Prognostic Value Of Deep Sequencing Approach For Minimal Residual Disease (MRD) Detection In Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1848-1848
Author(s):  
Joaquin Martinez-Lopez ◽  
Juan José Laheurta ◽  
Francois Pepin ◽  
Marcos González ◽  
Santiago Barrio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Value ◽  
Treatment Time ◽  
Negative Group ◽  
Employment Equity ◽  
Positive Group ◽  
Time Points ◽  
Diagnostic Samples ◽  
Equity Ownership

Abstract Background and Aim Most multiple myeloma (MM) patients will experience relapse due to the persistence of residual tumor cells, or MRD. We compared the prognostic value of traditional response criteria with MRD measured by three different methods: a sequencing-based method, termed the LymphoSIGHT™ platform, multiparameter flow cytometry (MFC) and ASO-PCR of Ig genes in a cohort of 133 uniformly-treated MM patients from the Spanish Myeloma Group trials. Methods Bone marrow samples were obtained from 133 patients at diagnostic and post-treatment time points on GEM clinical trials (GEM00 and GEM05). All 133 patients were either in CR or VGPR at the post-treatment time point. Using the sequencing assay, we identified clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, and IGK) genes in diagnostic samples. We then assessed MRD in follow-up samples, analyzing concordance between: sequencing, MFC and ASO-PCR of Ig genes MRD results, and comparing the prognostic value of each method with traditional response criteria. Results The sequencing assay detected the presence of a myeloma-specific gene rearrangement in diagnostic samples from 121 of 133 (91%) patients. We tested MRD in follow-up time points in 109 of the 121 patients. Of the 109 patients, 79 were positive by sequencing at MRD levels of 10-5 or higher and 30 were MRD negative. The Time to Tumor Progression (TTP) and Overall Survival (OS) were significantly longer in the MRD negative group compared with the MRD positive group by sequencing (TTP, median 80 vs. 31 months, p<0.0001; and OS, median not reached vs. 80 months p=0.02) (Figures 1A and 1B). All patients in VGPR, with the exception of 4 cases, were MRD positive by sequencing (92%). Three of the 4 cases with MRD negative and positive immunofixation became immunofixation negative after maintenance treatment. When restricting the analysis to the 61 patients that were in conventional CR (negative immunofixation), 35 of 60 patients were positive by sequencing at MRD levels at 10-5 and higher and 26 were MRD negative. There was a significantly improved TTP in the MRD negative group compared with the MRD positive group (median 131 vs. 35 months, p=0.001) (Figure 1C). A high correlation between MFC and sequencing MRD results was observed (r2=0.87); as well as between ASO-PCR of Ig genes and sequencing (r2=0.89). Discordant results between FCM and sequencing (SEQ) included: 14 cases who were positive by SEQ and negative by FCM, and 5 cases negative by SEQ but positive by FCM; while the remaining cases were concordant: 63 cases were positive by both methods and 16 were negative by both methods. Correlation between ASO-PCR and SEQ was possible in 45 patients: 10 were discordant (9PCR-SEQ+ and 1 PCR+SEQ-) while 35 were concordant (20 PCR+SEQ+, 15 PCR-SEQ-). Conclusions The sequencing applicability for MRD studies in MM is 91%, which is essentially equivalent with that of MFC (96% Rawstron AC et al, JCO 2013). There is a high correlation between MRD levels by sequencing, ASO-PCR and MFC. Based on these results, MRD assessment by sequencing is a useful method for patient risk stratification and can be used to determine molecular CR in MM. Disclosures: Pepin: Sequenta, Inc.: Employment, Equity Ownership. Weng:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Prognostic value of deep sequencing method for minimal residual disease (MRD) detection in multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8511-8511 ◽  
Author(s):  
Joaquin Martinez-Lopez ◽  
Ramon Garcia-Sanz ◽  
Francois Pepin ◽  
Rosa Ayala ◽  
Maria Angeles Montalban ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Value ◽  
Treatment Time ◽  
Group Versus ◽  
Response Criteria ◽  
Negative Group ◽  
Positive Group ◽  
Time Points ◽  
Diagnostic Samples

