scholarly journals M-Protein Sequencing and Monitoring in Serum of LC-Only Multiple Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4729-4729
Author(s):  
Mariya Liyasova ◽  
Natalia Migdal ◽  
Zac McDonald ◽  
Liqiang Yang ◽  
Bin Ma ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Protein A ◽  
Disease Status ◽  
Protein Sequencing ◽  
M Protein ◽  
Newly Diagnosed ◽  
Protein Levels ◽  
Non Invasive ◽  
Q Exactive

Abstract Background M-protein, a secreted antibody of malignant plasma cells, is a gold standard biomarker for monitoring the disease status in multiple myeloma (MM) patients (pts). The development of peripheral blood based ultrasensitive (MRD) methods of M protein detection is of high interest and importance. In 20% of MM pts, the M-protein consists of only the light chain (LC) of the immunoglobulin (Ig) molecule. For these LC-only MM pts, disease monitoring is challenging due to low levels of M-protein in serum. Urine protein electrophoresis (UPEP) and immunofixation electrophoresis (IFE), or serum free light chain (FLC) lack the sensitivity and/or specificity to track the M-protein in these pts, while bone marrow-based assays cannot be performed frequently due to their invasive nature. Thus, we evaluated the performance of EasyM, a mass spectrometry(MS)-based, non-invasive, sensitive assay for monitoring M-protein levels in LC-only patients in the MCRN-001 Canadian national and MD Anderson VRD-panobinostat frontline trials. Methods MCRN-001 trial is evaluating enhanced conditioning prior to ASCT for newly diagnosed MM (NDMM). After treatment with bortezomib (BTZ) based induction eligible MM pts received BuMel prior to ASCT. Busulfan was administered via IV at 3.2 mg/kg on days -5 to -3, or days -6 to -4 pre-ASCT (day 0) and melphalan was given at 140 mg/m 2 on day -2 or -3 pre-ASCT. Lenalidomide (LEN) administration began 100 days post-ASCT at 10 mg/d and continued until progressive disease (PD) onset. In the MDACC 2011-0192 frontline study in newly diagnosed MM, transplant-eligible pts received the novel combination of LEN, BTZ, dexamethasone (DEX) and panobinostat (RVD-panobinostat). The IMWG criteria were used to monitor clinical response in both trials. A total of 13 LC-only MM pts were selected for the study. Local IRB approval was obtained prior to the study. To derive the M-protein's full amino acid sequence, FLC was first enriched from the diagnostic serum sample. The FLC enrichment consisted of IgG depletion with protein A/G beads, followed by affinity purification of kappa or lambda LC containing Igs. Non-reducing PAGE was then used to separate FLC monomers, FLC dimers and full-length Igs. Finally, in-gel digestion of FLC monomers and dimers by multiple proteolytic enzymes were analyzed on a Q-Exactive mass spectrometer. Data analysis and sequence assembly were performed with the REmAb protein sequencing platform. To monitor M-protein levels in serum, unique, tryptic peptides from sequenced FLC were selected and quantified in diagnostic and follow-up samples with a PRM assay on a Q-Exactive instrument. Results M-protein sequencing The full FLC sequence was derived for 8 out of 13 (61.5%) LC-only pts. The M-protein was successfully sequenced even when the FLC concentration was as low as 147 mg/L. However, FLC concentration measured by FreeLite assay was not a reliable predictor of our ability to derive the full sequence. The appearance of a sharp FLC monomer and dimer bands on PAGE after FLC enrichment was a better predictor of the M-protein sequencing success. M-protein monitoring The M-protein of one pt did not contain any unique peptides. This pt was excluded for further analysis. In the remaining 7 pts, the M-protein contained at least one unique peptide and could thus be monitored by EasyM. For 6 LC-only pts, the M-protein monitored by EasyM correlated with the disease status measured by serum FLC, UPEP and urine IFE. A separate serial dilution test estimated that the limit of quantification can reach as low as 0.13 mg/L. Figure 1 shows representative data for two LC-only patients. One pt experienced relapse during the study; however, this relapse could not be detected by EasyM. This result could indicate a possible clonal switch at time of disease progression, but further investigation is needed to verify this. Conclusions Due to the rapid turnover and clearance of light chains conventional blood/urine tests have lacked the higher sensitivity needed to monitor disease state in LC only MM patients. To overcome the lower FLC concentration the current study successfully applied LC enrichment strategies to enable the sequencing and high sensitivity monitoring of FLC M-protein by MS in blood. The EasyM LC assay is non-invasive, sensitive, capable of assessing disease status, and has potential to be further investigated as a peripheral blood myeloma response and MRD monitoring biomarker. Figure 1 Figure 1. Disclosures Ma: Rapid Novor Inc.: Current holder of individual stocks in a privately-held company. Reece: Millennium: Research Funding; Amgen: Consultancy, Honoraria; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; BMS: Honoraria, Research Funding. Manasanch: GSK, Secura Bio,Takeda, Celgene, Sanofi, Janssen and Adaptive Biotechnologies: Consultancy; Sanofi, Quest Diagnostics, Novartis, JW Pharma, Merck: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Trudel: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals New Blood Based M-Protein Quantification Method 3,000 Times More Sensitive Than Standard SPEP

