scholarly journals Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2707-2707
Author(s):  
Nadine Abdallah ◽  
David L Murray ◽  
Angela Dispenzieri ◽  
Prashant Kapoor ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Univariate Analysis ◽  
M Protein ◽  
Urine Protein ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

scholarly journals Plasma Cell Proliferative Index Is an Independent Predictor of Progression in Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3160-3160
Author(s):  
Mohammed A Aljama ◽  
M Hasib Sidiqi ◽  
Arjun Lakshman ◽  
Angela Dispenzieri ◽  
Dragan Jevremovic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Confidence Interval ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Independent Predictor ◽  
Time To Progression ◽  
Proliferative Index ◽  
Advisory Committees

Abstract The plasma cell proliferative index (PCPI) provides an insight into plasma cell biology in plasma cell disorders. It recognizes cells that are actively synthesizing DNA and gives an indication of the proliferative rate of the malignant plasma cells.The PCPI has been shown to be a prognostic tool in patients with multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic impact of PCPI in 306 patients with smoldering multiple myeloma (SMM). The median age was 66 (56-73) years and 61% (n=186) were males. The median follow-up for the entire cohort was 10.2 years (95% confidence interval: 9.0-10.9). One-hundred sixty-nine (55%) patients were alive at the time of study analysis while 118 (39%) had progressive disease. The median time to progression was 5.9 years (95% confidence interval: 4.8-8.2). Symptomatic events at the time of progression included anemia in 41% (n=48), bone complications in 37% (n=44), renal complications in 9% (n=11), hypercalcemia in 2% (n=2) and development of amyloidosis in 2% (n=2). Seventeen patients (14%) were categorized as having progression due to rapid progressive elevation in the serum free light chains (sFLC) and/or progressive increase in the size of their M-spike. The median time between the diagnosis and PCPI date was 0 months (interquartile range 0-1). An elevated PCPI was defined as a level >0.5%. Seventy-nine (26%) patients had an elevated PCPI. Patients with an elevated PCPI were significantly older (median age: 69 years for elevated PCPI vs 64 years for low PCPI (p= 0.008) and predictably had more proliferative disease with a higher rate of patients with bone marrow plasma cells >20% (48% for elevated PCPI vs 34% for low PCPI, p=0.03). An elevated PCPI predicted a shorter time to progression (TTP); median 3.0 years versus 7.1 years for those with a low PCPI (p= 0.0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI; 49% versus 20% (p<0.0001). We constructed two multivariable models using the conventional and recently proposed Mayo risk stratification tools. In both models, an elevated PCPI was an independent predictor of to multiple myeloma. PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow up and consideration of early intervention trials. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Medscape: Consultancy; Apellis: Consultancy; Ionis: Honoraria. Lacy:Celgene: Research Funding. Dingli: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.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Oncogene Induced Senescence As a Potential Breakpoint Mechanism Against Malignant Transformation in Plasma Cell Disorders

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4474-4474
Author(s):  
Nicola Lehners ◽  
Elena Ellert ◽  
Jing Xu ◽  
Hartmut Goldschmidt ◽  
Mindaugas Andrulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Malignant Transformation ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Expression Levels ◽  
Plasma Cell Disorders

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

scholarly journals Circulating Tumor DNA in the Peripheral Blood As Early Predictor of Clinical Outcome in Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4350-4350
Author(s):  
Johannes M. Waldschmidt ◽  
Andrew J. Yee ◽  
Tushara Vijaykumar ◽  
Julia Frede ◽  
Praveen Anand ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Circulating Tumor Dna ◽  
Advisory Board ◽  
M Protein ◽  
Serological Markers ◽  
Advisory Committees ◽  
Tumor Dna

