Critical role of PET/CT-based novel quantitative techniques for assessing global disease activity in multiple myeloma and other hematological malignancies: why it is time to abandon reliance on examining focal lesions

To evaluate the role of FDG PET/CT before and after the treatment of multiple myeloma (MM) in our clinical practice, data from 32 patients (before therapy: 10 patients; after therapy: 22 patients) and from 46 examinations (before therapy: 10; after: 36) with a median time of follow-up of 24 months (before the therapy) and 26 months (after the therapy) were evaluated. FDG PET/CT positivity was characterized by SUVmax >2.5, SUVmax >4.2, focal lesions (FLs) >3, and presence of extramedullary disease (EMD). The median progression-free survival (PFS) and the median overall survival (OS) for FDG PET/CT positive patients were shorter than for negative patients, according to all parameters. Before the therapy, significant correlation was found only between PFS and the number of FLs (p = 0.033). After the treatment, significant correlation was found between PFS and SUVmax (cut-off value 2.5: p < 0.001; cut off value 4.2: p < 0.001), between PFS and the number of FLs (p = 0.009), and between PFS and the presence of EMD (p < 0.001). Significant correlation was found between OS and SUVmax (cut-off value = 2.5, p < 0.001 and 4.2, p = 0.009), between OS and the number of FLs (p = 0.007), and between OS and the presence of EMD (p = 0.022). Our results confirmed the reliability and good prognostic value of FDG PET/CT in MM.

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Deep Phenotyping Reveals Distinct Immune Signatures Correlating with Prognostication, Treatment Responses, and MRD Status in Multiple Myeloma

Cancers ◽

10.3390/cancers12113245 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3245 ◽

Cited By ~ 1

Author(s):

Konstantinos Papadimitriou ◽

Nikolaos Tsakirakis ◽

Panagiotis Malandrakis ◽

Panagiotis Vitsos ◽

Andreas Metousis ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Cell ◽

Residual Disease ◽

Critical Role ◽

Induction Treatment ◽

Molecular Characteristics ◽

Limited Information ◽

Incurable Disease ◽

Deep Phenotyping

Despite recent advances, Multiple Myeloma (MM) remains an incurable disease with apparent heterogeneity that may explain patients’ variable clinical outcomes. While the phenotypic, (epi)genetic, and molecular characteristics of myeloma cells have been thoroughly examined, there is limited information regarding the role of the bone marrow (BM) microenvironment in the natural history of the disease. In the present study, we performed deep phenotyping of 32 distinct immune cell subsets in a cohort of 94 MM patients to reveal unique immune profiles in both BM and peripheral blood (PB) that characterize distinct prognostic groups, responses to induction treatment, and minimal residual disease (MRD) status. Our data show that PB cells do not reflect the BM microenvironment and that the two sites should be studied independently. Adverse ISS stage and high-risk cytogenetics were correlated with distinct immune profiles; most importantly, BM signatures comprised decreased tumor-associated macrophages (TAMs) and erythroblasts, whereas the unique Treg signatures in PB could discriminate those patients achieving complete remission after VRd induction therapy. Moreover, MRD negative status was correlated with a more experienced CD4- and CD8-mediated immunity phenotype in both BM and PB, thus highlighting a critical role of by-stander cells linked to MRD biology.

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Evolving Role of FDG PET/CT in Multiple Myeloma Imaging and Management

American Journal of Roentgenology ◽

10.2214/ajr.12.9653 ◽

2013 ◽

Vol 200 (4) ◽

pp. 884-890 ◽

Cited By ~ 38

Author(s):

Ankit Agarwal ◽

Alin Chirindel ◽

Bhartesh A. Shah ◽

Rathan M. Subramaniam

Keyword(s):

Multiple Myeloma ◽

Fdg Pet ◽

Pet Ct ◽

Fdg Pet Ct

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The critical role of interleukin-6, interleukin-1B and macrophage colony-stimulating factor in the pathogenesis of bone lesions in multiple myeloma

International Journal of Clinical & Laboratory Research ◽

10.1007/bf02591662 ◽

1992 ◽

Vol 21 (2-4) ◽

pp. 283-287 ◽

Cited By ~ 33

Author(s):

Régis Bataille ◽

Daniel Chappard ◽

Bernard Klein

Keyword(s):

Multiple Myeloma ◽

Interleukin 6 ◽

Critical Role ◽

Bone Lesions ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Update on Risk Stratification Model of Smoldering Multiple Myeloma: A Systematic Review

