scholarly journals Evaluation of Current Clinical Models for Risk of Progression from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma or Related Malignancies in 2028 Persons Followed in the Czech Republic

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3376-3376 ◽  
Author(s):  
Viera Sandecka ◽  
Zdenek Adam ◽  
Ivan Spicka ◽  
Vlastimil Scudla ◽  
Evzen Gregora ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mayo Clinic ◽  
Plasma Cells ◽  
Reference Group ◽  
Low Risk ◽  
M Protein ◽  
The Czech Republic ◽  
Risk Of Progression ◽  
Clinical Models

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition associated with a risk of progression to multiple myeloma (MM) or related disorders. There are currently 2 clinical models predicting progression from MGUS to MM. The Mayo Clinic model uses levels and type of serum monoclonal protein (M-protein) and serum free light chain ratio (sFLC). The Spanish PETHEMA model uses flow cytometry of bone marrow plasmocytes (BMPC) and the presence of DNA aneuploidy. Purpose: The primary end point was to estimate the cumulative risk of hematologic disorders occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models suggested by the Mayo Clinic group and the Spanish PETHEMA group for the risk of progression from MGUS to MM or related malignancies and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of low-risk MGUS group. Group: Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. MGUS diagnosis was made according to IMWG criteria. In total, 2028 persons with MGUS were enrolled in the RMG study from May 2007 to June 2013. A total of 93% (1887/2028) of persons were evaluated. Results: 1887 MGUS persons were followed with median 4 years. Malignancies developed in 8.6% (162/1887) cases; MM occurred in 77.2% (125/162) of persons. The risk of progression was 1.5% at 1 year, 7.6% at 5 years and 16.5% at 10 years after diagnosis. The key predictors factors of progression were as follows: age ≥ 69 years, serum M- protein concentration ≥ 1.5 g/dL, BMPC > 5%, pathological sFLC ratio (< 0.26 or >1.65), immunoparesis of polyclonal immunoglobulins, levels of serum hemoglobin at baseline < 12.0 g/dL and the presence of normal plasma cells (nPC) in bone marrow ≤ 5 % identified by multiparametric flow cytometry techniques. Distribution of MGUS persons according to risk groups based on the Mayo Clinic model confirmed predictive power of Mayo Clinic model based on our data although isotype of M- protein was not found as independent predictor. At 10 years, no-risk group had 4.9% risk of progression compared to 16.3%, 24.6%, and 54.9% in groups with 1, 2 or 3 risk factors, respectively (p< 0.001). MGUS group with 1, 2 and 3 risk factors in comparison to the reference group without any risk factor had HR( 2.59 [95% CI: 1.39- 4.84]; p= 0.003, HR 4.79 [95% CI: 2.56-8.93]; p< 0.001, HR 12.97 [95% CI: 5.52-30.48];p< 0.001), retrospectively. Immunoparesis instead of DNA aneuploidy was used together with the presence of abnormal plasma cells (aPCs) to validate the modified PETHEMA model. The rates of progression at 3 years were 2.5%, 8.1% and 28.0% for groups with neither, one or both risk factors, respectively (p< 0.001). MGUS group with 1 and 2 risk factors in comparison to the reference group without any risk factor had HR (3.98 [95% CI: 1.60-9.91]; p= 0.003, HR 14.23 [95% CI: 2.86-70.76]; p< 0.001), retrospectively. Based on the 5 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥ 1.5 g/dL, BMPC > 5%, abnormal sFLC ratio and serum level of hemoglobin < 12.0 g/dL) we proposed a new CMG model. The created CMG model clearly detected MGUS persons at low risk 86.6% (828/956) with the risk of progression 5.6% at 5 years better than previously described models. As expected, the number of MGUS persons with the highest risk of progression was limited to 3.7% only (35/956), with the risk of progression 31.9% at 5 years. The MGUS group with 5 risk factors had 63 times higher hazard of progression compared to reference MGUS group (HR 63.17 [95% CI: 13.99-285.36]; p< 0.001). Conclusion: In the large cohort of MGUS persons, we confirmed validity of previously considered clinical models for the risk of progression from MGUS to MM by the Mayo Clinic group and the Spanish PETHEMA group (model used for SMM). New CMG model for the risk of progression from MGUS to MM or related malignancies was established with an advantage for better identification of MGUS persons at low risk (87% of persons with risk of progression below 10% in 5 years) as well as few persons at the highest risk of progression. As a consequence, limited evaluation and visits can be planned in majority of MGUS persons in follow-up. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n° 278570. Disclosures No relevant conflicts of interest to declare.

