Autologous-allogeneic versus autologous tandem stem cell transplantation and maintenance therapy with thalidomide for multiple myeloma patients less than 60 years of age: a prospective phase II study

The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma (MM) is controversial. Between 2008 and 2014 a total of 217 MM patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multi-center clinical trial to compare alloTSCT to auto tandem transplantation TSCT (autoTSCT) followed by a 2-year maintenance therapy with thalidomide (100 mg/d) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent second SCT (allo n = 132 and auto n = 46). PFS at 4 years after the second SCT was 47% (CI: 38-55%) for alloTSCT and 35% (CI: 21-49%) for autoTSCT (p = 0.26). This difference increased to 22% at 8 years (p = 0.10). The cumulative incidences of non-relapse mortality (NRM) and of relapse at 4 years were 13% (CI: 8-20%) and 2% (CI: 0.3-2%) (p = 0.044) and 40% (CI: 33-50%) and 63% (CI: 50-79%) for alloTSCT and autoTSCT (p = 0.04), respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (p = 0.002). Four-year OS was 66% (CI: 57-73%) for alloTSCT and 66% (CI: 50-78%) for auto TSCT (p = 0.91) and 8-year OS was 52% and 50% (p = 0.87), respectively. AlloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly.

Bortezomib consolidation following autologous transplant in younger and older patients with newly diagnosed multiple myeloma in two phase III trials.

OBJECTIVE: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). METHODS: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. RESULTS: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. CONCLUSION: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

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.

Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study.

This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m2) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43-1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150.

Autologous Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Drug Induction: A Retrospective Single-Center Analysis.

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥60 years (p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies.

Continuous lenalidomide treatment for newly diagnosed multiple myeloma.

BACKGROUND: Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma. METHODS: We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP. CONCLUSIONS: MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

Lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in newly diagnosed multiple myeloma patients aged 65 years or older: results of a randomized phase III trial.

The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).

Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone.

The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.

Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial.

BACKGROUND: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. DESIGN AND METHODS: We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. RESULTS: In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. CONCLUSIONS: Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00452569).

POEMS syndrome treated with melphalan high-dose therapy and autologous blood stem cell transplantation: a single-institution experience.

The acronym POEMS syndrome stands for a rare multi-system disorder, comprised of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Here, we present a single-center report of a series of five POEMS patients treated with melphalan high-dose therapy (HDT) with subsequent autologous blood stem cell transplantation (ABSCT). After a median follow-up of 52 months from time of diagnosis (range, 15-192) and a median follow-up of 18 months after ABSCT (range, 11-120), all patients were alive. Overall, no severe transplantation-associated complications such as engraftment syndrome or peri- or post-transplant death were noted. In two cases, HDT followed by ABSCT resulted in a complete hematologic response; in the additional three cases, partial responses (PR) were achieved including one very good hematologic PR. Only one patient with initial PR developed progressive disease nearly 2.5 years after transplantation. Consequently, a second HDT with ABSCT was successfully applied resulting in clinical improvement and hematologic PR. In line with previous single-center reports, melphalan HDT followed by ABSCT proved to be a first-line treatment option with tolerable side effects in severely affected POEMS patients with progressing symptoms.

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.

BACKGROUND: Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma. METHODS: This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. FINDINGS: 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. INTERPRETATION: Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. FUNDING: Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

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.

Multiple myeloma treatment strategies with novel agents in 2011: a European perspective.

The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. METHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). CONCLUSIONS: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)

Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study.

OBJECTIVES: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone. METHODS: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m(2), days 1-4, cycles 1-9; and prednisone 60 mg/m(2), days 1-4, cycles 1-9). RESULTS: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥ 3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m(2). Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P=0.0065], grade ≥ 2 PN (HR 2.205, P=0.0032), and grade ≥ 3 PN (HR 2.438, P=0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN. CONCLUSIONS: Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases.

Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma.

OBJECTIVES: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. METHODS: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338). RESULTS: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. CONCLUSIONS: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues.

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.

One CGIAR and the Integrated Agri-food Systems Initiative: From short-termism to transformation of the world's food systems.

Agri-food systems are besieged by malnutrition, yield gaps, and climate vulnerability, but integrated, research-based responses in public policy, agricultural, value chains, and finance are constrained by short-termism and zero sum thinking. As they respond to current and emerging agri-food system challenges, decision makers need new tools that steer toward multi-sector, evidence-based collaboration. To support national agri-food system policy processes, the Integrated Agri-food System Initiative (IASI) methodology was developed and validated through case studies in Mexico and Colombia. This holistic, multi-sector methodology builds on diverse existing data resources and leverages situation analysis, modeled predictions, and scenarios to synchronize public and private action at the national level toward sustainable, equitable, and inclusive agri-food systems. Culminating in collectively agreed strategies and multi-partner tactical plans, the IASI methodology enabled a multi-level systems approach by mobilizing design thinking to foster mindset shifts and stakeholder consensus on sustainable and scalable innovations that respond to real-time dynamics in complex agri-food systems. To build capacity for these types of integrated, context-specific approaches, greater investment is needed in supportive international institutions that function as trusted in-region 'innovation brokers.' This paper calls for a structured global network to advance adaptation and evolution of essential tools like the IASI methodology in support of the One CGIAR mandate and in service of positive agri-food systems transformation.

Current multiple myeloma treatment strategies with novel agents: a European perspective.

The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.