Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma

The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double‐blind, placebo‐controlled Phase III TOURMALINE‐MM1 study of ixazomib‐Rd (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression‐free survival versus placebo‐Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.     

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.     

Patient‐reported outcomes among patients with type 2 diabetes mellitus treated with dapagliflozin in a triple‐therapy regimen for 52 weeks

Patients with type 2 diabetes (T2DM) and inadequate glycaemic control on combination metformin (MET) and sulphonylurea (SU) were enrolled in a 24‐week, double‐blind, randomized, placebo‐controlled study with a 28‐week extension. The five‐dimension EuroQol questionnaire (EQ‐5D), SHIELD Weight Questionnaire‐9 (WQ‐9), Impact of Weight on Quality of Life‐Lite (IWQOL‐Lite) questionnaire and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were used to evaluate health status and health‐related quality of life (HRQoL) at baseline and week 52. Patients with dapagliflozin 10 mg + MET + SU (n = 108) were compared with patients treated with placebo + MET + SU (n = 108), using a repeated‐measures mixed model. EQ‐5D visual analogue scale scores, IWQOL‐Lite and DTSQ scores improved in the dapagliflozin and placebo groups from baseline to week 52; however, there was no significant difference between groups (p > 0.20). EQ‐5D index scores remained the same from baseline to week 52 for dapagliflozin and placebo (p = 0.54). A numerically greater proportion of the dapagliflozin group reported improvement in all nine SHIELD WQ‐9 items compared with placebo, and the difference was statistically significant for physical health (p = 0.017). Over 52 weeks of therapy, patients maintained their health status and HRQoL when dapagliflozin was added to the treatment.     

Patients’ experience of chronic lymphocytic leukaemia: baseline health‐related quality of life results from the LRF CLL4 trial

We examined the effects of active untreated chronic lymphocytic leukaemia (CLL) on health‐related quality of life (HRQoL), measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ‐C30) at randomisation into the Leukaemia Research Fund CLL4 trial. Patients were scored 0–100 within each of 15 domains. A difference between groups of ≥10 points was deemed clinically significant (asterisked * below). 431 valid baseline questionnaires were returned. Compared with population norms, patients had impaired HRQoL in 13/15 domains. The greatest differences were in fatigue*, sleep disturbance*, role functioning and global HRQoL. Fatigue was reported by 81% of patients, compared with the next most common symptoms: sleep disturbance (56%) and dyspnoea (49%). There was no association between spleen, liver or lymph node enlargement, or lymphocytosis and any HRQoL domain. Older age (≥70 years) was associated with poorer physical functioning (P < 0·001) but fewer financial difficulties (P < 0·001*). Impairment of HRQoL at baseline was most apparent in stage A‐progressive patients with B‐symptoms and stage C patients with haemoglobin <120 g/l: compared with all others, these patients had poorer physical, role and social functioning, more fatigue and dyspnoea and poorer global HRQoL (all P ≤ 0·001*). These findings support the recommendation to begin treatment when patients experience symptomatic disease, to improve HRQoL.     

Health‐related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy

Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life (HRQoL). Here, we report post‐hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT‐II study (N = 219). During the follow‐up period of 48 weeks, HRQoL and MF‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy (BAT)‐treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ‐C30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT‐General, FACT‐Lym trial outcome index, and FACT‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.     

Lenalidomide and low‐dose dexamethasone (Rd) versus bortezomib,melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials

There are currently no direct head‐to‐head clinical trials evaluating bortezomib‐melphalan‐prednisone (VMP) versus lenalidomide and low‐dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end‐points, respectively, and were investigated according to treatments administered over a 60‐months follow‐up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow‐up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd‐treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long‐term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.     

Clarithromycin (Biaxin)‐lenalidomide‐low‐dose dexamethasone (BiRd) versus lenalidomide‐low‐dose dexamethasone (Rd) for newly diagnosed myeloma

The objective of this case‐matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low‐dose dexamethasone (BiRd) vs. lenalidomide/low‐dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital‐Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention‐to‐treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very‐good‐partial‐response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time‐to‐progression (median 48.3 vs. 27.5 months, P = 0.071), and progression‐free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3‐year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3–4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case‐matchedanalysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Systematic review of patient‐reported outcome measures in the surgical treatment of patients with esophageal cancer