8511 Background: Most multiple myeloma (MM) patients will relapse due to persistence of residual tumor cells, or MRD. We compared the prognostic value of traditional response criteria and MRD measurement by a sequencing-based method, LymphoSIGHT, and multiparameter flow cytometry (MFC) in a cohort of 68 uniformly-treated MM patients from the Spanish Myeloma Group trials. Methods: Bone marrow samples were obtained from 68 patients at diagnostic and post-treatment time points on GEM clinical trials (GEM00 and GEM05). All patients were in CR or VGPR at the post-treatment time point. Using sequencing, we identified clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, and IGK) genes in diagnostic samples. We assessed MRD in follow-up samples, analyzed concordance between sequencing and MFC MRD results, and compared the prognostic value of each method with traditional response criteria. Results: The sequencing assay detected a myeloma-specific gene rearrangement in diagnostic samples from 59 of 68 (87%) patients. We tested MRD in follow-up time points in 56 of the 59 patients. We observed high correlation between MFC and sequencing MRD results (r2=0.86), with MFC underestimating the myeloma burden (Slope=0.4). Of the 56 patients, 45 were positive by sequencing at MRD levels of 10-5 or higher and 11 were MRD negative. There was significantly improved overall survival (OS) in the MRD negative group versus the MRD positive group (median not reached vs. 86 mos, p=0.026). Similar differences were found in progression free survival. When limiting the analysis to the 35 patients in conventional CR, 24 of 35 patients were positive by sequencing at MRD levels at 10-5 and higher and 10 were MRD negative. There was significantly improved OS in the MRD negative group versus the MRD positive group (median not reached vs. 80.92 mos, p=0.041). Conclusions: Our data shows high correlation between MFC and sequencing MRD levels in MM patients. For patients in CR by traditional response criteria, the presence or absence of MRD by sequencing delineated 2 groups of patients with significantly different OS. MRD negativity by sequencing may be a better prognostic indicator than CR by traditional response criteria.

Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4229-4229
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Mohit Narang ◽  
Jayesh Mehta ◽  
Howard R. Terebelo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Equity Ownership ◽  
Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1788-1788 ◽  
Author(s):  
Hiroyuki Takamatsu ◽  
Ryoichi Murata ◽  
Jianbiao Zheng ◽  
Martin Moorhead ◽  
Naoki Takezako ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Prognostic Value ◽  
Residual Disease ◽  
Employment Equity ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Background: Autologous stem cell transplantation (ASCT) in conjunction with therapeutic drugs such as bortezomib, thalidomide, and lenalidomide can dramatically improve response rates and the prognosis of patients with multiple myeloma (MM). However, most patients with MM are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Here we utilized a next-generation sequencing (NGS) approach for MRD assessment, which offers at least 1 to 2 logs greater sensitivity (10-6) compared to allele-specific oligonucleotide PCR (ASO-PCR) and flow cytometry, respectively (Faham et al Blood 2012). Previous studies have shown that NGS-based MRD assessment 90 days post-ASCT has prognostic value (Martinez-Lopez et al Blood 2014). In this study, we compared the prognostic value of MRD assessment in autografts and bone marrow (BM) samples from MM patients in the ASCT setting. Methods: One hundred and twenty-three Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients received ASCT and were followed between June 15, 2004 and April 25, 2015. All patients had achieved a partial response (PR) or better after ASCT. Analyzed samples included: (1) BM slides from 96 MM patients at diagnosis, (2) fresh/frozen BM cells from 27 MM patients at diagnosis, (3) autografts and/or (4) post-ASCT BM cells obtained at the time of best response based on serum and urine tests. IGH-based ASO-PCR was performed as described previously (Methods Mol Biol 2009). NGS-based MRD assessment was performed using the immunosequencing platform (Adaptive Biotechnologies, South San Francisco, CA) (Martinez-Lopez et al Blood 2014). Results: We compared MRD results in 51 samples assessed by ASO-PCR and NGS. We observed a high correlation between NGS and ASO-PCR results at MRD levels of 10-5 or higher (r=0.86, P<0.0001). Twenty-seven samples were positive by NGS and negative by ASO-PCR, demonstrating the higher sensitivity of NGS (10-6 or higher) vs ASO-PCR (10-4-10-5). We evaluated the association of clinical outcome with post-ASCT BM MRD assessment. Patients who were MRD negative by NGS (defined as <10-6) in post-ASCT BM cases (N=21) showed a significantly better progression free survival (PFS) compared to MRD positive patients (N=31) (P =0.005) (Fig 1A). When restricting the analysis to the 39 patients in complete response (CR), patients who were MRD negative by NGS (N=20) showed a significantly better PFS than those that were MRD positive (N=19) (P =0.042). We also evaluated the association of clinical outcome with autograft MRD assessment. 53 patients received post-ASCT therapy using novel agents such as bortezomib/lenalidomide/thalidomide, and 45 patients did not. Among the 45 patients who did not receive post ASCT treatment, patients with NGS-based MRD negativity in the autograft (N=11) had a significantly better PFS (P=0.012) and tended to have a better OS (p=0.203) than those who were MRD positive (N=34), with prognosis clearly stratified by the quantitative level of MRD (Figs 1B, 1C). MRD assessment from the 53 patients who did receive post ASCT treatment tended to show a similar pattern. Finally, we studied whether clinical outcomes would have been altered by treatment in this cohort. Patients whose autografts were negative by NGS-based MRD assessment (N=19) had 100% PFS and OS at 5 years post ASCT irrespective of whether or not they received post ASCT treatment. Conversely, post ASCT treatment had a significant effect on the outcome of patients whose autografts were MRD positive by NGS. Specifically, the NGS-based MRD positive patients who received post ASCT treatment (N=45) had a significantly better PFS (P=0.003) and tended to have a better OS than those that were untreated (N=34) (Figs 1D, 1E). Conclusions: In this study, we show the prognostic value of NGS-based MRD assessment in autografts of patients with MM. The NGS platform has improved sensitivity compared with ASO-qPCR in detecting MRD in autografts. Importantly, this retrospective study suggests that therapeutic intervention based on NGS-based MRD positivity has a significant effect on patient outcome in the post-ASCT setting. Disclosures Zheng: Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.

