and called upon well-established therapeutic components in the field of addictions. The participants in these studies were generally adults between 30 and 46 years old with a high school education and presenting a high risk or problematic use. More than three quarters of the studies showed a short-term decrease in use that was maintained 6 months later, but only two studies included a 12 months follow-up. Online interventions seem promising and appear to meet the needs of participants who are in the workforce and seeking help for the first time. Long-term efficacy studies should nonetheless be conducted.

Using Virtual Reality in the Treatment of Gambling Disorder: The Development of a New Tool for Cognitive Behavior Therapy.

Virtual reality (VR) can be used in the treatment of gambling disorder to provide emotionally charged contexts (e.g., induce cravings) where patients can practice cognitive behavior therapy (CBT) techniques in the safety of the therapist's office. This raises practical questions, such as whether the cravings are sufficient to be clinically useful but also manageable enough to remain clinically safe. Pilot data are also needed to test the development of a treatment manual and prepare large randomized control trials. This paper reports on three studies describing (a) cravings induced in VR compared to real gambling and a control game of skill with no money involved (N = 28 frequent gamblers and 36 infrequent gamblers); (b) the usefulness of a treatment protocol with only two CBT sessions using VR (N = 34 pathological gamblers); and (c) the safety of a four-session treatment program of CBT in VR (N = 25 pathological gamblers). Study 1 reveals that immersions in VR can elicit desire and a positive anticipation to gamble in frequent gamblers that are (a) significantly stronger than for infrequent gamblers and for playing a control game of skill and (b) as strong as for gambling on a real video lottery terminal. Study 2 documents the feasibility of integrating VR in CBT, its usefulness in identifying more high-risk situations and dysfunctional thoughts, how inducing cravings during relapse prevention exercises significantly relates to treatment outcome, and the safety of the procedure in terms of cybersickness. Results from Study 3 confirm that, compared to inducing urges to gamble in imagination, using VR does not lead to urges that are stronger, last longer, or feel more out of control. Outcome data and effect sizes are reported for both randomized control pilot trials conducted in inpatient settings. Suggestions for future research are provided, including on increasing the number of VR sessions in the treatment program.

A noninterventional observational registry of patients with multiple myeloma treated with lenalidomide in Taiwan.

BACKGROUND/PURPOSE: The incidence of multiple myeloma in Asia has risen in the past 30 years. Lenalidomide, an IMiD immunomodulatory agent, has improved the overall survival in patients with relapsed/refractory multiple myeloma (RRMM) when used with dexamethasone versus dexamethasone alone. This observational registry (T-CC-MM-009; NCT01752075) assessed the safety and efficacy of lenalidomide plus dexamethasone in a large Chinese population of patients with RRMM. METHODS: This registry followed the first 100 patients treated with lenalidomide plus dexamethasone in Taiwan. Patients were ≥18 years old and had ≥1 prior treatment. The recommended starting dose for the first four 28-day cycles was 25 mg lenalidomide on days 1-21 and 40 mg dexamethasone on days 1-4, 9-12, and 17-20. Thereafter, dexamethasone was given on days 1-4 only. The primary objective was safety; secondary objectives were efficacy, lenalidomide dosage, and reasons for discontinuation. RESULTS: The median duration of treatment was 34.6 weeks, and 75.5% completed ≥3 cycles. Most patients (82.7%) experienced ≥1 treatment-related adverse event; the most commonly reported were neutropenia (23.5%), thrombocytopenia (19.4%), anemia (16.3%), fatigue (16.3%), and hypoesthesia (15.3%). Bleeding events (25.5% of patients) were mostly grade 1/2 (80%). Three patients (3%) had venous thromboembolic events. Two invasive second primary malignancies were reported; however, time to onset was <1 year, suggesting they may not be related to lenalidomide. The overall response rate was 34.7%; median time to disease progression was 20.5 months. CONCLUSION: These data confirm the safety and efficacy of lenalidomide plus dexamethasone for patients with RRMM in Taiwan.

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma.

Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 - < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 - < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30.

Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma.

PURPOSE: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. METHODS: We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. RESULTS: In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). CONCLUSION: In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials.

Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone.

Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P <0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or high-dose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4;14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14). This study is registered at ClinicalTrials.gov as NCT01311687 and with EudraCT as 2010-019820-30.

Pomalidomide and Low-Dose Dexamethasone Improves Health-Related Quality of Life and Prolongs Time to Worsening in Relapsed/Refractory Patients With Multiple Myeloma Enrolled in the MM-003 Randomized Phase III Trial.

BACKGROUND: Health-related quality of life (HRQoL) is an important element for consideration in treatment decisions in patients with relapsed/refractory multiple myeloma (RRMM). The pivotal MM-003 (A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone vs. High-Dose Dexamethasone in Patients With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study [NIMBUS]) randomized, open-label, multicenter, phase III trial demonstrated improved progression-free survival (PFS) and prolonged overall survival (OS) with pomalidomide (POM) plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in patients with RRMM in whom lenalidomide (LEN) and bortezomib (BORT) had failed. MM-003 also investigated HRQoL as a predefined secondary end point. PATIENTS AND METHODS: Recruited patients (n = 455) were refractory to their last treatment and had failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Eight clinically relevant and validated HRQoL domains from the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-MY20, and EQ-5D questionnaires were selected for analysis. Time to symptom worsening based on minimally important differences (MIDs) was calculated. RESULTS: Clinically meaningful improvements in HRQoL as determined by MIDs, regression analyses, and best response analyses were observed more frequently in patients receiving POM + LoDEX than in those receiving HiDEX. POM + LoDEX significantly extended median time to clinically meaningful worsening in HRQoL versus HiDEX in 4 HRQoL domains and demonstrated a trend in an additional 3 domains. Patients in the HiDEX arm experienced earlier HRQoL deterioration compared with those in the POM + LoDEX arm in each domain analyzed. CONCLUSION: POM + LoDEX offer good clinical outcomes that lead to improved and prolonged HRQoL compared with HiDEX in patients with RRMM and end-stage disease.