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1905-1905
Author(s):  
Zac McDonald ◽  
Qixin Liu ◽  
Paul Taylor ◽  
Liqiang Yang ◽  
Bin Ma
Keyword(s):  
De Novo ◽  
De Novo Sequencing ◽  
Protein Quantification ◽  
Protein Sequencing ◽  
M Protein ◽  
Employment Equity ◽  
Protein Levels ◽  
Non Invasive ◽  
Quantification Method ◽  
Equity Ownership

Abstract Summary of Work The amino acid sequence of the M-protein for multiple myeloma (MM) is unique compared to the polyclonal antibodies in patients' blood. In this study we utilize this uniqueness to develop an ultra-sensitive M-protein detection method with mass spectrometry (MS). The method involves the de novo sequencing of the amino acid sequence of the M-protein from the baseline blood sample collected at the time of diagnosis, and a targeted MS assay to detect and quantify the unique M-protein sequence in the follow-up blood samples. This non-invasive method is purely blood based and is 3,000 and 300 times more sensitive than SPEP and IFE, respectively. De Novo Protein Sequencing The M-protein sequencing is carried out on an MS based platform (REmAb). The effectiveness of de novo protein sequencing has been proven with the sequencing of hundreds of monoclonal antibodies (McDonald et al., Poster 294737, ASMS, 2018). In the current study the M-protein from 4 MM patients' baseline blood samples were successfully sequenced, demonstrating robustness of the method in the presence of the polyclonal background. As little as 50ul of the serum was required for the de novo sequencing. Sensitivity of M-protein Quantification The lower limit of quantification (LLOQ) was studied with a serial dilution experiment. The baseline blood sample of one patient was sequentially diluted with a healthy donor's serum. The peptide sequence unique to the M-protein was monitored with mass spectrometry to detect and quantify the M-protein in the serial dilution. The M-protein could still be detected and quantified when the dilution ratio was 1:10,000 (the amount of M-protein relative to background polyclonal serum IgG). In a separate experiment, synthesized heavy labelled proteotypic peptides were used to estimate the LLOQ in IgG enriched serum at 60 ug/dL, over 3,000 times more sensitive than SPEP (0.2g/dL) (Bergen et al., Clin Chem 62: 1 243-251, 2016) and 300 times more sensitive than IFE (0.02g/dL) (IMWG, British Journal of Haematology, 121, 749-757, 2003). As little as 30ul of serum was required in these experiments for monitoring of M-protein levels. Case Study A targeted MS based assay was developed to monitor the M-protein levels of a serial patient sample set (73-year-old male, treatment: Elotuzumab/Lenalidomide/Dexamethasone, progression free survival 32 months). M-protein levels were quantified in a total of 10 serial samples from partial remission, through complete remission (CR), until relapse over a period of 2 years and 3 months (Figure 1). M-protein could be detected and quantified in all samples collected during the CR period with estimated M-protein levels never below 10mg/dL. Notably, a 2-fold increase in M-protein levels (in comparison to the lowest historic level) could be detected 320 days prior to the timepoint of relapse. The upward trend continued in the next 3 serial CR samples preceding relapse. Except for one sample (see Figure 1, 'CR Before Relapse 12-14-2016'), CR was based on the absence of M-protein in the IFE result in the relevant clinical data. Conclusion The work represents a first step in the application of de novo sequencing and MS based detection for the sensitive monitoring of M-protein levels in serum. It shows a much-improved sensitivity over current standard approaches and has the great potential to provide non-invasive assessment of MRD for multiple myeloma. The preliminary data warrant further development of this MS based non-invasive and highly sensitive M-protein quantification method. Disclosures McDonald: Rapid Novor Inc: Employment, Equity Ownership. Liu:Rapid Novor Inc: Employment, Equity Ownership. Taylor:Rapid Novor Inc: Employment, Equity Ownership. Yang:Rapid Novor Inc: Employment, Equity Ownership. Ma:Rapid Novor Inc: Equity Ownership.

