Medical Research Council Myeloma Research Articles

Serum free light chain levels and renal function at diagnosis in patients with multiple myeloma

BackgroundRenal impairment (RI) is common in multiple myeloma (MM) and is associated with poor survival. This study reports the associations between renal function and disease characteristics including serum free light chain (FLC) level at diagnosis in patients with MM.MethodsUsing data from the Medical Research Council Myeloma IX trial, a multicentre, randomized, open-label, phase III and factorial-design trial, we assessed the relationships between renal function, demographic, and disease characteristics, including serum FLC levels, in 1595 newly diagnosed MM patients. Multivariable linear regression was utilised to identify factors that were associated with renal function at diagnosis. A receiver operating characteristic curve (ROC) was used to identify the optimal threshold for serum FLC level at diagnosis to predict severe RI.Results52.8% of patients had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 (no RI), 37.3% an eGFR 30–59 ml/min/1.73 m2 (mild to moderate RI), and 9.8% an eGFR < 30 ml/min/1.73 m2 (severe RI). In a multivariable analysis, factors independently and negatively associated with eGFR at diagnosis were: higher serum FLC level, female gender, and older age. Elevated serum FLC level at diagnosis, irrespective of the paraprotein type, was strongly associated with severe RI. Receiver operating characteristic curve analysis showed a serum FLC level of > 800 mg/L as the optimal cut-off associated with severe RI (area under curve 0.86, 95% confidence interval 0.77–0.84).ConclusionThere was a strong relationship between higher serum FLC levels at diagnosis and the severity of RI that was irrespective of the paraprotein type. We report an increased risk of severe RI in patients presenting with serum FLC levels above 800 mg/L at diagnosis.

Bayesian statistical models to estimate EQ-5D utility scores from EORTC QLQ data in myeloma.

It is well documented that the modelling of health-related quality of life data is difficult as the distribution of such data is often strongly right/left skewed and it includes a significant percentage of observations at one. The objective of this study is to develop a series of two-part models (TPMs) that deal with these issues. Data from the UK Medical Research Council Myeloma IX trial were used to examine the relationship between the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/QLQ-MY20 scores and the European QoL-5 Dimensions (EQ-5D) utility score. Four different TPMs were developed. The models fitted included TPM with normal regression, TPM with normal regression with variance a function of participant characteristics, TPM with log-transformed data, and TPM with gamma regression and a log link. The cohort of 1839 patients was divided into 75% derivation sample, to fit the different models, and 25% validation sample to assess the predictive ability of these models by comparing predicted and observed mean EQ-5D scores in the validation set, unadjusted R2 , and root mean square error. Predictive performance in the derivation dataset depended on the criterion used, with R2 /adjusted-R2 favouring the TPM with normal regression and mean predicted error favouring the TPM with gamma regression. The TPM with gamma regression performs best within the validation dataset under all criteria. TPM regression models provide flexible approaches to estimate mean EQ-5D utility weights from the EORTC QLQ-C30/QLQ-MY20 for use in economic evaluation.

Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction

The detection of minimal residual disease (MRD) in myeloma using a 0.01% threshold (10(-4)) after treatment is an independent predictor of progression-free survival (PFS), but not always of overall survival (OS). However, MRD level is a continuous variable, and the predictive value of the depth of tumor depletion was evaluated in 397 patients treated intensively in the Medical Research Council Myeloma IX study. There was a significant improvement in OS for each log depletion in MRD level (median OS was 1 year for ≥10%, 4 years for 1% to <10%, 5.9 years for 0.1% to <1%, 6.8 years for 0.01% to <0.1%, and more than 7.5 years for <0.01% MRD). MRD level as a continuous variable determined by flow cytometry independently predicts both PFS and OS, with approximately 1 year median OS benefit per log depletion. The trial was registered at www.isrctn.com as #68454111.

Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results

Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma. We report on the safety of bisphosphonate therapy with long-term follow-up in the Medical Research Council Myeloma IX study. Patients with newly diagnosed multiple myeloma were randomised to zoledronic acid (ZOL; 4 mg intravenously every 21-28 d) or clodronate (CLO; 1600 mg/d orally) plus chemotherapy. Among 1960 patients (5.9-year median follow-up), both bisphosphonates were well tolerated. Acute renal failure events were similar between groups (ZOL 5.2% vs. CLO 5.8% at 2 years; incidence plateaued thereafter). The overall incidence of confirmed osteonecrosis of the jaw (ONJ) was low, but higher with ZOL (ZOL 3.7% vs. CLO 0.5%; P < 0.0001). ONJ events were generally low grade and most occurred between 8 and 30 months (median time to ONJ, 23.7 months). Among 10 patients with ONJ recovery data, four patients in the ZOL group completely recovered, two patients improved, and three patients experienced no improvement; one CLO patient experienced no improvement. Dental surgery or trauma preceded ONJ in six ZOL patients. The incidence of renal adverse events was similar for ZOL and CLO. ONJ incidence remained low and was lower with CLO compared to ZOL. We have seen no further ONJ cases to date.

Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment

Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years). At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics. Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01). Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.

The impact of response on bone-directed therapy in patients with multiple myeloma

Significant benefits for zoledronic acid (ZOL) over clodronate acid (CLO) were seen in the Medical Research Council Myeloma IX randomized trial. ZOL significantly reduced skeletal-related events (SREs), and improved progression-free survival and overall survival (OS), making it the bisphosphonate of choice for newly diagnosed myeloma patients. In this analysis of Myeloma IX data, we have investigated the impact of response on bone disease in 1111 transplant-eligible patients. At posttransplant day 100, complete response (CR) was seen in 48% of patients, very good partial response (VGPR) in 20%, and partial response (PR) in 23%. For patients in VGPR or less, ZOL was superior to CLO in reducing SREs (P = .048), whereas for patients in CR, both agents were equivalent (P = .83). For OS, ZOL was associated with a significant benefit in patients in PR (P = .0091). No difference in OS was seen with patients in CR (P = .91) or VGPR (P = .74). These findings indicate that response category posttransplant may influence the impact of bisphosphonate therapy.

Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma

Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.

Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study

To investigate the prognostic value of minimal residual disease (MRD) assessment in patients with multiple myeloma treated in the MRC (Medical Research Council) Myeloma IX trial. Multiparameter flow cytometry (MFC) was used to assess MRD after induction therapy (n = 378) and at day 100 after autologous stem-cell transplantation (ASCT; n = 397) in intensive-pathway patients and at the end of induction therapy in non-intensive-pathway patients (n = 245). In intensive-pathway patients, absence of MRD at day 100 after ASCT was highly predictive of a favorable outcome (PFS, P < .001; OS, P = .0183). This outcome advantage was demonstrable in patients with favorable and adverse cytogenetics (PFS, P = .014 and P < .001, respectively) and in patients achieving immunofixation-negative complete response (CR; PFS, P = .0068). The effect of maintenance thalidomide was assessed, with the shortest PFS demonstrable in those MRD-positive patients who did not receive maintenance and longest in those who were MRD negative and did receive thalidomide (P < .001). Further analysis demonstrated that 28% of MRD-positive patients who received maintenance thalidomide became MRD negative. MRD assessment after induction therapy in the non-intensive-pathway patients did not seem to be predictive of outcome (PFS, P = .1). MRD assessment by MFC was predictive of overall outcome in patients with myeloma undergoing ASCT. This predictive value was seen in patients achieving conventional CR as well as patients with favorable and adverse cytogenetics. The effects of maintenance strategies can also be evaluated, and our data suggest that maintenance thalidomide can eradicate MRD in some patients.

Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from myeloma patients at different stages of disease activity identifies acetylcarnitine as a novel marker of active disease.

