VAD Arm Research Articles

Identification and Validation of IMiD-14 Model Predictive of IMiD Resistance in Multiple Myeloma

Abstract BACKGROUND: Immunomodulatory derivatives (IMiDs) have become an integral part of multiple myeloma (MM) treatment, both in newly diagnosed and relapsed refractory patients. Long-term treatment with IMiDs is inevitably associated with relapse and emerging resistance. The precise mechanisms of IMiDs resistance are not entirely clear. Gene-expression profiling (GEP) can be used to elucidate resistance/response signature associated with IMiDs. PATIENTS AND METHODS: GEP of paired samples of CD138-purified plasma cells, obtained from patients prior to and 48 hours after single-agent therapy with thalidomide (42 newly diagnosed MM), lenalidomide (18 relapsed/refractory MM), or pomalidomide (18 relapsed/refractory MM) were compared. Samples were hybridized to Affymetrix expression arrays. Affymetrix U133Plus2.0 arrays were used in the pomalidomide study and Affymetrix U95Av2 arrays were used for thalidomide and lenalidomide pharmacogenomics studies. Among 176 genes that significantly changed pre- and post IMiD treatment (P<0.05 by SAM analysis, and with change in same direction), 14 genes were selected that had P values <0.05 based on univariate Cox regression analysis for PFS in thalidomide arm of TT 2 trial. These 14 genes were combined to create a continuous score based upon each patient's difference between the average log2-scale expression of the 4 prognosis-unfavorable (hazard ratio [HR] > 1) and the 10 prognosis-favorable (HR < 1) genes. An optimal cutoff for this IMiDs-based risk score (hereafter referred to as IMiD14) was then established with the running log-rank test, so that patients with scores higher than the cutoff were considered as IMiDs resistant patients. RESULTS: The IMiDs resistant group in TT2 (Thalidomide arm) training set exhibited significantly poor PFS (P < 0.001) and inferior OS (P < 0.001). Next, we examined whether IMiD14 model had outcome discriminatory power in several independent test cohorts treated with IMiDs. In validation cohort TT3a (induction with VT(thalidomide)D-PACE, and maintenance with VTD in the 1st year followed by TD for 2 years), there were significant differences in outcome between patients whom IMiD14 model predicted to have IMiDs resistance versus others, 3-year PFS and OS rates for the predicted IMiDs resistant patients were 63% and 71%, whereas for the rest of patients the corresponding rates were 87% and 90% (PFS P = 0.01, OS P < 0.001). In validation cohort TT3b (induction with VT(thalidomide)D-PACE, and maintenance with VRD for 3 years), 3-year PFS and OS rates for the predicted IMiDs resistant patients were 62% and 70%, whereas for the rest of patients the corresponding rates were 80% and 85% (PFS P = 0.002, OS P = 0.003). The discriminatory power of IMiD14 was also independently confirmed in the validation cohort HOVON65/GMMG-HD4 VAD arm (induction with vincristine, doxorubicin, and dexamethasone, and maintenance with thalidomide for 2 years); 3-year PFS and OS rates for the predicted IMiDs resistant patients were 16% and 38%, versus 54% and 82%, respectively for the rest of the patients (PFS P < 0.001, OS P < 0.001). CONCLUSION: We have identified IMiD14 gene expression signature that accurately predicts resistance to IMiD treatment and outcome in multiple myeloma patients. These predictive genes could provide novel targets for therapeutic intervention and are being evaluated in prospective datasets. Figure 1. Figure 1. Disclosures Barlogie: Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Novartis: Consultancy. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Usmani:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array BioPharma: Honoraria, Research Funding.

Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial

Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial

Influence of Renal Impairment and Genetic Risk Factors on Response to Induction Therapy in the HD4 and MM5 Trials of the GMMG

