First-line Bortezomib Research Articles

Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second-line daratumumab-bortezomib-dexamethasone (DVD) in AL amyloidosis in bortezomib-exposed patients. A total of 116 patients treated with second-line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second-line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event-free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2-year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second-line treatment in systemic AL amyloidosis in a bortezomib-exposed population. However, the response to DVD is poorer in those with an inadequate response to first-line bortezomib.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18–70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

A Multicenter Prospective Study for Validation of the Korean Simple Geriatric Assessment Tool in Elderly Patients with Multiple Myeloma

Purpose Frailty is a multidimensional state of diminished reserve (energy, physical ability, cognition and health) which gives rise to vulnerability to cancer treatment. Geriatric assessment (GA) with management should be integrated into the clinical care of older patients with multiple myeloma (MM). with ageing-related conditions. The purpose of this study was to prospectively validate the Korean Cancer Study Group Geriatric Score (KG)-7, a simplified frailty assessment tool, in older patients with multiple myeloma (MM) planned to undergo first-line chemotherapy. Materials and Methods The study included 95 newly diagnosed MM patients aged 70 years or older. Participants answered the KG-7 questionnaire before undergoing International Myeloma Working Group (IMWG) frailty score and first-line bortezomib- and/or lenalidomide- based chemotherapy. KG-7 scores ranged from 0 to 7, and higher scores indicated better conditions. Results The median age was 77 years and 50.5% of patients were older than 75 years. Fifteen patients (15.8%) had an ADL score ≤ 4, 24 (25.3%) an IADL score ≤ 5, and 19 (20.0%) a CCI ≥ 2. Based on the < 5 cut-off value of KG-7 for frail group, frail group was shown in 29 (30.5%). There was the negative correlation between KG-7 and IMWG frailty score (Pearson correlation, 0.547; P < 0.001). The cumulative incidence of grade ≥ 3 non-hematologic adverse events was 27.3% in non-frail and 48.3% in frail patients (HR, 2.5; P = 0.046). There was no significant difference between the two groups of KG-7 with regard to grade ≥ 3 hematological toxicity and dose modification at cycle one. There was no significant difference between the two groups (frail versus non-frail) in PFS (hazard ratio [HR] = 1.37; 95% CI = 0.52-3.65; P = 0.525) and OS (HR = 1.85; 95% CI 0.52-6.58, P = 0.341), which was attributed to the short FU period of 11.6 months. Interpretation Despite the interim analysis, KG-7 appears to be an easy-to-define prediction model for defining the vulnerable patients with MM. Whether KG-7 is helpful in predicting survival outcome requires longer follow-up.

Circulating RAS/RAF and DNA-Repair Gene Mutations Associates with High-Risk/Treatment Resistance in Primary Refractory Multiple Myeloma