BackgroundBiomarker identification is becoming increasingly important for the development of personalized or stratified therapies. Metabolomics yields biomarkers indicative of phenotype that can be used to characterize transitions between health and disease, disease progression and therapeutic responses. The desire to reproducibly detect ever greater numbers of metabolites at ever diminishing levels has naturally nurtured advances in best practice for sample procurement, storage and analysis. Reciprocally, since many of the available extensive clinical archives were established prior to the metabolomics era and were not processed in such an ‘ideal’ fashion, considerable scepticism has arisen as to their value for metabolomic analysis. Here we have challenged that paradigm.MethodsWe performed proton nuclear magnetic resonance spectroscopy-based metabolomics on blood serum and urine samples from 32 patients representative of a total cohort of 1970 multiple myeloma patients entered into the United Kingdom Medical Research Council Myeloma IX trial.FindingsUsing serial paired blood and urine samples we detected metabolite profiles that associated with diagnosis, post-treatment remission and disease progression. These studies identified carnitine and acetylcarnitine as novel potential biomarkers of active disease both at diagnosis and relapse and as a mediator of disease associated pathologies.ConclusionsThese findings show that samples conventionally processed and archived can provide useful metabolomic information that has important implications for understanding the biology of myeloma, discovering new therapies and identifying biomarkers potentially useful in deciding the choice and application of therapy.

Cost-effectiveness of zoledronic acid compared with clodronate in multiple myeloma.

In the U.K. Medical Research Council Myeloma IX trial (mmix), zoledronic acid 4 mg once every 3-4 weeks, compared with clodronate 1600 mg daily, reduced the incidence of skeletal related events (sres), increased progression-free survival (pfs), and prolonged overall survival (os) in 1970 patients with newly-diagnosed multiple myeloma. The incidence of confirmed osteonecrosis of the jaw was higher with zoledronic acid than with clodronate. The objective of the present study was to evaluate, based on the findings in mmix, the cost-effectiveness of zoledronic acid compared with clodronate in patients with newly-diagnosed multiple myeloma. An economic model was used to project pfs, os, the incidence of sres and adverse events, and expected lifetime health care costs for patients with newly diagnosed multiple myeloma who are alternatively assumed to receive zoledronic acid or clodronate. The incremental cost-effectiveness ratio (icer) of zoledronic acid compared with clodronate was calculated as the ratio of the difference in cost to the difference in quality-adjusted life years (qalys). Model inputs were based on results of mmix and published sources. Results were generated under different assumptions regarding the beneficial effects of zoledronic acid on os beyond 5 years after treatment initiation. Assuming lifetime treatment effects of zoledronic acid, treatment with zoledronic acid (compared with clodronate) increased qalys by 0.27 at an additional cost of CA$13,407, yielding an icer of CA$49,829 per qaly gained. If the threshold icer is CA$100,000 per qaly, the estimated probability that zoledronic acid is cost-effective is 80%. Assuming that the benefits of zoledronic acid on pfs and os diminish over 5 years beginning at the end of year 5, the icer is CAN$63,027 per qaly gained. If the benefits of zoledronic acid on pfs and os are assumed to persist for 5 years only, the icer is CAN$76,948 per qaly gained. Compared with clodronate, zoledronic acid represents a cost-effective treatment alternative in patients with multiple myeloma.

Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma

We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial

The Medical Research Council Myeloma IX Trial (ISRCTNG8454111) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid (ZOL) and oral clodronate (CLO) in 1960 patients with newly diagnosed multiple myeloma. Overall survival (OS) and skeletal-related event (SRE) data have been reported for the overall trial population. The present analysis investigated optimal therapy regimens for different patient populations in Myeloma IX. Patients were assigned to intensive or nonintensive treatment pathways and randomized to induction cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive). Patients were also randomized to ZOL or CLO. In the nonintensive pathway, CTDa produced better responses and lower SRE rates than melphalan and prednisolone. ZOL improved OS compared with CLO independently of sex, stage, or myeloma subtype, most profoundly in patients with baseline bone disease or other SREs. In patients treated for ≥ 2 years, ZOL improved OS compared with CLO from randomization (median not reached for either; P = .02) and also from first on-study disease progression (median, 34 months for ZOL vs 27 months for CLO; P = .03). Thalidomide-containing regimens had better efficacy than traditional regimens, and ZOL demonstrated greater benefits than CLO.

