Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

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Clinicopathological and Prognostic Characteristics of CD33-Positive Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.3409.3409 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3409-3409

Author(s):

Naohi Sahara ◽

Kazunori Ohnishi ◽

Takaaki Ono ◽

Yuya Sugimoto ◽

Miki Kobaysahi ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Serum Level ◽

Bone Marrow Cells ◽

Bone Lesion ◽

Prognostic Significance ◽

Clinical Information ◽

Prognostic Indicators ◽

Newly Diagnosed ◽

Β2 Microglobulin

Abstract In multiple myeloma (MM), there have been few reports about the CD33 expression on MM cells so far, showing that a part (6.5–12 %) of patients expressed CD33 on their MM cells. However in these reports, neither detailed clinical information nor its prognostic significance was described. Therefore, we analyzed the CD33 expression on MM cells from newly diagnosed patients by flow cytometry and the correlation with other clinical parameters to determine the clinicopathological significance of this molecule in MM. The CD33 expression on MM cells was studied in the bone marrow from newly diagnosed 63 patients with MM. The median age of the patients was 69 years (range 43–91). The monoclonal component was: IgG in 46%, IgA in 27%, and Bence Jones protein (BJP) in 22% of patients. The patients were distributed according to Durie-Salmon stage, as follows: stage I, 15%; II, 35%; III, 50%. Fifty-five of these patients were treated with either melphalan-prednisolone (n=23) or VMMD with (n=7), or without (n=20) interferon (IFN) a. Four patients were treated with VAD followed by auto-PBSCT. Heparinized bone marrow cells were obtained at diagnosis. Cells were incubated with FITC-labelled anti-CD38, PE-anti-CD13, anti-CD33, anti-CD49e, anti-CD56, Per CP-anti-CD45 or APC-anti-CD19 monoclonal antibody. Cells were gated by their forward and side scatter characteristics and strong CD38 expression (CD38++). An antigen was defined as positive when more than 20 % of MM cells expressed it. Of 63 patients evaluated for CD33 expression, 14 (22%) were positive and 49 (78%) were negative. Of 14 patients with CD33+ MM, more than 80% of MM cells were positive in 6 (9.5%). No significant differences were found between the two groups in terms of age, sex, bone lesion extension, presence of extramedullary involvement, or Durie-Salmon stage. In addition, several prognostic indicators such as the serum level of calcium, creatinine, WBC counts, prevalence of BJP in urine, and chromosomal aberrancies such as del(13q), t(4;14), or t(11;14) were similar in both groups of patients. On the other hand, the serum level of β2 microglobulin and LDH in the CD33+ patients were significantly higher than in the CD33− patients (P=0.002 and 0.001, respectively). In addition, the CD33+ patients had a higher incidence of anemia and thrombocytopenia (P=0.01 and 0.02, respectively). With a median follow up of 18 months, the estimated over all survival was significantly shorter in the CD33+ patients than the CD33− patients (median survival; 18 vs. 38 months, P=0.04). Especially, mortality within a year from diagnosis in the CD33+ patients was significantly higher than the CD33− patients(43 vs. 10 %, respectively, P=0.005). No correlation between CD33 and other surface markers such as CD13, CD45, CD49e, and CD56 was observed. We here found that CD33+ MM patients showed higher serum β2 microglobulin and LDH level and a higher incidence of anemia or thrombocytopenia with poor prognosis. These results suggest that CD33+ MM might be a discrete entity and CD33 might be a useful therapeutic target for these patients.

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MAGE-A3 or NY-ESO1 Expression and Spontaneous Antibody Responses to NY-ESO1 in Newly Diagnosed Multiple Myeloma Patients Are Associated with Worse Overall Survival

Blood ◽

10.1182/blood.v112.11.5110.5110 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5110-5110

Author(s):

