Pomalidomide‐bortezomib‐dexamethasone in relapsed or refractory multiple myeloma: Japanese subset analysis of OPTIMISMM

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression‐free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment‐emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.     

Risk of lung cancer and consumption of vegetables and fruit in Japanese: A pooled analysis of cohort studies in Japan

International reviews have concluded that consumption of fruit and vegetables might decrease the risk of lung cancer. However, the relevant epidemiological evidence still remains insufficient in Japan. Therefore, we performed a pooled analysis of data from four population‐based cohort studies in Japan with >200 000 participants and >1700 lung cancer cases. We computed study‐specific hazard ratios by quintiles of vegetable and fruit consumption as assessed by food frequency questionnaires. Summary hazard ratios were estimated by pooling the study‐specific hazard ratios with a fixed‐effect model. In men, we found inverse associations between fruit consumption and the age‐adjusted and area‐adjusted risk of mortality or incidence of lung cancer. However, the associations were largely attenuated after adjustment for smoking and energy intake. The significant decrease in risk among men remained only for a moderate level of fruit consumption; the lowest summary hazard ratios were found in the third quintile of intake (mortality: 0.71, 95% confidence interval 0.60–0.84; incidence: 0.83, 95% confidence interval 0.70–0.98). This decrease in risk was mainly detected in ever smokers. Conversely, vegetable intake was positively correlated with the risk of incidence of lung cancer after adjustment for smoking and energy intake in men (trend P, 0.024); the summary hazard ratio for the highest quintile was 1.26 (95% confidence interval 1.05–1.50). However, a similar association was not detected for mortality from lung cancer. In conclusion, a moderate level of fruit consumption is associated with a decreased risk of lung cancer in men among the Japanese population.     

Dose‐escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma

B‐cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti‐BAFF monoclonal antibody. This phase 1, multicenter, open‐label, nonrandomized, dose‐escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m². All patients had treatment‐emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose‐limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).     

Phase I/II study of bortezomib‐melphalan‐prednisolone for previously untreated Japanese patients with multiple myeloma

This phase I/II study was conducted to evaluate the safety and efficacy of bortezomib‐melphalan‐prednisolone in Japanese patients with previously untreated multiple myeloma who are ineligible for hematopoietic stem cell transplantation. One hundred and one patients were enrolled, and 99 patients received up to nine 6‐week cycles of bortezomib (0.7/1.0/1.3 mg/m²) on days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1–4 and on days 1, 8, 22, and 29 in cycles 5–9, with melphalan (9 mg/m²) and prednisolone (60 mg/m²) on days 1–4 of each cycle. The recommended dose was determined in the phase I portion, and the overall response rate and safety of bortezomib‐melphalan‐prednisolone at the recommended dose were assessed in the phase II portion. The recommended dose of bortezomib was determined to be 1.3 mg/m². Grade 3 or higher non‐hematological adverse events included diarrhea (12%) and peripheral neuropathy (10%); grade 4 hematological adverse events included lymphopenia (41%), neutropenia (30%), and thrombocytopenia (22%). Eleven patients had lung injury associated with bortezomib; two had grade 3 disease, and the other nine had grade 1 or 2 disease. Of the 86 patients treated with 1.3‐mg/m² bortezomib in phases I and II, the median number of treatment cycles was 4.5, and the overall response rate was 70% (95% confidence interval: 59–79%). Bortezomib‐melphalan‐prednisolone with 1.3‐mg/m² bortezomib was considered to be tolerable and effective in Japanese patients with previously untreated multiple myeloma. However, further investigation is needed to refine the administration schedule.     

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice

The histone deacetylase inhibitor panobinostat has shown efficacy in phase‐II and phase‐III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49‐87) and the median number of prior therapies was 5 (range 2‐17). Fourteen patients (58%) had high‐risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression‐free survival (PFS) and overall survival were 3.5 and 9.8 months, respectively. Significant differences between bortezomib‐sensitive and ‐refractory patients were observed. In bortezomib‐sensitive patients, median PFS was 6.3 months compared to 2.3 months in bortezomib‐refractory patients (P < .001). Median overall survival was not reached vs 4.8 months (P = .046) in bortezomib‐sensitive and bortezomib‐refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3 months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high‐risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.     