Cost-effectiveness of zoledronic acid vs clodronic acid for newly-diagnosed multiple myeloma from the United Kingdom healthcare system perspective

Objective:In the Medical Research Council Myeloma IX Study (MMIX), zoledronic acid (ZOL) 4 mg 3–4/week reduced the incidence of skeletal-related events (SREs), increased progression free survival (PFS), and prolonged overall survival (OS), compared with clodronic acid (CLO) 1600 mg daily, in 1970 patients with newly-diagnosed multiple myeloma (MM).Methods:An economic model was used to project PFS, OS, the incidence of SREs and adverse events and expected lifetime healthcare costs for patients with newly-diagnosed MM who are alternatively assumed to receive ZOL or CLO. The incremental cost-effectiveness ratio [ICER] of ZOL vs CLO was calculated as the ratio of the difference in cost to the difference in quality-adjusted life years (QALYs). Model inputs were based on results of MMIX and published sources.Results:Compared with CLO, treatment with ZOL increases QALYs by 0.30 at an additional cost of £1653, yielding an ICER of £5443 per QALY gained. If the threshold ICER is £20,000 per QALY, the estimated probability that ZOL is cost-effective is 90%.Limitations:The main limitation of this study is the lack of data on the effects of zoledronic acid on survival beyond the end of follow-up in the MMIX trial. However, cost-effectiveness was favourable even under the highly conservative scenario in which the timeframe of the model was limited to 5 years.Conclusions:Compared with clodronic acid, zoledronic acid represents a cost-effective treatment alternative in patients with multiple myeloma.

The Medical Research Council Myeloma IX Trial: New Clinical Insights on the Anticancer Effects of Zoledronic Acid in Patients With Multiple Myeloma

The bone microenvironment plays a key role in multiple myeloma (MM) disease pathogenesis and progression. 1 Raab M.S. Podar K. Breitkreutz I. Richardson P.G. Anderson K.C. Multiple myeloma. Lancet. 2009; 374: 324-339 Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar , 2 Ria R. Roccaro A.M. Merchionne F. Vacca A. Dammacco F. Ribatti D. Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003; 17: 1961-1966 Crossref PubMed Scopus (73) Google Scholar Clonal expansion and epigenetic variations of the microenvironment result in switching of plasma cell subsets to a proangiogenic phenotype, 3 Ribatti D. Nico B. Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene. 2006; 25: 4257-4266 Crossref PubMed Scopus (151) Google Scholar and these changes are accompanied by profound bone loss. 4 Aggarwal R. Ghobrial I.M. Roodman G.D. Chemokines in multiple myeloma. Exp Hematol. 2006; 34: 1289-1295 Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Due to the severity of bone resorption in MM disease, patients with MM are generally treated concomitantly with bisphosphonates (BPs) to preserve skeletal health and to reduce the risk of skeletal-related symptoms. Moreover, BPs naturally target the bone microenvironment and may potentially disrupt promyeloma signaling. Among the BPs, pamidronate and zoledronic acid (ZOL) are approved worldwide for patients with osteolytic bone lesions from MM, and clodronate (CLO) is approved in Europe.

MRC Myeloma IX, 6 Year Median Follow-up (FU) Highlights the Importance of Long-Term FU in Myeloma Clinical Trials and Differential Effects of Thalidomide in High- and Low-Risk Disease

Abstract Abstract 993 The Medical Research Council (MRC) Myeloma IX study evaluated the role of the addition of thalidomide to induction and maintenance therapy, ran from May 2003–November 2007, randomising 1,970 patients, and now has a median follow-up (FU) of 6 years, giving it improved power to detect clinically relevant changes. The trial comprised 2 patient pathways, which were not determined by strict age cut-off; one for younger fitter patients (intensive pathway), comparing CTD (cyclophosphamide, thalidomide, dexamethasone) (n=555 evaluable) with CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone) (n=556), all patients being planned to receive ASCT. The other pathway, for older, less fit patients (non-intensive pathway) compared MP (melphalan and prednisolone) (n=423) with an attenuated CTD (CTDa) (n=426). In both pathways, following initial treatment, patients were randomised to low-dose thalidomide or no maintenance until progression (n=820). Primary endpoints were response rate, progression free survival (PFS) and overall survival (OS). Adverse FISH groups were defined as any of t(4;14), t(14;16), t(14;20), 1q+, 17p−, or 1p32− (in the intensive pathway only); the remainder being defined as standard risk. We have previously presented data from the study with a median FU of 3.7 years, where there appeared to be emergent survival benefits for thalidomide induction, though not reaching significance. The 6 year median FU OS analysis provides us with the ability to analyze the impact of these regimens on the long-term survival of this group of patients. This late analysis is important, as while early FU is more sensitive to the impact of treatments on higher-risk disease, longer term FU is more sensitive to the impact of therapies on standard-risk disease, where thalidomide may exert its most important effects. The results of this late analysis at a median of 6 years will inform our use of thalidomide based on FISH risk status. The same arguments apply to the use of thalidomide maintenance on high- and standard-risk disease defined by FISH, where the early analysis showed significantly improved PFS with a hint of improved OS in the standard-risk group, whereas there was no impact on PFS for high-risk disease with significantly impaired OS. The results of this long-term analysis will allow us to further analyse the potential for an emergent OS benefit for thalidomide maintenance in the standard-risk disease group. In conclusion, we will present the late analysis of this important study, which will specifically inform how the use of thalidomide as induction and maintenance can impact on OS in standard-risk disease defined by FISH. Disclosures: Morgan: Celgene: Honoraria, Speakers Bureau. Davies:Celgene: Honoraria, Speakers Bureau. Gregory:Celgene: Honoraria. Bell:Celgene: Honoraria. Cook:Celgene: Speakers Bureau. Owen:Celgene: Honoraria, Speakers Bureau. Jackson:Celgene: Speakers Bureau. Child:Celgene: Honoraria.

