SWOG S0120 Observational Trial for MGUS and Asymptomatic Multiple Myeloma (AMM): Imaging Predictors of Progression for Patients Treated At UAMS,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3955-3955
Author(s):  
Christoph Heuck ◽  
Rachael Sexton ◽  
Madhav Dhodapkar ◽  
Qing Zhang ◽  
Saad Usmani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Research Funding ◽  
Cox Regression ◽  
Time Dependent ◽  
M Protein ◽  
Risk Scores ◽  
Imaging Studies ◽  
Focal Lesions ◽  
Pet Ct

Abstract Abstract 3955 Background: MGUS counts for the majority of monoclonal gammopathies and can be found in approximately 3% of adults older than 50 years. MGUS progresses to active Multiple Myeloma (MM) at a rate of 1–2% per year, thus imparting an average risk of 25% for progression (PRO) over a lifetime once diagnosed. Unfortunately no single laboratory, molecular or imaging variable can reliably predict PRO. S0120 accrued 363 patients at 69 sites across the US between January 1, 2004 and November 1, 2011, of whom 166 had MGUS and 190 AMM, defined according to IMWG criteria, on whom laboratory, gene expression and imaging studies were collected in a prospective fashion. Here we report the results of imaging studies as predictors of progression. Methods: 262 patients with evaluable follow-up were enrolled at the University of Arkansas for Medical Sciences (UAMS) site. MRI and PET-CT studies were performed at baseline and serially thereafter until PRO to symptomatic MM defined by standard variables of M-protein, bone marrow findings and CRAB criteria, according to protocol. Lab studies were performed at three months, six months and one year after registration, then every 12 months for a total of 5 years from registration as well as within 14 days of decision to discontinue observation or within 14 days of progression. MRI parameters included the number of focal lesions (FL) recognized by short TI inversion recovery (STIR) analysis of the axial bone marrow along with an account of bone marrow background intensity compared to adjacent muscles (hypo-, iso-, hyper-intense). PET-CT parameters included number of FDG-avid focal lesions (PET-FL), SUVmax of PET-FL, presence of extra-medullary disease (EMD) as well as the FDG avidity score at L5 (SUV-L5). Evaluable baseline MRI and PET studies were available for 235 and 224 patients, respectively. Results: In the 262 eligible patients enrolled and followed at UAMS, the two subgroups of MGUS and AMM differed by definition in M-protein and bone marrow plasmacytosis; in addition, IgA subclass and Hyperdiploidy molecular subgroup were overrepresented in the AMM group. Patients in the AMM group also had higher risk scores defined by the GEP 70-gene risk model (GEP70). At 24 months from study entry, 18.8% of all patients had progressed to MM (25.6% of AMM patients and 8.2% of MGUS patients) and 11.5% had begun MM therapy (15.8% of AMM patients and 4.5% of MGUS patients). Univariate Cox regression strongly indicated that age ≥ 65, serum albumin <3.5g/dL, B2M >+3.5mg/L, detection of any cytogenetic abnormalities (CA), and suppression of uninvolved light chains were adversely associated with time to PRO. The AMM-constituting features, bone marrow plasmacytosis >10%, M-protein >30g/L, and abnormal K/L ratio also conferred greater hazard of PRO. Risk scores > −0.26 and >1.5 for GEP70 and GEP80, respectively, as well as detection of focal lesions by MRI at baseline carried an elevated HR for PRO. A multivariate Cox regression showed only elevated M-protein, abnormal K/L ratio and GEP70 risk scores > =0.26 to be strongly associated with time to PRO. In the context of this MV model, disease subtype (AMM v MGUS) was insignificant. Inclusion of development of MRI-FL or and PET-FL as time-dependent variables showed that they were associated with time to PRO with HRs of 27.12 and 32.18 respectively. Abnormal K/L ratio and elevated M-protein were lost in this MV model. Analyzing variables linked to initiation of MM therapy, abnormal K/L ratio, elevated BM plasmacytosis, elevated M-protein, GEP70 risk scores >-0.26 as well as detection of MRI-FL at baseline (≥1 FL: HR=4.90; ≥3FL: HR=10.00) were univariately significant. On multivariate analysis, abnormal K/L ratio, elevated M-protein and GEP70 risk scores > – 0.26 were associated with time to treatment for MM. Inclusion of development of MRI-FL or PET-FL as a time dependent variable were associated with time to treatment with HRs of 29.12 and 36.50 respectively. Conclusion: To our knowledge, this is the first comprehensive effort that has used available imaging modalities along with established laboratory and pathology investigations in an attempt to distinguish features predictive of PRO from MGUS to active MM. In addition to the established “high-risk” MGUS/AMM features, we found that presence of MRI-FL at baseline, presence of CA and GEP70 scores >-0.26 carry a higher risk of PRO. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

scholarly journals Extracting Prognostic Molecular Information from PET-CT Imaging of Multiple Myeloma Using Radiomic Approaches