Esophageal cancer is currently the eighth most common cancer worldwide. Improvements in operative techniques and neoadjuvant therapies have led to improved outcomes. Resection of the esophagus carries a high risk of severe complications and has a negative impact on health‐related quality of life (QOL). The aim of this study was to assess which patient‐reported outcome measures (PROMs) are used to measure QOL after esophagectomy for cancer. A comprehensive search of original articles was conducted investigating QOL after surgery for esophageal carcinoma. Two authors independently selected relevant articles, conducted clinical appraisal, and extracted data (PJ and JS). Out of 5893 articles, 58 studies were included, consisting of 41 prospective and 17 retrospective cohort studies, including a total of 6964 patients. These studies included 11 different PROMs. The existing PROMs could be divided into generic, symptom‐specific, and disease‐specific questionnaires. The European Organisation for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ C‐30) along with the EORTC QLQ‐OESophagus module OES18 was the most widely used; in 42 and 32 studies, respectively. The EORTC and the Functional Assessment of Cancer Therapy (FACT) questionnaires use an oncological module and an organ‐specific module. One validation study was available, which compared the FACT and EORTC, showing moderate to poor correlation between the questionnaires. A great variety of PROMs are being used in the measurement of QOL after surgery for esophageal cancer. A questionnaire with a general module along with a disease‐specific module for assessment of QOL of different treatment modalities seem to be the most desirable, such as the EORTC and the FACT with their specific modules (EORTC QLQ‐OES18 and FACT‐E). Both are developed in different treatment modalities, such as in surgical patients. With regard to reproducibility of current results, the EORTC is recommended.     

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.     

Tadalafil for the Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign Prostatic Hyperplasia: Results from a 12‐week Placebo‐controlled Dose‐finding Study with a 42‐week Open‐label Extension

Objectives: To examine the efficacy, safety, and dose response of tadalafil once daily in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH‐LUTS). Methods: Men ≥45 years with moderate‐to‐severe BPH‐LUTS were randomized to once‐daily placebo (N = 140), tadalafil 2.5 mg (N = 142), or tadalafil 5.0 mg (N = 140), in a 12‐week double‐blind phase, followed by a 42‐week, tadalafil 5.0 mg open‐label extension (OLE) phase (N = 394). The primary outcome was total International Prostate Symptom Score (IPSS) change from baseline to last available observation in the double‐blind phase. Results: The least squares (LS) mean difference between placebo and tadalafil in total IPSS change from baseline was ?0.7 (P = 0.201) and ?1.1 (P = 0.062) for tadalafil 2.5 and 5 mg, respectively (ANCOVA; a dose‐dependent improvement in placebo‐adjusted total IPSS for tadalafil 5 mg versus 2.5 mg of 57%). Repeated‐measures analyses identified a significant total IPSS change for tadalafil 5 mg (LS mean difference between placebo and tadalafil 5 mg: ?1.2; P = 0.035), but not tadalafil 2.5 mg, at week 12. Significant improvements for tadalafil 5 mg were demonstrated (ANCOVA) for IPSS obstructive subscore (P = 0.033) and IPSS quality of life index (P = 0.022). Numerical improvements in IPSS scores were maintained over the OLE phase. Tadalafil was well tolerated with no unexpected adverse events. Conclusion: Tadalafil (5.0 mg) had a favorable benefit‐to‐risk profile, supporting further investigation of tadalafil (5.0 mg) in Japanese men with BPH‐LUTS.     

A randomized,double‐blind,placebo‐controlled trial of pramipexole,a dopamine agonist,in patients with fibromyalgia receiving concomitant medications

Objective

To assess the efficacy and safety of pramipexole, a dopamine 3 receptor agonist, in patients with fibromyalgia.

Methods

In this 14‐week, single‐center, double‐blind, placebo‐controlled, parallel‐group, escalating‐dose trial, 60 patients with fibromyalgia were randomized 2:1 (pramipexole:placebo) to receive 4.5 mg of pramipexole or placebo orally every evening. The primary outcome was improvement in the pain score (10‐cm visual analog scale [VAS]) at 14 weeks. Secondary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MDHAQ), the pain improvement scale, the tender point score, the 17‐question Hamilton Depression Inventory (HAM‐d), and the Beck Anxiety Index (BAI). Patients with comorbidities and disability were not excluded. Stable dosages of concomitant medications, including analgesics, were allowed.

Results

Compared with the placebo group, patients receiving pramipexole experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status. At 14 weeks, the VAS pain score decreased 36% in the pramipexole arm and 9% in the placebo arm (treatment difference –1.77 cm). Forty‐two percent of patients receiving pramipexole and 14% of those receiving placebo achieved ≥50% decrease in pain. Secondary outcomes favoring pramipexole over placebo included the total FIQ score (treatment difference –9.57) and the percentages of improvement in function (22% versus 0%), fatigue (29% versus 7%), and global (38% versus 3%) scores on the MDHAQ. Compared with baseline, some outcomes showed a better trend for pramipexole treatment than for placebo, but failed to reach statistical significance, including improvement in the tender point score (51% versus 36%) and decreases in the MDHAQ psychiatric score (37% versus 28%), the BAI score (39% versus 27%), and the HAM‐d score (29% versus 9%). No end points showed a better trend for the placebo arm. The most common adverse events associated with pramipexole were transient anxiety and weight loss. No patient withdrew from the study because of inefficacy or an adverse event related to pramipexole.

Conclusion

In a subset of patients with fibromyalgia, ∼50% of whom required narcotic analgesia and/or were disabled, treatment with pramipexole improved scores on assessments of pain, fatigue, function, and global status, and was safe and well‐tolerated.