Background:In the HOVON65/GMMG HD4 trial in patients with newly diagnosed multiple myeloma we have previously shown that patients with renal impairment (RI) (creatinine > 2 mg/dl) have higher response rates and better survival when receiving bortezomib both in the induction and maintenance therapy before and after high-dose chemotherapy (HDT) (Scheid et al. Haematologica 2014). In addition patients with RI showed a higher prevalence of genetic high-risk features such as del17p or t(4;14). The aim of this analysis was to further elucidate the interaction between renal and genetic risk factors in well defined homogeneously treated myeloma patients.Methods:For this study we selected 2 cohorts of patients entered into 2 consecutive prospective trials with centralised FISH-assessement on CD138-selected bone marrow cells. The first cohort (1) comprises 395 patients from the HOVON65/GMMG HD4 trial having been treated in the German centers and the second cohort (2) consisted in the 601 patients (intention-to-treat population) from the recently closed GMMG MM5 trial. Patients lacking FISH results were excluded from the analysis, which was the case for 53 (13.4%) patients in cohort 1 and 43 (7.2%) patients in cohort 2. In cohort 1 induction treatment was vincristine or bortezomib + doxorubicin and dexamethason followed by tandem HDT followed by bortezomib or thalidomide maintenance. Cohort 2 received doxorubicin or cyclophosphamide + bortezomib and dexamethason as induction followed by 1- 2 HDT and consolidation and maintenance with lenalidomide.Results: In cohort 1 38 (10%) had RI and del 17p was found in 12/33 (36.4%) evaluable patients compared to 24/302 (7.9%) patients without RI (p<0.001). t(4;14) was present in 11/33 (33.3%) patients with RI and 38/304 (12.5%) without RI (p=0.005). Gain of 1q21 (> 2 copies) was present in 14/33 (42.4%) patients with RI and 92/298 (30.9%) without RI (n.s.). In cohort 2 68/601 (11.3%) had RI and 7/63 (11.1%) had del17p compared to 56/495 (11.3%) patients without RI (n.s.) while 29/63 (46%) patients with RI had t(4;14) versus 265/495 (53.5%) without RI (n.s.). Gain1q21 (>2 copies) was found in 36/63 (57.1%) with RI versus 209/495 (42.2%) without RI (p=0.025). In cohort 1 the response rate with at least VGPR after induction was low with and without RI in the VAD arm (15 vs 7.1 %) and reduced in patients with RI in the PAD arm compared to those without RI (22.2 vs 37.9%). This trend was not found in cohort 2: Patients with RI had VGPR or better in 42.4% in the PAD and 52.9% in the VCD arm, compared to 33.5% and 33.1% without RI respectively. Del17p and t(4;14) which were more frequent in patients with RI in cohort 1 did not have a negative impact on response rates after induction. Similarly gain1q was more frequent among patients in cohort 2 with RI but did not impact on response to induction.Conclusions:We analysed the effect of RI and genetic risk factors on the response to induction therapy in two different patient cohorts from two consecutive prospective trials. High-risk genetic features where found more frequently in patients with RI, but the pattern was entirely different between cohort 1 and 2 and they did not seem to influence response rates after induction. Our results confirm that bortezomib-based induction regimens achieve high response rates in myeloma patients with RI similar to those in patients without RI, independent of the presence of genetic risk factors. DisclosuresScheid:Janssen: Honoraria; Celgene: Honoraria. Salwender:Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

Bortezomib Induction and Maintenance Treatment Improves Survival In Patients With Newly Diagnosed Multiple Myeloma:Extended Follow-Up Of The HOVON-65/GMMG-HD4 Trial

BackgroundWe investigated if bortezomib during induction and maintenance improves survival in newly diagnosed Multiple Myeloma (MM). Methods827 eligible patients with newly diagnosed symptomatic MM were randomized to receive induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n=414) or PAD (bortezomib, doxorubicin, dexamethasone; n=413) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT). Maintenance consisted of daily thalidomide 50 mg (VAD) or 2-weekly bortezomib 1.3 mg/m2 i.v. (PAD) for 2 years. The primary analysis was progression-free survival (PFS) adjusted for ISS stage. We here report long-term results of this trial (P. Sonneveld et al., J Clin Oncol 2012;30:2946-2955). ResultsThe number of eligible patients, patient characteristics and disease characteristics are similar to those reported before. The response rates during protocol treatment have improved slightly since all patients have now completed treatment: CR+nCR 49% vs 35%, VGPR 26% vs 21% and ≥PR 91% vs 83% (PAD vs VAD).After a median follow-up of 67 months, 111 of patients treated with VAD and 131 of patients treated with PAD were progression-free and alive. Progression-free survival (PFS) defined as time from randomization until progression, relapse or death (censored at date of alloSCT, if applicable), was superior with PAD when adjusted for ISS, (HR=0.78, 95% CI [0.66-0.91], P=.002) and in multivariate analysis (HR=0.76 (95% CI [0.64-0.90], P=.001). For the secondary endpoint overall survival (OS) the PAD arm was superior when adjusted for ISS (HR=0.80, 95% CI [0.65-1.00], P=.047) as well as in multivariate analysis (HR=0.78, 95% CI [0.63-0.97], P=.027). Landmark analysis from start of maintenance for PFS did not show a significant difference between Thalidomide and Bortezomib maintenance, however, for OS the PAD arm was superior (P=.035) (HR=0.71, 95% CI [0.52-0.98]). Subgroup analysis performed on patients with renal failure at presentation (serum creatinine ≥2 mg/dL; 45 VAD, 36 PAD) showed that the PAD arm was significantly superior for PFS (HR=0.44, 95% CI [0.26-0.75], P=.003) and OS (HR=0.38, 95% CI [0.21-0.69], P<.001). 35/45 (78%) patients treated with VAD had died as compared with 16/36 (44%) patients with PAD. In bortezomib treated patients with serum creatinine ≥2 mg/dL OS and PFS were not significantly different from those in bortezomib-treated patients with normal renal function. Analysis for the effect of study group, concentrating on the difference of single HDM (sHDM, HOVON policy) vs double HDM (dHDM, GMMG policy) with ASCT indicated that dHDM was not superior across treatment arms for PFS, but in multivariate analysis remained superior for OS (HR=0-72, 95% CI [0.58-0.90], P=.004). Comparison of study group and treatment arms for OS at 5 years indicated that PAD plus dHDM was superior (72% vs 59% (PAD+sHDM) vs 63% (VAD+dHDM) vs 56% (VAD+sHDM), logrank P=.004. When patients were classified by prognostic characterization by FISH and ISS (K. Neben et al. Blood 2012;119:940-948) subgroup analysis in patients treated with dHDM showed that in the VAD arm, PFS was significantly lower in intermediate risk (IRi) (HR 2.26, 95% CI [1.42-3.58], P<0.001) and poor risk (PRi) (HR 5.02, 95% CI [2.89-8.73], P<0.001) as compared to good risk (GRi), while in the PAD arm the HR for PRi was 2.04, 95% CI [1.20-3.48], P=0.009, and for IRi 1.26, 95% CI [0.82-1.92], P=0.29. These data suggest that with PAD+dHDM only high-risk remains an independent unfavourable group for PFS. For OS a comparable difference was observed. Finally, the actuarial probability to develop a second primary malignancy was not different between treatment arms (PAD 3% at 5 years vs VAD (5%), P=.22). ConclusionsBortezomib during induction and maintenance improves CR and achieves superior PFS and OS. Subgroup analysis after long follow-up confirms the favourable outcome in patients with renal failure. Comparison of study subgroup analysis suggests that bortezomib treatment combined with double intensive treatment may be beneficial for PFS/OS.This trial has been registered as NTR213; EudraCT no. 2004-000944-26; ISRCTN: 64455289.This trial was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to support this trial by Novartis, AMGEN, Chugai and Roche. Disclosures:Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Salwender:janssen: Honoraria. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Schmidt-Wolf:janssen: Research Funding; novartis: Honoraria. van de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Goldschmidt:janssen: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; chigai: Honoraria, Research Funding; roche: Honoraria, Research Funding.