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1906-1906
Author(s):  
Christopher Wardell ◽  
Terri Lynn Alpe ◽  
Phil Farmer ◽  
Michael W Rutherford ◽  
Yan Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Somatic Mutations ◽  
Ct Scans ◽  
Focal Lesions ◽  
Advisory Committees ◽  
Pet Ct ◽  
Ngs Data

Abstract Introduction: Invasive bone marrow sampling is used in multiple myeloma (MM) diagnosis to obtain biological material, which can then be used to generate prognostically important genetic features. Physically sampling the bone marrow can be uncomfortable for the patient. Also, spatial heterogeneity is a common feature in MM, with multiple focal lesions (FLs) occurring throughout the skeleton, meaning a single sample from the iliac crest may be insufficient to capture intrapatient heterogeneity. An alternative strategy is to extract data directly from diagnostic positron emission tomography-computed tomography (PET-CT) scans of patients. These radiomic features can be used as a proxy from which to infer molecular and clinical phenotypes. Compared to physical sampling, there are several advantages, including rapid analysis, minimalizing patient discomfort, reduced cost and widespread availability of the required scanning equipment in hospitals. Methods: A series of 439 newly diagnosed MM patients were selected, all of which had diagnostic PET-CT scans. A radiologist examined these data and identified focal lesions in the axial skeleton of 136/439 (31%) patients. Focal lesions were manually segmented from the PET portion of the original DICOM data using a density-based thresholding method in 3DSlicer version 4.9.0. Pyradiomics version 1.3 was used to resample the voxels in the PET data to 4x4x4 mm and extract radiomic features from each FL. A combination of 10 filters and 7 feature classes were used and a total of 1679 radiomic features were generated per lesion. Radiomic features were a mixture of first order characteristics such as maximum intensity, shape characteristics and gray level matrix features. Hierarchical clustering was applied to the radiomic features, using the Pearson correlation between features as the distance metric and Ward's method for clustering. Next generation sequencing (NGS) data was available for samples from 58/136 (43%) patients with FLs in whole genome (WGS), whole exome (WES) or targeted panel (TP) modalities. The NGS data was used to detect translocations, copy number aberrations and somatic mutations. Results: There were 789 FLs identified in 136 patients, with each patient containing an average of 5.8 FLs. The median FL volume was 4350 mm3, with a median maximum 3D diameter of 29 mm. Hierarchical clustering across all FLs and radiomic features separated the FLs into 5 discrete clusters associated with various clinical and molecular features. However, clustering appeared to be independent of other classification systems based on gene expression profiling (GEP), including the UAMS classification system and GEP70 risk score. Clustering was also independent of the International Staging System (ISS) status suggesting that it can add additional prognostic information. Clusters also appeared to be independent of somatic mutations in genes previously reported as significantly mutated in MM. Patients commonly had FLs occurring in multiple clusters, suggesting that this method takes into account the heterogeneity between lesions in the same patient. Larger FLs were grouped primarily into two clusters consistent with them having distinct features that can be recognized by this approach. Looking across the different clusters distinct differences in clinical outcome were seen between the groups, with significant differences in both PFS (p=0.007) and overall survival (p=0.005), with worse prognosis being led by a cluster of smaller lesions. Conclusions: Radiomics provides a novel method to extract potentially important data from PET-CT scans which can define individual clusters that have different clinical, molecular and prognostic features. This can provide a novel non-invasive method to assess FLs based on both their physical and radiomic characteristics. Larger study sizes will be needed to confirm the differences in outcomes seen between groups. Disclosures Boyle: Celgene: Honoraria, Other: travel grants; Janssen: Honoraria, Other: travel grants; La Fondation de Frace: Research Funding; Abbvie: Honoraria; Amgen: Honoraria, Other: travel grants; Gilead: Honoraria, Other: travel grants; Takeda: Consultancy, Honoraria. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Davies:TRM Oncology: Honoraria; MMRF: Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria.

scholarly journals Evaluation of Whole-Body MRI (WB-MRI) in Smoldering Multiple Myeloma (SMM)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Elizabeth Hill ◽  
Baris Turkbey ◽  
Evrim Turkbey ◽  
Candis Morrison ◽  
Peter Choyke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Fdg Pet ◽  
High Sensitivity ◽  
Focal Lesions ◽  
Pet Ct ◽  
18F Fdg ◽  
Whole Spine ◽  
Fdg Pet Ct ◽  
Spine Mri