Blood ◽

10.1182/blood-2019-132260 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5512-5512

Author(s):

Saad Ullah Malik ◽

Ahmad Abu-Hashyeh ◽

Muhammad Sardar ◽

Mohammad M Alhousani ◽

Emilia Cindy Leigh ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Cell Maturation ◽

B Cell Maturation ◽

Smoldering Multiple Myeloma ◽

Pet Ct ◽

M Proteins ◽

Pet Ct Scan ◽

Bence Jones Proteins

Background: Smoldering multiple myeloma (SMM) was stratified into risk classes based on several models including Mayo clinic and Spanish myeloma working group models. After the revision of diagnostic criteria for multiple myeloma (MM) in 2014, the ultra-high risk SMM patients (>80% clonal plasma cells at two years) were re-classified as active MM patients. Thus, predictors of progression in patients currently diagnosed as SMM are unknown and reassessment of existing models is required. We aim to identify the risk factors associated with progression in SMM patients classified according to updated guidelines. Methods We performed a literature search following PRISMA guidelines and used following bibliographic databases: MEDLINE (Ovid and PubMed), EMBASE, The Cochrane Library and Cochrane Central Register of Controlled Trials (CENTRAL), as well as annual meetings abstracts from inception till 1st,August 2019. We used MeSH and Emtree terms as well as performed open search for "smoldering multiple myeloma", "smoldering myeloma", and "asymptomatic multiple myeloma". Two independent reviewers screened the literature. We used snowballing technique to screen abstracts and reference within articles to include titles. Cochrane collaboration tool was used to asses risk of bias among included studies Results Our search retrieved 419 titles. After going through the titles and abstracts 38 articles were selected for full text review. Final review led to inclusion of 11 articles. Levels of serum M proteins, percentage of bone marrow plasma cells (BMPCs), serum free light chain ratio (FLCr) and PET/CT scan findings of whole body were most consistently and reliably indicated the progression of SMM to MM (Table 1). New studies are suggesting that B-cell maturation levels (BCMA), evolving M-proteins (eMP) and evolving hemoglobin levels (eHb) are also an accurate measure of SMM progression and should be incorporated in the risk stratification models. A study by Gonsalves WI et al. also suggested that levels of circulating clonal plasma cells with a cutoff of 150 was an important prognostic marker in their study. Immunoparesis status and role of Bence Jones proteins in reliably predicting the progression of SMM was debatable because they were significant in univariate analysis but were not significant in multivariate analysis (Table 1). Conclusion Serum M protein levels (2 g/dL), percentage of BMPCs (20%), serum FLCr (20) and PET/CT scan were reliable in predicting the prognosis of smoldering MM. New techniques like B-cell maturation levels(74.4 ng/mL), evolving M-proteins and evolving hemoglobin levels can play a significant role in proposing future risk predictive models of SMM. Role of immunoparesis and Bence Jones proteins is debatable. Table 1 Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

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Anti-Leukemia and Multiple Myeloma Selective Activity of CXCR4 Antagonist 4F-Benzoyl-TN14003 Involves Apoptotic Death Pathway.

Blood ◽

10.1182/blood.v114.22.3857.3857 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3857-3857

Author(s):

Katia Beider ◽

Michal Begin ◽

Michal Abraham ◽

Hanna Wald ◽

Ido Weiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Hematological Malignancies ◽