Influence of Renal Function on Outcome of VAD or Bortezomib, Doxorubicin, Dexamethasone (PAD) Induction Treatment Followed by High-Dose Melphalan (HDM): A Subgroup Analysis From the HOVON-65/GMMG-HD4 Randomized Phase III Trial for Newly Diagnosed Multiple Myeloma

AbstractAbstract 2396 Introduction:Renal impairment is a frequent complication in patients with multiple myeloma (MM) and is correlated with an inferior prognosis. Bortezomib can be applied independently of renal function and has been shown to improve response and overall survival in patients with relapsed MM. We wanted to investigate the role of renal impairment in the context of a large randomized study comparing a bortezomib-containing induction regimen (PAD) with standard VAD followed by HDM and maintenance with either thalidomide or bortezomib. Methods:Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as bortezomib 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, 17–20). Patients received one (HOVON) or two (GMMG) cycles of high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T): 50 mg daily (arm A) or bortezomib (B): 1.3 mg/m2, 2-weekly (arm B) for 2 years. As of July 2010 data from the first consecutively enrolled 626 patients of the HOVON-65/GMMG-HD4 trial have been analyzed. 613 patients have been evaluable (n=305 in arm A and n=308 in arm B, respectively). For this analysis patients were grouped according to renal function at baseline with creatinine < 2 mg/dl (177 μ mol/l, n=553), 2–5 mg/dl (177-442 μ mol/l, n=46) or > 5 mg/dl (> 442 μ mol/l, n=13). Frequencies were compared by logistic regression, survival data by Cox PH regression. The analysis was intention-to-treat, with PFS censored for patients treated with allo-SCT (n=46). Results:Data are summarized in tables 1 –3. Response rates tended to be lower on patients with renal impairment. The overall response rate (at least PR) after HDM in the VAD arm for patients with a creatinine of 2–5 mg/dl was 48% compared to 83% with creatinine < 2 mg/dl. However in the PAD arm the response rate was 84% vs. 89% respectively (Table 1). Progression-free survival (PFS) was significantly influenced by renal function, with 24 months rates of 64%, 50% or 31% for the 3 groups (p=0.006). In patients with creatinine < 2 mg/dl 2yr PFS was 61% (VAD) vs. 67% (PAD), while it was markedly different for creatinine of 2–5 mg/dl: 78% in the PAD arm vs. 30% in the VAD arm (p=0.002) (Table 2.). Overall survival at 24 months was 86% for patients with creatinine < 2 mg/dl in both arms. With a creatinine of 2–5 mg/dl it was similar with PAD (89%) but significantly inferior with VAD (44%, p<0.001)(Table 3).Table 1Response rate, all in %Creatinine (mg/dl)Treatmentat least PR after Indat least PR after HDMVGPR+CR after IndVGPR+CR after HDMCR after IndCR after HDM<2 (n=553)VAD61831741210PAD798943627222-5 (n=46)VAD264872604PAD58842642016>5(n=13)VAD7575132500PAD6060204000 Discussion:Experience in patients with relapsed MM suggests those with an impaired renal function may in particular benefit from a bortezomib-containing therapy-regimen. In this subgroup analysis of a large randomized study testing bortezomib both in the induction and maintenance-treatment before and after HDM in newly diagnosed MM we could show that patients with elevated creatinine (2-5 mg/dl) have a markedly inferior response, progression-free and overall survival when receiving VAD and thalidomide-maintenance, while the treatment results in the bortezomib-containing arm were similar to those in patients with creatinine < 2 mg/dl. We conclude that combining HDM with a bortezomib-containing induction- and maintenance regimen is able to overcome the negative prognostic impact of an impaired renal function in patients with newly diagnosed MM.The HOVON-65/GMMG-HD4-trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to perform this trial by Novartis, AMGEN, Chugai and Roche. Disclosures:Scheid: Ortho Biotech: Honoraria. Off Label Use: Bortezomib in newly diagnosed myeloma. Sonneveld: Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees. Schmidt-Wolf: Janssen Cilag:; Celgene: Membership on an entity's Board of Directors or advisory committees. van de Velde: Johnson & Johnson: Employment. Duehrsen: Ortho Biotech: Honoraria. Delforge: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Weisel: Ortho Biotech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Goldschmidt: Ortho Biotech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding.Table 3Overall survival (all in %)Creatinine (mg/dl)TreatmentOS 12 moOS 24moOS 36moOS 48 mo<2 (n=553)VAD93867770PAD938678732-5 (n=46)59441616PAD89898383>5 (n=13)VAD75505017PAD606060NRTable 2Progression free survival, censored at allo-SCT (all in %)Creatinine (mg/dl)TreatmentPFS 12moPFS 24moPFS 36moPFS 48mo<2 (n=553)VAD86614531PAD886748332-5 (n=46)VAD473013NRPAD89785647>5(n=13)VAD75252525PAD604040NRNR = not yet reachedTable 2Progression free survival, censored at allo-SCT (all in %)Creatinine (mg/dl)TreatmentPFS 12moPFS 24moPFS 36moPFS 48mo<2 (n=553)VAD86614531PAD886748332-5 (n=46)VAD473013NRPAD89785647>5(n=13)VAD75252525PAD604040NRNR = not yet reached