Introduction Whole-body magnetic resonance imaging (WB-MRI), including multiplanar multisequence technique with diffusion weighted images, is a novel imaging technique being evaluated for patients with multiple myeloma (MM). WB-MRI is ideal for this population due to its high sensitivity for bone marrow signal changes and full anatomic coverage from vertex to mid-thighs. It is well established that patients with unequivocal focal lesions on MRI have worse outcomes. Currently the IMWG recommends that all patients with smoldering multiple myeloma (SMM) undergo WB-MRI (or whole spine MRI if WB-MRI is not available) to rule out two or more focal lesions which would classify the patient as having symptomatic myeloma requiring treatment. There is a clear benefit of using MRI for the detection of early focal myeloma lesions however less is known about findings in the SMM population. Detection of subtle findings such as one small focal lesion or heterogeneous bone marrow in WB-MRI has unknown clinical significance that needs to be further evaluated. This study aimed to evaluate the sensitivity of WB-MRI compared to other highly sensitive functional imaging modalities in patients with SMM both at baseline and after treatment. Methods Imaging of patients with WB-MRI performed at the National Institutes of Health Clinical Center Myeloma Program were reviewed and compared to whole spine MRI and 18F-FDG PET/CT completed at the same timepoint. The majority of patients were being evaluated for enrollment on clinical trials. Patients had undergone a WB-MRI with a 3-Tesla system either as a baseline study, after completion of induction treatment, or during follow up determined by the time DWI became available at our institution. The imaging protocol included sagittalT1 weighted (W) and Short tau inversion recovery (STIR) for spine and coronal, axial T1W and axial T2 TSE pulse sequences. The functional component included diffusion weighted imaging in the axial plane (b=0 and 900sec/mm2). Radiological interpretation was performed by two readers using myeloma response assessment and diagnosis system (My-RADS) {Messiou, 2019 #340}. WB-MRIs were categorized as positive if focal lesions or diffuse/heterogenous pattern of bone marrow infiltration were present. Similarly, 18F-FDG PET/CTs and whole spine MRIs were classified as positive if focal lesions or diffuse/heterogenous pattern of bone marrow were present. Results A total of 34 patients with SMM and 5 patients with relapsed refractory multiple myeloma (RRMM) had sequential WB-MRI and 18F-FDG PET/CT. Figure 1 summarizes the radiological data of the SMM population. Eleven of these patients had PET/CT, whole spine MRI, and WB-MRI at baseline. Twenty-five patients had PET/CT and WB-MRI completed after at least 8 cycles of treatment. Thirteen patients had consistently negative imaging at baseline, 7 of which also had negative imaging after treatment, while 2 patients were found to have new lesions seen on WB-MRI after treatment. Six patients had resolution of positive imaging seen at baseline after treatment. Among the 17 patients with a positive WB-MRI, 12 (71%; 95% CI 47% - 87%) had a negative correlating PET/CT. Among 5 patients with positive PET/CT at the same time point as a WB-MRI, only 1 (20%; 95% CI 2% - 64%) correlated to a negative WB-MRI. Figure 2 depicts findings from patients with RRMM for comparison. All imaging modalities showed multiple focal findings in all 5 patients. Conclusions This study depicts the high sensitivity of WB-MRI in the SMM population. Such a high sensitivity is especially needed in SMM and early myeloma when disease burden is lower and the decision for treatment is being considered. In comparison to the RRMM population where all three imaging modalities easily detect multiple focal lesions, WB-MRI tends to identify myeloma involvement in the SMM patients more than the other imaging techniques. This suggests the importance of utilizing WB-MRI when diagnosing SMM. In the SMM population, the prognostic significance of lesions that are discrepant between MRI and FDG PET/CT is not yet known. Further follow up is needed to evaluate any difference in hard endpoints such as progression free survival between patients with positive findings described by WB-MRI. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prevalence of Smoldering Multiple Myeloma: Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 151-151
Author(s):  
Sigrun Thorsteinsdottir ◽  
Gauti Kjartan Gislason ◽  
Thor Aspelund ◽  
Sæmundur Rögnvaldsson ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Population Based ◽  
M Protein ◽  
Screening Study