     

Aleglitazar,a dual peroxisome proliferator‐activated receptor‐α/γ agonist,improves insulin sensitivity,glucose control and lipid levels in people with type 2 diabetes: findings from a randomized,double‐blind trial

The present single‐centre, randomized, double‐blind, placebo‐controlled phase II study investigated the effect of the balanced dual peroxisome proliferator‐activated receptor‐α/γ agonist aleglitazar on whole‐body and liver insulin sensitivity, β‐cell function and other components of cardiometabolic syndrome after 16 weeks of treatment in patients with type 2 diabetes inadequately controlled with metformin monotherapy who received once‐daily 150 µg aleglitazar or matching placebo as add‐on therapy to metformin. Baseline and 16‐week assessments included a two‐step hyperinsulinaemic–euglycaemic clamp, followed by a hyperglycaemic clamp, as well as evaluation of glycated haemoglobin (HbA1c), lipids and safety variables. The primary endpoint was change in whole‐body insulin sensitivity (M‐value) from baseline compared with placebo, derived from the second clamp step. M‐value improved significantly from baseline with aleglitazar (n = 16) compared with placebo (n = 24; p = 0.05 for difference between arms). We found statistically significant treatment differences with aleglitazar versus placebo in fasting hepatic insulin resistance index (p = 0.01), and in total glucose disposal (p = 0.03) at the second insulin infusion step. Aleglitazar treatment resulted in significant improvements in HbA1c and lipids and was well tolerated.     

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS).

Methods

This was a randomized, multicenter, double‐blind, placebo‐controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24‐week double‐blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index.

Results

The spine SPARCC score in placebo‐treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab‐treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo‐treated patients and by 52.9% in adalimumab‐treated patients (P = 0.017). The response in adalimumab‐treated patients was maintained at week 52. Placebo‐treated patients were switched to open‐label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab‐treated patients, a reduced C‐reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018).

Conclusion

Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

     

Interpreting important health‐related quality of life change using the Haem‐A‐QoL

The Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL) measures health‐related quality of life (HRQoL) in adults with haemophilia; however, change score thresholds for identifying individuals experiencing a HRQoL benefit have not been appropriately investigated. The objective of this analysis was to derive appropriate HRQoL responder definitions (RDs) for two Haem‐A‐QoL domains that reflect key impairments, ‘Physical Health’ and ‘Sports & Leisure,’ and the Haem‐A‐QoL ‘Total Score’ using anchor‐ and distribution‐based methods. In this analysis, data from adults in A‐LONG and B‐LONG, two Phase 3 clinical studies of rFVIIIFc in haemophilia A and rFIXFc in haemophilia B, respectively, were used. The anchor‐based approach identified Haem‐A‐QoL changes corresponding to EQ‐5D item improvements between baseline and 6 months; the distribution‐based methods examined the magnitude at baseline of one‐half standard deviation and the standard error of measurement. Through triangulation, the most appropriate RDs were derived. Of the 133 A‐LONG and 73 B‐LONG subjects with baseline Haem‐A‐QoL scores, 67 and 51 subjects, respectively, completed the Haem‐A‐QoL questionnaire at both baseline and 6 months follow‐up. Triangulation of anchor‐ and distribution‐based estimates with the observed Haem‐A‐QoL change scores identified a 10‐point reduction in the ‘Physical Health’ and ‘Sports & Leisure’ domains, and a 7‐point reduction in ‘Total Score’ as the RD thresholds most indicative of HRQoL benefit. These empirically derived RDs for two key Haem‐A‐QoL domains and ‘Total Score’ are reasonable and practical thresholds for identifying subjects with notable improvements in HRQoL, and provides HRQoL RDs that can be used for further analysis and interpretation of data from haemophilia clinical trials.     

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.     

Pomalidomide in combination with dexamethasone results in synergistic anti‐tumour responses in pre‐clinical models of lenalidomide‐resistant multiple myeloma

Pomalidomide is an IMiD^® immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, 2004 ; San Miguel et al, 2013; Richardson et al, 2014; Scott, 2014 ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti‐proliferative and pro‐apoptotic activity in both lenalidomide‐sensitive and lenalidomide‐resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single‐agent treatment in xenografts of lenalidomide‐resistant H929 R10‐1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide‐sensitive H929 MM cell lines, were also observed in PomDex‐treated lenalidomide‐resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide‐sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex‐treated samples, highlighted by the modulation of pro‐apoptotic pathways in lenalidomide‐resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide‐resistant setting.     

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).

Methods

In a multicenter randomized, double‐blind, placebo‐controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.

Results

The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA −2.6 ± 3.4 versus placebo −2.0 ± 3.8, mean ± SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA‐treated patients versus 33.9% of placebo‐treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA −5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA‐treated patients compared with placebo‐treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life‐threatening reactions or serious safety issues were identified during this study.

Conclusion

The overall results confirm that DHEA treatment was well‐tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

     

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized,double‐blind,double‐dummy,symptom study (RELIEF)

The randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV )‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV ‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n  = 54) or hydroxycarbamide (prerandomization dose/schedule; n  = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS ‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P  =  0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS ‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P  =  0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV ‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.