Metastatic Bone Survey in Monoclonal Gammopathy of Undertermined Significance: Useful or Not?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2728-2728
Author(s):  
Vrushali s Dabak ◽  
Esther Urbaez Duran ◽  
Muath Dawod ◽  
Amr Hanbali
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Serum Calcium ◽  
Plasma Cells ◽  
Bone Marrow Aspiration ◽  
Hemoglobin Concentration ◽  
M Protein ◽  
Risk Of Progression ◽  
Male Sex

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a serum monoclonal protein &lt;3g/dl, with fewer than 10% plasma cells in bone marrow and absence of lytic bone lesions, anemia, hypercalcemia and renal insufficiency. Incidence increases with age, especially over 70 and its progression to malignant disease occurs at 1% per year. However, so far there are no studies which can reliably distinguish patients who would progress from those who would remain stable. Based on available literature, it is concluded that MGUS has low risk of progression when M-protein is less than 1.5 g/dl, with no reduction in polyclonal immunoglobulins and bone marrow plasma cells less than 5%. The recommended testing with suspected MGUS is hemoglobin concentration, protein studies, serum calcium, and creatinine. Metastatic bone survey (MBS) and bone marrow aspiration are felt unnecessary if M-protein is less than 1.5 g/dl. However literature to support the use of MBS at diagnosis based on the level of M-protein is limited. Also our observation has been that due to lack of clear guidelines, most physicians obtain a baseline MBS and some follow patients with yearly or every other year MBS irrespective of the level of M-protein. Hence, we decided to review patients diagnosed with MGUS at our institution to determine the importance of MBS and if possible identify risk factors like age, race, M-protein level, hemoglobin concentration, serum calcium or creatinine level, which would identify a subgroup of patients needing a MBS. In doing so we were hoping to separate out those patients in whom we could recommend against unnecessary use of the skeletal survey below a certain defined M protein level. Study: We reviewed charts on 1906 patients at Henry Ford hospital diagnosed with MGUS between 1990 and 2007. All patients with at least one M-protein and one MBS done were included in the analysis. We excluded patients with a level of M-protein &gt;3.0 g/dl, who never had a skeletal survey in our system, had a light chain myeloma, plasmacytoma, chronic lymphocytic lymphoma(CLL), amyloidosis or protein evaluation done for diagnosis other than MGUS. We had 620 such patients. We collected data regarding their age, sex, ethnicity, date of diagnosis, type and level of the M-protein, hemoglobin level, serum calcium and creatinine at baseline, result of the MBS, date of progression to multiple myeloma (MM) if any and the date of last follow up if they did not progress to MM. Positive MBS is defined as x ray findings consistent with myelomatous changes with bone marrow aspiration confirming diagnosis of MM. Results: Of 620 patients, 36 had a positive MBS and applying non parametric Mann Whitney test and a chi-squared test, positive results seemed to correlate with higher level of M-protein, IgG subtype, lower hemoglobin and higher creatinine. Male sex and older age were other risk factors. Using the LOES curve to graph the risk of a positive skeletal event with the level of M-protein, risk was noted to increase significantly with M-protein in the range of 1.8– 3.0 (odds ratio 8.84 compared with 1.31 if level was less than 1.8), which was highly statistically significant as shown in figure 1. Further for 97/620 who progressed to multiple myeloma, the risk of progression was significantly higher for males, younger age at diagnosis of MGUS, lower hemoglobin, higher level of M-protein, IgG subtype and a positive skeletal event. Discussion: Our study is a retrospective chart review with its own limitations. However to our knowledge this is the first study to define the level of M-protein in patients with MGUS above which obtaining a MBS may be of value. Our study identifies 1.8 as a cut off value of M-protein below which doing routine MBS without symptoms of bone pains or other laboratory features suggesting progression to multiple myeloma might be unnecessary. Other risk factors for a positive event and progression to MM like lower hemoglobin, higher creatinine, older age, male sex and IgG subtype in our study are in keeping with what has been described in the literature. Conclusion: Based on our study, obtaining baseline MBS in all patients with suspected MGUS was not beneficial. Hence, we would not recommend obtaining MBS in patients with M-protein &lt;1.8 g/dl in absence of other risk factors for progression to multiple myeloma. Figure 1: LOES curve showing increased likelihood of positive MBS for increasing MPEV level. Figure 1:. LOES curve showing increased likelihood of positive MBS for increasing MPEV level.

scholarly journals Smoldering Multiple Myeloma: Usefulness of Serum Heavy/Light Chain Measurements for the Evaluation of Evolving Pattern

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4514-4514
Author(s):  
Carlos Fernandez de Larrea ◽  
Ignacio Isola ◽  
Esther Moga ◽  
Maria Teresa Cibeira ◽  
Ester Lozano ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Light Chain ◽  
Protein Level ◽  
Progressive Increase ◽  
M Protein ◽  
Smoldering Multiple Myeloma ◽  
Risk Of Progression