Abstract Background Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). Emerging data from clinical trials indicate that - compared to watchful monitoring - initiation of therapy at the SMM stage might be indicated. Currently, there is no established screening for SMM in the general population and therefore patients are identified incidentally. Here, we define for the first time, epidemiological and clinical characteristics of SMM in the general population based on a large (N&gt;75,000) population-based screening study. Methods The iStopMM study (Iceland Screens Treats or Prevents Multiple Myeloma) is a nationwide screening study for MM precursors where all residents in Iceland over 40 years of age and older were invited to participate. Participants with a positive M-protein on serum protein electrophoresis (SPEP) or an abnormal free light chain (FLC) analysis entered a randomized controlled trial with three arms. Participants in arm 1 continued care in the Icelandic healthcare system as though they had never been screened. Arms 2 and 3 were evaluated at the study clinic with arm 2 receiving care according to current guidelines. In arm 3 bone marrow testing and whole-body low-dose CT (WBLDCT) was offered to all participants. SMM was defined as 10-60% bone marrow plasma cells on smear or trephine biopsy and/or M-protein in serum ≥3 g/dL, in the absence of myeloma defining events. Participants in arm 3 were used to estimate the prevalence of SMM as bone marrow biopsy was performed in all participants of that arm when possible. The age- and sex-specific prevalence was determined with a fitted function of age and sex, and interaction between those. Diagnosis at baseline evaluation of the individuals in the study was used to define the point prevalence of SMM. Results Of the 148,704 individuals over 40 years of age in Iceland, 75,422 (51%) were screened for M-protein and abnormal free light chain ratio. The 3,725 with abnormal screening were randomized to one of the three arms, and bone marrow sampling was performed in 1,503 individuals. A total of 180 patients were diagnosed with SMM, of which 109 (61%) were male and the median age was 70 years (range 44-92). Of those, a total of 157 (87%) patients had a detectable M-protein at the time of SMM diagnosis with a mean M-protein of 0.66 g/dL (range 0.01-3.5). The most common isotype was IgG in 101 (56%) of the patients, 44 (24%) had IgA, 2 (1%) had IgM, and 5 (3%) had biclonal M-proteins. A total of 24 (13%) patients had light-chain SMM. Four patients (2%) had a negative SPEP and normal FLC analysis at the time of SMM diagnosis despite abnormal results at screening. A total of 131 (73%) patients had 11-20% bone marrow plasma cells at SMM diagnosis, 32 (18%) had 21-30%, 9 (5%) had 31-40%, and 8 (4%) had 41-50%. Bone disease was excluded with imaging in 167 (93%) patients (MRI in 25 patients, WBLDCT in 113 patients, skeletal survey in 27 patients, FDG-PET/CT in 1 patient), 13 patients did not have bone imaging performed because of patient refusal, comorbidities, or death. According to the proposed 2/20/20 risk stratification model for SMM, 116 (64%) patients were low-risk, 47 (26%) intermediate-risk, and 17 (10%) high-risk. A total of 44 (24%) had immunoparesis at diagnosis. Using the PETHEMA SMM risk criteria on the 73 patients who underwent testing with flow cytometry of the bone marrow aspirates; 39 (53%) patients were low-risk, 21 (29%) patients were intermediate-risk, and 13 (18%) patients were high-risk. Out of the 1,279 patients randomized to arm 3, bone marrow sampling was performed in 970, and 105 were diagnosed with SMM (10.8%). The prevalence of SMM in the total population was estimated to be 0.53% (95% CI: 0.49-0.57%) in individuals 40 years of age or older. In men and women, the prevalence of SMM was 0.70% (95% CI: 0.64-0.75%) and 0.37% (95% CI: 0.32-0.41%), respectively, and it increased with age in both sexes (Figure). Summary and Conclusions Based on a large (N&gt;75,000) population-based screening study we show, for the first time, that the prevalence of SMM is 0.5% in persons 40 years or older. According to current risk stratification models, approximately one third of patients have an intermediate or high risk of progression to MM. The high prevalence of SMM has implications for future treatment policies in MM as treatment initiation at the SMM stage is likely to be included in guidelines soon and underlines the necessity for accurate risk stratification in SMM. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Janssen: Other: IDMC; Celgene: Research Funding; Takeda: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

scholarly journals Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3359-3359 ◽  
Author(s):  
Philippe Moreau ◽  
Michel Attal ◽  
Lionel Karlin ◽  
Laurent Garderet ◽  
Thierry Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Whole Body ◽  
High Dose ◽  
High Dose Therapy ◽  
Focal Lesions ◽  
Diffuse Infiltration ◽  
Dose Therapy ◽  
Pet Ct

Abstract Introduction Magnetic resonance imaging (MRI) of the spine and the pelvis is an important tool to evaluate bone disease in patients with symptomatic multiple myeloma (MM) at the time of diagnosis. In the context of high-dose therapy and autologous stem cell transplantation (ASCT), it has also been reported that the number of MRI focal lesions (> 7) and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol; 25:1121-1128 2007). MRI might help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron emission tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting. Moreover, imaging techniques have rarely been compared to minimal residual disease (MRD) evaluated by flow cytometry from bone marrow aspiration in the context of frontline therapy including novel agents and ASCT. The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT. Patients and methods In the prospective IFM-DFCI 2009 trial, 700 patients with de novo symptomatic MM eligible for high-dose therapy have been randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by high-dose therapy and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134 / 700 patients were also included in the IMAJEM trial (NCT01309334, also supported by STIC program granted by the French NCI) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging negativity, secondary end-point). PET-CT and MRI results before maintenance were also compared with MRD assessed by 8-color flow cytometry. MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field. Results At diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p-value = 0.33). MRI patterns of marrow involvement were the following: (1) normal in 7 cases (5%); (2) focal lesions (FL) in 46 cases (34%); (3) homogeneous diffuse infiltration in 41 cases (31%); (4) combined diffuse infiltration and FL in 35 cases (26%); and (5) variegated or "salt-and-pepper" pattern with inhomogeneous bone marrow with interposition of fat islands in 5 cases (4%). PET-CT patterns were the following: (1) normal in 12 cases (9%); (2) FL in 44 cases (33%); (3) diffuse infiltration in 12 cases (9%); (4) combined diffuse infiltration and FL in 66 cases (49%); (5) extramedullary disease in 10 cases (7.5%). The median number of FL assessed by PET-CT was 3. Conclusion MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis. The prognosis relevance of both MRI and PET-CT, and the comparison with MRD assessed by flow cytometry will be presented at the meeting. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Janssen: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:Celgene Corporation: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

scholarly journals The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Elizabeth Hill ◽  
Neha Korde ◽  
Candis Morrison ◽  
Alexander Dew ◽  
Ashley Carpenter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Clinical Trials ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Data Monitoring ◽  
Independent Data ◽  
Genetics Research ◽  
Pet Ct

