ALBERT

Description: 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.

Description: Key Points The use of ZOL is better than CLO in the improvement of SREs and survival in symptomatic myeloma patients at diagnosis. Response category posttransplant may influence the impact of bisphosphonate therapy.

Description: Introduction: Multiple myeloma (MM) is more common in men than women but the mechanism(s) driving this are not understood. In our previous study (Myeloma IX) we found sex disparities in the cytogenetic lesions present in myeloma cells at the time of diagnosis and that female sex was associated with reduced overall survival in the context of treatment with traditional chemotherapy (CVAMP/MP) and thalidomide combinations. Here, we evaluate sex differences in almost 4000 patients recruited to the UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Methods: Myeloma XI recruited newly diagnosed patients of all ages, with pathways for transplant eligible (TE) and ineligible (TNE) patients. An induction randomisation compared the triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). Eligible patients underwent autologous stem cell transplant (ASCT) and in both pathways a maintenance randomisation compared lenalidomide (+/-vorinostat) until disease progression versus observation. We compared baseline characteristics of males and females using Fisher's Exact test for categorical characteristics and the Wilcoxon-Mann-Whitney test for continuous characteristics with p1 lesion present. Results: Of 3894 patients enrolled in the trial 2268 (58%) were male and 1626 (42%) were female, in keeping with the known sex disparity in MM. There was no difference in the median age, WHO performance status, ethnicity and most laboratory values of the two groups. Females were more likely to have the molecular risk lesions t(14;16) and del(17p) and had proportionately more HiR and UHiR disease, Table 1. Despite these differences, PFS and OS from induction randomisation did not significantly differ (PFS: Males 25 months, [95% CI 24, 26], Females 24 months, [95% CI 22, 25] and OS: Males 67 months, [95% CI 62, 70], Females 70 months, [95% CI 64, 74]). Molecular lesions that have been associated with outcome remained prognostic in both sexes, with a stepwise reduction in PFS and OS with cumulative risk lesions. PFS: Males SR 29 months, HiR 23 months, UHiR 16 months (p 〈 0.0001), Females SR 27 months, HiR 18 months, UHiR 17 months (p = 0.0007); OS: Males SR 77 months, HiR 59 months, UHiR 34 months (p 〈 0.0001), Females SR 82 months, HiR 54 months, UHiR 41 months (p 〈 0.0001). There was, however, no significant difference in PFS or OS when we compared males and females with a given cytogenetic lesion or cytogenetic risk. There was a significant difference in the proportion of patients of either sex who continued through the trial and underwent ASCT in the TE pathway (Males 72%, Females 67%; p = 0.031), but no significant difference in those that entered the maintenance randomisation (TE: Males 56%, Females 50%, p = 0.107; TNE Males 45%, Females 42%, p = 0.249). There was no significant PFS or OS difference by sex when analysed within each treatment pathway (TE, TNE), induction regimen (CTD, CRD) and maintenance approach (lenalidomide maintenance, observation). Conclusions: Females had a higher proportion of the adverse molecular risk lesions del(17p) and t(14;16) and were more likely to have HiR and UHiR disease. In the context of Myeloma XI trial treatment this did not correspond to a difference in PFS or OS, either overall or within the induction or maintenance randomisation treatment options (even though males were more likely to undergo ASCT). This suggests that in women the treatment delivered may have been able to overcome some of the adverse effect of the risk lesions present or that other factors affecting outcome were more important. on behalf of the NCRI Haematological Oncology Clinical Studies Group. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Abbvie, Janssen: Honoraria; Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Russell:DSI: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. OffLabel Disclosure: CTD/CRD induction therapy for myeloma, Lenalidomide maintenance 10mg 21/28 days