Occupational sitting time and subsequent risk of cancer: The Japan Public Health Center‐based Prospective Study

Although occupational sitting time has been associated with adverse health outcomes and mortality, the association with cancer incidence remains unknown. This study investigated the association between occupational sitting time and risk of total and site‐specific cancer in a Japanese population. We evaluated 33 307 participants aged 50‐79 years who responded to a questionnaire in 2000‐2003 in the Japan Public Health Center‐based Prospective Study and were followed until 2013. Participants were grouped by sitting time at work. Hazard ratio (HR) and 95% confidence interval (CI) of cancer incidence were calculated with adjustment for potential confounders including moderate‐to‐vigorous physical activity. During 10.2 years of follow‐up, 3807 newly diagnosed cases of cancer were identified. Occupational sitting time was marginally associated with total cancer, with multivariable HRs for the ≥7 h/d vs 1 to <3 h/d category of 1.12 (95% CI, 0.99‐1.26; P for trend = .071) in men, but not women. Among findings for cancers at specific sites, long occupational sitting time was associated with increased risk of pancreas cancer, with multivariable HRs for the ≥7 h/d vs 1 to <3 h/d category of 2.25 (95% CI, 1.17‐4.34; P for trend = .021) in men, and lung cancer, with multivariable HRs for the ≥7 h/d vs 1 to <3 h/d category of 2.80 (95% CI, 1.33‐5.90; P for trend = .013) in women. Extended sitting time at work was associated with an increased risk of pancreas cancer in men and lung cancer in women.     

Budget impact analysis of treatment‐free remission in nilotinib‐treated Japanese chronic myeloid leukemia patients

Treatment‐free remission (TFR), in which patients discontinue pharmacotherapy and remain in molecular remission, is an emerging treatment goal for patients with chronic myeloid leukemia (CML). Attainment of TFR requires an increased frequency of molecular monitoring, to ensure that patients maintain a deep molecular response. The objective of this analysis was to assess the economic impact of stopping nilotinib among Japanese TFR‐eligible patients. A Markov model evaluated the economic impact of TFR among the study population, TFR‐eligible CML patients diagnosed since 2012. The model compared patients who had discontinued tyrosine kinase inhibitor (TKI) treatment (ie, attempted TFR) with patients that continued TKI treatment. A 3‐y time horizon was modeled from a Japanese public payer perspective. Costs associated with drug treatment, hospital/physician visits, and molecular monitoring were considered. TFR‐eligible patients were calculated from Japanese CML incidence rates and efficacy was derived from nilotinib trials. Japanese co‐payment maximums were utilized to assess the patient perspective. An estimated 761 and 140 patients were eligible for first‐ and second‐line nilotinib, respectively, in 2019. Assuming that 100% of eligible patients complied, TFR was associated with cost savings of ¥7 625 174 640 (US$66 567 775) over 3 y. In scenarios with reduced willingness to attempt TFR, cost savings persisted. Achievement of TFR was estimated to markedly reduce out‐of‐pocket expenses for CML patients, regardless of the timing of relapse. Stopping nilotinib for TFR‐eligible patients in Japan may result in significant cost savings to both payers and patients. Monitoring costs contributed little to overall annual costs and decreased over time.     

Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol.     

Increase in incidence of adult T‐cell leukemia/lymphoma in non‐endemic areas of Japan and the United States

Adult T‐cell leukemia/lymphoma (ATLL) is a peripheral T cell neoplasm that is associated with infection by the human T‐cell leukemia virus type I (HTLV‐1). Although the high incidence of ATLL in HTLV‐1‐endemic areas is well known, population‐based evidence concerning the incidence of ATLL in non‐endemic areas is scarce. To answer this, we estimated the age‐standardized incidence of ATLL from 1993 to 2006 for Japan and 1993 to 2008 for the US and assessed its trend using data from a population‐based cancer registry in Japan and Surveillance Epidemiology and End Results (SEER) in the US. The Japanese data were collected from 15 prefectures. A total of 2055 patients in the three prefectures in Kyushu and 1380 patients in the 12 prefectures in Honshu were diagnosed with ATLL in the study period. In the US, a total of 140 patients were diagnosed with ATLL. The results showed that the age‐standardized incidence in non‐endemic areas in Japan and in the US significantly increased during this period (annual percent change [95%CI]; Japan‐Honshu: +4.6% [1.1, 8.2]; US: +6.2% [1.5, 11.1]), while in the endemic areas of Japan there was no change (annual percent change [95%CI]; Japan‐Kyushu: 0.0% [?1.6, 1.7]). This result indicates that the disease has been spread by carriers to non‐endemic areas, and suggests the necessity of establishing a standard preventive strategy.     