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.

scholarly journals Using Current Clinical Markers to Define High Risk Smoldering Multiple Myeloma: Agree to Disagree

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1794-1794
Author(s):  
Elizabeth Hill ◽  
Neha Korde ◽  
Sham Mailankody ◽  
Candis Morrison ◽  
Alexander Dew ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
M Protein ◽  
Advisory Committees ◽  
Rate Of Progression

Introduction Defining high risk (HR) smoldering multiple myeloma (SMM) is becoming increasingly important as multiple clinical trials are actively investigating the role of early treatment. On average, patients with SMM progress to multiple myeloma (MM) at a rate of 10% per year for the first 5 years (Kyle 2007). Several classification systems have been developed to identify patients with a higher rate of progression, including two commonly used models: the 2008 Mayo Clinic model and the PETHEMA (Programa de Estudio y Tratamiento de las Hemopatias Malignas) model. The 2008 Mayo Clinic model incorporates M-protein (>3 g/dL), bone marrow plasma cell percentage (BMPC%) >10%, and a ratio of involved to uninvolved serum free light chains (sFLCr) >8. Patients with all three characteristics had a 76% risk of progression to MM in 5 years (Dispenzieri 2008). The PETHEMA model uses the proportion of BMPCs with aberrant plasma cell phenotype on flow cytometry (>95%) and reduction in uninvolved immunoglobulins (immunoparesis) to identify HR patients. Patients with both risk factors had a 5-year rate of progression to MM of 72% (Perez-Persona 2007). The 2008 Mayo Clinic model was validated prior to the International Myeloma Working Group reclassification of MM in 2014. Therefore, in 2018, Mayo Clinic proposed a new model to define HR SMM referred to as "2/20/20": M-protein >2 g/dL, BMPC% >20%, and sFLCr >20 (Lakshman 2018). The median time to progression for the HR group (2-3 risk factors) was 29 months, compared to 110 months in the low risk (LR) group (0 risk factors). Previously, a high discordance rate among the 2008 Mayo model and the PETHEMA model was reported (Cherry 2013). In this study, we aim to define the concordance among patients defined as HR SMM by the aforementioned models in an independent sequential patient cohort. Methods The medical records of patients sequentially assigned a diagnosis of SMM by the myeloma program at the NIH Clinical Center between April 2010 to July 2019 were reviewed. Patients with myeloma defining events were excluded (i.e. MM). Each patient was assigned a risk score based on the 2008 Mayo Clinic model, the 2018 Mayo Clinic model, and the PETHEMA model. The distribution of patients in the LR, intermediate (IR), and HR groups were compared between the models. Concordance ratios were calculated between the three models. Results A total of 236 patient records were reviewed and per the 2014 IMWG criteria, 138 patients were identified as having SMM. Two patients did not have bone marrow flow cytometry samples and thus could not be classified by the PETHEMA model. Therefore, 136 patients were stratified by risk based on all three models (Table 1,2). The rate of concordance between the 2008 Mayo Model and the PETHEMA model was 31.6% (95% CI: 24.4-39.8%), similar to previously published results. The concordance between the 2018 Mayo Model and the PETHEMA model was slightly higher at 44.8% (95% CI: 36.7-53.2%; P=0.0337). There was significant discordance between the models in classifying patients as HR versus non-HR (Table 3). However, the 2018 Mayo Clinic model had a higher concordance with the PETHEMA model (27.2%; 95% CI: 20.4-35.3%) than the 2008 Mayo Clinic model (4.4%; 95% CI:1.8-9.5%). Conclusions The accurate identification of SMM patients at highest risk of developing MM remains elusive and no one model has been found to be superior than the other. As this study indicates, a significant number of patients may be classified as "HR" according to the PETHEMA model while simultaneously be defined as "LR" based on the Mayo Clinic models. While the 2018 Mayo Clinic model has a higher concordance rate to the PETHEMA model, it remains significantly discordant. These results indicate that the current clinical variables used to determine risk are not reliable. This is likely due to the fact that they are markers of disease burden rather than biology and risk is subject to increase over time (Landgren 2019). It is time for genomic signatures which signify varying biology to be incorporated into risk models. The treatment of HR SMM is currently being investigated in multiple clinical trials. As the results from these trials are published, the data will need to be scrutinized as to how patients were defined as "HR" in order to compare results. At this time, it remains unclear which patients warrant early intervention and it is imperative that patients with SMM be exclusively treated on clinical trials. Disclosures Mailankody: Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Merck: Other: IDMC; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; 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: 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; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Prospective Evaluation of 18-F FDG PET/CT and Biopsies of Osteolytic Lesions and Random Bone Marrow Samples in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3180-3180
Author(s):  
Sandra Sauer ◽  
Christos Sachpekidis ◽  
Simone Brandelik ◽  
Daniel Spira ◽  
Stefanie Huhn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Iliac Crest ◽  
Median Number ◽  
Advisory Board ◽  
Whole Body ◽  
Focal Lesions ◽  
Pet Ct ◽  
18F Fdg