Introduction: Treatment of multiple myeloma (MM) has improved over the last decade. Although long-term survival is noted in some patients, emergence of resistant disease still prevents cures. The objective of this study was to define "liquid biopsy" parameters that identify patients who do not benefit from a particular treatment before relapse becomes evident by serological markers. Having such parameters at hand will potentially inform changes in treatment. Methods: Here, we apply low-pass whole genome sequencing to profile a uniform cohort of 45 relapsed and refractory MM (RRMM) patients who have been treated in a multicenter phase II trial evaluating the combination of elotuzumab, pomalidomide, bortezomib and dexamethasone (elo-PVd; NCT02718833). Peripheral blood plasma samples were acquired for circulating tumor DNA (ctDNA) evaluation at four different timepoints (screening, cycle 3 day 1 (C3D1), cycle 5 day 1 and end of treatment). The concentration, relative fraction and copy number profile of myeloma-derived ctDNA were determined across all timepoints. Results: At the time of this preliminary analysis, 17 patients (35%) continue on treatment whereas 28 patients (58%) have developed progressive disease (PD). Our data suggest that ctDNA levels at screening and C3D1 strongly correlate with progression-free survival (PFS). Patients with available follow-up samples (n=40) were stratified according to ctDNA levels at C3D1 of treatment. Patients with a residual ctDNA level <10% showed a significantly longer PFS (median 17.6 months (95% CI: 1.4-6.5)) as compared to those with ctDNA levels ≥10% (median 5.9 months (95% CI: 0.2-0.7), log-rank Mantel-Cox test P=0.0006). The kinetics of ctDNA were largely concordant with the course of M protein and serum-free light chains (SFLC). To test our hypothesis that ctDNA assessment could be particularly useful for patients with inconclusive serological markers (minimal response (MR)/ stable disease (SD) by IMWG criteria), we performed a subgroup analysis of all patients with MR/SD at first follow-up (C3D1). In this group of 19 patients a residual ctDNA fraction ≥10% translated into a significantly shorter median PFS (1.6 months, 95% CI: 0.1-0.8) as compared to ctDNA levels <10% (5.8 months, 95% CI: 1.2-11.4, P=0.02). Conclusions: These data indicate that "liquid biopsy" evaluation of ctDNA may refine prognostication and provide added predictive value over serological markers alone. While in the large majority of cases ctDNA has excellent concordance with M protein and SFLC for monitoring of MM disease progression, ctDNA may identify patients where relapse is imminent before it can be detected by serological parameters. This approach may therefore complement our framework for treatment decisions. Notably, this approach is highly scalable, cost-efficient and provides information about the clonal evolution of MM without the need for a bone marrow biopsy. Disclosures Yee: Adaptive: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Lipe:amgen: Research Funding; Celgene: Consultancy; amgen: Consultancy. O'Donnell:Sanofi: Consultancy; Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy. Munshi:Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Oncopep: Consultancy. Richardson:Bristol-Myers Squibb: Research Funding; Takeda: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Anderson:OncoPep: Other: Scientific founder ; Sanofi-Aventis: Other: Advisory Board; Janssen: Other: Advisory Board; C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board. Raje:Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Lohr:T2 Biosystems: Honoraria; Celgene: Research Funding. OffLabel Disclosure: This abstract reports on the quadruple regimen elotuzumab, pomalidomide, bortezomib and dexamethasone which is not yet approved for the treatment of multiple myeloma in the United States.

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.

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3180-3180
Author(s):  
Felix Lopez-Cadenas ◽  
Blanca Xicoy ◽  
Silvia Rojas P ◽  
Kaivers Jennifer ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Rank Test ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