scholarly journals Targeted Mass Spectrometry-Based Serum M-Protein Monitoring for Early Relapse Detection

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4347-4347
Author(s):  
Zac McDonald ◽  
Mariya Liyasova ◽  
Paul Taylor ◽  
Xin Xu ◽  
Kathleen Gorospe ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Fold Increase ◽  
Protein Sequencing ◽  
M Protein ◽  
Patient Specific ◽  
Advisory Committees ◽  
Protein Levels ◽  
Equity Ownership ◽  
Early Relapse Detection

Background For most Multiple Myeloma (MM) patients, M-protein is the gold standard biomarker for disease diagnosis and monitoring. Traditional methods such as serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (IFE) lack the sensitivity to detect M-protein in patients with minimal residual disease. At ASH 2018, we reported a Mass Spectrometry (MS)-based highly sensitive assay (REmAb) for detecting and quantifying M-protein. This assay exploits the uniqueness of the M-protein sequence and can detect 1 M-protein in 10,000 polyclonal IgG. The current study utilized this established assay to first sequence then monitor M-protein in sera from diagnosis through treatment for patients from the first MCRN-001 Canadian national trial with bortezomib (BTZ)-based pre-induction (PI), augmented high-dose chemotherapy with busulfan + melphalan (BuMel) before ASCT and lenalidomide (Len) maintenance post-ASCT. Methods MCRN-001 trial patients were first induced with BTZ before harvesting stem cells. Eligible MM patients received BuMel prior to ASCT. Busulfan was administered IV at 3.2 mg/kg on days -5 to -3, or days -6 to -4 days pre-ASCT (Day 0) and melphalan was given at 140 mg/m2 on day -2 or -3 pre-ASCT. Len administration began 100 days post-ASCT at 10 mg/d (increased when appropriate to 15 mg/d) and continued until progressive disease (PD) onset. IMWG criteria was used to monitor clinical response and PD. 78 patients enrolled in this trial; only 58 offered consent for M-protein monitoring with MS. Serum samples were acquired at time of pre-induction (PI), before ASCT (screening sample), post-ASCT on day 100, every 3 months for the first year and then every 6 months until PD. The M-protein sequence was determined with the REmAb protein sequencing platform from either PI or screening samples when the PI sample was unavailable. For M-protein quantification, each sample was digested with trypsin prior to analysis by liquid chromatography tandem MS with an Orbitrap Fusion Tribrid or Q-Exactive instrument. Patient-specific, unique tryptic peptides, with at least one peptide from each Heavy and Light chain, were targeted by the MS assay. To monitor changes in M-protein levels per patient post-diagnosis and through treatment to complete remission (CR) and/or PD, this study used MS peak areas of patient-specific unique peptides normalized against peak areas of human serum albumin or spiked-in standard peptides. Results M-protein sequencing In this study, the lowest M-protein serum concentration required for sequencing was 0.2 g/dL. 48 out of 58 (83%) patient-specific M-proteins were sequenced from serum. 5 out of 48 patients sequenced discontinued the study early and were excluded from further analysis. M-protein monitoring 24 out of the 43 achieved CR. The M-proteins of these patients were monitored by MS to study early relapse detection. M-protein levels could be monitored by MS in all these patients from diagnosis through CR to PD onset, even when M-protein was undetectable by SPEP and IFE. A separate serial dilution test estimated that the limit of quantification can reach as low as 0.03 mg/dL. 3 patients who had achieved CR eventually relapsed (PD). In all 3 PD patients, a 2 to 200 fold increase in M-protein in 2 consecutive tests half a year apart was detected by MS 6 months earlier than clinical confirmation of PD by conventional testing. The other 21 had not progressed at time of analysis. In the non-progressor group, the M-protein levels detected by MS either continued to decrease during CR or remained relatively stable. Only 3 out of 21 patients demonstrated a 2-fold increase in M-protein level in any 2 consecutive tests. Figure 1 shows representative data for two patients. Conclusions This study demonstrates that M-protein sequencing and targeted MS assay can be used to monitor serum M-protein levels sensitively even when SPEP and IFE fail to detect M-protein. Based on this assay, a 2-fold increase in serum M-protein levels in the past 6 months can reliably predict disease progression in the next 6 months for patients achieving CR. In the 24 studied patients, the method has 100% sensitivity and 86% specificity at predicting disease progression from CR prior to detection by standard methods. Future work will analyze more patient samples to confirm the findings and investigation into criteria surrounding the 2-fold M-protein increase observed in CR patients and relapse post CR. Disclosures McDonald: Rapid Novor Inc Kitchener: Employment, Equity Ownership, Research Funding. Liyasova:Rapid Novor Inc Kitchener: Employment. Taylor:Rapid Novor Inc Kitchener: Employment. Xu:Rapid Novor Inc Kitchener: Employment. Gorospe:Rapid Novor Inc Kitchener: Employment. Yao:Rapid Novor Inc Kitchener: Employment. Liu:Rapid Novor Inc Kitchener: Employment, Equity Ownership. Yang:Rapid Novor Inc Kitchener: Employment. Ma:Rapid Novor Inc Kitchener: Equity Ownership. Reece:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Merck: Research Funding; BMS: Research Funding. Trudel:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: The use of IV busulfan and melphalan as conditioning for myeloma transplants is off-label.