Abstract Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. A number of prognostic factors to identify patients at a higher risk of progression have been described, such as the size of the M protein, proportion of abnormal bone marrow plasma cells (BMPCs), immunoparesis and serum free light chain (FLC) k/l ratio. More recently, isotype-specific uninvolved heavy and light chain (HLC) pair suppression measured with the Hevylite assay was also associated with an increased risk of progression. Recent studies have evaluated the key prognostic impact of an increase in M-protein levels during follow-up ("evolving" pattern). However, an important limitation could be the evaluation of M-protein level variations based on serum protein electrophoresis (SPE) in patients with a small size M-spike. The aim of this study was to prospectively analyze the changes in M-protein according to SPE and HLC measurements, as well as other risk factors for progression, in patients with SMM. Methods: Thirty patients newly diagnosed with SMM at a single institution from January 2014 through September 2017 were prospectively included in the study. For each patient, baseline levels of known prognostic factors (serum M-protein, serum and urine immunofixation, clonal BMPCs percentage, total immunoglobulins, involved/uninvolved FLC and involved/uninvolved HLC pairs) were recorded. During the follow up, M-protein level, FLC and isotype specific HLC pairs were also analyzed. Evolving change in M-protein level according to SPE was defined as ³ 10% increase within the first 6 months of diagnosis (if M-protein was ³ 30 g/L) and/or ³ 25% increase within the first 12 months (for any level of M-protein); evolving change according to HLC was defined as a ³ 10% increase in the involved pair. A sequential increase in each of three or more consecutive measurements from diagnosis was considered an evolving change regardless of its magnitude. Results: The clinical characteristics of the total of patients, as well as of the patients with evolving changes in M-protein according to HLC are summarized in Table 1. During the study period, 5/30 (17%) of patients demonstrated an evolving behavior of the M-protein according to SPE. Four of these patients (4/5) also showed a progressive increase in the M-protein in the HLC measurements. One patient showed stable HLC levels even though both the M-protein and the involved FLC progressively increased. This patient was of intermediate and low risk according to Mayo Clinic and PETHEMA scores, respectively. On follow up, no progressive suppression of the isotype-specific uninvolved HLC pair or increase in the FLC ratio was noted, and there have been no signs of progression after a follow up of 3 years. According to involved HLC-pair levels, 12/30 (40%) of patients demonstrated an evolving behavior. Five out of 7 patients that were not classified as evolving by SPE, were IgA isotype. Eight out of 12 patients showed severe isotype-specific suppression of the uninvolved HLC-pair (> 50% below lower level of normal) as well as a highly abnormal FLC ratio (<0.125 or >8). Three out of the 4 remaining patients showed either severe isotype-specific HLC pair suppression or highly abnormal FLC ratio in follow up measurements. Compared to patients with no "HLC-evolving pattern", evolving patients were more likely to have highly abnormal FLC ratios (90 vs. 33%, p=0.009), severe suppression of the other isotypes (64 vs. 19%, p=0,024), highly abnormal isotype-specific HLC ratios (67 vs. 33%, p=NS), severe isotype-specific HLC-pair suppression (75 vs. 50%, p=NS), and immunoparesis (67 vs. 39%p=NS). Five patients progressed to symptomatic multiple myeloma during follow up; 4 of them showed a progressive increase in the involved HLC pair from diagnosis. The remaining patient demonstrated a progressive increase in the involved HLC pair that started 19 months prior to progression, followed 4 months later with an increase in M-protein as measured by SPE. Conclusions: In our series, the Hevylite assay allowed us to identify patients with a progressive increase in M-protein (clonal heavy/light chain pair) that was not evident with SPE measurements. This "HLC evolving pattern" was associated with other risk factors for progression to symptomatic disease and with worsening of other prognostic parameters during follow up. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Immunoparesis Defined By Heavy/Light Chain Pair Suppression in Smoldering Multiple Myeloma Patients Shows Isotype Specificity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-3
Author(s):  
Ignacio Isola ◽  
David Moreno ◽  
Esther Moga ◽  
Mari-Pau Mena ◽  
Natalia Tovar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Heavy Chain ◽  
Light Chain ◽  
The Other ◽  
M Protein ◽  
Time To Progression ◽  
Advisory Committees ◽  
Risk Of Progression