Updated Outcomes of Fludarabine/Melphalan/Bortezomib (Flu/Mel/Vel) Conditioning for Upfront Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5885-5885
Author(s):  
Taiga Nishihori ◽  
Claudio Anasetti ◽  
Rachid Baz ◽  
Jose L Ochoa-Bayona ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Genetics Research ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Background: Multiple myeloma remains incurable despite impressive array of available novel agents and therapeutic strategies. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for patients with multiple myeloma but it is limited by its toxicities. We previously reported initial result of a phase 2 study of upfront allogeneic HCT in myeloma patients achieving at least very good partial response (VGPR) after initial therapy (Nishihori, et al. ASH 2013 abstract 3390) and here we report more mature results after a median follow up of 3 years. Methods: Twenty seven myeloma patients received allogeneic HCT between 01/2010 and 02/2015 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving first ≥ VGPR or complete response (CR), and have 8/8 HLA-matched related or unrelated donors. Conditioning regimen consisted of fludarabine 30 mg/m2 for 4 days (days -6, -5, -4, and -3) and melphalan 70 mg/m2 for 2 days (days -4 and -3) followed by a single dose of bortezomib 1.3 mg/m2 on day -3 (Flu/Mel/Vel regimen). GVHD prophylaxis was initially left to the discretion of physicians but later modified to only tacrolimus/methotrexate. No maintenance therapy was prescribed after allogeneic HCT. Results: The median age at transplant was 50 (range, 25-58) years. Disease status at the time of allogeneic HCT was VGPR (n=17: 63%) and CR/stringent CR (n=10: 37%). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched related donors (n=14) or HLA-matched unrelated donors (n=13). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus either methotrexate (n=19: 70%), or mycophenolate mofetil (n=4), or sirolimus (n=4). All patients achieved neutrophil engraftment with a median of 15 (range, 11-19) days. Platelet engraftment was achieved with a median of 17 (range, 13 - 35) days and 2 patients did not recover platelets. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 63.6% (95% confidence interval (CI): 43.1-81.1) and 19.6% (95%CI: 5.4-39.9), respectively. The cumulative incidence of moderate to severe chronic GVHD was 56.4% (95%CI: 36.3-75.5) at 1-year. The cumulative incidences of transplant-related mortality at day 100, 1 year and 2 years were 7.4% (95%CI: 0.8-20.0), 11.1% (95%CI: 2.7-25.4), and 11.1% (95%CI: 2.7-25.4), respectively. Progression-free survival estimates at 1, 2, and 3 years were 74.1% (95%CI: 53.2-86.7), 65.1% (95%CI: 43.3-80.2), and 65.1% (95%CI: 49.9-87.5), respectively. With a median follow up of 39 months for surviving patients, overall survival estimates at 1, 2 and 3 years were 85% (95%CI: 64.9-94.1), 75.4% (95%CI: 52.6-88.3), and 69.1% (95%CI: 53.8-93.5), respectively. Conclusions: The results of the this phase 2 trial of upfront allogeneic HCT with fludarabine/melphalan/bortezomib (Flu/Mel/Vel) conditioning are promising and provide the rationale for reasonable potentially curative option to younger and fit patients who are eligible for upfront intensive consolidation strategy. This approach may be potentially valuable for those with high-risk myeloma and a multicenter study is currently being conducted (BMT CTN protocol 1302:NCT02440464). Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Signal Genetics: Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Alsina:Signal Genetics: Consultancy; Novartis: Research Funding; Takeda/Millennium: Research Funding; Amgen/Onyx: Consultancy, Speakers Bureau.

scholarly journals Real-World Outcomes for Standard-of-Care Treatments in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4075-4075
Author(s):  
Michel Delforge ◽  
Marie-Christiane Vekemans ◽  
Sébastien Anguille ◽  
Julien Depaus ◽  
Nathalie Meuleman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Retrospective Chart Review ◽  
Standard Of Care ◽  
Real World Data ◽  
Advisory Committees ◽  
Treatment Regimens