Phase I Study of BT062 Given as Repeated Single Dose Once Every 3 Weeks in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1862-1862 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Sundar Jagannath ◽  
Leonard T. Heffner ◽  
David Avigan ◽  
Kelvin P. Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
M Protein ◽  
Advisory Committees ◽  
Elimination Phase ◽  
Protein Levels ◽  
Dose Levels

Abstract Abstract 1862 Poster Board I-887 Background: Biotest AG (Dreieich, Germany) is developing the immunoconjugate BT062, which comprises the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent maytansinoid (DM4). Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4. At present, CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. Preclinical investigations demonstrated significant in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in relapsed or relapsed/refractory MM. Clinical response was assessed as per the international working group criteria (Durie et al., 2006). Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulating agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients are enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: To date 20 patients have been treated with BT062 at 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has not been defined to date with continued enrollment at 200 mg/m2 dose. None of the patients treated experienced serious hypersensitivity reactions or humoral responses (HAHA) against BT062. The most frequently reported adverse events to date cover primarily events expected for the underlying disease. Nevertheless, a few adverse events have also been observed involving skin and mucosa (tissues of epithelial origin with CD138 expressing cells). No grade 4 toxicity has been reported. Preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase at dose levels up to 120 mg/m2, whereas a more typical clearance profile was observed for all 3 patients at the 160 mg/m2 dose. Interestingly, even in phase I study decreased urine M-Protein or serum FLC levels have been observed in 2 patients. One of these patients showed a decrease in urine M-Protein by more than 50% after administration of 8 repeated low doses. At a high dose level another patient without detectable M-Protein levels, showed a decrease of serum FLC by more than 50% after having received the second dose of BT062. Furthermore, evidence of clinical benefit has been observed in at least 6 patients with early stabilization of M-protein levels (and light-chain burden) in serum and /or urine. Conclusion: Development of a monoclonal antibody in MM remains an important therapeutic option and BT062 is an exciting possibility. Preliminary data from this phase I study, demonstrate an acceptable toxicity profile of BT062 in the clinics. Even in phase I study, evidence of clinical activity is observed. These encouraging results and the unique PK observed support investigation of a more frequent dosing regimen for optimizing anti-MM responses. Updated data on safety, PK and efficacy of BT062 from this clinical trial will be presented at the meeting. Disclosures: Jagannath: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding. Lutz:Immunogen, Inc.: Employment. Haeder:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Uherek:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Biotest AG: Consultancy, Research Funding.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: 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. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, 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. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4396-4396
Author(s):  
Patrick Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia Griepp ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Risk Modeling ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals Raised ?2-Microglobulin as a Surrogate Marker in Non-Secretory Multiple Myeloma