Conflicts Of Interest ◽

K562 Cells ◽

Jurkat Cells ◽

G1 Arrest ◽

Dependent Manner ◽

Hl60 Cells

Abstract Abstract 3857 Poster Board III-793 The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the development and progression of a diverse number of hematological malignancies, including leukemia, lymphoma and multiple myeloma (MM). Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways and effector molecules that regulate cell chemotaxis, adhesion, survival, apoptosis and proliferation. It was previously shown that CXCR4 signaling can directly induce caspase-independent cell apoptosis through the interaction with the HIV gp120 envelope protein. In the present study we investigated the effect of CXCR4 specific antagonists 4F-benzoyl-TN14003 (T140) and AMD3100 on the survival and proliferation of different human hematological cancer cells. Here, we demonstrate that T140, but not AMD3100, exhibits preferential cytotoxicity towards malignant cells of hematopoietic origin, as compared to primary normal cells or solid prostate and breast tumor cells. The in vitro treatment with T140, but not with AMD3100, significantly decreased the number of viable chronic myeloid leukemia K562 cells, acute T cell leukemia Jurkat cells, acute promyelocytic leukemia NB4 and HL60 cells, and four different MM cell lines (U266, NCI-H929, RPMI8226 and ARH77), demonstrating the highest sensitivity to T140 (p<0.01). Notably, T140 inhibited the growth of freshly isolated leukemia and MM cells obtained from consenting patients. T140 inhibits the growth of MM and leukemic cells by inducing their apoptotic cell death. The apoptotic changes in the cells were associated with morphological changes, phosphatidylserine externalization, sub-G1 arrest, DNA double-stranded breaks, decrease in mitochondrial membrane potential, release of cytochrome c, and caspase 3 activation. The important role of CXCR4 in T140-mediated cell death was confirmed by demonstrating that CXCR4 over-expression in NB4 and K562 cells increased their sensitivity to T140. Furthermore, pretreatment of NB4 and HL60 cells with AMD3100 abolishes the effect of T140 on these cells, indicating the involvement of CXCR4 in T140-induced apoptosis. Importantly, the combination with novel anti-myeloma agent bortezomib significantly augments anti-myeloma activity of T140. The anti leukemic and MM effect of T140 was confirmed in xenograft in vivo tumor models. Subcutaneous (s.c.) or intra-peritoneal (i.p.) injections of T140 (100 or 300 mcg/mouse) significantly reduced, in a dose-dependent manner, the tumor size in immuno-deficient mice that were previously inoculated s.c. with human acute leukemia cells NB4 or MM cells RPMI8226 (p<0.01). Tumors from animals treated with T140 had smaller sizes and weights, larger necrotic areas and high apoptotic scores. Taken together, these data support the unique anti-cancer effect of T140 in hematological malignancies and indicate the potential therapeutic role of T140 in MM and leukemia patients. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v118.21.3955.3955 ◽

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.

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Impact Of Initial FGD-PET CT and Serum Free Light Chain On Transformation Of Solitary Plasmacytoma To MM

Blood ◽

10.1182/blood.v122.21.1888.1888 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1888-1888

Author(s):

Guillemette Fouquet ◽

Stéphanie Guidez ◽

Charles Herbaux ◽

Zoé Van de Wyngaert ◽

Sarah Bonnet ◽

...

Keyword(s):