Abstract Background: With the advent of immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and, more recently, anti-CD38 monoclonal antibodies (mAbs), prognosis of patients with multiple myeloma (MM) has improved considerably. Unfortunately, even with these 3 major MM drug classes, most patients ultimately relapse and require further therapy. There remains an incomplete understanding of how patients who have received extensive therapy and with relapsed/refractory multiple myeloma (RRMM) are treated in routine clinical practice, as no standard-of-care exists for these patients, and what the outcomes are in this real-world setting. Objective: This study aims to evaluate the outcomes of patients with triple-class (IMiD, PI and anti-CD38 mAb) and triple-line exposed RRMM using real-world data from patients in Belgium. Methods: A multicenter, observational study, involving 7 non-academic and academic Belgian centers, was conducted based on a retrospective chart review of adult RRMM patients who started subsequent treatment from March 2017 through May 2021 after having received ≥3 lines of therapy including at least an IMiD, a PI, and anti-CD38-directed therapy (tri-exposed). Data were captured in an electronic case report form (Castor EDC). Patients with an ECOG performance status of ≥2, who received prior CAR-T treatment or prior BCMA-targeted therapy, or with a known active or prior history of CNS involvement (or with clinical signs thereof), were excluded. All treatment lines initiated after becoming eligible were used in the analysis. Specifically, all treatment lines for patients meeting the eligibility criteria more than once in their entire follow-up were included as separate observations, with date of treatment initiation as specific baseline for each treatment line. Cox proportional hazards models were fitted to explore the prognostic value with Overall Survival (OS), Progression Free Survival (PFS), and Time to Next Therapy (TTNT). Results: A total of 112 patients with 237 eligible treatment lines were included in the analysis; median follow-up was 16.6 months. In 45% of the initiated treatment lines, patients were refractory to 4 or 5 therapies, 62% had received ≥5 prior lines, 22% had extramedullary disease and in 48% of observations the time to progression in prior line was shorter than 4 months. After patients became tri-exposed, more than 50 unique treatment regimens were initiated, with the following being the most common: carfilzomib + dexamethasone (14%), pomalidomide + dexamethasone + chemotherapy (8%), and ixazomib + lenalidomide + dexamethasone (6%). Additionally, 4% of included observations were exposed to anti-BCMA agents. Overall, the following treatment classes were the most frequently started: PI only (19%), PI + IMiD combinations (17%), and regimens including anti-CD38 antibodies (15%). Median OS was 9.79 months [95% CI: 7.79; 12.22], median PFS was 3.42 months [95% CI: 2.79; 4.27], median TTNT was 3.61 months [95% CI: 3.09; 4.57]. Higher refractory status (p&lt;0.001), being male (p=0.001), older age (p&lt;0.001), shorter duration of prior lines (p&lt;0.001), shorter time to progression in prior line (p=0.025), and higher LDH levels (p&lt;0.002) were prognostic for worse outcomes for both OS (Figure 1) and PFS. Conclusions: This retrospective chart review of patients with tri-exposed RRMM in Belgium shows that real-world outcomes in terms of OS, PFS and TTNT are poor for these patients, with a median OS of &lt;10 months. A wide variety of treatment regimens used in clinical practice confirm the absence of a clear standard-of-care in this patient population. The literature also confirms that these poor outcomes observed in Belgium, for this subset of MM patients, are similar in other countries. These real-world data highlight the high unmet medical need in this patient population and critical need for new and effective treatment options. MD and MCV contributed equally to this work. Figure 1 Figure 1. Disclosures Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Vekemans: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceutica: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Depaus: Takeda: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Meuleman: iTeos Therapeutics: Consultancy. Strens: Realidad bvba: Consultancy. Van Hoorenbeeck: Janssen: Current Employment. Moorkens: Janssen-Cilag: Current Employment. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Dalhuisen: Janssen: Current Employment. Vandervennet: Janssen: Current Employment.