BACKGROUND Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. Prognostic factors to identify patients at higher risk of progression have been described, including the suppression of uninvolved polyclonal immunoglobulins (Ig) or immunoparesis (IP). Novel serum assays allow the quantification of each isotype-specific heavy and light chain pair (HLC), enabling the study of a new type of IP: the suppression of the uninvolved light chain counter part of the same heavy-chain Ig isotype (isotype matched immunoparesis). AIM: To prospectively characterize the prevalence and severity of immunoparesis as determined by HLC measurements, its association with other risk factors for progression and its prognostic significance, in patients with SMM diagnosed at a single institution. METHODS: Fifty-four patients newly diagnosed with SMM from January 2014 through March 2019 were prospectively included. Serum samples obtained at baseline and during follow-up were tested for M-protein level, free light chain (FLC) and HLC concentrations (all three isotype pairs at baseline, involved isotype pair at follow up visits). Isotype matched immunoparesis (IMI) was defined by the HLC assay, based on the levels of the Ig with the same heavy chain of the monoclonal isotype but of the alternative light chain (e.g. IgG-kappa suppression in a patient with IgG-lambda SMM). Aditionally, HLC immunoparesis (IP) was defined by suppression of any Ig with a heavy chain different to the M-protein (e.g. IgA kappa/lambda pair suppression in a patient with IgG-lambda SMM). Severe immunoparesis was defined by Ig values suppressed by 50% or greater below the lower limit of normal (LLN). RESULTS: Median age at diagnosis was 73 years, with the following heavy chain isotype distribution: 31 IgG, 20 IgA, 2 biclonal IgG-IgA and 1 light-chain only SMM. Median follow up for the series was 2.5 years. Isotype specificity of immunoparesis was reflected in the greater prevalence of IMI vs. noninvolved isotype IP (Figure 1, A). HLC measurements identified IMI in 42 out of the 53 patients with IgG, IgA or biclonal SMM (82%), with severe IMI observed in 27 patients (53%). Suppression of at least one HLC pair of an uninvolved isotype was present in 37 patients (72%), with severe suppression observed in 20 patients (38%). Eleven patients presented severe IMI without severe IP of uninvolved isotypes. On the other hand, only one out of the 37 patients with IP of uninvolved isotypes presented without IMI. In the case of the 12 patients that showed IP of any IgM HLC pair, they all had concomitant severe IMI and IP of the other uninvolved heavy chain isotype. Analysis of other risk factors for progression between groups of patients with i) no severe immunoparesis (n=22), ii) severe IMI without severe IP of uninvolved isotypes (n=11) and iii) severe IMI and severe IP of one or more HLC pairs of uninvolved isotypes (n=18), showed significantly different FLC ratios and lower % of normal plasma cells in bone marrow (Figure 1, B). There was a trend, although statistically not significant, towards higher M-protein levels. Progression to malignant symptomatic gammopathy was observed in 12 patients. The suppression of any IgM HLC pair was associated with a shorter time to progression (p=0.007; HR=4.2; 95% CI, 0.84-21) (Figure 1, C). Severe IMI alone or severe IMI plus severe IP of a different isotype were associated only with a statistically not significant trend towards a shorter time to progression. Eight patients demonstrated an evolving behavior (≥ 10% increase in the involved HLC pair in 3 or more consecutive determinations from diagnosis), 7 of which presented with severe IMI at diagnosis. Of the five evolving patients that progressed, four had severe IMI and the remaining one developed severe IMI during follow up. Patients with severe IMI at diagnosis maintained the same level of HLC suppression throughout the follow up period. CONCLUSION: The significantly greater incidence of IMI over IP of uninvolved isotypes pairs supports an isotype specificity of early Ig suppression mechanisms in the case of IgG and IgA SMM. That would be of special interest at the time of initial evaluation of patients with SMM using HLC pairs. Both IMI and IP of uninvolved isotypes are associated with other recognized risk factors for progression, but the later appears to develop with more advanced disease and associate with a higher risk of progression. Disclosures Cibeira: Amgen: Honoraria, Other: Educational lectures; Celgene: Honoraria, Other: Educational lectures; Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational lectures. Bladé:Oncopeptides: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

Idiopathic Bence Jones Proteinuria: Clinical Course and Prognosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3493-3493 ◽  
Author(s):  
Robert Kyle ◽  
Terry Therneau ◽  
Angela Dispenzieri ◽  
Dirk Larson ◽  
Matthew Plevak ◽  
...  
Keyword(s):  
Relative Risk ◽  
Plasma Cell ◽  
Light Chain ◽  
Mayo Clinic ◽  
Hazard Ratio ◽  
M Protein ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Bence Jones Proteinuria