scholarly journals Prognostic Molecular Stratification in Relapsed/Refractory Multiple Myeloma - Results of the Pomalidomide Mukseven (NCT02406222) Biomarker Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4327-4327
Author(s):  
James Croft ◽  
Andrew Hall ◽  
Amy L Sherborne ◽  
Katrina Walker ◽  
Sidra Ellis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
T Cell ◽  
High Risk ◽  
Real World ◽  
Research Funding ◽  
Unmet Need ◽  
Employment Equity ◽  
Equity Ownership

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

Bortezomib Plus Melphalan–Prednisone Continues to Demonstrate a Survival Benefit Vs Melphalan–Prednisone in the Phase III VISTA Trial in Previously Untreated Multiple Myeloma After 3 Years' Follow-up and Extensive Subsequent Therapy Use.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3859-3859 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Paul G Richardson ◽  
Rudolf Schlag ◽  
Nuriet K Khuageva ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Ortho Biotech ◽  
Equity Ownership

Abstract Abstract 3859 Poster Board III-795 The initial results of the pivotal, international, phase III VISTA trial demonstrated the superiority of bortezomib (Velcade®) plus melphalan–prednisone (VMP) versus MP alone across all efficacy end points, including overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008). We conducted a planned updated survival analysis of VISTA after a median >3 years of follow-up and with the majority of patients having received subsequent therapy. We confirmed the previously demonstrated OS benefit of VMP versus MP, examined the use of subsequent therapy and its efficacy following VMP and MP, and evaluated the survival of patients who had received subsequent therapy. Patients were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies. The median age of patients was 71 years, 30% were aged ≥75 years, 34% had ISS stage III MM, and 33% had β2-microglobulin >5.5 mg/L. After median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP vs MP (hazard ratio [HR] 0.653, p=0.0008); median OS was not estimable vs 43.1 months, and 3-year OS rates were 68.5% vs 54.0% with VMP vs MP, respectively. This OS benefit was seen consistently across patient subgroups predefined by baseline characteristics. Within the VMP arm, OS was longer among patients aged <75 vs ≥75 years (HR 1.664, p=0.011; 3-year OS: 74.1% vs 55.5%); by contrast, there were no significant differences, although there were trends to longer OS among patients with creatinine clearance ≥60 versus <60 mL/min (HR 1.291, p=0.238; 3-year OS: 74.5% vs 63.1%) and patients with standard- vs high-risk cytogenetics (HR 1.346, p=0.399; 3-year OS 71.6% vs 56.1%). At data cut-off (16 March 2009), 178 (52%) VMP and 233 (69%) MP patients had received subsequent therapy; median time to subsequent therapy (28.1 vs 19.2 months, HR 0.527, p<0.0001) and median treatment-free interval (17.6 vs 8.4 months, HR 0.543, p<0.0001) were superior with VMP vs MP. Receipt of and response to subsequent bortezomib-, thalidomide-, and lenalidomide-based therapy are summarized in the Table. Median survival from start of subsequent therapy following VMP and MP was 30.2 vs 21.9 months (HR 0.815, p=0.21) among all patients receiving subsequent therapy. This updated analysis of VISTA confirms that VMP results in significantly longer OS compared with MP, despite 50% of MP patients being rescued with bortezomib-based therapy in the relapsed setting. VMP treatment used upfront appears more beneficial than treating with conventional agents and saving bortezomib- and other novel-agent-based treatment until relapse. Subsequent therapies appeared similarly effective in the VMP and MP arms, with our analysis also demonstrating the benefit of retreatment with bortezomib-based therapies following VMP. In addition, post-relapse survival among all patients receiving subsequent therapy appeared longer following VMP, indicating that frontline bortezomib use does not induce more resistant relapses. Table Response among patients who received subsequent therapy VMP (N=178) MP (N=233) Received subsequent therapy containing:*     Bortezomib, n (%) 43 (24) 116 (50)     Thalidomide, n (%) 81 (46) 110 (47)     Lenalidomide, n (%) 57 (32) 30 (13) Overall response rate (%) to subsequent therapy:     Bortezomib-based 47 59     Thalidomide-based 41 53     Lenalidomide-based 59 52 * Patients could have received >1 agent, either in combination or separately in different subsequent lines of therapy Disclosures: Mateos: Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Kropff:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Millennium: Research Funding. Schots:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esseltine:Millennium: Employment, Equity Ownership. Liu:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Follow-up of Real Life Treated Multiple Myeloma Patients: Response, Disease Progression and Overall Survival,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3937-3937
Author(s):  
Hareth Nahi ◽  
Johan Liwing ◽  
Katarina Uttervall ◽  
Johan Andreasson ◽  
Astrid Gruber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Real Life ◽  
M Protein ◽  
Novel Agents ◽  
Response Distribution ◽  
Employment Equity ◽  
Study Population ◽  
Equity Ownership

