Bortezomib,melphalan, prednisone (VMP) versus melphalan,prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case‐matched study

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression‐free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty‐six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2‐microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow‐up of 34 months (range, 1–92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52–0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32–0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control‐case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT. Am. J. Hematol. 89:355–362, 2014. © 2013 Wiley Periodicals, Inc.     

A phase 2 study of modified lenalidomide,bortezomib and dexamethasone in transplant‐ineligible multiple myeloma

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m² weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population.     

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.     

Phase II trial of R‐CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601

Bortezomib is active in mantle cell lymphoma (MCL), with approval in upfront and relapsed settings. Given inevitable recurrence following induction chemoimmunotherapy, maintenance approaches are a rational strategy to improve clinical outcomes. We conducted a phase II study to evaluate the safety and efficacy of six cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib (1·3 mg/m² days 1 and 4 of 21 d cycles) followed by bortezomib maintenance (1·3 mg/m² days 1, 4, 8, and 11 every 3 months for 2 years). Sixty‐five eligible patients were enrolled. The treatment was well tolerated and toxicities were mainly haematological. The rate of grade ≥3 peripheral neuropathy was low (5%). With a median follow‐up of 6·8 years, 2‐year progression‐free survival (PFS) was 62%, and 2‐year overall survival (OS) was 85%. At 5 years, PFS was 28% and OS was 66%. MCL International Prognostic Index scores were significantly associated with 2‐year PFS, but did not predict long‐term (≥5‐year) PFS. Baseline Ki‐67 index was significantly associated with survival. Combination R‐CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared historically with R‐CHOP alone, with prolonged remissions in a subset of patients. These results suggest that inclusion of bortezomib with induction chemotherapy and/or maintenance is promising in MCL and warrants further exploration.     

A phase 2, randomized,double‐blind,placebo‐controlled study of siltuximab (anti‐IL‐6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma

We compared the safety and efficacy of siltuximab (S), an anti‐interleukin‐6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high‐dose dexamethasone could be added to S/plc. Response and progression‐free survival (PFS) were analyzed pre‐dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C‐reactive protein, a marker reflective of inhibition of interleukin‐6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all‐grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma. © 2014 Wiley Periodicals, Inc. Am. J. Hematol. 90:42–49, 2015. © 2014 Wiley Periodicals, Inc.     

Phase II study of bortezomib,cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial

We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21‐day cycles of VCD prior to autologous stem‐cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator‐based assessment was 85·4%. Most patients (74%) underwent successful central laboratory‐based molecular cytogenetic analysis. No clinically relevant differences in ORR post‐induction were seen between patients with or without high‐risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow‐up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow‐up, 55·5 months); median progression‐free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high‐risk versus standard‐risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P < 0·0001), and median OS was 54·7 months versus not reached (P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long‐term follow‐up, cytogenetic high risk is associated with markedly reduced PFS and OS post‐ASCT.     

Combination therapy with bortezomib,continuous low‐dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low‐dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re‐induction and maintenance therapy. Secondary endpoints were response to treatment and progression‐free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow‐up was 27·1 (0·46–54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13–43·5) and the median OS was 28·1 months (range 0·13–54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low‐dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.     

局部治疗联合EGFR-TKIs在晚期耐药肺腺癌中的临床应用研究

目的探讨表皮细胞生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)使用后耐药进展的肺腺癌患者给予局部治疗(冷冻消融、支气管动脉栓塞)联合EGFR-TKIs的临床疗效。方法回顾性分析2012年3月至2018年10月应急总医院经病理证实并完成随访的原发性EGFR敏感突变型晚期肺腺癌患者,进展后再行EGFR基因检测为T790M阴性,继续应用EGFR-TKIs的同时联合局部治疗,分别统计PFS1(从使用EGFR-TKIs到疾病进展时间)、PFS2(从冷冻消融到疾病进展时间)、OS(总生存期)、OS1(冷冻消融后的生存期),及冷冻消融后的并发症情况。分析OS及PFS的统计学相关影响因素。结果32例符合入组标准的晚期肺腺癌患者,PFS1平均时间为(12.4±8.6)个月。其中14例患者冷冻消融前行支气管动脉栓塞治疗,共消融病灶38个。PFS2为(6.7±2.9)个月。OS为(31.5±13.5)个月,其中OS1为(15.5±7.6)个月。统计分析显示PFS1与PFS2与OS存在显著相关性(P<0.05),靶向治疗进展后至氩氦冷冻消融的时间与患者的OS及OS1存在相关性,支气管动脉栓塞联合氩氦消融治疗后并发症主要为气胸及肺内出血,对症处理后均可缓解。结论EGFR-TKIs耐药进展后晚期肺腺癌中,EGFR-TKIs继续使用并联合冷冻消融等局部治疗可延长患者生存,并发症少,取得临床获益。     

Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

Del17p is a genomic imbalance occurring in ～7%‐10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib‐based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M‐Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M‐Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.     