Description: Abstract 335 Background Induction treatment for myeloma has focused on improving response rates and many centres have evaluated and used triplets of therapy based on either IMiD or proteosome inhibitor drugs. Other strategies rely on combining the two classes of novel agents and excellent response rates have been obtained. An alternative approach to this, which moves some way towards personalised therapy, is to use sequential combinations of the two classes of novel agents dependent on the response achieved. The aim of this approach is to maximise responses and, by so doing, improve survival. Methods In order to test this concept, we have carried out a trial, Myeloma XI, which compared responses to cyclophosphamide, thalidomide and dexamethasone (CTD) with cyclophosphamide, lenalidomide and dexamethasone (CRD). Following the randomised use of either of these triplets, given to maximum response, patients achieving no response (NC or PD) received further therapy with a triplet composed of cyclophosphamide, bortezomib and dexamethasone (CVD). In order to test if a bortezomib combination could improve the response of maximally treated patients, those with a suboptimal response (MR or PR) were randomised to either no further therapy or to CVD. For patients achieving ≥ VGPR no further induction was given. Younger fitter patients went on to receive HDM plus ASCT whereas older less fit patients did not. All patients were eligible for a maintenance randomisation to no maintenance, lenalidomide or lenalidomide/vorinostat maintenance. For patients receiving CVD, treatment was continued to a maximum of 8 cycles, with response being assessed using IMWG criteria after each cycle and therapy continued to maximum response or intolerance. Here we present the response rates for patients who have received CVD. Results At the time of this initial analysis 1424 patients have been randomised overall; 790 in the intensive pathway and 634 in the non-intensive pathway. Across both pathways, of the refractory patients with no response to induction treatment, an upgrade in response from NC or PD to ≥MR was seen after CVD treatment in 58% of patients, with 31% going on to achieve a VGPR or CR. In the other group of patients, those with a suboptimal response to induction treatment and randomised to receive CVD, 45% went on to achieve VGPR or CR. These patients reduced their paraprotein value by a mean of 74% from the start of CVD suggesting that the improvement in response is significant and not the result of patients marginally crossing the boundaries of response criteria. It seems that even in a group of maximally treated patients that response rates can be increased further by the use of a proteosome inhibitor drug. In the MRC Myeloma IX study the response rates at a similar time point for those treated with similar thalidomide based induction were PD/NC 7.1%, MR/PR 41.8%, VGPR/CR 37.5%. Assuming at least the same response rates in the current study then we calculate that it would be possible to get approximately 45% extra patients from MR/PR and 31% from PD/NC to ≥VGPR, equating to an approximate 21% increase in the ≥VGPR rate to 59% of the total patients. Conclusions We have demonstrated an improvement in response with the addition of a bortezomib based regimen in the group of patients who had a suboptimal response following induction chemotherapy with an IMiD based regimen. Particularly encouraging is the excellent rate of achievement of CR/VGPR in patients with no initial response to treatment. We anticipate that together this will significantly improve the percentage of patients achieving ≥VGPR, approximating 60% of all patients following induction, a response rate that should improve further following ASCT. Further follow up is required to know whether or not this will translate into an improvement in OS or PFS, however from previous studies we would expect this to be the case. Disclosures: Pawlyn: Celgene: Unrestricted educational grant Other. Off Label Use: Lenalidomide and vorinostat as maintenence therapy. Davies:Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other; Ortho Biotech: Honoraria, Speakers Bureau. Gregory:Celgene: Unrestricted educational grant Other. Szubert:Celgene: Unrestricted educational grant Other. Bell:Celgene: Unrestricted educational grant Other. Ouzman:Celgene: Unrestricted educational grant Other. Drayson:Celgene: Unrestricted educational grant Other. Owen:Celgene: Unrestricted educational grant Other. Jackson:Celgene: Honoraria, Unrestricted educational grant Other. Russell:Celgene: Unrestricted educational grant Other. Morgan:Ortho Biotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other.

Description: Key Points The type of antibody secreted at relapse can serve as a marker of clonal heterogeneity. It is important to monitor for serum FLC in the suspicion of clinical relapse to ensure that FLC relapse is not missed.