Abstract Abstract 3937 Treatment results in clinical practice and in real life can be different from each other. Therefore, evaluating real life outcomes in Multiple Myeloma (MM) patients in order to understand treatment outcome in clinical practice is very important. All patients diagnosed with MM and treated between Jan 2000 and Jul 2010 at Karolinska University Hospital, Huddinge and Södersjukhuset were included. Furthermore, all diagnosed patients between Jan 2005 and Jul 2010 at Karlolinska University Hopital, Solna were included. At diagnosis data regarding age, gender, type of myeloma and skeleton destruction as well as Ca, Hb, β2-microglobelin, albumin and creatinine were collected. For each treatment line, drugs given and specific start and stop dates for each drug were collected. Serum and urine M-protein was collected at baseline and each time the measurement differed from the previous. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis but not always confirmed by immunofixation since it was not required in clinical practice. Partial response (PR) was defined as a 50% reduction in M-protein. No response (NR) was defined as less than 50% reduction of M-protein. Progress was considered when M-protein increased with ≥ 25%. Novel agents were defined as bortezomib, lenalidomide and thalidomide. In the total population n=674, 89 (13%) patients were excluded due to non treatment demanding disease or plasmacytoma without MM diagnosis setting the study population to n=585. The median follow up of the study population was 815 days. The median age in the study population was 68 years and 45% were women. High dose treatment (HDT) was given to 214 (37%) patients. The median age in the HDT population was 58 years and 34% were women. The median age in the non-HDT population was 75 years and 51% was women. The median number of given treatment lines was 2. The proportion of patients receiving more treatment lines were declining rapidly with the number of received lines of therapy. The response distribution for the entire population nCR/PR/NR was 27/41/32 in 1st line, 18/34/48 in 2nd line. In the HDT population the same response distribution was 50/38/12 in 1st line and 28/38/34 in 2nd line. In the non-HDT population the response distribution was 14/43/43 in 1st line and 12/33/55 in 2nd line. The depth of the responses was significantly dependent on the line of therapy. Responses were significantly better in the HDT population vs. the non-HDT population in the first two treatment lines. There seems to be a correlation between the responses in 1st and 2nd line in the entire population. Improving the responses in 2nd line compared to 1st line seems not very likely. Statistical analysis shows that the non-HDT patients receiving novel agents in 1st line had a significantly higher probability of achieving nCR, 25% vs 9%.The same statistical difference was seen in the HDT patients with nCR rates of 65% vs 47%. The median TTP/TTNT for the study population was 309/381 days in the 1st line and 182/210 in 2nd line. In the HDT population the TTP/TTNT was 538/639 days in 1st line and 199/257 in 2nd line. In the non-HDT population the TTP/TTNT was 244/295 days in 1st line and 177/193 in 2nd line. In the HDT population both the TTP and the TTNT in the 1st line were significantly better than in the non-HDT population with no difference in the 2nd line. There was a significant trend of increasing TTP/TTNT in 1st line depending on the increased depth of the response. Statistical analysis showed that the use of novel agents in 1st line predicted a longer TTP for the non-HDT population. Median OS was 4.3 years 95% CI [3.9;5.0] with 53% censored. HDT patients had a significant longer median OS 6.3 years 95% CI [5.4;8.5] than the non-HDT patients OS 3.0 years 95% CI [2.2;3.6]. The median OS for non-HDT patients with 1st line best response nCR was 4.9 years, PR 3.3 years and NR 1.5 years. Kaplan-Mayer analysis shows that use of novel agents in the 1st line predicted a longer OS, median 5.1 years vs. 4.1 years. Patients receiving 2nd and 3rd line treatment were declining rapidly. To get a good response in 1st line increases the likelihood of having a good response in 2nd line. Receiving an nCR in 1st line seems to be very important and this study confirms the prognostic impact of achieving at least nCR. The use of novel agents improves the outcome for patients in clinical practice. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Näsman:Janssen-CIlag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

PROGNOSTIC VALUE OF SPONTANEOUS PLATELET AGGREGATION IN SURVIVORS OF MYOCARDIAL INFARCTION DURING FOUR YEARS FOLLOW UP

1987 ◽  
Author(s):  
M D Trip ◽  
V Manger Cats ◽  
J Vreeken
Keyword(s):  
Myocardial Infarction ◽  
Platelet Aggregation ◽  
Cardiac Death ◽  
Prognostic Value ◽  
Negative Group ◽  
Cardiac Events ◽  
Positive Group ◽  
Spontaneous Platelet Aggregation ◽  
Recurrent Infarction

Platelet aggregation has been implicated in the pathogenesis of atherosclerosis and its complications. We studied the prognostic value of the presence of spontaneous platelet aggregation (SPA) after myocardial infarction in 165 patients during a four years follow up period. Shortly after infarction 78 (47%) showed SPA and 87 (53%) showed no SPA. There were no differences in sex, age, infarct size or localisation and subsequent treatment between both groups. Patients in the SPA-positive group remained predominantely positive and patients in de SPA-negative group negative during the entire follow up period.In the SPA-positive group 25(32%) cardiac events (12 × cardiac death, 13× non fatal recurrent infarction) occurred.In the SPA-negative group 13(15%) cardiac events ( 5× cardiac death, 8× non fatal recurrent infarction) occurred (p < 0.01)In conclusion: the presence of spontaneous platelet aggregation after myocardial infarction is associated with a higher risk for fatal or non fatal recurrent myocardial infarction.

scholarly journals Prognostic Value of Clone Size in Paroxysmal Nocturnal Hemoglobinuria (PNH) for Thrombotic Events in Untreated Patients in the International PNH Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1038-1038
Author(s):  
Regis Peffault De Latour ◽  
Jaroslaw P. Maciejewski ◽  
Austin G. Kulasekararaj ◽  
Loree Larratt ◽  
Ronald S. Go ◽  
...  
Keyword(s):  
Research Funding ◽  
Prognostic Value ◽  
Disease Onset ◽  
Employment Equity ◽  
Advisory Committees ◽  
Clone Size ◽  
Equity Ownership ◽  
The Relationship ◽  
Pnh Clone