Influence of Different Dosages of Cyclophosphamide on Stem Cell Mobilization and Engraftment In Newly Diagnosed Multiple Myeloma Patients Treated with a Thalidomide Containing Regimen.

AbstractAbstract 3494 Introduction:Treatment of multiple myeloma (MM) patients (<65 yrs) consists of induction chemotherapy for 3–6 months followed by peripheral blood stem cell collection and transplantation. Both high dose cyclophosphamide (HD-C, 2 gr/m2/day, on days 1–2) and lower dosage of cyclophosphamide (1 gr/m2/i.v.on day 1) combined with doxorubicin (15 mg/m2/day, on days 1–4) and dexamethason 40 mg orally, days 1–4 (LD-C) are used, in combination with G-CSF, to mobilize hematopoietic stem/progenitor cells. A great variability was observed in the engraftment of different hematopoietic lineages post-ASCT. Therefore we questioned whether the dose of cyclofosfamide as mobilizing agent might affect the neutrophil and platelet recovery post-ASCT. The studied MM patients were treated with VAD or TAD (Blood 2010;11:115). Peripheral blood stem cells were collected after LD-C and HD-C with the Cobe Spectra; in each collection, 10 – 12 L of blood was processed in 3 – 4 hours. The target yield was 10 × 106/kg CD34+ cells. Results:92 patients were treated according to VAD and 41 patients with TAD. In the VAD arm 89% of the patients reached the target yield of CD34+ cells after 1 collection compared to 61% in patients treated with TAD (p = 0.0003). The number of CD34+ cells collected at the first day and the total CD34 yield after HD-C or LD-C was significantly higher in patients treated with VAD compared with TAD: 16.6 ± 11.6 × 106/kg vs. 10.4 ± 9.3 × 106/kg (p=0.003), and 16.9 ± 11.1 × 106/kg vs 12.3 ± 8.6 × 106/kg (p=0.02). No significant difference was observed in the total yield of collected CD34+ cells in the VAD arm or TAD arm between HD-C vs. LD-C.In all patients high dose melphalan (200 mg/m2) was used as conditioning regimen followed by reinfusion of peripheral blood stem cells. In the VAD arm no difference in neutrophil and platelet engraftment (absolute neutrophil count > 0.5 × 109/L and platelet count > 20 × 109/L without platelet transfusions) was noticed between patients mobilized with LD-C (22 ±12 days and 23 ±13 days) or HD-C (18 ± 5 (p=0.1) and 21 ±11 days (p=0.5)); in contrast a significant difference was demonstrated in neutrophil and platelet engraftment between patients treated according the TAD arm and mobilized with LD-C (20 ± 8 days and 20 ±19 days) or HD-C (34 ± 11 days (p<0.0001) and 43 ±22 days (p=0.001)). These differences could not be ascribed to differences in the number of infused CD34+ cells: VAD arm: LD-C: 5.7 ± 2.6 × 106/kg, HD-C: 5.7 ± 2.5 × 106/kg: TAD arm: LD-C: 5.2 ± 2.5 × 106/kg and TAD-HD-C 6.4 ± 2 × 106/kg. It might be assumed that the higher dosage of cyclophosphamide had a positive effect on tumor response. However the impaired engraftment was not associated with differences in relapse free survival between the different arms (p = 0.2). In summary these data demonstrate that thalidomide containing regimen in MM patients impair mobilization of stem/progenitor cells and that a mobilization with high dose cyclophosphamide and not low dose cyclophosphamide after treatment with thalidomide prolong the engraftment post-transplantation. Disclosures:No relevant conflicts of interest to declare.