Abstract Background The degree of plasma cell (PC) infiltration in the bone marrow (BM) is an important diagnostic and prognostic marker in multiple myeloma. An infiltration of 60% or more has been included into the new criteria of the IMWG defining myeloma. PC infiltration can vary significantly within and among individual patients regarding growth patterns (focal, diffuse or mixed), bone destruction (best visible in CT), which may or may not be concomitantly present, and levels of PC metabolism (best detected by PET). Usually, BM examinations are performed by random biopsy and aspirate from the pelvis. It is up for debate whether the PC infiltration at this location is representative for the whole BM compartment or merely represents a local picture detail of the disease. In this prospective study we evaluated PC infiltration of osteolytic lesions (OL) and random BM biopsies and aspirates (RA) at the iliac crest with local parameters whole-body imaging with PET/CT. Patients and Methods 64 transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) were enrolled in this ongoing prospective study to investigate the genetic heterogeneity of malignant cells from OL in different parts of the BM compared with a RA of the pelvis. Target OLs were identified by low-dose whole-body CT scan. Sample pairs (n=64) were obtained by CT-guided biopsies of OLs as well as simultaneous RAs of the iliac crest at diagnosis and before maintenance therapy (n=19). To analyze differences between PC infiltration of the BM in RA compared to OL, we performed immunohistochemistry (IHC) on trephines of the iliac crest and on samples from OL. Whole-body 18F-FDG PET/CT was performed at diagnosis (n=53) and before initiation of maintenance therapy (n=42) assessing PET/CT characteristics like uptake patterns, number of focal lesions, maximal Standardized Uptake Value (SUVmax) of the respective lesion, SUVmax of normal BM as reference and delta SUVmax (SUVmax lesion-SUVmax reference) at diagnosis and before maintenance therapy. Results and Discussion: At baseline, samples from OLs were obtained in the pelvis (47 patients), in the spine (18) or in the extremities (4). PET/CT at diagnosis showed 3 different infiltration patterns: focal lesions in 11 patients, diffuse infiltration in 11 patients, and a mixed pattern in 31 patients. The median number of focal lesions per patient was 7 (range, 0 to >20). PET/CT-detectable lesions were most frequent in patients with a mixed pattern (median, 8 OL, 14/31 patients had >10 lesions). Patients with a focal pattern had a median number of 3 focal lesions; only one patient had >10 OLs. Interestingly, the number of PET/CT-detectable focal lesions at diagnosis neither correlates with ISS stage of the patients nor with their response to therapy. At diagnosis, PC infiltration in OL was significantly higher in comparison to PC in random samples of the iliac crest (p=0.001). In 23 of 36 patients with a PC percentage in OL >=60%, the respective PC infiltration in RA of the iliac crest was <60%. The size of lesions (max. axial diameter measured in the accompanying CT scan) correlated with the extent of PC infiltration in IHC of OL (p=0.00014). However, comparing estimates of cellularity in CT and PET/CT, neither Hounsfield units (HU) nor SUV showed any correlation with PC infiltration of OL samples. In a preliminary follow-up analysis of 19 patients, neither PC infiltration, size, HU nor SUV of OL showed any significant association with the outcome seen at the time of imaging analysis. However, our analysis showed that after induction therapy and ASCT, 9 of 10 patients with remaining PET-CT-detectable, 18F-FDG avid OLs would progress within 12 months (90%, 4 patients with focal, 6 patients with mixed patterns at baseline). Conclusion Our data suggests that the routine assessment of PC infiltration in RA of the iliac crest might underestimate the degree of PC infiltration in the whole skeleton of NDMM. PC infiltration correlated significantly with the size of the lesion in CT but neither with HU nor SUVmax of OL in PET-CT. This raises the question whether the imaging techniques being used will pick up signatures of non-viable tumor, such as necrotic tissue or inflammation, instead of or in addition to malignant plasma cells. Interestingly, patients with PET-detectable, 18F-FDG avid residual lesions after therapy were at high risk of progression within 12 months. Disclosures Goldschmidt: Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Chugai: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; ArtTempi: Honoraria. Hillengass:Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; Sanofi: Research Funding; BMS: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; amgen: Consultancy, Honoraria, Other: Advisory Board.

scholarly journals Low-Dose 28-Day Metronomically Scheduled Therapy (METRO) for Newly Diagnosed High-Risk Multiple Myeloma: A Pilot Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5770-5770
Author(s):  
Rashid Z Khan ◽  
Yogesh Jethava ◽  
Xenofon Papanikolaou ◽  
Caleb K Stein ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Focal Lesions ◽  
Advisory Committees ◽  
Pet Ct ◽  
Metronomic Therapy ◽  
Total Therapy