A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial

The association of genetic lesions detected by FISH with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council (MRC) Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short PFS and OS in multivariate analysis were +1q21, del(17p13) and an adverse IGH translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with 1 adverse lesion and a high risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the ISS and so was integrated with the ISS to identify an ultra-high risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8 % of patients and was associated with a median OS of 19.4 months.

Results of the Medical Research Council (MRC) Myeloma IX study: Effects of zoledronic acid (ZOL) on overall survival (OS) in patients with multiple myeloma (MM)

Results of the Medical Research Council (MRC) Myeloma IX study: Effects of zoledronic acid (ZOL) on overall survival (OS) in patients with multiple myeloma (MM)

Cost-Effectiveness of Zoledronic Acid Versus Clodronate In Patients with Multiple Myeloma From a Canadian Healthcare System Perspective.

Abstract Abstract 3812 Background: The Medical Research Council (MRC) Myeloma IX study compared the intravenous (IV) bisphosphonate, zoledronic acid (ZOL) 4 mg q 3–4 wk with the oral bisphosphonate, clodronate (CLO) 1,600 mg/d PO, in 1,970 patients with newly-diagnosed multiple myeloma (MM). After a median follow-up of 3.7 yrs (max. follow-up 6 years), ZOL prolonged OS (median 50.0 vs. 44.5 months; HR=0.842; p=0.0118), increased PFS (median 19.5 vs. 17.5 months; HR=0.883; P=0.0179), and reduced the incidence of skeletal related events (SREs) (27.0% vs. 35.3%; HR=0.74; P=0.0004) compared with CLO. The incidence of acute renal failure (ARF) was similar in the two groups (5.8% vs. 6.1% with ZOL vs. CLO). The incidence of osteonecrosis of the jaw (ONJ) was 3.5% with ZOL and 0.3% with CLO. The objective of this study was to evaluate the cost-effectiveness of ZOL vs. CLO in patients with newly-diagnosed MM based on the reported findings of the MRC Myeloma IX trial. Methods: An economic model was used to project PFS, OS, the incidence of SREs (vertebral and other fractures, radiotherapy, bone surgery, and spinal cord compression) and adverse events (ARF, ONF, thromboembolism, and infection) as well as expected lifetime healthcare costs for patients with newly diagnosed MM who are alternatively assumed to received bishphosphonate therapy with ZOL or CLO. Cost-effectiveness was expressed in terms of the incremental cost per quality-adjusted life-year (QALY) gained with ZOL vs. CLO. Clinical data were based on reported results of the MRC Myeloma IX trial. OS for CLO and ZOL up to 5 years were based on reported Kaplan-Meier survival curves. For CLO, OS after 5 years was projected based on a Weibull survival function fitted to the reported Kaplan-Meier curve. For ZOL, OS after 5 years was obtained by applying the estimated HR for ZOL vs. CLO to the estimated Weibull survival function for CLO. PFS for CLO and ZOL were estimated based on reported medians and the HR for ZOL vs. CLO, assuming proportional hazards Weibull distributions (Kaplan-Meier curves were not reported for PFS). Costs and utility values were obtained from published sources. Costs were in 2009/10 Canadian dollars. Costs and QALY were discounted at 5% annually. Results: Expected lifetime costs of bisphosphonate therapy (including administration and monitoring costs) were $11,967 greater with ZOL vs. CLO ($14,267 vs. $2,301). Expected costs of SREs were reduced by $720 with ZOL ($4,152 vs. $4,872). Expected costs of adverse events were increased by $663 with ZOL ($3,225 vs. $2,562). Expected