Abstract Chronic Idiopathic Bence Jones Proteinuria (first reported in 1982) is an asymptomatic plasma cell proliferative disorder that is associated with a risk of progression to symptomatic multiple myeloma (MM) or primary amyloidosis (AL). We defined it as the presence of a monoclonal light chain in the urine, absence of an intact immunoglobulin M protein (IgH expression) in the serum, fewer than 10% bone marrow plasma cells (if done), and no evidence of MM, AL or other related plasma cell proliferative disorders. Following approval by the Mayo Clinic Institutional Review Board, we searched a computerized database and reviewed the records of all patients who were seen at Mayo Clinic within 30 days of the recognition of a monoclonal light chain (Bence Jones protein) in the urine between 1960 and 1996. Patients found to have end-organ damage at diagnosis as the result of the plasma cell proliferative disorder (including MM or AL), received chemotherapy, or had a nephrotic syndrome were excluded. Follow-up included review of each subject’s medical record at Mayo Clinic as well as review of death certificates for patients who died. Patients were sent letters of inquiry if they had not visited Mayo Clinic in the preceding year. The risk of progression to MM and AL was compared to those expected on the basis of Surveillance, Epidemiology and End Results (SEER) rates for MM in Iowa and the prevalence of AL in Olmsted County, Minnesota. Two-hundred twenty-three patients fulfilled the criteria for Idiopathic Bence Jones Proteinuria during the 37-year period (1960 – 1996). The median age at diagnosis was 69 yrs (range, 36–90 yrs) and only 1% were < 40 years of age. Sixty-seven percent were male. The urine M protein ranged from unmeasurable to 4.7 g/24h. The median was 0.09 g/24h and only 8% were > 1 g/24h. Kappa light chain accounted for 57% while lambda was present in 43%. Eighty-one percent of patients died during follow-up. Twenty-six percent had a monoclonal light chain in the serum on immunofixation. Concentrations of uninvolved (normal, polyclonal or background) immunoglobulins were reduced in 45%. During 1408 person years of follow-up, 11 patients developed symptomatic MM (relative risk 28.5; 95% CI, 14.3 – 51.1) and an additional 9 patients developed AL (relative risk 61.8; 95% CI, 28.3 – 117.4). The cumulative probability of progression to active MM or AL was 7% at 5 yrs, 13.5% at 10 yrs., and 18% at 15 yrs. The factors evaluated with respect to predicting progression to MM or AL included sex, hemoglobin value, serum albumin, amount of urine M protein/24h, type of urine light chain (kappa or lambda), reduction of uninvolved (background) immunoglobulins, and elevation of serum calcium or creatinine. The amount of the urine M protein/24h was the only significantly predictive parameter for progression. As a continuous variable, a higher urine M protein was associated with an increased risk of progression (hazard ratio = 2.1 for a 1g increase, p=0.003). The amount of the urine M protein was also significant as a dichotomous variable. Patients who had a urine M protein ≥ 1g/24h had an increased risk of progression (hazard ratio = 3.6, p=0.007). We conclude that patients with Idiopathic Bence Jones Proteinuria are at risk for the development of MM or AL and need to be followed indefinitely.

scholarly journals Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4452-4452
Author(s):  
Benedetta Dalla Palma ◽  
Valentina Marchica ◽  
Fabrizio Accardi ◽  
Daniela Guasco ◽  
Laura Notarfranchi ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Plasma Cells ◽  
Activin A ◽  
M Protein ◽  
Monoclonal Protein ◽  
Risk Of Progression ◽  
Standard Risk

Abstract The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients. We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis. With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001). In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

scholarly journals Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4506-4506
Author(s):  
Aránzazu García Mateo ◽  
Maria-Victoria Mateos ◽  
Alberto Orfao ◽  
Teresa Contreras Sanfeliciano ◽  
Luzalba del Carmen Contreras Sanfeliciano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Plasma Cells ◽  
Risk Group ◽  
Clonal Expansion ◽  
Low Risk ◽  
Advisory Committees ◽  
Risk Of Progression