Abstract Introduction: Gene expression profiling (GEP)-defined high-risk de novo multiple myeloma (HI-MM) has a dismal prognosis with median PFS and OS stagnating at 2 and 3 years, respectively, despite the incorporation of novel agents into our Total Therapy (TT) trials. Having seen encouraging results in relapsed-refractory MM with an extended 16-day metronomic therapy (Papanikolaou, Haematologica 2014), we tested this approach in a small cohort of untreated patients with HI-MM. METRO emphasizes targeting neo-angiogenesis and other components of the bone marrow micro-environment while avoiding cytokine surges with recovering hematopoiesis following myelotoxic therapy. Patients and Methods: 10 previously untreated patients with HI-MM, who were either ineligible or unwilling for our Total Therapy protocols received a single cycle of METRO. Therapy comprised of SC bortezomib 1.0mg/m2 (0.8mg/m2 in case of grade >2 peripheral neuropathy) on days 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28 schedule, PO dexamethasone 12mg (8mg in case of prior intolerance of higher dose or diabetes mellitus) on days 1 to 4, 7 to 10, 13 to 16, 19 to 22 and 25 to 28, PO Thalidomide 100mg (50mg in case of peripheral neuropathy grade >2) and continuous IV infusions of doxorubicin and cisplatin at 1.0mg/m2 daily for 28 days. Cisplatin was dose-reduced for Cr >2mg/dL and omitted for Cr >3mg/dL. Arsenic tri-oxide was given at a fixed dose of 0.01mg/kg on the days after bortezomib. Laboratory monitoring for response and toxicities were done on a Monday-Wednesday-Friday schedule. Maximal responses, based on current IMWG definitions, were measured within 30 days of completion of cycle 1, and at least monthly thereafter. KM curves were current as of 07/31/14. The Institutional Review Board granted permission for our retrospective data review, the results of which are presented here. Results: Patient characteristics included age >=65 in 8, 5 male, 5 female with ISS III in 5 patients. Metaphase cytogenetic abnormalities (CA) were detected in 7 patients. GEP70 based high risk MM was present in all 10 patients, and GEP proliferation (PR) subgroup was dominant in 8 out of 10 patients. All 10 patients achieved at least PR, including 3 qualifying for VGPR and 4 for CR. Bone Marrow responses were equally encouraging in that 8 of 10 patients qualified for complete morphologic negativity including 4 with no minimal residual disease (MRD) by 8-color flow cytometry. Of 8 patients with FDG-avid PET-CT focal lesions, 6 achieved PET-CT CR; all patients showed decreases in SUV-max and SUV-diff (background SUV). Number and/or apparent diffusion coefficient (ADC) mapping of focal lesions and background marrow on diffusion-weighted MRI improved in all 7 evaluable patients. GEP70 risk morphed from high risk to low risk in 3/4 evaluable patients. Pre and post serologic, urinary and radiologic responses are shown in Figure 1. The median follow-up time for the population was 3.2 months (98 days). All 10 patients are alive from 1 to 7 months, and 1 suffered progression (Figure 2). Overall tolerance was good. Non-hematologic grade 3/4 SEs included fatigue, electrolyte abnormalities (20%), dyspnea, hypotension, LE edema and transaminitis (10%). Conclusion: Primary 28-day metronomic therapy is highly effective and well-tolerated in patients with previously untreated HI-MM. Further prospective studies with longer follow-up are currently being devised in an attempt to improve outcomes in this population. Figure 1: Individual responses Figure 1:. Individual responses Figure 2 Figure 2. Figure 3 Figure 3. Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

Gene Expression Profiling (GEP) Analysis of Plasma Cells (PC) Obtained From MRI-Defined Focal Lesions (FL) Under CT-Guided Fine-Needle Aspiration Provides Better Risk Stratification in Patients with Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2896-2896
Author(s):  
Qing Zhang ◽  
Pingping Qu ◽  
Emily Hansen ◽  
Christoph Heuck ◽  
Saad Usmani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Risk Score ◽  
Expression Profiling ◽  
Research Funding ◽  
Risk Scores ◽  
Classification Models ◽  
Focal Lesions ◽  
Molecular Subgroup ◽  
Subgroup Classification

Abstract Abstract 2896 Background: Focal lesions (FL) are a well-recognized consequence of active multiple myeloma (MM), and distinguish it from its antecedent monoclonal gammopathy of undetermined significance (MGUS). We have recently reported on the superior performance of gene expression profiling (GEP) based on random trephine bone marrow aspirate sampling (RS) in distinguishing between 85% of patients with low-risk (LO) MM and 15% with high-risk (HI) MM compared to conventional prognostic variables. MM occasionally presents as macro-focal disease, in which cases RS may be inconclusive because of paucity of malignant cells in the sample. Here we report the comparison of GEP data from paired FL and RS samples from 106 untreated patients. Methods: We identified 106 newly diagnosed patients with paired samples, who were treated on Total Therapy (TT) protocols (3 in TT2, 19 in TT3, 75 in TT4, and 9 in TT5) in our multiple myeloma database. GEP risk scores, molecular subgroup classifications, overall survival (OS), and event-free survival (EFS) were compared and tested with the RS-derived 70-gene risk prediction and molecular subgroup classification models. Results: GEP defined molecular subgroups were correlated in 90 of 106 patients (85%). Looking at GEP-defined risk designation, we found a high degree of correlation between RS and FL samples with 95 of 106 samples showing the same designation (90%). For the 11 patients with divergent GEP designations, 8 (73%) were located at the boundary of the RS GEP risk score cutoff of +0.66 (range +0.43 to +0.84). For these risk designation-divergent patients, FL- but not RS-defined risk determined clinical outcome. Conclusion: Both the 70-gene risk prediction and molecular subgroup classification models can be used in FL-GEP samples. But, more importantly, for patients with RS-GEP risk score close to cutoff boundary (about 14% in our current data sets), FL-GEP provides better risk stratification, suggesting that the FL signal more adequately reflects to disease biology, progression and treatment response in MM. We therefore recommend that, for patients with borderline RS-based GEP risk scores, FL-GEP be used for staging and prognosis assessment in myeloma. Studies are in progress to determine, among multiple FL samples from the same patient, the variability in risk score compared to multiple RS samples. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

