Hematologic Malignancies: Multiple Myeloma and Related Plasma Cell Disorders

Introduction. The prognosis of multiple myeloma is still unfavorable due to inherent characteristics of the disease and the often-delayed diagnosis due to widespread and unspecific symptoms such as back pain and fatigue. Therefore, a simple diagnostic blood test would be helpful to speed up the diagnostic procedure in such patients (pts.). Here, we evaluated the diagnostic value of plasma levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in the peripheral blood and bone marrow of pts. with plasma cell disorders and in healthy controls. Materials and Methods. Immunoreactive CEACAM6 was determined in the peripheral blood and bone marrow (n=95/100) of pts. with monoclonal gammopathy of unknown significance (MGUS: 28/37), newly diagnosed multiple myeloma (NDMM: 42/40), and relapsed/refractory multiple myeloma (RRMM: 25/23) by sandwich ELISA. Results. Median CEACAM6 levels in the peripheral blood of pts. with plasma cell disorders were significantly higher than those of healthy controls (healthy controls: 15.2 pg/ml (12.1-17.1); MGUS: 19.0 pg/ml (16.4-22.5); NDMM: 18.0 pg/ml (13.4-21.2); and RRMM: 18.9 pg/ml (15.2-21.5); p<0.001). Plasma levels of CEACAM6 discriminated healthy subjects from MGUS/NDMM pts. (AUC=0.71, 95% CI: 0.6-0.8); i.e., a CEACAM6 level>17.3 pg/ml has an 82% (95% CI: 70-90) predictive probability for the identification of MGUS or NDMM. Moreover, CEACAM6 levels in the bone marrow were significantly higher in RRMM pts. than in NDMM pts. (p=0.04), suggesting a role of this molecule in disease progression. Conclusion. CEACAM6 plasma levels can noninvasively identify pts. with a plasma cell disorder and should be evaluated prospectively as a potential diagnostic marker. Moreover, due to high CEACAM6 levels in the bone marrow in RRMM pts., this adhesion molecule might be a therapeutic target in multiple myeloma pts.

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Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2018023200 ◽

2018 ◽

Vol 2 (20) ◽

pp. 2607-2618 ◽

Cited By ~ 11

Author(s):

Tilmann Bochtler ◽

Maximilian Merz ◽

Thomas Hielscher ◽

Martin Granzow ◽

Korbinian Hoffmann ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Clonal Evolution ◽

Statistical Significance ◽

Hematologic Malignancies ◽

Absolute Difference ◽

Plasma Cell Dyscrasia ◽

Al Amyloidosis ◽

Clone Size

Abstract Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.

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Regular Recreational Physical Activity and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study

Blood ◽

10.1182/blood.v120.21.887.887 ◽

2012 ◽

Vol 120 (21) ◽

pp. 887-887

Author(s):

Roland B. Walter ◽

Sarah A. Buckley ◽

Emily White

Keyword(s):