Abstract Background/Objective: The association between paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size at disease onset and outcomes in patients with PNH remains unclear. Most but not all reports examining the relationship have shown a positive correlation between clone size and thrombotic events [TEs] in patients with PNH, but without a clear temporal association showing the prognostic value of clone size on the risk of TEs. The ongoing International PNH Registry (NCT01374360) is the largest prospective, observational study of patients with PNH conducted to date. The objective of this analysis was to examine the relationship between PNH granulocyte clone size at disease onset and risk of thrombosis after disease onset while untreated with a complement inhibitor in patients enrolled in the Registry. Methods: The current analysis included patients enrolled in the Registry as of April 2018 who had known demographics, were untreated with complement inhibitor therapy at enrollment, and had ≥12 months of untreated follow-up after disease onset. Baseline was defined as disease onset (earliest of a reported PNH clone, date of PNH diagnosis, or reported PNH symptom), and patients were stratified into 5 cohorts based on clone size at baseline (using the earliest reported clone prior to enrollment): cohort 1, clone size: 0.01-1%; cohort 2, clone size: >1-5%; cohort 3, clone size: >5-10%; cohort 4, clone size: >10-50%; cohort 5, clone size: >50%. Event rates for TEs and all major adverse vascular events (MAVEs; including TEs) were calculated for the time period from baseline to last follow-up. Other outcomes of interest included LDH ratio (LDH/LDH upper limit of normal [ULN]), hemoglobin levels, platelet counts, absolute neutrophil counts, and absolute reticulocyte counts at last follow-up. Results: A total of 2489 patients were eligible for the analysis. The majority of patients in the overall study population were female (54.0% [1343/2489]) and white (79.2% [1967/2484]). Mean (standard deviation [SD]) age at PNH start ranged from 36.4 (16.53) in cohort 5 to 44.2 (20.70) in cohort 1. Median time from baseline to last follow-up was 3.7 years in cohort 1, 4.3 years in cohort 2, 4.7 years in cohort 3, 5.6 years in cohort 4, and 6.8 years in cohort 5. Results for the outcomes of interest are summarized in the Table. All cohorts showed a risk of MAVE and TE during follow-up. Although estimated rates of MAVE and TE were highest in the >50% clone size cohort, there was no difference in the rate of MAVE or TE during follow-up across the 4 cohorts with clone size <50% at disease onset. Mean LDH ratio (LDH/LDH ULN) at last follow-up showed a statistically significant difference by clone size at baseline among the cohorts, ranging from a mean (SD) of 1.1 (1.34) in the patients with clone size <1% and increasing to 5.1 (3.81) in the patients with clone size >50% (P<0.0001). No difference in hemoglobin level at last follow-up was observed in the smaller clone size cohorts, although mean hemoglobin level was lower in patients with clone size >50% (P<0.0001). Similar trends were seen in mean platelet and absolute neutrophil counts across the smaller clone size cohorts, while patients with clone size >50% showed higher values (P<0.0001). Mean absolute reticulocyte count at last follow-up was lowest in patients with clone size 0.01-1%, and were incrementally higher in each successive clone-size cohort (P<0.0001). Conclusions: In this study, all patients with a PNH clone at disease onset were at risk for TEs and other MAVEs. Patients in the highest baseline PNH clone size strata (clone size >50%) had an approximately 2-times higher risk of TEs than patients with smaller clone sizes; Patients with small clone sizes (0.01-1%) were older and showed a higher prevalence of BMD. There was no difference in the prognostic value of clone size at disease onset on the risk of TEs and other MAVEs in patients with small (0.01-1% and 1-5%) versus medium-sized (5-10% or 10-50%) clones. Table Table. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.