scholarly journals EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4569-4569 ◽  
Author(s):  
Frits van Rhee ◽  
Sharmilan Thanendrarajan ◽  
Carolina D. Schinke ◽  
Jeffery R. Sawyer ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Early Results ◽  
Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

scholarly journals A Cross Sectional Epidemiological and Survival Analysis of All Patients with Plasma Cell Disorders Recorded between 2011- 2017 in the Social Insurance System of Turkey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5847-5847
Author(s):  
Metin Dag ◽  
Meral Beksac
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Survival Analysis ◽  
Board Of Directors ◽  
Healthcare System ◽  
Plasma Cell ◽  
Real World ◽  
Real World Data ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Background and Aim: The incidence and outcomes of patients with cancer diagnoses are reported annually as SEERs in few but not all countries. Clinical trials or myeloma group studies have documented the survival of patients with plasma cell disorders to improve with the approval of new drugs, early diagnosis and better follow-up. The outcome of patients included in clinical trials do not represent the real world data. There are two major pharma sponsored international prospective or retrospective analysis of real World data where patients from Turkey are also included (Mohty et al Clin Lymphoma Myeloma Leuk 2018 and Kumar et al. Leuk Lymphoma 2018). However the results do not confer to patients of any country in particular. According to the SGK's 2016 annual report, 98,6% of the population of Turkey is covered by the Healthcare Insurance System (SGK). Electronic data recording system (2007) and e- prescribing (2010) have been introduced to the healthcare system in Turkey. The aim of this study is to analyze and report the epidemiological features of patients who are recorded and received drugs approved and reimbursed by the Turkish Healthcare system . Patients and Methods: The study is performed following Ethical Committee approval by Ankara University and also by permission for publication from SGK. Patients recorded with the ICD of C90 between 2011-2017 and has received either of these medications: Melphalan, Thalidomide, Bortezomib, Lenalidomide, Bendamustine or high dose therapy with stem cell support(ASCT) were included in the analysis. This approach was taken to prevent false ICD entry or exclude patients with Monoclonal Gamopathy of Undetermined Significance or Smoldering Multiple Myeloma who are not being treated. Additionally patients who were privately insured or received drugs within clinical trials or compassionate/early access programs were also excluded. Patients registered earlier than 2011 were not included in the analysis to allow survival analysis. Statistical analysis were performed using the SQL, SPSS, MS Office software packages. Results: A total of 10146 patients were evaluated as eligible. Annual number of patients during the 2011-2017 period were as follows: 1168, 824, 2245, 1811, 1537, 1183, 1378. Males/females: 5655/4491, Median age of patients were constant with a minor increase from 63.8(2011) to 65.2(2017). ASCT (once or more)was received by 4060 (40%)patients. Overall survival (OS) of patients improved if diagnosed younger (Fig 1a), if they are female (Fig 1b) and received ASCT(Fig 1d). There was no OS benefit if ASCT was given more than once. Approval and reimbursement of novel drugs such as Bortezomib and Lenalidomide were achieved in 2005 and 2010 respectively. Both Carfilzomib and Pomalidomide are approved but only conditionally reimbursed since 2015 and 2016. Patients who started treatment during more recent years (after 2015)are able to survive longer than those who started earlier(Fig 1c). Conclusions: This is the first and most extensive epidemiological report for Multiple Myeloma from Turkey. It informs about annual incidence of patients eligible for treatment (approximately 1400), treatment success (OS: median 4 years) during a seven year period. Our results are supporting the survival advantage of ASCT (median 5 vs. 2 years, p=0.000) and younger age(p=0.000) plus female gender (p=.0.005). Patients who initiated treatment recently have better OS than patients starting earlier (p=0.001). More detailed survival and cost benefit analyses are aimed to be presented during the meeting. Disclosures Beksac: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Comparison of MALDI-TOF Mass Spectrometry Analysis of Peripheral Blood and Bone Marrow Based Flow Cytometry for Tracking Measurable Residual Disease (MRD) in Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3060-3060
Author(s):  
Marion Eveillard ◽  
Even H Rustad ◽  
Mikhail Roshal ◽  
Yanming Zhang ◽  
Amanda Kathryn Ciardiello ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
M Protein ◽  
Advisory Committees ◽  
Maldi Tof Ms ◽  
Maldi Tof ◽  
Active Disease ◽  
Tof Ms