Prognostic Impact of Genetic Subgroups and Development of Gene Classifiers for Response, PFS and OS In Multiple Myeloma Patients Treated with Bortezomib or Conventional Agents In HOVON65/GMMG-HD4 Trial

AbstractAbstract 445 Background.In newly diagnosed myeloma patients, bortezomib treatment induces high rates of complete response (CR) and very good partial response (VGPR). Recently, we published the clustering of gene expression profiles in 320 MM patients, who were included in a large prospective, randomized, phase III transplantation trial with bortezomib (PAD) versus conventional vincristine (VAD) based induction treatment (HOVON65/GMMG-HD4). We identified 12 distinct subgroups CD-1, CD-2, MF, MS, PR, HY, LB, Myeloid, including three novel defined subgroups NFκB, CTA, and PRL3 and a subgroup with no clear gene expression profile (NP). Aim.To look at the prognostic impact of these 12 clusters in the trial and group clusters together into a high risk (HR) and low risk (LR) group in the different treatment arms. Furthermore, to define a high risk signature to identify the patients at increased risk of disease progression. Methods.Gene expression profiles of myeloma cells obtained at diagnosis of 320 HOVON65/GMMG-HD4 patients were available. Response, progression free survival (PFS) and overall survival (OS) data were available for the first 628 patients, resulting in analysis of gene expression in relation to prognosis in 229 patients. The prognostic impact of the genetic subgroups separately and grouped into high and low risk were evaluated using Kaplan Meier and Cox regression analysis using exhaustive search (R). For the high risk gene signature the HOVON65 gene expression data was used as training set with PFS as outcome measure. Two independent myeloma datasets with survival data were used as an external validation, UAMS (GSE2658) and APEX (GSE9782)). The signature was generated by a Cox proportional hazard model in combination with LASSO (Least Absolute Shrinkages and Selection Operator) for simultaneous parameter estimation and variable selection using the R package glmnet. ISS stage was implemented by adjusting the individual covariant penalization factors of the LASSO. Results.The highest CR+nCR rates were found in the PRL3 and NP clusters, i.e. 78% and 86%, respectively (VAD), and 100% (PAD). The lowest CR+nCR rate was 17% in the CD1 cluster (PAD) and 0% in the CD2, MF and PR clusters (VAD). Based on the impact of clusters on PFS and OS in the VAD arm, the MS, MF, PR and CTA clusters were included into a High Risk (HR) group. This HR group showed a median PFS of 13 months and OS of 21 months vs. the Low Risk (LR) group consisting of the remainder of clusters with a median PFS of 31 months and a median OS not reached (P<.001).In contrast, in the PAD arm, only the PR cluster conferred a poor prognosis and exclusively formed the HR group, showing a median PFS of 12 months and OS of 13 months vs. the LR groups consisting of the remainder of clusters with a median PFS of 32 months and a median OS not reached (P=.004). In the poor prognostic subgroup MF, a striking difference in outcome on PAD vs. VAD was observed, i.e. 24 vs. 3 months (PFS) and 39 vs. 4 months (OS), respectively. In the multivariate analysis, including the covariates recurrent translocations, 17p deletion, 13q loss, LDH and ISS stage, the HR group definition remained independent poor prognostic indicators for both treatment arms. A LASSO-based high-risk signature was generated (48 probe sets). External validation was performed in the data sets UAMS TT2 and APEX. In both studies, the high-risk signature identified a high-risk population of 13% with highly significant log rank p-values (7.7*10−8 and 4.2*10−9, respectively). Combination of all validation data, n=615, corrected for type of treatment and study, resulted in an overall Cox proportional hazard model's hazard ratio of 3.8 with p <2*10−16. Conclusion.Distinctive gene expression clusters affect prognosis, which differ depending on treatment. In the conventional treatment arm (VAD), MS, MF, PR and CTA clusters confer a worse prognosis while with bortezomib based treatment, only the PR cluster affects prognosis negatively. These HR groups remain independent poor prognostic indicators. Based on the HOVON65/GMMG-HD4 study population, a high-risk signature was generated with strong and highly significant predicting ability in two independent data sets. Disclosures:Mulligan:Millenium: Employment. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees; Ortho Biotech: Membership on entity's Board of Directors or advisory committees; Ortho Biotech: Research Funding; Celgene: Research Funding; Chugai Pharma: Research Funding; Amgen: Research Funding. Sonneveld:Ortho Biotech: Research Funding; International Myeloma Foundation: Research Funding; Ortho Biotech: Consultancy.

HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) Vs VAD Followed by High-Dose Melphalan (HDM) and Maintenance with Bortezomib or Thalidomide In Patients with Newly Diagnosed Multiple Myeloma (MM)

AbstractAbstract 40 Introduction:This independent trial was designed to evaluate the efficacy of bortezomib (B) during induction and maintenance on progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients were randomly assigned to 3 cycles of standard VAD (arm A) or PAD (Arm B); PAD was dosed as B 1.3 mg/m2, days 1,4,8,11, doxorubicin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, 17–20). Patients received one (HOVON) or two (GMMG) high-dose melphalan (HDM) 200 mg/m2 with ASCT. Maintenance consisted of thalidomide (T) 50 mg daily (arm A) or B 1.3 mg/m2, 2-weekly (arm B) for 2 years. Primary endpoint was PFS, other endpoints were complete response (CR) (EBMT), immunofixation positive CR (nCR), VGPR pre-and post HDM and survival (OS). The protocol specified analysis was intention-to-treat and censored for patients who received allo-SCT after HDM1 (n=46). We report the analysis of the first 626 randomized patients. The final analysis of all patients will be presented at the meeting. Results:13 patients were excluded (7 not eligible, 6 not evaluable). The two arms (A:n=305;B:n=308) were well balanced for age, Salmon/Durie stage II/III, renal failure (11%), and serum B2M. Medium follow-up is 40 months. 89% of patients completed induction and HDM1. In GMMG after HDM1 80% of patients received 2nd HDM. Full dose B could be administered in 82% of patients. Polyneuropathy (PNP) WHO gr 3+4 occurred in 7% (arm A) and 16% (arm B). 204 (67%, arm A) and 174 (57%, arm B) patients started maintenance. 64% of patients tolerated full dose B and 27% reduced dose. 47% of patients on B maintenance went off protocol because of toxicity (9%), progression (29%) or other (9%). In contrast 64 % on T maintenance went off protocol because of toxicity (31%), progression (31%) or other (2%).nCR/CR rates were 7/9% (arm A) vs 9/21% (arm B) at 3 months after HDM-1 and 12/26% (arm A) vs 12/38% (arm B) on protocol. ≥VGPR in arm-A vs arm-B were 40% vs 60% after HDM-1 and 61% vs 75% on protocol. PFS was superior in arm B (HR 0.81, p=0.047; adjusted for ISS: HR 0.81, p=0.056). PFS at 36 months was 42% (arm A) vs 46% (arm B). Multivariate Cox regression showed treatment arm (p=0.037), IgA (p=0.007), ISS stage (p=0.007), WHO Performance Status (p<0.0001), del13/13q- (p=0.015) and study group (2nd HDM) (p=0.015) as significant PFS variables. Patients treated with bortezomib had a better OS (HR 0.74, p=0.048), with study arm, WHO, IgA, ISS stage and del13/13q- as significant variables. Subgroup analysis of response at 12 months showed no impact on PFS and an impact of VGPR/nCR/CR on OS only in arm A. Adverse cytogenetic markers (p<0.05) in the combined group were 13q14, 17p-, t(4;14) for PFS and OS. Detailed FISH data are reported separately. The response and survival data of the subgroup analysis are given below. We conclude that B achieves high nCR/CR during induction, that B maintenance is well tolerated and is associated with additional responses. Bortezomib achieves superior PFS and results in an improvement of survival.Table:PFS, OS, minimal response achieved on protocol and subgroup analysisVAD/HDM/thalidomidePAD/HDM/bortezomibNnCR/CR %VGPR %PR %PFS 36m %OS 36m %NnCR/CR %VGPR %PR %PFS 36m %OS 36m %All30538618742713085075924878ISS1514165935281515377945686ISS2203357833077304775884573ISS3293762793350194670863969Creatinin 2–5 mg/dL353948631316245079875683-13/13q-12637628629591125583944482t(4;14)28436889224326547785326517p-322247751619154760872760This trial (EudraCT no. 2004-000944-26) was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and a grant from Janssen-Cilag. Disclosures:Sonneveld:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; millennium: Membership on an entity's Board of Directors or advisory committees. Off Label Use: bortezomib, induction treatment prior to high dose therapy. Schmidt-Wolf:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-Cilag: Research Funding. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Delforge:celgene: Membership on an entity's Board of Directors or advisory committees; janssen-cilag: Membership on an entity's Board of Directors or advisory committees. Weisel:orthobiotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:orthobiotech: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; amgen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; orthobiotech: Honoraria, Research Funding; roche: Honoraria, Research Funding.