2017 ◽  
Vol 16 (1) ◽  
pp. 142-145
Author(s):  
Bimal K Agrawal ◽  
Anshul Sehgal ◽  
Vikas Deswal ◽  
Prem Singh ◽  
Usha Agrawal
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Rare Case ◽  
Plasma Cells ◽  
Medical Science ◽  
Protein A ◽  
Surrogate Marker ◽  
M Protein ◽  
Review Of Literature ◽  
Lytic Lesions

Multiple myeloma is a neoplasm of plasma cells in the bone marrow. It is characterised by lytic lesions in the bones, marrow plasmacytosis and presence of M protein in serum and/or urine. Serum ?2 microglobulin is also raised and can be used for classification and prognostication of the disease. In the absence of M protein, the disease is known as non-secretory myeloma. It is proposed that raised ?2 microglobulin can be used for diagnosis and therapeutic guidance in the absence of M protein. A rare case of nonsecretory myeloma with neurocognitive impairment along with review of literature is being presented. The patient had multiple lytic lesions in bones with marked increase in plasma cells in bone marrow. M protein was not detectable in serum or urine but serum ?2 microglobulin was much elevated.Bangladesh Journal of Medical Science Vol.16(1) 2017 p.142-145

Chromosome 1q Amplification Is Associated with a History of Prior Malignancies Among Patients Newly Diagnosed with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2193-2193
Author(s):  
Elizabeth B Lamont ◽  
Andrew J. Yee ◽  
Stuart L. Goldberg ◽  
Andrew D Norden
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Usual Care ◽  
Real World ◽  
Research Funding ◽  
Newly Diagnosed ◽  
History Of ◽  
Equity Ownership ◽  
Prior Malignancy