scholarly journals JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 957-957 ◽  
Author(s):  
Sham Mailankody ◽  
Myo Htut ◽  
Kelvin P. Lee ◽  
William Bensinger ◽  
Todd Devries ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: B-cell maturation antigen (BCMA) is expressed on malignant plasma cells and is an attractive therapeutic target for multiple myeloma. BCMA CAR T-cells, antibody drug conjugates and bispecific T-cell engagers have demonstrated substantial preclinical and clinical activity to date. JCARH125 is a BCMA-targeting CAR T product containing a lentiviral CAR construct with a fully human scFv, optimized spacer, 4-1BB co-stimulatory and CD3z activation domains. The construct has shown minimal tonic signaling and lack of inhibition by soluble BCMA. JCARH125 is generated using a manufacturing process developed to optimize various aspects, including increased consistency of cell health, in the drug product. Methods: EVOLVE (NCT03430011) is a multi-center, phase 1/2 trial of JCARH125 in patients with relapsed and/or refractory multiple myeloma, who have received 3 or more prior regimens, which must include autologous stem cell transplant, a proteasome inhibitor, immunomodulatory drug and an anti-CD38 monoclonal antibody, unless not a candidate (i.e. contraindicated) to receive one or more of the above treatments. Lymphodepleting chemotherapy (LDC) consisting of 3 days of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) is given 2 to 7 days prior to JCARH125 infusion. A single dose of JCARH125 is given on day 1. Dose escalation is determined using the modified toxicity probability interval 2 (mTPI-2). A minimum of 3 patients are evaluated at each dose level (DL). The first 2 DLs evaluated were 50 and 150x 106 CAR+ T cells. Additional DLs are planned, followed by an expansion at the recommended phase 2 dose (RP2D). The primary objectives of the phase 1 portion are safety and identifying a RP2D. Results: At the time of the July 12, 2018 data analysis, 19 patients have been enrolled (i.e. apheresed) and 13 patients dosed with JCARH125. Only one patient was unable to receive JCARH125, due to sepsis after LDC, leading to death before JCARH125 administration. Eight patients were evaluable for safety (≥ 1 mo follow-up). (n = 5 DL1; n = 3 DL2). Three patients (all from DL1) were evaluable for confirmed response (≥ 2 mo follow-up) per International Myeloma Working Group (IMWG) criteria. Data reported here are from these initial 8 patients. Median follow-up is 5 weeks (range 4 - 13 weeks). Median age is 53 years (range 36 - 66) with a median time from diagnosis of 4 years (range 2 - 12). Patients had received a median of 10 prior regimens (range 4 - 15). Of these 8 patients, 4 (50%) were refractory (no response or progression within 60 days of last therapy) to bortezomib, carfilzomib, lenalidomide, pomalidomide and an anti-CD38 monoclonal antibody. Seven of 8 (88%) had prior autologous stem cell transplant and 4 of 8 (50%) have IMWG high risk cytogenetics. As of the data cut, no DLTs have been observed at the first 2 DLs. Cytokine release syndrome (CRS), all grade 1 or 2, was observed in 6 of 8 (75%) patients. Median onset of CRS was 9 days (range 4 - 10) with a median duration of 4.5 days (range 2 - 19 days). None of the patients with grade 2 CRS required vasopressor support and only 1 patient received tocilizumab. No patients had grade ≥ 3 CRS. Three of 8 (38%) patients experienced neurologic adverse events (AE). Two patients had grade 1 events, and 1 had a grade 3 event (lethargy), which resolved within 24 hours after receiving steroids. Onset of neurologic AEs was 9,11 and 12 days with a duration of 2, 3 and 1 days respectively. Notably, the patient who experienced grade 3 neurotoxicity (NT), developed secondary plasma cell leukemia (PCL) just prior to receiving LDC. All 8 patients have evidence of objective response (≥ MR), including the patient with secondary PCL. 3 patients, all treated at DL1 (50 x 106 CAR+ T-cells), have confirmed responses (1 PR, 2 sCR) with the remainder unconfirmed (1 CR, 2 VGPR, 1 PR, 1 MR). As of the data cut, no patients have progressed. Additional clinical and translational data on at least 30 patients and additional follow up of at least 4 months will be available at time of presentation. Conclusion: At initial lower dose levels, JCARH125 showed an acceptable safety profile with no DLTs reported thus far. Incidence of grade ≥ 3 NT was low and no grade ≥ 3 CRS has occurred with clear clinical activity. Although durability of response and response rate in a greater number of patients remain to be determined, early experience with JCARH125 support a favorable risk-benefit profile and rapid clinical development. Disclosures Mailankody: Takeda: Research Funding; Janssen: Research Funding; Physician Education Resource: Honoraria; Juno: Research Funding. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Devries:Junot Therapeutics: Employment. Piasecki:Juno Therapeutics: Employment, Equity Ownership; Cascadian Therapeutics: Patents & Royalties; Amgen: Patents & Royalties. Ziyad:Juno Therapeutics: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Byon:Juno Therapeutics: Employment, Equity Ownership. Jakubowiak:Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria.