Background Multiple myeloma (MM) is an incurable plasma cell malignancy with a median overall survival (OS) of 5 years in newly diagnosed (ND) patients. Real-world data reveals that 23% of transplant eligible newly diagnosed MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ~50% will fail secondary therapy and die within 18 months of diagnosis. It is currently impossible to identify these high-risk patients and genomic studies could potentially inform alternative secondary therapeutic options. We propose that circulating tumour DNA (ctDNA) analysis could provide a more holistic approach to gain an insight into the genomics of high-risk patients than bone marrow (BM) tumour DNA analysis in this genetically heterogenous multi-site malignancy. Methods A total of 186 paired peripheral blood plasma and BM samples were obtained at baseline, cycle 3 day 1 (C3D1), end of study (EOS) and/or relapse, whichever appeared earlier, from a Phase II single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible ND MM patients who were refractory or had a suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group MM17 trial). Somatic variants were identified with ultra-sensitive targeted amplicon sequencing of BM and plasma for 22-genes known to be mutated in MM. The mutational profiles were combined with the International Staging System (ISS), SKY92 MMProfilerTM risk profile - standard-risk (SR) or high-risk (HR) or EuroFlow minimal residual disease (MRD) status and correlated to progression-free survival (PFS). Longitudinal monitoring of ctDNA variant allele frequency was also plotted to observe alterations in ctDNA kinetics at relapse compared to baseline and C3D1. Results We performed a comparison of the available baseline ctDNA and BM mutational profiles between patients who did relapse (R) (n=18 ctDNA and n=10 BM) or did not relapse (NR) (n=29 ctDNA and n=21 BM). Utilising data derived from all variants identified, there were no significant differences in the relative proportions of specific mutations between R and NR in the BM samples whereas there were significant ctDNA differences between R and NR for both BRAF (p=0.02) and TP53 (p=0.06) mutations (chi-square test). We next performed a comparison of only those ctDNA variants with variant allelic frequencies (VAF) >1%, a threshold known to have a prognostic impact, and identified a statistically significant difference in mutational proportions between R and NR for RAS/RAF (22.2% vs 3.4%, p=0.04) and DNA damage repair genes (DDR) (ATM/ATR/TP53) (55.5% vs 20.6%, p=0.01). Subsequently, we combined ctDNA RAS/RAF and/or DDR mutational detection (>1% VAF, referred to as ctDNA+) with risk status as defined by ISS, SKY92 or MRD. Patients in ISS 2+3/ctDNA+ (compared to ISS 2+3/ctDNA-, ISS 1/ctDNA+, ISS 1/ctDNA-, Figure 1A); SKY92 HR/ctDNA+ (compared to SKY92 HR/ctDNA- and SKY92 SR/ctDNA+ or SKY92 SR/ctDNA-) and MRD+/ctDNA+ (compared to MRD+/ctDNA- and MRD-/ctDNA+ or MRD-/ctDNA-) all had significantly shorter PFS (p<0.01; p<0.01 and p<0.05; respectively, Log-rank tests). Importantly, patients that were ctDNA+ also had a shorter PFS on KTd compared to ctDNA- (p<0.01, 28.4 months for ctDNA+ vs not reached for ctDNA-, Log-rank test, Figure 1B). Conversely, parallel combined analyses with BM mutations revealed no significant prognostic differences. Longitudinal monitoring of ctDNA demonstrated that in 87.5% of patients, 1 or more of the dominant mutations present at the time of relapse were already present at the start of KTd salvage therapy. Conclusions These data demonstrate that combining ctDNA mutational profiling with available platforms for MM risk-stratification significantly enhances the identification of high-risk patients. Moreover, the impact in this context of RAS/RAF and DDR mutations provides a rationale for the design and implementation of novel treatment paradigms utilising RAS/RAF inhibitors or DNA-repair modulators in these high-risk MM patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 3373: Circulating tumour DNA mutations correlate with relapse in a phase II trial of bortezomib-primary refractory multiple myeloma patients receiving salvage therapy

Abstract Background: Multiple myeloma (MM), an incurable plasma cell malignancy, has a relative 5-year overall survival (OS) of 48.5% for newly diagnosed patients. Prospective real-world data reveals that 23% of transplant eligible MM patients relapse within 12 months of starting first-line bortezomib based therapy with a median OS of only 16.8 months (high-risk - HR). Genomic studies for these HR patients could inform rational secondary therapeutic options and prolong survival. Bone marrow (BM) genomic analysis in MM has methodological and conceptual shortcomings owing to the spatially and genomically heterogeneous nature of MM that can be largely overcome with circulating tumour DNA (ctDNA) analysis. Objective: To determine whether ctDNA analysis can define the mutational spectrum of patients with HR MM. Design: Phase II, multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible newly diagnosed MM patients from September 2016 to April 2018 (Australasian Leukaemia and Lymphoma Group (ALLG) - MM17 trial) who were refractory (REF) to or demonstrated a suboptimal response (SOR) to bortezomib-based induction therapy. A total of 186 peripheral blood plasma and BM samples were obtained at baseline, at Cycle 3 day 1 (C3D1), end of the study (EOS) and/or at relapse. Somatic variants were identified with an ultra-sensitive targeted amplicon sequencing (TAS) assay incorporating 22-genes known to be mutated in MM. The mutational spectrum was correlated with progression-free survival (PFS) and OS. Results: TAS of 31 BM samples and 48 ctDNA samples revealed that in BM, KRAS mutations were detected in 42% of patients followed by ATR in 29% while in ctDNA, ATR mutations were prominent (36%), followed by FGFR3 and ATM (27% and 26.8%). We compared the ctDNA mutational spectrum at baseline between non-relapse and relapse patients on KTd and identified a significant difference in the proportion of patients with specific mutations - RAS/RAF: 3% vs 25%; ATM/ATR/TP53: 17% vs 41%, respectively (p&amp;lt;0.0001). Patients with RAS/RAF and/or ATM/ATR/TP53 ctDNA mutations at baseline had significantly shorter PFS and OS (p=0.003 and p=0.02, respectively). Comparative ctDNA TAS for baseline, C3D1, EOS/relapse, demonstrated that in 87.5% of patients, one or more dominant mutations driving relapse in KTd were already present prior to starting salvage therapy. We also performed ctDNA analysis to compare patients who were REF or SOR to front-line therapy and identified 62% of REF patients had RAS/RAF or ATM/ATR/TP53 mutation compared to 35% of SOR patients (p=0.0002, Fisher’s exact test). Conclusions: Our results demonstrate that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA are prognostic biomarkers of outcome to secondary salvage therapy in HR patients thus enabling design of targeted therapeutic approaches to improve survival. Citation Format: Sridurga Mithraprabhu, John Reynolds, Anna Kalff, Krystal Bergin, Rose Turner, Hang Quach, Noemia Horvath, Ian Kerridge, Flora Yuen, Kawa Choi, Malarmathy Ramachandran, Ashley George, Tiffany Khong, Brian Durie, Andrew Spencer. Circulating tumour DNA mutations correlate with relapse in a phase II trial of bortezomib-primary refractory multiple myeloma patients receiving salvage therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3373.