Physical Activity ◽

B Cell ◽

Plasma Cell ◽

High Intensity ◽

Hematologic Malignancy ◽

Health Benefits ◽

Hematologic Malignancies ◽

Recreational Physical Activity ◽

Plasma Cell Disorders ◽

Reduced Risk

Abstract Abstract 887 Background: Recreational physical activity (PA) provides numerous health benefits, including a reduction in cardiovascular and metabolic diseases and promotion of mental health. Increasing evidence from epidemiological studies also links PA to a reduced risk of major human cancers, particularly those of the colon and breast. On the other hand, previous case-control and cohort studies examining the relationship of PA and incident hematologic malignancies yielded inconsistent results. Given these conflicting findings, we used a large prospective cohort study to examine this association. Patients and Methods: 65,322 men and women aged 50–76 years were recruited from 2000–2002 to the VITamins And Lifestyle (VITAL) study. The PA questionnaire at baseline asked about walking by intensity and two broader categories of activities (mild and moderate/strenuous exercise) by type over the past 10 years. For each activity, a corresponding metabolic equivalent (MET) intensity was assigned. Incident hematologic malignancies (n=666) after study enrollment were identified through December 2009 by linkage to the SEER cancer registry. Hazards ratios (HRs) for total incident hematologic malignancies and cancer subcategories associated with PA averaged over the previous 10 years before baseline were estimated by Cox proportional hazards models. Models were adjusted for age, sex, race/ethnicity, education, smoking, self-rated health, daily fruit and vegetable consumption, body mass index, fatigue, self-reported anemia, and family history of leukemia/lymphoma. Results: After adjustment, there was a decreased risk of hematologic malignancies associated with any PA (HR=0.75 [95% CI: 0.61–0.94]) as well as any moderate/high-intensity activity (HR=0.72 [95% CI: 0.57–0.92]). The reduction in risk was greatest among the physically most active participants, both with regard to number of weekly episodes of activity (>4.8 episodes of all activities per week: HR=0.66 [95% CI: 0.51–0.86], P=0.005 for trend; >3.5 episodes of moderate/high-intensity activities per week: HR=0.60 [95% CI: 0.44–0.82], P=0.002 for trend) and metabolic activity (>13.625 MET of all activities per week: HR=0.71 [95% CI: 0.54–0.92], P=0.029 for trend; >11.2972 MET of moderate/high-intensity activities per week: HR=0.65 [95% CI: 0.48–0.89], P=0.005 for trend), respectively. To address the possibility of reverse causation, i.e. the possibility that study participants were physically less active as a result of a yet undiagnosed hematologic malignancy, we repeated these analyses after exclusion of the 146 incident cases that occurred within 2 years of baseline: the reduction in risk of incident hematologic malignancies among the physically most active participants in this study subset was relatively similar to that of the entire study cohort. When we stratified malignancies by WHO disease classification, we found that the association between PA and incident hematologic malignancy was strongest for myeloid neoplasms (HR=0.48 [95% CI: 0.29–0.79] for highest tertile of all PA, P=0.013 for trend; HR=0.40 [0.21-0.77] for highest tertile of moderate/high-intensity PA, P=0.016 for trend). There were also significant associations between episodes of moderate/high intensity PA and incident mature B-cell lymphomas other than chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or plasma cell disorders (>3.5 episodes per week: HR=0.59 [95% CI: 0.36–0.97], P=0.035 for trend) and between episodes of all activities and incident CLL/SLL (>4.8 episodes per week: HR=0.52 [95% CI: 0.26–1.03], P=0.023 for trend). No associations were found with incident plasma cell disorders. Conclusion: Our study offers the strongest epidemiological evidence to date to suggest that regular recreational PA is associated with a dose-dependently reduced incidence of certain hematologic malignancies, with a greater than 50% reduction of risk for the development of neoplasms of myeloid origin for individuals within the top tertile of all or moderate/high-intensity activities. Our data also suggest a trend toward reduced risk for CLL/SLL and other mature B-cell NHLs except plasma cell disorders, although further studies in larger cohorts of participants will be required to assess these associations further. Together, our findings may thus suggest additional important health benefits attributable to regular PA. Disclosures: No relevant conflicts of interest to declare.

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Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders

British Journal of Haematology ◽

10.1111/bjh.15003 ◽

2017 ◽

Vol 180 (1) ◽

pp. 71-81 ◽

Cited By ~ 13

Author(s):

Brad Foulk ◽

Mike Schaffer ◽

Steve Gross ◽

Chandra Rao ◽

Denis Smirnov ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Myeloma Cells ◽

Plasma Cell Disorders

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

Blood ◽

10.1182/blood-2021-153209 ◽

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.

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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 ◽

10.1182/blood-2018-99-118185 ◽

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.

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Clinical implication of PET/CT and skeletal bone survey in evaluation of multiple myeloma and related monoclonal disorders.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18574 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18574-e18574

Author(s):

Muhammad Jawad Popalzai ◽

Homam Alkaied ◽

Maryah Mansoor ◽

Arnold Brenner ◽

Qun Dai

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Skeletal Survey ◽

Whole Body ◽

Bone Lesions ◽

Positive Finding ◽

Pet Ct ◽

Plasma Cell Disorders ◽

Smoldering Myeloma

e18574 Background: Whole body skeletal x-ray is considered a gold standard for detecting bone lesions in patients with plasma cell disorders. PET/CT has been increasingly used but its role is yet to be defined. We conducted this study to compare the role of these two imaging modalities in evaluation of plasma cell disorders. Methods: This is single institution, retrospective study to evaluate the role of skeletal survey and PET/CT in patients with multiple myeloma, smoldering myeloma and MGUS. Patients’ records, imaging reports and subsequent management plan were reviewed and compared. Results: A total of 16 patients were reviewed. Among them, 11 patients had multiple myeloma, 2 had smoldering myeloma, and 3 had MGUS. 7/11 patients with multiple myeloma had concordant findings on skeletal survey and PET. 3 of these patients had negative skeletal surveys but had positive finding on PET/CT. PET/CT also identified plasmacytomas in 2 patients. In 2 patients with smoldering myeloma, both skeletal survey and PET/CT were negative. 2/3 patients with MGUS had lytic lesions on skeletal surveys which were not revealed by subsequent PET/CT’s. Both patients were observed without treatment and at 2 years follow up did not show disease progression. Conclusions: Our retrospective analysis showed that skeletal survey is still important for base-line evaluation of bone lesions in multiple myeloma and related monoclonal disorders. PET/CT is more sensitive for detection of bone lesions and can also detect extraosseous lesions such as plasmacytomas. Using tumor metabolic activity, PET/CT may improve diagnostic accuracy and is complementary to conventional skeletal survey. [Table: see text]

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