Bone Marker Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Primary Analysis Results of the Z-MARK Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5122-5122
Author(s):  
Noopur Raje ◽  
Robert Vescio ◽  
Charles W. Montgomery ◽  
Ramakrishnan Parameswaran ◽  
Diep Tran ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Bone Marker ◽  
Primary Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Skeletal Complications ◽  
Equity Ownership

Abstract Abstract 5122 Background: Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers. Materials and Methods: MM patients (N=121) who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL q4 or q12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol Cr - infusion q4 weeks, uNTX<50 nmol/mmol Cr - infusion q12 weeks). Patients who developed a skeletal related event (SRE) or had disease progression requiring a change in their MM therapy while on study were treated q4 weeks thereafter regardless of their uNTX values. The primary endpoint of the study is the proportion of patients who experience at least one SRE during study Year 1. This primary analysis (PA) includes all enrolled patients who completed study Year 1 or have discontinued from the study. Results are summarized by Group A (consisting of patients receiving ZOL q12 weeks only, N=83) and all others in Group B (N=38). Results: As of the May 9, 2011 data cut-off date, 31.3% (9.6% due to AEs, 14.5% withdrew consent, and 7.2% due to other reasons) in A and 36.8% (15.8% due to AEs, 10.5% withdrew consent, and 10.5% due to other reasons) in B discontinued early. The mean age was 63.8 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated CrCl was 21.3 (11.8) nmol/mmol Cr and 84.8 (34.7) mL/min, respectively. Based on the International Staging System, 79.5% of the patients were stage I or II and 14.5% were stage III at enrollment in A. The same in B were 71.1% and 21.1%. The median time from initial MM diagnosis to enrollment was 18.4 months in both groups. In A, 67.5% had ≥1 osteolytic lesions and of these 37.5% had >6; in B, 73.7% had ≥1 and of these 42.9% had >6. In A, 83.1% had received ZOL only, 13.3% had received PAM only; in B, 92.1% had received ZOL only and 2.6% had received PAM only prior to enrollment. The median duration of prior BP therapy was 13.8 in A and 14.8 months in B. In A, 73.5% had ≥1 SREs at enrollment; in B the same was 76.3%. Four patients started study ZOL treatment on the q4-weeks dosing schedule and 117 patients started on the q12-weeks schedule (based on uNTX values at study entry). Thirty four of 117 patients assigned to q12-week dosing were switched to q4 weeks (14 due to increased uNTX, 4 due to SREs, and 16 due to disease progression). In study Year 1, no patient in A had any SRE while 7 patients in B had SREs (3 pathologic fractures, 3 spinal cord compressions, 4 radiations to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). Only 5.8% of patients had any SRE in the first year. In A, 90.4% of patients had any adverse event (AE) while it was 100% in B. The most common AEs were upper respiratory tract infection (23.1%), fatigue (23.1%), cough (19%), diarrhea (19%), pneumonia (18.2%), pyrexia (18.2%), arthralgia (16.5%) and nausea (15.7%). The percentage of patients with any serious AE was 26.5 in A and 57.9 in B. Overall, 14.9% (12.0% in A, 21.1% in B) of patients had an AE leading to ZOL discontinuation. At Week 48, the median % change in uNTX was −11.1 in A and 12.5 in B. For serum Cr, no change in the median was observed in either group at Week 48. One death was reported on study (not suspected to be related to ZOL). There were 3 reports of osteonecrosis of the jaw (ONJ) in A, suspected to be related to ZOL, and no report of ONJ in B; the median time on ZOL was 17.0 months for A and 17.3 months for B. Discussion: These Z-MARK PA results show that bone marker directed dosing is feasible in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed within 1 year of study follow up is possibly due to the persistent protective effects from IV BP treatment prior to study entry and on study. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment. Disclosures: Raje: Acetylon: Research Funding; Astra Zeneca: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma(bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

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