Myeloablative allogeneic stem cell transplantation for advanced stage multiple myeloma: very long‐term follow up of a single center experience

We aimed to review the long‐term outcome of myeloablative allogeneic stem cell transplantation (SCT) performed for multiple myeloma (MM) at our institution. Records of all patients who received standard myeloablative allogeneic SCT for MM were retrospectively reviewed. Overall survival (OS), progression‐free survival (PFS), and event‐free survival (EFS) were calculated using the Kaplan–Meier method. In total 37 transplants had been performed. Median follow up post‐SCT was 108 months (range: 33–148). The majority of patients suffered advanced stage disease and/or had received multiple prior therapies prior to SCT. Transplant‐related mortality (TRM) at 100 days was 32%. Grades 2–4 acute graft‐vs.‐host disease (GVHD) occurred in 18 patients (49%), and extensive stage chronic GVHD in seven (28%) of 25 patients surviving greater than day 100. Median OS, PFS, and EFS were 28 months, 66 months and 13 months, respectively, with 5 year OS, PFS, and EFS 40%, 54% and 24%. Our results suggest that allogeneic SCT, even when performed in advanced stage, heavily pretreated MM, still results in long‐term EFS in a significant minority of patients. Efforts should continue on alternative allogeneic SCT approaches to reduce the high early TRM rate associated with myeloablative conditioning.     

Long‐term outcome after allogeneic stem‐cell transplantation with reduced‐intensity conditioning in patients with multiple myeloma

This study examines the long‐term outcomes of a cohort of patients with myeloma who were treated with reduced‐intensity conditioning (RIC) regimens after a minimum follow‐up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem‐cell transplantation (Allo‐SCT) between January 2000 and January 2007 were identified. The median follow‐up of living patients was 84 months (51–141). The median age of the MM patients was 50 (28–70) years. Fifty‐one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo‐SCT was 34 months (6–161), and the median time between auto‐SCT and Allo‐SCT was 10 months (1–89). Fifty‐one patients (96%) received at least one auto‐SCT; 24 patients (45%) received a tandem auto‐Allo‐SCT. At last follow‐up, 21 patients (40%) are alive > 5 years post RIC Allo‐SCT. At last follow‐up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re‐induction with one of the new anti‐myeloma drugs (bortezomib or lenalidomide) after Allo‐SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo‐SCT. Disease status and occurrence of cGvHD were significantly associated with progression‐free survival (PFS); hazard ratio (HR) = 0.62 (0.30–1.29, P = 0.20). Acute GvHD was correlated with higher transplant‐related mortality; HR = 4.19 (1.05–16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long‐term disease control can be expected in a subset of MM patients undergoing RIC Allo‐SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo‐SCT stabilizes in time with a plateau after 6 years post Allo‐SCT. Am. J. Hematol. 88:370–374, 2013. © 2013 Wiley Periodicals, Inc.     

Good clinical activity and favorable toxicity profile of once weekly bortezomib,fotemustine, and dexamethasone (B‐MuD) for the treatment of relapsed multiple myeloma

Since multiple myeloma (MM) is still not‐curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B‐MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80–100 mg/m² i.v.) on day 1. The original 21‐day schedule was early amended for extra‐hematological toxicity and a 35‐day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty‐four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression‐free survival (PFS) was 19.1 months. B‐MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib‐naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B‐MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase. © Am. J. Hematol., 88:102–106, 2013. © 2012 Wiley Periodicals, Inc.     

Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma

The proteasome inhibitor, bortezomib, potentially increases cell sensitivity to chemotherapy. This study was performed to determine the overall response rate (ORR), overall survival (OS), progression‐free survival (PFS) and toxicity of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) compared to CHOP + bortezomib chemotherapy in mantle cell lymphoma (MCL) patients at first relapse. Forty‐six patients were randomly assigned to standard dose CHOP ± bortezomib 1·6 mg/m² given on a 21‐d cycle for up to eight cycles of treatment. Median age was 71 years (CHOP arm) and 69 years (CHOP‐bortezomib arm). Median Eastern Cooperative Oncology Group performance status was 1 (CHOP) and 0 (CHOP‐bortezomib) with 65% and 52%, respectively, having a disease stage of IV. ORR was 47·8% (CHOP) and 82·6% (CHOP‐bortezomib). Complete response rate was 21·7% (CHOP) vs. 34·8% (CHOP‐bortezomib); partial response rate was 26·1% (CHOP) vs. 47·8% (CHOP‐bortezomib). Median OS was 11·8 months (CHOP) and 35·6 months (CHOP‐bortezomib) (P = 0·01, Hazard ratio [HR] 0·37 [95% confidence interval (CI) 0·16–0·83)] and there was a non‐significant improvement in PFS: 8·1 months (CHOP) and 16·5 months (CHOP‐bortezomib) [P = 0·12, HR 0·60 (95% CI 0·31–1·15)]. Severe (≥grade 3) sensory neuropathy was similar in both arms (4·3% CHOP vs. 6·5% CHOP‐bortezomib). We conclude that the addition of bortezomib to CHOP chemotherapy for relapsed MCL significantly improves outcome with a manageable increase in toxicity.     