Abstract Introduction: Studies have shown that a large monoclonal protein (MP) and immunoparesis in MGUS/SMM have predictive value of progression since they may be indirectly related to the degree of clonal expansion of bone marrow plasma cells (BMPC). A recently available assay, the Hevylite® (HLC), has allowed a more precise determination of MP and the quantification of isotype-matched immunosuppression (i.e. suppression of the monoclonal isotype but of the alternative light chain) which has shown prognostic value in some studies. In this study, we aim to evaluate the association between the alteration of the HLC parameters in MGUS patients with already known prognostic factors, but also, with less studied biomarkers such as circulating clonal plasma cells (cCPC) by Next Generation Flow (NGF) (Flores-Montero et al., Leukemia, 2017). Methods: A total of 175 MGUS patients diagnosed between October 2008 and September 2015 were included in the study. The median follow-up was 64 months (range: 1-100 months). MGUS and MGUS progression were defined according to the International Myeloma Working Group (IMWG) criteria. Clinical records were retrieved for all patients. HLC determinations were carried on a SPA+ turbidimeter analyzer and using specific reagents (Binding Site®, UK). The 6 HLCs pairs (IgGk, IgGl, IgAk, IgAl, IgMk and IgMl) were analyzed in all samples. HLC normal ranges were defined by the laboratory based on normal sera. Statistical analysis was done using IBM-SPSS-22. Results: HLC ratio was altered in 56.3% of the 111 patients with available sera (47.5% for IgG MGUS and 73.9% and 87.5% for IgA and IgM), respectively (p = 0.026). Patients with altered HLC ratio presented an MP significantly higher (Table 1) than those with normal ratio (0.62 g/dL vs 0.33 g/dL, p<0.0001; HR: 53.23 with 95% CI (2.82 / 1005.54), p=0.008); 100% of the patients had MP>1.5 g/dL (p = 0.044)). Interestingly, it also correlated with a greater frequency and a greater amount of cCPC by NGF (68.29%, p=0.001; 0.2864 /mL vs 0.0139 /mL p=0.0001). Regarding BMPC infiltration, there was a correlation between altered HLC ratios and greater percentages of infiltration of BMPC (3.72% vs. 2.43%, p = 0.001) and higher percentage of BMPC measured by multiparameter flow cytometry (MFC) (54.42% vs 24.42%, p <0.001; HR: 1.02 with 95% CI (1.01 / 1.03), p = 0.007). Patients with altered HLC ratio presented MP> 1.5 mg/dL (100%, p = 0.044), non-IgG (78,12%, p = 0.003) and ratio of altered CLL (77,77%, p = 0.011). Patients with normal HLC ratios correlated with other low risk of progression to MM parameters, such as a MP <1 g/dL (100%, p=0.0001) or <0,5 g/dL (87.8%, p=0.0001) or less than 5% of BMPC (91.3%, p=0.007).Considering the IMWG risk stratification model, 100% of the patients classified as intermediate risk (p = 0.0001) had an altered HLC ratio, while in the low risk group, ratios were evenly distributed. When considering the Spanish (GEM) model, 92% of the patients in the low risk group had normal HLC ratios (p = 0.010). Uninvolved HLC suppression >25% was observed in 15.2% of the patients. These patients presented significantly higher MP (0.91 g/dL vs 0.42 g/dL, p<0.0001; HR: 7.22 with 95% CI (1.11 / 46.83), p=0.038), greater infiltration of BMPC by MFC (70.54% vs 35.52%, p<0.0001; HR: 1.02 with 95% CI (1 / 1.04), p=0.040) and a greater amount of cCPC (0.8905 /mL vs 0.0256 /mL, p=0.030) compared to those without HLC suppression. Patients with moderate (<25%) or no suppression correlated with less aggressive parameters, such as the lower MP, <1 g/dL (95.8%, p = 0.0001) or < 0.5 g/dL (70.5%, p = 0.005). However, no significant correlation was found between the IMWG or the Spanish risk stratification models, and the frequency of HLC suppression. Conclusions: HLC abnormalities have been associated with negative prognostic factors previously established, reinforcing the idea that the HLC parameters are directly related to a greater propensity of clonal expansion, or a greater tumor load. However, the short follow-up time did not allow the confirmation of the prognostic value of HLC alterations regarding greater risk of progression to MM. A re-evaluation of the results at 10 years is foreseen. We expect to be able to access whether an evolving pattern exists for the HLC parameters mainly to investigate if the immune suppression by HLC progressively intensifies in patients closest to progressing to MM. Disclosures García Mateo: Celgene: Honoraria; Amgen: Honoraria; Binding Site: Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puig:Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Queizan:Janssen: Consultancy. Olivier:Celgene: Honoraria; Jassen: Honoraria.

scholarly journals Prediction of Progression of Smouldering into Therapy Requiring Multiple Myeloma By Easily Accessible Clinical Factors [in 527 Patients]

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2071-2071 ◽  
Author(s):  
Roman Hajek ◽  
Viera Sandecka ◽  
Anja Seckinger ◽  
Ivan Spicka ◽  
Vlastimil Scudla ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Plasma Cells ◽  
Risk Model ◽  
Validation Cohort ◽  
M Protein ◽  
Tumour Mass ◽  
Clinical Parameters ◽  
Clinical Factors ◽  
Risk Of Progression