Circulating tumor DNA analysis and association with relapse in patients with primary refractory multiple myeloma receiving secondary salvage therapy.

8037 Background: Multiple myeloma (MM) is an incurable plasma cell malignancy with a 5 year-median overall survival (OS) in newly diagnosed (ND) patients. Real-world data reveals that 23% of transplant eligible (TE) ND MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ̃50% will fail secondary therapy and die within 18 months. It is currently impossible to identify these high-risk patients and genomic studies could potentially inform alternative secondary therapeutic options. We propose that circulating tumour DNA (ctDNA) analysis could provide a more holistic approach to determine genomics of high-risk patients than bone marrow (BM) tumour DNA analysis in this genetically heterogenous multi-site malignancy. Methods: Peripheral blood plasma and BM samples (n = 186) were obtained at baseline, cycle 3 day 1 (C3D1), end of the study (EOS) and/or relapse, whichever appeared earlier, from a Phase II multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 TE ND MM patients who were refractory or registered suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group - MM17 trial). Somatic variants were identified in BM or ctDNA with ultra-sensitive targeted amplicon sequencing of 22-genes known to be mutated in MM. Mutational spectrum was correlated to standard MM risk factors including International Staging System (ISS), response to 1LB and KTd, cytogenetics/FISH, lactate dehydrogenase (LDH) levels, progression-free survival (PFS) and OS. Results: Our initial analysis of ctDNA mutational proportions between patients who did not or did experience relapse on KTd revealed a significantly higher proportion of RAS/RAF (3% vs 25%), or ATM/ATR/TP53 (17% vs 41%; p &lt; 0.0001), respectively, in relapse patients. Subsequently, we correlated ctDNA RAS/RAF and/or ATM/ATR/TP53 mutational presence to standard MM risk factors. We identified a shorter PFS and OS for ISS Stage 2 and 3 compared to Stage 1 patients (p = 0.002 and p = 0.02, respectively) and a significantly higher proportion of RAS/RAF or ATM/ATR/TP53 mutations in patients with refractory as compared to sub-optimal response to 1LB therapy (p = 0.0002). Patients with RAS/RAF or ATM/ATR/TP53 mutations in ctDNA at the time of starting salvage therapy also had a shorter PFS and OS on KTd (p = 0.003 and p = 0.02, respectively). Sequential ctDNA analysis discovered that in 87.5% of patients, one or more of the dominant mutations present at the time of relapse were already present at the start of salvage therapy. Conclusions: Our analysis reveals that RAS/RAF and ATM/ATR/TP53 mutations in ctDNA could be prognostic biomarkers of response to secondary salvage therapy in primary refractory patients thus providing the opportunity to design targeted salvage treatment paradigms in high-risk MM patients.

Ixazomib-based regimens for relapsed/refractory multiple myeloma: are real-world data compatible with clinical trial outcomes? A multi-site Israeli registry study.

Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22months. Median age was 68 (range 38-90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24months (95% CI 17-30). PFS was 77% and 47% at 12 and 24months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24months after a bortezomib induction and for those who have a more indolent disease phenotype.

Clinical outcomes of bortezomib-based therapy in Taiwanese patients with multiple myeloma: A nationwide population-based study and a single-institute analysis

In a retrospective cohort study, we report the current epidemiology of patients with multiple myeloma (MM) and analyze the real-world clinical outcomes of bortezomib-based therapy. This retrospective study was mainly designed to evaluate the characteristics, treatment outcomes, and prognostic factors of patients with MM who received bortezomib-based therapy. We identified 5,726 patients in Taiwan with MM newly diagnosed between 2007 and 2015. Confidential data from the National Health Insurance Research Database (NHIRD) was used under strict guidelines, as it was made available in an electronic format for research purposes. In addition, we analyzed 96 patients who have been diagnosed with MM and were treated at the Tri-Service General Hospital (TSGH) between January 1, 2002, and December 31, 2018. Patients receiving first-line treatment with bortezomib had longer overall survival (OS) compared to those who received non-first-line treatment (p<0.001). In addition, the statistically lowest risk of mortality was when patients received first-line bortezomib followed by an autologous hematopoietic stem cell transplant (adjusted hazard ratio = 0.39, p<0.001). In the TSGH study, the patients were enrolled between January 1, 2002, and December 31, 2018, with an initial diagnosis of MM; there were 96 individuals treated with bortezomib. There was no statistically significant difference in the OS or progression-free survival (PFS) according to the gender, myeloma type, International Staging System stage, or treatment regimen. There was a significant difference in the PFS in patients receiving first-line bortezomib treatment with transplantation compared to those without transplantation (p = 0.021). Bortezomib as a first-line treatment extended the OS in four-year mortality tracking and lowered the mortality risk according to the NHIRD analysis. In the TSGH analysis, the results indicated that the initial conditions of patients with MM have a lower influence on the OS and PFS after bortezomib-based therapy was administered.

Cost-effectiveness analysis on binary/triple therapy on the basis of ixazomib or bortezomib for refractory or relapsed multiple myeloma

This study analyzed the cost utility on the use of ixazomib/lenalidomide/dexamethasone (IRD), lenalidomide/dexamethasone (RD), bortezomib/thalidomide/dexamethasone (VTD), or bortezomib/dexamethasone (VD) for patients with refractory or relapsed multiple myeloma (rrMM). Patients’ lifelong direct medical costs and quality-adjusted life years (QALYs) are simulated by using the Markov model on the basis of the China’s healthcare system. VTD, RD, and IRD are 0.12, 0.32, and 0.42 QALYs higher than VD, and $9401, $16,868, and $39,671 higher than those of VD in terms of lifelong cost. The incremental cost-effectiveness ratios are 78,342, 52,713, and 94,455, respectively. IRD can extend the life years of patients with rrMM, improve the quality of life, and increase the cost of medical treatment. The use of VD has a comparative advantage of cost utility. For patients who cannot tolerate bortezomib or were drug-fast with first-line bortezomib, RD plan is another economical and effective strategy.

Impact of t(11;14) on outcomes in African American (AA) and non-AA (NAA) patients (Pts) with newly diagnosed multiple myeloma (NDMM): Connect MM registry.