Population‐based cohort study on health effects of asbestos exposure in Japan

Occupational asbestos exposure occurs in many workplaces and is a well‐known cause of mesothelioma and lung cancer. However, the association between nonoccupational asbestos exposure and those diseases is not clearly described. The aim of this study was to investigate cause‐specific mortality among the residents of Amagasaki, a city in Japan with many asbestos factories, and evaluate the potential excess mortality due to established and suspected asbestos‐related diseases. The study population consisted of 143 929 residents in Amagasaki City before 1975 until 2002, aged 40 years or older on January 1, 2002. Follow‐up was carried out from 2002 to 2015. Standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated by sex, using the mortality rate of the Japanese population as reference. A total of 38 546 deaths (including 303 from mesothelioma and 2683 from lung cancer) were observed. The SMRs in the long‐term residents’ cohort were as follows: death due to all causes, 1.12 (95% CI, 1.10‐1.13) in men and 1.07 (95% CI, 1.06‐1.09) in women; lung cancer, 1.28 (95% CI, 1.23‐1.34) in men and 1.23 (95% CI, 1.14‐1.32) in women; and mesothelioma, 6.75 (95% CI, 5.83‐7.78) in men and 14.99 (95% CI, 12.34‐18.06) in women. These SMRs were significantly higher than expected. The increased SMR of mesothelioma suggests the impact of occupational asbestos exposure among men and nonoccupational asbestos exposure among women in the long‐term residents’ cohort. In addition, the high level of excess mortality from mesothelioma has persisted, despite the mixture of crocidolite and chrysotile no longer being used for three or four decades.     

Cancer in adolescents and young adults in Japan: epidemiology and cancer strategy

According to national cancer registry data in Japan, approximately 20,000 adolescents and young adults (AYAs, age 15–39 years) are newly diagnosed with cancer each year. Improvements in treatment and care for AYAs with cancer are included in the Phase Three Basic Plan to Promote Cancer Control Programs in Japan. This article reviews current cancer incidence and survival for AYAs with cancer in Japan using population-based cancer registry data. Mortality data through 2019 from the Vital Statistics of Japan are also described. Encouragingly, the 5-year survival probability for AYA cancers has continued to improve, in parallel with childhood cancers, and the mortality rate has decreased. There has been increasing attention to these vulnerable patients and improved partnerships and collaboration between adult and pediatric oncology; however, obstacles to the care of this population still exist at multiple levels. These obstacles relate to specific areas: research efforts and enrollment in clinical trials on AYA malignancies, AYA-specific psychosocial support such as education, financial support, and oncofertility care, and cancer care systems. It is important for Japanese oncologists, health care providers, and health policy makers to recognize that the AYA population remains vulnerable and still have unmet needs.

     

Safety and effectiveness of alectinib in a real‐world surveillance study in patients with ALK‐positive non–small‐cell lung cancer in Japan

We conducted a large‐scale surveillance study as a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK‐positive non–small‐cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice‐daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18‐month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first‐line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK‐positive NSCLC in Japan.     

Burden of cancer associated with type 2 diabetes mellitus in Japan, 2010–2030

Diabetes mellitus constitutes a major disease burden globally, and the prevalence of diabetes continues to increase worldwide. We aimed to estimate the burden of cancer associated with type 2 diabetes mellitus in Japan between 2010 and 2030. In this study, we estimated the population attributable fraction of cancer risk associated with type 2 diabetes in 2010 and 2030 using the prevalence estimates of type 2 diabetes in Japan from 1990 to 2030, summary hazard ratios of diabetes and cancer risk from a pooled analysis of eight large‐scale Japanese cohort studies, observed incidence/mortality of cancer in 2010 and predicted incidence/mortality for 2030 derived from the age–period–cohort model. Our results showed that between 2010 and 2030, the total numbers of cancer incidence and mortality were predicted to increase by 38.9% and 10.5% in adults aged above 20 years, respectively. In the number of excess incident cancer cases associated with type 2 diabetes, an increase of 26.5% in men and 53.2% in women is expected between 2010 and 2030. The age‐specific analysis showed that the population attributable fraction of cancer will increase in adults aged >60 years over time, but will not change in adults aged 20–59 years. In conclusion, this study suggests a modest but steady increase in cancers associated with type 2 diabetes.     