Background: Over the past 20 years, observational data from usual care clinical oncology settings has been leveraged to inform estimates of cancer treatment-associated benefits and risks among patients not treated on clinical trials. Increasing genomic testing to inform treatment decisions in usual care settings now meaningfully augments traditional observational data, positioning it to provide insights beyond clinical care into tumor biology. We studied patients with newly diagnosed multiple myeloma (MM), comparing cytogenetic test patterns according to history of prior malignancy. Methods: In this retrospective cohort study, we identified 2,380 patients from the COTA real-world database (RWD) who were newly diagnosed with MM in the years 2010-2018. The COTA RWD is a de-identified composite of both abstracted electronic health record and administrative data pertaining to patients receiving their cancer care at one of COTA's clinical oncology practice partners. Among these patients, 1769 (74%) had evidence of MM-associated cytogenetic testing with fluorescent in-situ hybridization (FISH) within the 120 days surrounding their date of diagnosis. The 1,769 patients form the analytic cohort. We compared patients' FISH results for t(4;14), deletion(17p), t(14;16), deletion(13), t(14;20), t(6;14), t(11;14), deletion (1p), and amplification(1q) according to their history of prior malignancy. Results: Within the cohort, 263 prior malignancies were identified in 241 patients (14%, 241/1,769). Two-hundred and twenty-one patients (92%) had one prior malignancy, 28 (7.9%) had two prior malignancies, and one (<1%) had four prior malignancies. The most common prior malignancies were prostate (n=50), breast (n=19), melanoma (n=14), skin (n=13), and cervix (n=6). Amplification of the long arm of chromosome one (amp(1q)) was noted in 31% of patients (75/241) with a prior malignancy vs. 24% of patients (370/1,528) without (chi2 test p=0.02). Overall 25% of patients had amp(1q). No other translocations, amplifications, deletions were associated with prior cancers. A non-parametric test for trend revealed a strong positive association between patients' malignancy count (range 0-4) and amp1q (p<0.01). MM patients with prior lymphomas and prior melanomas also had high rates of amp(1q), though these were not significantly different from patients without these prior malignancies. In a multivariable logistic regression model that adjusted for patient demographic attributes, other known potentially collinear MM poor prognostic factors (i.e., revised ISS stage, IgA sub-type, lambda light chains) and adjusted standard errors for clustering of patients within treatment settings, a history of prostate cancer remained clinically and statistically significantly positively associated with amp(1q) (OR 2.1, 95% CI: 1.9-2.2) as did history of two or more prior malignancies (OR 2.8, 95% CI: 2.3-3.3). Of note, amp(1q) was positively associated with IgA subtype (OR 1.5, 95% CI: 1.3-1.6) and the presence of lambda subtype (OR 1.3, 95%CI: 1.3-1.4). Conclusions: Using RWD, we found that newly diagnosed MM patients with histories of prostate cancer and those with two or more prior malignancies were more likely to have amp(1q), a poor prognostic marker in MM. Gains in 1q have previously been identified among patients with prostate and lymphoid cancers, but to our knowledge this is the first study to identify an association with a prior history of cancer, especially prostate cancer, and amp(1q) in MM. This relationship is worth further exploration of whether there is a common pathway associated with for example risk of prostate cancer and amp(1q) in MM. Clinical trials are less likely to answer this question as patients with prior malignancies are often excluded from enrollment. Overall, the results reported suggest that RWD is an efficient and comparatively inexpensive tool to support research in cancer biology through hypothesis generating and testing analyses of linked real-world phenotypic and genotypic data. Disclosures Lamont: COTA: Employment. Yee:Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Norden:COTA: Employment, Equity Ownership.

Elevated Normal Immunoglobulins and Stable M-Protein Levels in Multiple Myeloma Patients on Erythropoietin Treatment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4747-4747
Author(s):  
Noa Gadassi ◽  
Sari Prutchi Sagiv ◽  
Howard S. Oster ◽  
Drorit Newmann ◽  
Moshe Mittelman
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
M Protein ◽  
Immunological Parameters ◽  
Humoral Immune ◽  
Protein Levels ◽  
Humoral Immune Responses ◽  
Human Erythropoietin ◽  
Erythropoietin Treatment ◽  
Cellular Immune

Abstract Recombinant human erythropoietin (rHuEPO) is a well-known treatment for anemia in multiple myeloma (MM) patients. We have previously reported that rHuEPO treatment was associated with prolonged survival of several patients suffering from advanced disease (Mittelman et al., 1997). Recently we have demonstrated that treatment of MM patients with rHuEPO is associated with significant improvements of certain immunological parameters and functions (Prutchi-Sagiv et al., 2006), mainly related to the cellular compartment. The objective of the present retrospective study was to determine whether rHuEPO treatment, in addition to its effects on the cellular immune compartment, also modulates the humoral arm of the immune system in MM patients. Medical charts of eighteen consecutive IgG and IgA MM patients were analyzed and the levels of normal immunoglobulins (Ig) and M-protein before and during rHuEPO treatment were recorded. We have found a significant increase in the levels of normal Ig (IgG, IgA and IgM) in response to rHuEPO, during the 3–9 months fromtreatment initiation. Importantly, the levels of M-protein remained stable for a period of 10–12 months from treatment initiation. These results are in line with previous studies, including our study in murine models (Katz et al., 2007), demonstrating that EPO improves humoral immune responses. The current study highlights the concept that EPO’s immunomodulatory actions on MM patients might also involve the humoral compartment of the immune system.

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