Description: The role of maintenance therapy for the long term control of the plasma cell clone in patients induced into response with either intensive or conventional treatment is an important outstanding question. We addressed this in the MRC Myeloma IX study which incorporates intensive and non-intensive pathways selected according to PS and age. In the intensive pathway patients were randomised to either CTD or CVAD induction, followed by High Dose Melphalan (HDM) before being randomised to either thalidomide or no maintenance. In the non-intensive pathway patients were randomised to either MP or attenuated CTD prior to the maintenance randomisation. For patients randomised to thalidomide it was initiated at d100 following HDM or at the end of induction in the non-intensive arm with the aim of delivering 100mg daily until relapse. A dose reduction algorithm for side effects was used. Between the years of 2003–8, 820 patients were entered into the maintenance randomisation, median age 64 (intensive 59, non-intensive 73), median follow-up 32 months. Prognostic features were evenly distributed between the arms. FISH and cytogenetics were done using standard methods. Response was assessed by IWG criteria. For overall survival (OS) there was a non-significant trend in favour of the no maintenance arm, which enables us, by calculating confidence limits on the hazard ratio, to make the assertion that no maintenance could be up to 7% worse than thalidomide at 5 years (p=.005). Further analysis showed that there was no significant difference in OS in either the intensive or the non-intensive arm. The duration of time on thalidomide maintenance appeared to make no difference to OS. There was a non-significant improvement in progression free survival (PFS) across the maintenance randomisation as a whole and in the intensive pathway a significant benefit of maintenance was seen in the patients achieving less than a VGPR post initial induction therapy prior to HDM, (hazard ratio 1.9, p=.007). This PFS difference did not translate into a survival benefit because the survival after progression in the PR patients receiving maintenance thalidomide was poor (p=.002). In addition we looked at the time spent off thalidomide, the recovery time, (the time between stopping thalidomide and progression) as a possible predictor of survival after progression. Treated as a continuous variable in the Cox model this showed a trend for longer survival after relapse in those with longer recovery time (p=.056). In the non-intensive pathway a similar but less pronounced effect of thalidomide maintenance on PFS was seen. These results are consistent with a consolidation rather than a maintenance effect for thalidomide in this setting. The impact of maintenance in different cytogenetic subgroups was also determined [17p-, 13q-, 14q abnormalities including t(4;14), t(14;16), t(6;14), t(14;20) and t(11;14)]. For the 17p- group, the difference in OS between no thalidomide and thalidomide is large (HR = 4.55, p=.02) with the thalidomide patients faring worse, although this is based on only 30 patients. For the non 17p- group there is no difference in PFS (HR = 1.24, p=.37), in the 17p- group, however, the PFS is worse. In addition, of the 22, 17p- patients receiving CTD or CTDa as initial therapy, the 10 who received no thalidomide maintenance are all still alive, whereas 9/12 of those who went on to receive thalidomide maintenance have died. It seems that thalidomide given at induction and again in maintenance, may be particularly detrimental in 17p- patients. Although thalidomide maintenance may improve PFS, there is no demonstrable benefit on OS. It is important to identify 17p- in order to exclude these patients from receiving thalidomide maintenance.

Description: To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-κB pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111.

Description: Abstract 623 Background: Although a meta-analysis has suggested that a consistent PFS benefit is seen with maintenance thalidomide therapy in multiple myeloma (MM) patients, the impact on OS remains unclear (Hicks LK, et al. Cancer Treat Rev 2008;34:442-452). This could be due to a lack of effect, differing biological subgroups in relatively small studies with short follow-up, or lack of effective relapse treatment. Aims: The study was set up to evaluate the effect of thalidomide maintenance therapy in newly diagnosed MM patients aged ≥ 18 years with OS and PFS as end points, and to examine differential effects in fluorescence in situ hybridization (FISH) identified molecular subgroups. Methods: Following induction treatment in an intensive pathway for younger fitter patients and a non-intensive pathway for the remaining patients, eligible patients were randomized to open-label thalidomide maintenance until progression (50 mg/day escalating to 100 mg/day after 4 weeks assuming good tolerance) or no maintenance. Patients of all ages were included in the randomization. FISH was performed using standard approaches. 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 were defined as favorable. Results: Overall, 820 patients were eligible of which 818 were evaluable. Median patient age was 65 years (range, 31−89). Median follow-up from maintenance was 38 months (range 12−66 months). Median time on maintenance was 7 months (range 0−50 months). Maintenance thalidomide significantly improved PFS, with a difference between the curves of 13% (95% confidence interval [CI] 6%−20%) established by 24 months and maintained till the current maximum follow-up at 66 months (hazard ration [HR] 1.36; 95% CI 1.15−1.61; logrank P 〈 0.001). However, in the initial analysis there was no apparent impact on OS (P = 0.40). These findings were consistent regardless of prior intensive or non-intensive induction treatment. At 66 months follow-up, a PFS benefit was seen in the favorable FISH group (P = 0.004) with no effect on OS (P = 0.6). In the adverse FISH group there was no effect on PFS (P = 0.48) and a negative effect on OS (P = 0.009). Subsequently, we evaluated the effect of relapse treatment on outcomes and used this data in a mathematical model to determine if OS benefit would have accrued from the prolonged PFS if all patients had received effective treatment at relapse. A total of 523 patients have progressed to date and of these, 47% received thalidomide as initial relapse treatment (either as a single agent or in combination), 30% received novel agents (either bortezomib or lenalidomide), and 27% received alkylating agents or steroids. Median survival after progression was significantly worse in patients who received thalidomide maintenance than those who did not (P 〈 0.005); this could, at least partly, be attributed to patients who received thalidomide at progression. In those patients, the median OS after progression was significantly greater in the no maintenance group versus the thalidomide maintenance group (P = 0.004). Among patients treated with novel agents at progression, prior thalidomide maintenance therapy had no impact on OS and these patients were effectively salvaged. The mathematical model employed to examine the effect of effective salvage therapy at progression suggested that a significant survival benefit of 5.5% at 3-years in favor of thalidomide maintenance would have accrued if all patients had received effective therapy at progression (HR 0.77; 95% CI 0.60–0.99; P = 0.04). Next, we examined whether continuous thalidomide therapy was associated with a consolidation or maintenance effect. Upgrading of response with thalidomide maintenance was not common. Importantly, there was no difference in response over time between maintenance therapy and no maintenance. In contrast to what has been reported previously, these findings suggest a maintenance effect. Conclusions: Maintenance thalidomide significantly improves PFS and if effective relapse treatment is available this translates into an OS advantage. The median duration of maintenance thalidomide therapy of 7 months in the present study was short. The clinical impact of maintenance would be improved if patients could remain on therapy for longer, suggesting that the use of other agents such as lenalidomide, with better tolerability profiles, may produce better results. Disclosures: Off Label Use: THALOMID (thalidomide) in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma. Davies:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: BACKGROUND: Minimal residual disease (MRD) in CLL is an independent predictor of progression-free and overall survival after chemo-immunotherapy. Data from the DCLLSG trials indicate that a high, intermediate and low risk of disease progression is seen in patients with 〉1%, 0.01-1%, or 1% vs. 0.01-1% vs 1% MRD predicts equivalent or worse outcome than a clinical PR. PB MRD analysis at 18 months after randomisation (~1 year after treatment) was also strongly predictive of outcome: 98% of patients with 1%, 0.01-1%, or 1% MRD equating to 1% MRD equating to