Abstract Background Several models predict the progression from smouldering multiple myeloma (SMM) to therapy requiring multiple myeloma (MM). Three models comprise the assessment of tumour mass by different clinical parameters to stratify in risk groups: 1) the Mayo Clinic model uses bone marrow plasma cells percentage (BMPC) and serum monoclonal protein (M-protein), 2) the PETHEMA model uses immunoparesis and the percentage of abnormal plasma cells by flow cytometry, 3) the Heidelberg group assesses tumour mass by either the percentage of malignant plasma using iFISH or the Mayo assessment depicted above, and the presence of chromosomal aberrations associated with adverse prognosis. Besides tumor mass, they find the number of focal lesions in whole body MRI (>1) as strong prognostic factor. Aim To assess a combination of easily accessible clinical factors identifying patients at ≥ 80% risk of progression to MM requiring treatment within two years from the diagnosis of SMM. Methods Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic for 287 SMM patients enrolled from May 2007 to June 2013. A cohort comprising 240 SMM patients from Heidelberg, Germany was used for validation (Neben et al. JCO 2013). Results During the follow up period (median 2.4 years; range 0.6 - 18.0) progression to MM was observed in 51.9% (149/287) patients in the study cohort, representing 16% risk of progression at 1 year, 31.2% at 2 years, 54.8% at 5 years and 73.4% at 10 years. In univariate analysis factors significantly associated with progression were as follows: serum free light chain (iFLC/uFLC) ratio > 30 (HR 2.4 [95% CI: 1.4 - 4.1]; p< 0.001) plasma cell infiltration in bone marrow cytology ≥ 15% (HR 2.1 [1.5-3.0]; p< 0.001), immunoparesis (HR 2.0 [1.3-2.9]; p< 0.001), M - protein concentration ≥ 2.3 g/dL (HR 2.00 [1.4-2.7]; p< 0.001), beta2 microglobulin ≥ 2.0 mg/l (HR 1.8 [1.2-2.7]; p= 0.001), and thrombocyte count ≤ 250 x 109/l (HR 1.7 [1.1-2.4]; p= 0.005). In multivariate analysis, 3 parameters showed independent predictive value (immunoparesis, serum M-protein quantity ≥ 2.3 g/dL and iFLC/uFLC > 30). Combining these factors, we proposed a new risk model for SMM patients (CMG model). The risk of progression from SMM to MM at 2 years was 18.5%, 20.9%, 41.9% and 78.7% if 0 (reference group), 1, 2 or 3 risk factors are present (p< 0.001) (Figure 1) with HR of 1.5 [0.7-2.9]; p=0.283, 2.5 [1.3-5.0]; p= 0.008, 6.8 [3.0-15.2]; p<0.001, n=139), respectively. The CMG model was validated on 240 SMM patients from Heidelberg published in 2013. The risk of progression from SMM to MM at 2 years was 5.3%, 7.5%, 44.8% and 81.3% if 0, 1, 2 or 3 risk factors were present, respectively (p< 0.001) (Figure 1) with HR of 4.2 ([0.5-36.1]; p=0.189), 21.5 ([2.9-159.1]; p= 0.003, HR 38.6 [4.7- 317.7]; p<0.001, n=113). Conclusion We propose and validate a new risk model for SMM patients with prediction of 80% (78.7% on our CMG model; 81.3% on data from Heidelberg) risk of progression to therapy requiring myeloma within two years based on easily accessible clinical parameters (CMG model). The model could especially be used to identify high-risk patients to be included in early treatment clinical trials. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n°278570 and “OverMyR”, as well as the Deutsche Forschungs-Gemeinschaft (DFG) SFB/TRR79. Figure 1: CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Figure 1:. CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Disclosures Seckinger: Novartis: Research Funding.

scholarly journals New risk model is able to identify patients with a low risk of progression in systemic sclerosis

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001524
Author(s):  
Nina Marijn van Leeuwen ◽  
Marc Maurits ◽  
Sophie Liem ◽  
Jacopo Ciaffi ◽  
Nina Ajmone Marsan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Systemic Sclerosis ◽  
High Risk ◽  
Disease Progression ◽  
Risk Model ◽  
Immunosuppressive Drugs ◽  
Low Risk ◽  
Expert Assessment ◽  
Risk Of Progression

ObjectivesTo develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity.MethodsA machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in ≥1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment.ResultsOf the 492 SSc patients (follow-up range: 2–10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (<0.197, NPV:1.0; 29% of patients), intermediate risk (0.197–0.223, NPV:0.82; 27%) and high risk (>0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide.ConclusionOur machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as ‘low risk’. In this group, annual assessment programmes could be less extensive than indicated by international guidelines.

scholarly journals Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4762-4769 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
MF Basle
Keyword(s):  
High Risk ◽  
Bone Resorption ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Bone Biopsy ◽  
Low Risk ◽  
Early Symptom ◽  
Major Interest ◽  
Bone Biopsies

To determine if excessive osteoclastic-mediated bone resorption (BR) is an early tumor-induced event in multiple myeloma (MM), BR was assessed at first presentation on quantitative bone biopsy in 87 individuals evaluated for monoclonal gammopathy of undetermined significance (MGUS) and reinterpreted according to the presenting features and subsequent follow-up evaluation. As a reference population, 48 patients with previously untreated overt MM were evaluated under similar conditions. The median level of BR was significantly higher in 48 overt MM versus 87 MGUS patients (12.2% v 5.1% [normal level, <6%], P <.01). Actually, 93% of overt MM patients had an excessive BR versus 45% of MGUS patients at presentation (P <.01) According to simple presenting parameters (> or <5% plasma cells within the bone marrow, presence or absence of mild anemia/neutropenia), 31 individuals were classified as low-risk MGUS, 32 high-risk MGUS, and 24 indolent MM. An excessive BR was observed in 16% of low-risk MGUS, 46% of high-risk MGUS (P <.01 v low-risk MGUS), 79% of indolent MM (P <.05 v high-risk MGUS), and 93% of overt MM patients. Of major interest, the level of BR in indolent MM (11.2%) was identical to that in overt MM (12.2%) but significantly higher than in both low-risk (4%, P <.01) and high-risk (5.6%, P <.01) MGUS. When considering the follow-up evaluation of MGUS patients, an excessive BR at presentation was observed in 52% of MGUS cases that turned out to be unstable or developed subsequent MM, but in only 4% of stable MGUS (P <.01). More precisely the level of BR of low-risk MGUS that either turned out to be unstable or that developed into MM was significantly higher at presentation than that of subsequent stable MGUS (4.4% v 2.9%, P <.05). The same difference was observed in both high-risk MGUS and indolent MM according to subsequent follow-up studies (8.1% v 3.4% and 11.7% v 6%, respectively, P <.05). Of major interest, the level of BR in 11 stable high-risk MGUS cases actually fulfilling the diagnostic criteria of smoldering MM was very low (3.4%) and similar to that in stable low-risk MGUS (2.9%). We conclude that a quantifiable excess of BR in MGUS is significantly associated with progression and thus is an early symptom of malignancy in these individuals.