total lifetime costs were increased by $11,878 ($30,103 vs. $18,225). Life expectancy (undiscounted) was increased by 0.83 years with ZOL (6.43 vs. 5.60). QALYs gained from increased PFS and OS with ZOL vs. CLO were 0.56. QALYs gained from SREs averted with ZOL vs. CLO were &lt;0.01. QALYs lost due to adverse events (predominantly ONJ) were 0.02. Total QALYs gained with ZOL vs. CLO (undiscounted) were 0.56 (4.43 vs. 3.87). On a discounted basis, total QALYs gained were 0.37 (3.51 vs. 3.14). Cost effectiveness with ZOL vs. CLO was $32,210 per QALY gained. In probabilistic sensitivity analyses, the probability that ZOL is preferred to CLO was 85% with a cost-effectiveness threshold of $50,000 per QALY and a 98% with a threshold of $100,000 per QALY. Cost-effectiveness was $43,487 per QALY gained if benefits of ZOL on OS are conservatively assumed to persist for 6 years only (i.e., HR for OS=1.0 after 6 years). Results were sensitive to methods used to estimate PFS and OS (i.e., Kaplan Meier or Weibull models, independent or proportional hazards assumption), and the estimated costs and QALYs lost with ONJ. Conclusions. The cost per QALY gained with ZOL vs. CLO in patients with newly-diagnosed MM is below the commonly-accepted threshold of $50,000 per QALY gained. More precise estimates await release of additional results from the MRC Myeloma IX study. Disclosures: Delea: Novartis: Consultancy, Research Funding. Off Label Use: Zoledronic acid for prevention of skeletal related events in patient with multiple myeloma. Ougari:Novartis: Employment. Rotter:Novartis: Consultancy, Research Funding. Wang:Novartis: Consultancy, Research Funding. Kaura:Novartis: Employment. Morgan:Novartis: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Pharmion: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Ortho Biotech: Research Funding.

Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study.

8021 Background: Bisphosphonates (BPs) are standard of care for reducing the risk of skeletal-related events (SREs) in pts with bone metastases from solid tumours or bone lesions from MM. Several BPs have also demonstrated anticancer activity in preclinical models. With the highest level of activity among approved BPs, ZOL has shown anticancer activity in preclinical and clinical studies in various cancer types, including MM. Of note, in pts with early breast cancer, ZOL improved disease-free survival by 36% (P = 0.01) vs endocrine therapy alone (Gnant, et al. NEJM. 2009). Among other endpoints, the MRC Myeloma IX Study investigated effects of ZOL vs clodronate (CLO) on SREs, progression-free survival (PFS), and OS in MM pts. Methods: Newly diagnosed MM pts were randomised to ZOL (4 mg q 21-28 days) or CLO (1,600 mg q day) plus antimyeloma therapy. Treatment continued at least until disease progression. Results: Of 1,970 pts randomised,1,960 were evaluable, with a median follow-up of 3.7 yrs. To date, app...

UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M‐proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)

Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Helier Hospital, Carshalton, Surrey, UK, Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Medicine, Malmo University Hospital, Malmo, Sweden, Division of Immunity and Infection, University of Birmingham, Birmingham, Department of Clinical Biochemistry, Frenchay Hospital, Bristol, Department Haematology, University College, London, Glasgow Western Infirmary, Glasgow, UK, Department of Haematology, NTNU/St Olavs Hospital, Trondheim, Department of Haematology, Ulleval University Hospital, Oslo, Norway, Department of Haematology Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, and Myeloma UK.