Recent progress in the treatment of multiple myeloma: updates and highlights from ASH 2008

Recent progress in the treatment of multiple myeloma: updates and highlights from ASH 2008

B152 First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) vs. VAD as Induction Treatment Prior to High-dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)

The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18-65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1-4, dexamethasone 40 mg days 1-4, 9-12, and 17-20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1-4, dexamethasone 40 mg days 1-4, 9-12, and 17-20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 300 (150 per arm) randomized patients. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 137 patients (91%) completed PAD or 136 (91%) completed VAD and 132 patients (88%) in each arm completed HDM-1. Full dose bortezomib could be administered in 95% (PAD1), 89% (PAD2) and 85% (PAD3) of patients. Successful stem cell apheresis was achieved in all 137 PAD treated patients who received CAD mobilization . Peripheral polyneuropathy CTC grade 3-4 during PAD vs VAD was 16% vs 6%, while DVT/pulmonary embolism was diagnosed in 3% during VAD and 4% during PAD. Responses were assessed according to EBMT criteria including VGPR and nCR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR/nCR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1). Deletion of chromosome 13q or presence of t(4;14) did not have a significant impact on VGPR or (n)CR. We conclude that PAD induces significantly more PR+VGPR+(n)CR as compared with VAD, and that this effect is sustained after HDM-1.

First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Adriamycine, Dexamethasone (PAD) Vs VAD as Induction Treatment Prior to High Dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM)

The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18–65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 150 (75 per arm) randomized patients. The data of the initial 300 registered patients (150 per arm) will be available by November 1, 2008 and presented. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 134 patients (89%) completed PAD/VAD and 130 patients (87%) completed HDM-1, with no difference between the treatment arms. Full dose bortezomib could be administered in 95 % (PAD1), 79 % (PAD2) and 85 % (PAD3) of patients. Successful stem cell apheresis was achieved in all 132 patients who received CAD. Adverse events CTC grade 2–4 during PAD vs VAD included neurologic or polyneuropathy (PNP) 38% vs 21 %, constitutional symptoms 30 % vs 24 %. PNP of CTC grade 1–4 was more frequent in the PAD arm (p=0.01), while DVT/pulmonary embolism was diagnosed in 10 % during VAD and 6 % during PAD. Responses were assessed according to EBMT criteria including VGPR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1)Response ITT (%)PADVADp-valuePAD+ HDM-1VAD+ HDM-1p-valueCR500.061540.05≥VGPR41170.00159470.14≥PR80640.0392770.01The (preliminary) overall complete response rate including maintenance was 27 % (PAD arm) and 5% (VAD arm) (p=0.001). Deletion of chromosome 13q did not have a significant impact on response. We conclude that PAD induces significantly more PR+VGPR+CR as compared with VAD, and that this effect is sustained after HDM-1. This trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Johnson and Johnson

Successful Harvesting of Peripheral Hematopoietic Stem Cells after Induction Treatment with Bortezomib, Adriamycin, Dexamethasone (PAD) in Patients with Newly Diagnosed Multiple Myeloma (MM)

The HOVON-65/GMMG-HD4 trial is a prospective, randomized phase III trial to evaluate the efficacy of bortezomib prior to high-dose melphalan (200 mg/m2, HDM) on response and progression-free survival (PFS) in patients with newly diagnosed MM stage II or III according to Salmon & Durie (SD). Until May 2008 in total 833 patients aged 18–65 years were included in the trial. Patients were randomized to receive three cycles of VAD (arm A; vincristin 0,4mg, days 1–4, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20) or PAD (arm B; bortezomib 1.3 mg/m2, days 1,4,8,11, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20). Hematopoietic stem cells were mobilized in patients using the CAD regimen (cyclophosphamide 1000 mg/m2 iv day 1, adriamycin 15mg/m2, days 1–4, dexamethasone 40mg, days 1–4) and G-CSF. After stem cell harvesting all patients received one or two cycles of HDM with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) and bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively.As of August 2008 stem cell harvesting data from the first consecutively enrolled 150 patients (75 per arm) were analyzed. The data of the initial 300 patients (150 per arm) will be available by November 2008. Both treatment arms did not differ in age, SD stage of disease, ISS stage, and FISH abnormalities. 132 patients (88%) were treated with CAD plus G-CSF. Dosing and type of G-CSF treatment were comparable in both arms.In all patients stem cell collection was successful and at least two autografts could be harvested (minimal number of stem cells permitted per autograft was 2.0 ×106 CD 34+ cells per kg BW).Induction treatmentDays until first leukapheresis Median (range)Number of leukaphereses Median (range)Number of harvested CD34+ stem cells (× 106) per kg BW Median (range)PAD110 (96–149)1 (1–4)10.5 (4.1–37.6)VAD111 (95–156)1 (1–5)9.3 (4.0–37.0)In 64% of the patients in arm A (VAD) and 79% of the patients in arm B (PAD) only one leukapheresis was sufficient for stem cell harvesting. In all patients hematopoietic reconstitution was achieved after HDM followed by autografts harvested after PAD or VAD. We conclude that stem cell harvesting after PAD is very well feasible.