Presence of an Abnormal Serum Free Light Ratio Is an Independent Risk Factor for Progression in Monoclonal Gammopathy of Undetermined Significance (MGUS).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3647-3647
Author(s):  
S. Vincent Rajkumar ◽  
Robert A. Kyle ◽  
Terry M. Therneau ◽  
L. Joseph Melton ◽  
Arthur R. Bradwell ◽  
...  
Keyword(s):  
Risk Factor ◽  
Risk Group ◽  
Life Time ◽  
Hazard Ratio ◽  
Low Risk ◽  
M Protein ◽  
Serum Samples ◽  
Baseline Serum ◽  
Risk Of Progression ◽  
Normal Ratio

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) affects 3% of persons age 50 yrs or greater. Reliable predictors of progression of MGUS to myeloma or related malignancy are needed. We hypothesized that the presence of monoclonal unbound (free) kappa or lambda immunoglobulin light chains in MGUS, as detected by an abnormal serum kappa/lambda free light chain (FLC) ratio would indicate clonal evolution in the neoplastic plasma cell and increase risk of progression to malignancy. Methods: Patients (pts) from Southeastern Minnesota with MGUS seen at the Mayo Clinic from Jan 1, 1960 through Dec 31, 1994 who had baseline serum samples collected and stored at the time MGUS was first recognized were studied. Free kappa and lambda chains were measured using the serum FLC assay (FREELITETM, The Binding Site Ltd). Results: Of 1384 pts with MGUS during the defined time period, baseline serum samples obtained within 30 days of diagnosis of MGUS were available in 1148 pts. At a median follow-up of 15 yrs, malignant progression has occurred in 87 (7.6%) pts: myeloma (53 pts), IgM lymphoma (17), primary amyloidosis (6), macroglobulinemia (6), chronic lymphocytic leukemia (3) and plasmacytoma (2). An abnormal kappa/lamda FLC ratio (kappa/lambda ratio <0.26 or >1.65) indicating presence of monoclonal FLC was detected in 379 (33%) pts. In a Cox proportional hazards model, the risk of progression in pts with an abnormal kappa/lamda FLC ratio was significantly higher (hazard ratio 3.5, 95% CI 2.3–5.5; p<0.001) compared to pts with a normal ratio. After adjusting for the size of the serum monoclonal (M) protein by multivariate analysis, the hazard ratio was only slightly reduced to 2.8, p<0.001. The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal kappa/lambda FLC ratio versus 5% with a normal ratio; corresponding rates at 20 years were 35%, and 13%, respectively. MGUS pts with both an abnormal serum FLC ratio and high serum M protein had a risk of progression at 20 years of 46% (high-risk), versus 26% with one of two risk factors (intermediate-risk) and 7% with no risk factors (low-risk) (Table). The true life-time (28 year) risk of myeloma or related malignancy in the low-risk group was only 5.3% when other competing causes of death were taken into account. Conclusions: Presence of monoclonal FLC in the serum as detected by an abnormal kappa/lamda FLC ratio is a major independent risk factor for progression of MGUS to myeloma or a related malignancy. The new risk-stratification identifies a low-risk subset with a remarkably small life-time risk of progression, a finding of significant importance for the management of MGUS. Risk-stratification of MGUS using the size of the serum M spike and free light chain ratio Risk Group No. of patients Hazard ratio Absolute risk of progression at 20 years Low-risk (Serum M protein <1.5 gm/dL and normal FLC ratio [0.26–1.65]) 606 1 7% Intermediate-risk (Either risk factor present) 373 3.5 26% High-risk (Serum M protein >/=1.5 gm/dL and abnormal FLC ratio [<0.26 or >1.65]) 169 6.8 46%

Sign in / Sign up

Export Citation Format

Share Document