Introduction In multiple myeloma (MM), the absence of measurable residual disease (MRD) after completed therapy is associated with longer progression free survival. Different techniques are available to detect low levels of plasma cells in bone marrow (BM) either by flow cytometry or by next-generation sequencing as a gold standard of molecular methods. But these techniques are limited because they require a representative bone marrow sample obtained by an invasive procedure. Therefore, detecting low levels of disease in blood would be ideal, because serial sampling is much easier and fully representative, and it would allow for the detection of extramedullary disease. Mass spectrometry-based methods have been shown to be more sensitive for detecting monoclonal proteins (M-protein) in serum. In this study, we were motivated to evaluate MALDI-TOF mass spectrometry (MALDI-TOF MS) head-to-head with an established BM-based MRD assays. Patients and Methods This cohort included 71 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) who had serum samples available at 2 timepoints including during active disease and within 60 days of MRD results as determined by flow cytometry of bone marrow aspirates (Flow-BM-MRD). The cohort enrolled 26 females and 45 males with a median age of 61 years (range 37-78 years). Twenty-seven patients had high-risk cytogenetics at baseline. The median time between diagnosis and the MRD timepoint was 13.4 months (3.4-91 months). MALDI-TOF MS analysis was performed according to the method published by Mills et al. Immunoglobulins were purified from serum samples using CaptureSelect beads specific of each isotype and were then eluted from the beads. Light chains and heavy chains were separated by the addition of a reducing agent. Purified samples were mixed in matrix and spotted onto a stainless steel MALDI plate and were analyzed using a Microflex LT MALDI-TOF mass spectrometer (Bruker). Samples taken during active disease were used to identify the mass to charge ratio (m/z) of the M-protein and served as a surrogate marker in the analysis of subsequent samples. MALDI-TOF MS results were compared to the Flow-BM-MRD assay, performed using the MSKCC's ten-color, single-tube method. Results MALDI-TOF MS detected an M-protein in all 71 active disease samples and in 25 MRD samples. MALDI-TOF-MS results at the MRD timepoint were concordant with Flow-BM-MRD for 44/71 patients (p=0.342, chi-square test). Eight patients were positive and 36 negative by both techniques. Twenty-seven patients were discordant, including 10 patients detectable only by Flow-BM-MRD and 17 detectable only by MALDI-TOF MS. Among the 10 patients detectable by flow cytometry but not by MALDI, the median MRD level was 0.00092% (+<0.0001% - 0.011%). The M-protein could have been present but below the polyclonal background. Regarding the 17 patients positive only by MALDI-TOF-MS, the BM sample for flow analysis was not suitable for 3 patients due to hemodilution. The others 14 samples reached the target of sensitivity with a limit of detection of 0.0001%. Alternatively, the MALDI-TOF result could be a false positive in terms of disease detection. MS is likely not falsely detecting M-proteins and indeed, immunofixation was also positive in 11/17 of these samples. However, low levels of M-protein may not indicate the presence of active disease. Indeed, a confounding factor is that immunoglobulins have a long half-life in serum. To determine the clinical utility of more sensitive M-protein detection, we evaluated the clinical outcome for the 48 newly diagnosed MM patients in CR at the MRD timepoint with a median follow-up of 11 months. Of these 48 patients, 2 of the 3 that were positive by both techniques relapsed during follow-up. One out of 27 patients that were negative by both techniques relapsed. None of the 10 patients who were positive only by MALDI-TOF relapsed and 1 of the 8 patients who were positive only by Flow-BM-MRD relapsed. Conclusions This study is important because it is a first step in understanding how to use a more sensitive blood test for the follow-up of MM patients. MALDI-TOF MS analysis may provide complementary results to Flow-BM-MRD especially for the follow-up of patients in CR and during maintenance therapy to detect poor responders that would be positive by both techniques. In summary, our results suggest that MALDI-TOF may be quite useful for early detection of relapse. Disclosures Roshal: Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Hassoun:Celgene: Research Funding; Janssen: Research Funding; Novartis: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Lesokhin:Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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