Adam D Cohen ◽

Ping Lu ◽

Sacha Gnjatic ◽

James Hoffman ◽

Erika Ritter ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Soft Tissue ◽

Induction Therapy ◽

Plasma Cells ◽

Prognostic Significance ◽

Antibody Responses ◽

Newly Diagnosed ◽

Bone Marrow Plasma

Abstract The cancer-testis antigens (CTA) are highly immunogenic antigens expressed in various tumors but not in normal tissues (except during gametogenesis), making them an attractive target for cancer immunotherapy. Expression of CTAs such as MAGE-A3, MAGE-C1 (CT7), MAGE-C2 (CT10), NY-ESO1 and the SSX antigens has been previously reported in multiple myeloma (MM). To date, however, these reports have included a heterogeneous group of newly diagnosed and relapsed/refractory patients, all in different stages of treatment. Therefore, the extent and prognostic significance of CTA expression, and of de novo immune responses against CTA in newly-diagnosed MM patients are not known. We now report on both CTA expression and antibody responses in MM patients at diagnosis and on their prognostic significance. From 8/00-11/04, we treated 67 newly-diagnosed, symptomatic patients with a thalidomide, doxorubicin, and dexamethasone-based induction regimen. (Brit J Haematol2006;132:155). Median age was 58; 54% were ISS stage I, 28% ISS II, and 18% ISS III. Nine of 63 tested (14%) had deletion 13q by FISH, while 24% had soft tissue involvement by MM. Responses to induction therapy included 10 (15%) CR, 16 (24%) VGPR, 26 (39%) PR, 6 (8%) stable or progressive disease, and 9 (13%) inevaluable. Post-induction 54 underwent autoSCT and 9 also underwent alloSCT.. Median overall survival (OS) has not been reached with 61% alive at median follow up of 65 months. Cryopreserved pre-treatment bone marrow plasma cells were used to assess CTA expression by RT-PCR. Pre- and post-treatment sera were used to assess antibody (Ab) responses against CTA proteins by ELISA. Fifty-two patients had sufficient RNA for PCR, and 46 had baseline serum for ELISA. OS of these groups did not differ significantly from the entire cohort. At least 1 CTA was expressed in 77% of cases, including MAGE-A3 (52%), SSX1 (40%), CT7 (29%), CT10 (25%), NY-ESO1 (21%), and SSX5 (17%). Three or more CTA were expressed in 29% of cases. Individually MAGE-A3 or NY-ESO1 expression at diagnosis conferred a poorer prognosis (MAGE-A3: median OS 66 mos. vs. not reached, p=0.02 by log-rank; NY-ESO1: median OS 65 mos. vs. not reached, p=0.09). These poorer outcomes were independent of ISS stage, presence of del 13q, or response to induction therapy. No other CTA was associated with an OS difference, nor was the total number of CTA expressed prognostically significant. Baseline Ab responses, all at titers > 1:1600, were noted to NY-ESO1 in 6/46 (13%) patients, 5 of whom also had Ab to the NY-ESO1 homologue LAGE-1. Ab responses were also noted to CT7 (n=2), CT10 (n=1) and SSX4 (n=1). No Ab responses were noted to MAGE-A3. The effect of induction therapy on antibody titers was inconsistent, with increases, decreases, and no changes seen. Interestingly, 2 of the 6 NY-ESO1 Ab+ patients had no NY-ESO1 expression in bone marrow plasma cells. Both, however, had extensive soft tissue (ST) plasmacytomas, suggesting another source of NY-ESO1 antigen. Presence of NY-ESO1 Ab correlated significantly with baseline ST involvement, with 67% of Ab+ patients having ST disease compared with 20% of Ab− patients (p=0.05). NY-ESO1 Ab+ patients also had significantly poorer OS (med 21 mos. vs. not reached, p=0.009), independent of other prognostic factors. In sum, CTA expression is frequent in newly diagnosed MM patients, and expression of MAGE-A3 or NY-ESO1 is associated with worse long-term survival. Spontaneous antibody responses against NY-ESO1 are seen in untreated patients, and are associated with ST involvement and poorer survival. Further exploration of biologic differences between CTA+ and CTA-MM, as well as immunotherapeutic strategies which target these antigens, are warranted.

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The prognostic significance of CD45 expression by clonal bone marrow plasma cells in patients with newly diagnosed multiple myeloma

Leukemia Research ◽

10.1016/j.leukres.2016.03.003 ◽

2016 ◽

Vol 44 ◽

pp. 32-39 ◽

Cited By ~ 10

Author(s):

Wilson I. Gonsalves ◽

Michael M. Timm ◽

S.Vincent Rajkumar ◽

William G. Morice ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Prognostic Significance ◽

Newly Diagnosed ◽

Bone Marrow Plasma

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PS1408 PROGNOSTIC SIGNIFICANCE OF CD56 EXPRESSION ON BONE MARROW PLASMA CELLS OF NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS

HemaSphere ◽

10.1097/01.hs9.0000563908.04283.a9 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 647

Author(s):

G. Rivoli ◽

N. Bisso ◽

A. Cagnetta ◽

S. Aquino ◽

M. Bruzzone ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cells ◽

Prognostic Significance ◽

Newly Diagnosed ◽

Bone Marrow Plasma ◽

Cd56 Expression

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Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma

Annals of Oncology ◽

10.1093/annonc/mdi362 ◽

2005 ◽

Vol 16 (11) ◽

pp. 1824-1828 ◽

Cited By ~ 76

Author(s):

L.A. Moulopoulos ◽

D. Gika ◽

A. Anagnostopoulos ◽

K. Delasalle ◽

D. Weber ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Myeloma ◽

Bone Marrow ◽

Magnetic Resonance ◽

Prognostic Significance ◽

Resonance Imaging

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Prognostic significance of esterase gene expression in multiple myeloma

British Journal of Cancer ◽

10.1038/s41416-020-01237-1 ◽

2021 ◽

Author(s):

Romika Kumari ◽

Muntasir Mamun Majumder ◽

Juha Lievonen ◽

Raija Silvennoinen ◽

Pekka Anttila ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

Prognostic Markers ◽

Prognostic Significance ◽

Genomic Variation ◽

High Expression ◽

Genetic Profile ◽

Esterase Gene ◽

Low Expression

Abstract Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P < 0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.

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Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8010 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8010-8010

Author(s):

Noemi Puig ◽

Bruno Paiva ◽

Teresa Contreras ◽

M. Teresa Cedena ◽

Laura Rosiñol ◽

...