DNA Flow Cytometry and Metaphase Cytogenetics Can Predict Progression of Asymptomatic Monoclonal Gammopathies (AMG) to Symptomatic Multiple Myeloma (MM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2915-2915
Author(s):  
Xenofon Papanikolaou ◽  
Sarah Waheed ◽  
Madhav V. Dhodapkar ◽  
Saad Z Usmani ◽  
Christoph Heuck ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Dna Content ◽  
Research Funding ◽  
Statistical Significance ◽  
S Phase ◽  
M Protein ◽  
Clinical Staging ◽  
The Impact

Abstract Abstract 2915 Background: AMG is the most common plasma cell dyscrasia, currently classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM), based on the level of monoclonal immunoglobulin (M-protein), bone marrow plasmacytosis and other criteria defined by the International Myeloma Working Group. While information is available on the impact of clinical variables such as bone marrow plasmacytosis, free light chains, isotype and M-protein on the hazard of progression to symptomatic MM (MM), little is known about the value of the karyotype and DNA content, as determined by DNA/cIg flow cytometry, on the risk of progression from AMG to MM. Methods: Patients from the Myeloma Institute for Research and Therapy (MIRT) with AMG that were enrolled in a prospective observational clinical trial were evaluated. All patients underwent detailed clinical staging at entry and were followed at pre-specified intervals per protocol. Cox proportional hazards regression was used to model univariate and multivariate associations of baseline features with progression to MM. The number of distinct DNA stem lines in the flow cytometry assay, their percentages, respective DNA Indices (DI), cytoplasmic Immunoglobulin Indices (cIgI), and percent of cells in S phase were evaluated alone and in relation to the karyotype report at baseline. A DI between 0.99 and 1.01 referred to diploidy, lesser than 0.99 to hypodiploidy and more than 1.01 hyperdiploidy. Results: Data from 267 eligible MIRT patients with AMG were analyzed. Of these patients 99% (265/267) had performed DNA/cIg flow cytometry and had a karyotype report at diagnosis. Cytogenetic abnormalities were detected in 20 of the 265 patients from whom data were available. From the 265 patients from whom DNA/cIg flow cytometry data were available, no abnormal clones were identified in 14% (37/265), one clone was identified in 95 patients (36%), two clones in 122 patients (46%), three clones in 10 (4%), and in 1 patient 4 clones were identified. Most patients with abnormal DNA content had hyperdiploid clones (132/243 patients). The second most frequent finding was diploid DI, in 39% (104/243) of patients; 3% (7/243) had a hypodiploid DI. The median DI was 1.01 (0.9–2.02) and median cIg was 7 (1–50). Interestingly, the median cIgI value in AMG was more than twice that of its value (3.4, 1–22) in Total Therapy 3 MM patients (p=0.001). In univariate analysis of the parameters in this study, the presence of an abnormal karyotype (p=0.032, HR=2.62), the number of DNA/cIg clones (p=0.016, HR=1.69) and the percentage of the dominant clone (p=0.003, HR=1.03) were significantly related to progression to MM. Ploidy by DNA/cIg analysis, the S-phase fraction, and cIg did not reach statistical significance (p=0.863, p=0.132 and p=0.240, respectively). In multivariate analysis, only the number of abnormal clones (p=0.013, HR=1.78) retained statistical significance, while the percentage of the dominant clone neared significance (p=0.070, HR=1.02). Using running log rank tests we were able to identify optimal cut-points for the percentage of the dominant clone and the number of clones (12% and 2 clones respectively). From these, a risk score was obtained which identifies three distinct groups with 3-yr MM progression probabilities of 12%, 30% and 67% (p<0.001) (Figure 1). Conclusions: Abnormal metaphase cytogenetics and DNA/cIg flow cytometry have a prognostic value in the prediction of progression of AMG to MM. Hyperdiploidy is the dominant finding in AMG, however, its presence or absence does not predict progression. Clonal heterogeneity, as portrayed through DNA/cIg flow cytometry analysis, with the number of abnormal clones and the percentage of the dominant clone were major prognostic factors for progression to MM. Taken together they identify three distinct subgroups with a low (12%), moderate (30%) and high (67%) probability of 3-year time to progression to MM. Disclosures: Dhodapkar: Celgene: Research Funding; KHK: Research Funding.

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