Dexamethasone+Thalidomide (Dex/Thal) Compared to VAD as a Pre-Transplant Treatment in Newly Diagnosed Multiple Myeloma (MM): A Randomized Trial.

Since 2003, 204 patients (pts) younger than 66 yrs with untreated active MM were randomly assigned to receive a 4 month treatment with Dex/Thal (n=100) or with a VAD-like regimen (n=104). Then, all pts were intended to proceed to peripheral blood stem cell (PBSC) mobilization using cytoxan 4 g/m2 + G-CSF 5 μg/kg and to receive high dose therapy (HDT) with melphalan 200 mg/m2 and autologous PBSC support. Pts in the Dex/Thal arm received orally Thal for 3 mths at a fixed dose of 200 mg/d combined with Dex, 40 mg/d for 4 days every other wk for 2 mths and then monthly for 2 mths. Pts in the VAD arm received the same Dex regimen plus 3 courses of 4 days continuous infusions of Doxorubicin (9 mg/m2/d for 4 days) and Vincristine (0.4 mg/d for 4 days), 4 wk apart. Anticoagulation prophylaxis wasn't systematically given.Main characteristics of pts included in both arms were similar, including age (mean 55.1 yr in the Dex/Thal arm vs 56.4 yr in the VAD arm), MM stage (stage III 78% vs 85%), isotype (IgA: 21% vs 32%, p=.55), serumβ2m (mean 5.2 mg/L vs 3.9 mg/L, p=.24) serum creatinine (≤300 μmol/L in all pts) and albumin levels. Data were analyzed in an intent to treat basis. Primary objective was the achievement of at least a very good partial response (VGPR), defined as a decrease in serum and urine monoclonal immunoglobulin by 90% or greater.In both arms, 91% of pts proceeded to PBSC mobilization, PBSC harvests were similarly successful and 83% of pts received HDT and autotransplant. Before PBSC collection, 24.7% and 7.3% of pts were in VGPR in the Dex/Thal arm and in the VAD arm, respectively (p=.0027). Before HDT, VGPR rate was 34.7% in the Dex/Thal arm as compared to 12.6% in the VAD arm (p=.002). At 6 mths post transplant, the benefit of Dex/Thal wasn't further observed with VGPR rates of 44.4% in the Dex/Thal arm and 41.7% in the VAD arm (p=.87). Six pts died in the Thal/Dex arm (including 4 early deaths, within 4 mths post randomization) as compared to 9 pts in the VAD arm (including 3 early deaths).Venous thrombosis or pulmonary embolism were recorded in 22.8% of pts in the Dex/Thal arm and in 7.5% in the VAD arm (p=.004). A symptomatic peripheral neuropathy was observed in 17.4 % and 12.9% of pts, respectively (p=.42). Otherwise, toxicity profile were similar in both groups. Before PBSC mobilization, mean duration of hospitalization, whatever the cause, was 8.3 days in the Dex/Thal arm as compared to 20 days in the VAD arm (p=.0001).This randomized study confirms that oral Dex/Thal is an effective first line treatment for symptomatic MM, and supports its use as an induction regimen which could be preferred to infusional VAD in candidates for HDT.

A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A southwest oncology group study

Multiple myeloma is considered to be a drug responsive disease; however, there is no cure for this disease and virtually all patients will develop drug resistance. One form of drug resistance that has been documented is the multidrug resistance phenotype or MDR. A randomized trial of the combination of vincristine, doxorubicin, and dexamethasone (VAD) and VAD plus oral verapamil (VAD/v) in drug refractory multiple myeloma patients was performed by the Southwestern Oncology Group. Verapamil was used as a chemosensitizing agent to attempt to overcome or prevent MDR and improve the therapeutic outcome. Response rates between the two treatment arms were similar with an overall response rate of 41% for the VAD alone arm and 36% for the VAD/v arm. Overall survival of patients was also similar with a median survival of 10 months for the VAD arm and 13 months for the VAD/v arm. The toxicity profile was also similar for both treatments, with myelosuppression being the dose-limiting toxicity. No significant correlation was observed between expression of P-glycoprotein, serum verapamil levels, and response to therapy. No beneficial effect was observed from the addition of oral verapamil to the VAD chemotherapy regimen for the treatment of drug-resistant myeloma patients. More effective and less toxic chemosensitizers are needed to study the role of chemosensitizers in reversing MDR in the clinic.