8023 Background: t(11;14) is a common cytogenetic abnormality historically associated with standard-risk and generally favorable MM outcomes, but has shown poor prognosis in some retrospective analyses. Connect MM is a prospective, US, observational, multicenter registry that collects data on management and natural history of NDMM pts in clinical practice. The impact of t(11;14) on survival outcomes was assessed in AA and NAA pts. Methods: Adult NDMM pts who completed induction and were tested for t(11;14) by FISH/cytogenetics were grouped by race (AA vs NAA). Endpoints were PFS and OS. Kaplan-Meier analyses were adjusted for differences in cohort, age, ISS stage, transplant intent, t(4;14), hemoglobin, platelets, calcium, creatinine, and diabetes history. Data cutoff was Jul 7, 2016. Results: 3011 pts were enrolled in 2 cohorts (Cohort 1: n = 1493, Sep 2009–Dec 2011, median follow-up = 39.3 mos; Cohort 2: n = 1518, Dec 2012–Apr 2016, median follow-up = 16.4 mos). Of 1539 (52%) pts tested for t(11;14), 363 (24%) were t(11;14)-positive, including 53 (26%) of 205 AA and 310 (23%) of 1334 NAA pts. First-line bortezomib exposure was similar across groups. A trend of shorter PFS was observed in AA pts with t(11;14) vs AA without t(11;14) (Table). AA pts with t(11;14) had significantly higher risk of death compared to those without t(11;14) and higher rate of early mortality than NAA pts. No differences in PFS or OS were noted in NAA pts with or without t(11;14). For OS, the interaction between race and t(11;14) status was statistically significant ( P= 0.004). Conclusions: In Connect MM, the effect of t(11;14) on OS was significantly different between AA and NAA pts. t(11;14) was associated with poorer survival outcomes in AA pts, and thus, may be a risk factor for poor prognosis. Additional analyses will be conducted to elucidate the role of induction treatment, transplant and maintenance in AA and non-AA pts with t(11;14). Clinical trial information: NCT01081028. [Table: see text]

Early mortality in multiple myeloma: Experiences from a single institution

Objective: Multiple myeloma (MM) is a hematological malignancy that presents with infection, anemia, bone lesions, renal function impairment, and hypercalcemia. The survival of MM patients has improved in recent decades; however, early mortality remains a critical problem. The aim of this study was to identify the etiologies and clinical variables associated with early mortality in MM. In addition, the effects of bortezomib on reducing early mortality incidence were investigated.Method and materials: Medical records from 122 MM patients diagnosed between November 2007 and December 2013 were retrospectively reviewed. Early mortality was defined as death by any cause within the first 180 days after pathological diagnosis.Results: In newly diagnosed MM patients, early mortality occurred in 22.95% of patients. Infection accounted for 67.86% of early deaths. Multivariate analyses by Cox proportional-hazards regression showed that higher β2-microglobulin (P < 0.001) and serum lactate dehydrogenase (P < 0.001) levels, and lower serum albumin levels (P < 0.001) were associated with early mortality. Both first-line and greater than or equal to second-line bortezomib treatments were not associated with superior 180-day overall survival (P = 0.546 for first-line bortezomib treatment; P = 0.066 for greater than or equal to second-line bortezomib treatment).Conclusion: Our results suggest that infection is the leading cause of early death in MM. High β2-microglobulin, high serum lactate dehydrogenase, and low serum albumin levels are poor prognostic factors for early mortality. Bortezomib therapy does not appear to reduce the incidence of early mortality in MM patients.

Outcomes of light-chain amyloidosis patients treated with first-line bortezomib: a collaborative retrospective multicenter assessment.

Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected 'real-world' AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n=50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70yr, lack of cardiac and peripheral neurologic involvement, and co-administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6months of induction. First-line bortezomib-based regimen resulted in favorable response and survival in newly diagnosed patients. Co-administration of an alkylating agent improved outcome without increasing treatment-related toxicity.

Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052)

BackgroundThis was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18weeks (PFSR-18)1 as primary end-point. MethodsChemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75mg/m2 on day 1 and bortezomib 1.3mg/m2 on days 1, 4, 8, 11 every 3weeks. The primary end-point validation utilised the landmark method. ResultsBetween 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42–64%). The overall survival (OS) was 13.5months (95% CI 10.5–15) with 56% (95% CI 44–66%) alive at 1year. The median PFS was 5.1months (95% CI 3.3–6.5) and the response rate was 28.4% (95% CI 18.9–39.5%).The most frequent grade 3–4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest.End-point validation showed that patients with no progression/progression at 18weeks had median OS of 16.9/11.9months, respectively. Hazard ratio was 0.46 (CI 0.32–0.67), logrank test and C-index were 0.007 and 0.60. ConclusionThe 50% PFSR-18 for CB was contained within the 80% CI for (42–64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.

Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial

The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.

First-line bortezomib benefits patients with multiple myeloma

Bortezomib-based regimens are beneficial in the treatment of patients with symptomatic, newly diagnosed and relapsed or refractory multiple myeloma. researchers who investigated the efficacy and safety of single-agent bortezomib as first-line therapy in patients with myeloma have particularly emphasized the incidence and management of peripheral neuropathy, which is the most common adverse effect of bortezomib administration.