Multivariate Analysis ◽

Solitary Plasmacytoma ◽

Focal Lesions ◽

Serum Free ◽

Serum Free Light Chain ◽

Pet Ct ◽

Fdg Pet Ct ◽

Post Therapy

Abstract Background Solitary plasmacytoma (SP) is characterized by a localized proliferation of monoclonal plasma cells resulting in a mass in either bone (SBP: Solitary Bone Plasmacytoma) or soft tissue (EMP: Extra-Medullary Plasmacytoma), without evidence of Multiple Myeloma (MM). The prognosis of SP is marked by a high risk of transformation to MM. SBP (as compared to EMP), older age, tumor size > 5 cm, and persistence of monoclonal immunoglobulin after treatment were prognostic for progression to MM. More recently, studies demonstrated that presence of focal lesions on magnetic resonance imaging (MRI) favored progression to MM in patients (pts) with plasmacytoma. The exact role of FGD-PET CT (PET) in MM remains debatable, although it clearly provides additional valuable information to assess plasmacytoma in the context of MM, compared with MRI. The prognostic role of PET in identifying progression to MM of SP has not been formally demonstrated. We aimed to determine the impact of PET pre and post therapy on the risk of transformation of SP to overt MM. Method We retrospectively reviewed the medical records of 43 pts diagnosed with one SP clinically, confirmed with histology, either EMP (10 pts) or SBP (33 pts). All pts had one SP clinically, and were treated locally with surgery and/or radiotherapy. PET and MRI were performed at diagnosis prior to (initial) and at the end of therapy. SP was diagnosed as outlined in international consensus criteria. All pts had complete follow up records pre and post therapy. Results The median age was 57.5 years with 33% pts older than 65, the sex ratio was 1.8, IgG kappa was the most frequent isotype, the maximum M-spike value was 30g/L, 48% pts had abnormal involved serum free light chain (isFLC) value and 64% had abnormal sFLC ratio (K/L). 33% had 2 hypermetabolic lesions on initial PET, and 20% had 2 focal lesions on initial MRI. Out of the SBP, 56% were localized on spine or pelvis. With a median follow-up of 50 months (mo), the median overall survival (OS) was not reached for the whole cohort, with a 6-year OS at 79.4%. The median time to MM progression (TTMM) was 71 mo (95%CI: 59;101). The TTMM was not significantly different in SBP versus (vs) EMP although the 5-year TTMM was 58% and 83%, respectively. The TTMM for the 2 hypermetabolic lesions on initial PET group was 23 mo (9;37) vs not reached otherwise (p=0.003). Conversely, MRI at diagnosis did not have any impact on TTMM in our study, although the median TTMM for the 2 focal lesions on initial MRI group was 30 mo (9;51) vs not reached otherwise. Age had no impact on TTMM, but abnormal initial K/L ratio (p=0.022) and abnormal initial isFLC (p=0.002) did impact TTMM, 36 mo (14;58) and 21 mo (0;42) vs not reached otherwise, respectively. A normalized PET at completion of treatment did not reach significance, as to normalized MRI, but the absence of normalized isFLC value also impacted TTMM, 21 mo (10;32) vs not reached otherwise (p=0.016). Using multivariate analysis, independent variables that impacted TTMM were abnormal initial isFLC (OR=10, 95%CI=1-87; p=0.008) and initial PET (OR=5, 95%CI=0-9; p=0.032). Interestingly, initial PET did not influenced OS, median 71 mo for the 2 hypermetabolic lesions on initial PET group vs not reached otherwise, respectively (p=ns). This data suggested that pts with SP that transformed into MM did not have a worse prognostic at time of MM. The median OS of pts with SP from start of MM was not reached, the 4-year OS was 66%. With a special focus on SBP, we identified the exact same prognostic factors for TTMM as to the whole cohort in univariate and multivariate analysis. The localization of SBP in the spine is usually considered of poor prognosis, but we did not find any confirmation of this observation in our study. Conclusion FDG-PET CT and involved sFLC value at diagnosis of SP are important predictors of the risk of progression to MM. This data analysis may lead to a different management of SP for patients with one or the 2 abnormal indicators, irrespective to the solitary clinical aspect of SP. One may consider to embrace treatment of MM for SP when FDG-PET CT and involved sFLC value are abnormal at diagnosis, while surgery and/or radiotherapy would remain the appropriate therapeutic procedure for SP otherwise. Disclosures: Facon: JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Leleu:JANSSEN: Honoraria; CELGENE: Honoraria.

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Development of a new risk stratification system for patients with newly diagnosed multiple myeloma using R-ISS and 18F-FDG PET/CT

Blood Cancer Journal ◽

10.1038/s41408-021-00577-2 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Hee Jeong Cho ◽

Sung-Hoon Jung ◽

Jae-Cheol Jo ◽

Yoo Jin Lee ◽

Sang Eun Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Stratification ◽

Fdg Pet ◽

Survival Rates ◽

Newly Diagnosed ◽

Focal Lesions ◽

Pet Ct ◽

Stratification System ◽

Fdg Pet Ct ◽

Risk Stratification System

AbstractIn multiple myeloma (MM), a high number of focal lesions (FL) detected using positron emission tomography/computed tomography (PET/CT) was found to be associated with adverse prognosis. To design a new risk stratification system that combines the Revised International Staging System (R-ISS) with FL, we analyzed the data of 380 patients with newly diagnosed MM (NDMM) who underwent 18F-fluorodeoxyglucose (18F-FDG) PET/CT upon diagnosis. The K-adaptive partitioning algorithm was adopted to define subgroups with homogeneous survival. The combined R-ISS with PET/CT classified NDMM patients into four groups: R-ISS/PET stage I (n = 31; R-ISS I with FL ≤ 3), stage II (n = 156; R-ISS I with FL > 3 and R-ISS II with FL ≤ 3), stage III (n = 162; R-ISS II with FL > 3 and R-ISS III with FL ≤ 3), and stage IV (n = 31; R-ISS III with FL > 3). The 2-year overall survival rates for stages I, II, III, and IV were 96.7%, 89.8%, 74.7%, and 50.3%. The 2-year progression-free survival rates were 84.1%, 64.7%, 40.8%, and 17.1%, respectively. The new R-ISS/PET was successfully validated in an external cohort. This new system had a remarkable prognostic power for estimating the survival outcomes of patients with NDMM. This system helps discriminate patients with a good prognosis from those with a poor prognosis more precisely.

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