Characterization of haematological parameters with bortezomib-melphalan-prednisone versus melphalan-prednisone in newly diagnosed myeloma, with evaluation of long-term outcomes and risk of thromboembolic events with use of erythropoiesis-stimulating agents: analysis of the VISTA trial

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis‐stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade^® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high‐dose therapy, and evaluates the impact of ESA use or red‐blood‐cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time‐to progression (TTP) was similar between ESA/non‐ESA [hazard ratio: 1·03 (95% confidence interval 0·76–1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three‐year overall survival (OS) rates were similar between ESA/non‐ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0·0001) versus non‐RBC‐transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.     

Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre,single‐arm,phase 2 study

The multicentre, open‐label, two‐stage, single‐arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)‐1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Fifty‐eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non‐haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.     

Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95 % confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine ± adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95 % CI 0.55–0.93) and 0.77 (95 % CI 0.60–0.99), respectively. However, when compared with the vincristine + adriamycin-based regimen, the OS was similar (HR?=?0.87, 95 % CI 0.57–1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy.     

Extranodal NK/T‐cell lymphoma,nasal type: Clinical features,outcome, and prognostic factors in 101 cases

Objectives

We aimed to define the clinical features, outcome, and prognostic factors for extranodal NK/T‐cell lymphoma (ENKTL) patients in Taiwan.

Methods

We retrospectively reviewed 101 ENKTL patients diagnosed between February 1998 and October 2015.

Results

The median age of 101 patients was 52 years old (range 22‐85); 76.2% of patients were Ann Arbor stage I/II disease. The 5‐year progression‐free survival (PFS) and overall survival (OS) were 49.9% and 54.8%, respectively. Patients with log[EBV‐DNA] ≥ 3.8 and bone marrow hemophagocytosis at diagnosis had inferior PFS and OS. Most stage I/II patients received combined chemoradiotherapy with anthracycline‐containing regimen, with overall response rate of 96.7%, complete response rate 86.9%, 5‐year PFS 65%, and OS 72%. The relapse rate was 29.3% with a short median disease‐free survival of 6.2 months. In advanced stage patients, overall response rate was only 13.6%, with median PFS 2.3 months, and OS 4.8 months. Age ≥ 60 (HR 3.773, 95% CI 1.733‐8.215, P = 0.001) and stage III/IV (HR 7.785, 95% CI 2.312‐26.213, P = 0.001) were unfavorable prognostic factors for PFS and OS by multivariate analyses.

Conclusions

Age ≥ 60 and stage III/IV are independent poor prognostic factors for PFS and OS. Early‐stage ENKTL patients had good response to combined chemoradiotherapy with anthracycline‐containing regimen but with a high relapse rate and short disease‐free survival. Anthracycline‐containing regimen in advanced stage had poor response and dismal outcome.

     

Allogeneic bone marrow transplantation in aggressive non-Hodgkin's lymphoma (excluding Burkitt and lymphoblastic lymphoma): a series of 73 patients from the SFGM database

The place of allogeneic bone marrow transplantation (BMT) in the treatment of aggressive non-Hodgkin's lymphoma (NHL) remains controversial. We conducted a retrospective study of French experience in allografting NHL between 1984 and 1994. To improve the homogeneity of the study population, cases of low-grade, Burkitt and lymphoblastic NHL were excluded. 73 patients were included in the analysis. Median age at transplantation was 35 years (range 9-61 years); 64 patients were in stage IV and 45 had bone marrow involvement at diagnosis. At the time of transplantation, 46 patients had sensitive disease (25 in complete remission; CR). The overall survival (OS) and progression-free survival (PFS) rates were 41% and 40% respectively at 5 years (median follow-up of survivors 90 months). The probability of disease progression was 30% at 5 years, and only one relapse occurred after 15 months. 32 patients died of transplantation-related complications. In multivariate analysis, pretransplant complete remission was the main factor associated with longer survival (OS at 60 months of 76% among the 25 patients in CR at transplant and of 23% among the 48 patients not in CR at transplant). Neither acute nor chronic graft-versus-host disease (GvHD) influenced the relapse rate. In conclusion, in this high-risk population the overall results of allogeneic BMT were encouraging, despite a high transplant-related mortality rate. We believe this procedure should be studied further in prospective controlled trials.     

A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy,organomegaly, endocrinopathy,monoclonal gammopathy,and skin changes (POEMS) syndrome

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty‐one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21‐70 years). Twenty‐one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534‐14 328 pg/mL) to 832 pg/mL (95‐6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment‐related deaths occurred and no patients suffered from lenalidomide‐related grade 3 or above adverse events. After a median follow‐up of 34 months, median overall survival (OS) and progression‐free survival (PFS) were not reached, with an estimated 3‐year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620.     

Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non‐Hodgkin lymphoma: a multicentre phase II study

There is a lack of published data examining non‐cytotoxic options for the frontline treatment of patients with high‐tumour burden (HTB) indolent non‐Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty‐two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40–86); 38% bulky disease; 19% malignant effusions; 91% advanced‐stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent‐to‐treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50‐month median follow‐up, 4‐year progression‐free survival (PFS) was 44% with 4‐year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four‐year PFS for FLIPI 0–2 vs. 3–5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non‐cytotoxic therapeutic regimen that was well tolerated and resulted in long‐term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.