Keyword(s):

Mass Spectrometry ◽

Multiple Myeloma ◽

Bone Marrow ◽

Minimal Residual Disease ◽

Peripheral Blood ◽

Prognostic Value ◽

Residual Disease ◽

Newly Diagnosed ◽

Time Points ◽

Minimal Residual

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

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Prognostic Implications of Metabolic Total Volume and Total Lesion Glycolysis Assessed By PET/CT Combined with High Levels of Bone Marrow Plasma Cells Percentages As a Potential Risk Model in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-126784 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3193-3193

Author(s):

Toshiki Terao ◽

Yoichi Machida ◽

Takafumi Tsushima ◽

Akihiro Kitadate ◽

Daisuke Miura ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Risk Stratification ◽

Tumor Volume ◽

Mononuclear Cells ◽

Total Lesion Glycolysis ◽

Whole Body ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Pet Ct

Introduction: Multiple myeloma (MM) is a heterogeneous malignant plasma cell (PC) disorder and the survival ranges from several months to > 10-years. Several risk stratification systems such as the Revised International Staging System (R-ISS) have been developed. PET/CT allows the direct assessment of metabolic tumor burden in various malignancies. Therefore, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), which are volumetric parameters applicable to PET/CT, are emerging tools for MM prognostication. This study was aimed to determine the value of MTV and TLG using PET/CT in the prognostication and in combination with various hematologic parameters such as bone marrow PC (BMPC) percentages and circulating tumorous PCs (CPCs) to identify the patients with high-risk features. Methods: A total of 196 consecutive patients with newly diagnosed MM (NDMM) who underwent baseline whole-body PET/CT between January 2009 and June 2019 at Kameda Medical Center, Kamogawa-shi, Japan, were retrospectively analyzed. PET/CT was performed using dedicated PET/CT scanners (Discovery ST Elite Performance; GE Healthcare, Milwaukee, USA). The standard uptake value (SUV) was normalized according to the injected dose and lean body mass. The baseline SUVmax of all lesions was recorded, and the highest value was considered as the SUVmax of the patient. MTV was defined as the myeloma lesions volume visualized on PET/CT scans with SUV greater than or equal to the fixed absolute threshold of SUV = 2.5. TLG was calculated as the sum of the product of average SUV (SUVmean) and MTV of all lesions. Computer‐aided analysis of PET-CT images for MTV and TLG calculations was performed using an open-source software application of Metavol (Hokkaido University, Sapporo, Japan). The CPCs were measured using an 8-color flowcytometry and reported as the percentage per total mononuclear cells using the monoclonal antibodies of CD19, 38, 45, 56, 117, 200, κ, λ, and CD138. The BMPC was calculated by counting the percentages of CD138-stained PCs among the all nucleated cells on bone marrow biopsy samples. Eleven patients (13.8%) were excluded because the MTV data could not be retrieved. Ultimately, 185 patients were included in our analysis. Written informed consent was obtained from all patients. Results: Among the 185 patients, 28 patients (15.1%) were negative for avid lesion on PET/CT. Whole-body MTV and TLG ranged from 0 to 2440.7 mL, with a median of 34.2 mL and from 0 to 12582.4 g, with a median of 97.0 g, respectively. The best cut-off values of MTV and TLG that discriminate the survival using a receiver-operating-characteristic curve analysis were 56.4 mL and 166.4 g, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with a lower cut-off value of MTV (≤56.4 mL) had better survival with not reached (NR) and 37.3 months as compared to those with a higher cut-off value (>56.4 mL) that reached 52.9 and 23.8 months, respectively (p=0.003 and 0.019). Similarly, the OS and PFS of patients with a lower cut-off value of TLG (≤166.4 g) showed better survivals with NR and 37.3 months as compared to those with a higher cut-off value (>166.4 g) that reached 54.3 and 28.8 months, respectively (p=0.0047 and 0.012). Next, we explored the prognostic impact of the clinical variables including MTV or TLG, CPCs, and BMPC. High levels of CPCs and BMPCs levels were defined as ≥0.018% of the total mononuclear cells and BMPCs of ≥57%, respectively. Univariate analysis showed that age≥70, serum creatinine≥2.0 mg/dL, R-ISS stage 3, higher cut-off value of MTV, and higher cut-off value of TLG were the associated with shorter OS. To measure the tumor volume with accuracy, we combined BMPC or CPCs and MTV or TLG. On multivariate analysis, age≥70 and the combination of higher cut-off value of MTV or TLG and high level of BMPC percentage were significantly associated with shorter OS [Hazard Ratio (HR) 2.12, p=0.038, HR 2.66, p=0.027 and HR 2.57, p=0.029, respectively] and PFS (Not assessed, HR 2.52, p=0.018 and HR 2.7, p= 0.011, respectively) (Figure 1). Conclusion: Our findings demonstrated that MTV and TLG calculated from pretreatment PET/CT were useful for risk stratification in patients with NDMM when combined with BMPC. The prognostic performance of the combined high-burden of TLG or MTV and high levels of BMPC were independent of the established risk factors. Disclosures Matsue: Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria.

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