The efficacy and safety of bortezomib and dexamethasone as a maintenance therapy in patients with advanced multiple myeloma who are responsive to salvage bortezomib-containing regimens

BACKGROUND:

Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness. Thus, the identification of effective salvage strategies remains a priority.

METHODS:

In this trial, the authors evaluated the safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/mq); D: on days 1‐2 and 15‐16, every 28‐day cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage therapy that used a bortezomib‐containing regimen.

RESULTS:

Forty‐nine MM patients were enrolled in this study between October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a 50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression‐free survival of 61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression, which was adjusted for competitive risk events, was 14%. Non‐dose‐limiting toxicities included neuropathy (predominantly grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/mq. No grade 3 or 4 toxicities were recorded.

CONCLUSIONS:

The use of bortezomib and dexamethasone as MT in advanced MM was effective and well tolerated. The twice‐monthly bortezomib infusion appeared to reduce the incidence of grade 3 and 4 neuropathies in comparison to similar experiences in other settings. Cancer 2011. © 2010 American Cancer Society.     

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30‐expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21‐day cycle up to 16 cycles. In the phase I part of a dose‐escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large‐cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose‐limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large‐cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI‐111650).     

Diabetes mellitus and cancer risk: Pooled analysis of eight cohort studies in Japan

Although a growing body of evidence suggests a link between diabetes and cancer, it is not clear whether diabetes independently increases the risk of cancer. We conducted a comprehensive assessment of the association between pre‐existing diabetes and total and site‐specific cancer risk based on a pooled analysis of eight cohort studies in Japan (>330 000 subjects). We estimated a summary hazard ratio by pooling study‐specific hazard ratios for total and site‐specific cancer by using a random‐effects model. A statistically increased risk was observed for cancers at specific sites, such as colon (hazard ratio; HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Increased risk was also suggested for other sites, and diabetes mellitus was associated with an overall 20% increased risk in total cancer incidence in the Japanese population. The association between these two diseases has important implications for reiterating the importance of controlling lifestyle factors and may suggest a possible strategy for cancer screening among patients with diabetes. Studies continuously investigating the risk factors for diabetes are also important.     

Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma

This phase 4, single‐arm, non‐randomized, open‐label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m², twice weekly for 2 weeks, followed by a 10‐day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre‐specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) C_max (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non‐Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half‐life (t_1/2), area under the plasma concentration‐time curve from time 0 to infinity (AUC_∞), volume of distribution (V_z), and systemic clearance were not assessable. All patients experienced treatment‐emergent adverse events (TEAEs); 78% were drug‐related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUC_last [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non‐Asian population (AUC_last [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.     

Carfilzomib,lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m², followed by 27 mg/m². Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.     

Disseminated histoplasmosis in HIV‐infected patients: determinants of relapse and mortality in a north‐eastern area of Brazil

Many relapses and deaths resulting from disseminated histoplasmosis (DH) in acquired immunodeficiency syndrome (AIDS) patients have been observed in an endemic area in north‐eastern Brazil. The objective of this study was to evaluate the risk factors associated with the clinical outcomes of DH/AIDS coinfection in patients from the state of Ceará, Brazil. A retrospective cohort of AIDS patients, after their hospital discharge due to first DH episode in the period 2002–2008, was followed until December 31, 2010, to investigate the factors associated with relapse and mortality. A total of 145 patients were evaluated in the study. Thirty patients (23.3%) relapsed and the overall mortality was 30.2%. The following variables were significantly (P < 0.05) associated with relapse and overall mortality (univariate analysis): non‐adherence to highly active antiretroviral therapy (HAART), irregular use of an antifungal, non‐recovery of the CD4+ count and having AIDS before DH; histoplasmosis relapse was also significantly associated with mortality. In the multivariate analysis, non‐adherence to HAART was the independent risk factor that was associated with both relapse (Adj OR = 6.28) and overall mortality (Adj OR = 8.03); efavirenz usage was discovered to be significant only for the overall mortality rate (Adj OR = 4.50). Adherence to HAART was the most important variable that influenced the outcomes in this specific population.