Description: Abstract 2980 Introduction: Deletion of chromosome 13, detected by conventional chromosome analysis (CC), has been suggested to be an independent indicator of poor prognosis in myeloma (MM). With the exception of a single study using conventional therapy this has not been confirmed in multicenter randomized controlled trials which have mostly used FISH analysis. We set out to assess the prognostic value of del(13) and compare its detection by FISH and CC. Methods: We have examined the effect of del(13) in a large multicenter randomized controlled phase III trial, MRC Myeloma IX (ISRCTN68454111), which tested the effect of induction therapy with a thalidomide combination in both an intensive (CTD vs CVAD prior to single HDM plus ASCT) and a non-intensive (CTDa vs MP) setting. From June 2003 to November 2007 samples from newly presenting MM patients were sent from hospitals throughout the UK to a central laboratory where CD138 purification for FISH was performed, with conventional cytogenetic culture(s), using unpurified cells, being set up wherever possible. Results: 1960 evaluable patients were entered into the trial (1111 intensive, 849 non-intensive) of which 1036 were evaluable for del(13) by FISH (613 intensive, and 423 non-intensive); del(13) was seen in 45% (470/1036) with a similar incidence in both pathways. With a median follow up of 3.7 years del(13) detected by FISH was associated with impaired OS (median, 42 vs 52 mo, p=0.004). The effect was stronger in the non-intensive pathway (median OS 25 vs 37 mo, p=0.001) than in the intensive one (median 58 mo vs not reached, p=0.095). However, this adverse prognostic impact was negated when the strong association of del(13) with the bad prognosis IGH translocations t(4;14), t(14;16) and t(14;20) (bad IGH) was taken into account. In comparison, 639 patients were evaluable for CC results (378 intensive, 261 non-intensive) with an overall abnormality rate of 35% (224/639). We note that the impact of detecting any abnormal karyotype was not significantly different from a normal/failed karyotype irrespective of intensive or non-intensive treatment being used (whole trial p=0.213, intensive p=0.249, non-intensive p=0.252) suggesting that the capacity to generate abnormal metaphases alone is not an adverse prognostic factor. Del(13) was seen in 45% of abnormal karyotype cases (102/224) and 16% of all cases tested for CC. Overall the detection of del(13) by CC was associated with an adverse prognostic effect on OS (median 34 vs 47 mo, p=0.039). However, the entire effect was in the non-intensive pathway (median 20 vs 34 mo, p=0.018) (Fig1A), with no detectable effect in the intensive pathway (median 69 vs not reached, p=0.679) (Fig1B). We addressed the impact of the treatment used, and in a comparison of the thalidomide and non-thalidomide regimes for all del(13) CC patients there was no significant impact on OS (p=0.538). However, in the non-intensive pathway there was a significant improvement in favour of thalidomide (median 33 vs 18 mo p=0.03). Multivariate analysis of the prognostic impact of genetic factors within abnormal metaphases showed that bad IGH (p=0.001), gain of 1q (p=0.001) and deletion of 17p (p=0.001) were the only independent prognostic factors. In further analyses including all FISH-detected abnormalities, the markers bad IGH (p