Beta-2-Microglobulin Is an IndependentPredictor of Progression in AsymptomaticMultiple MyelomaDavide Rossi, MD1; Marco Fangazio, MD1; Lorenzo De Paoli, MD1; Alessia Puma, MD1; Paola Riccomagno, MD1;

Valeria Pinto, MD1; Paola Zigrossi, MD1; Antonio Ramponi, MD2; Guido Monga, MD2; and Gianluca Gaidano, MD, PhD1

BACKGROUND: Although serum beta-2 microglobulin (B2M) represents a key variable for symptomatic multiple my-

eloma (MM) prognostication, its role in predicting the risk of progression of asymptomatic MM to symptomatic dis-

ease has not been explored. METHODS: This study was bases on a consecutive series of 148 patients with

asymptomatic MM and explored the cumulative probability of progression to symptomatic MM as the primary end-

point. RESULTS: In univariate analysis, a serum B2M level >2.5 mg/L was associated with an increased probability of

disease progression (5-year risk, 64.5%; P < .001) along with serum monoclonal component (sMC) (P < .001), urinary

monoclonal component (uMC) (P < .001), and bone marrow plasma cells (BMPCs) (P < .001). In multivariate analysis,

serum B2M was selected as an independent predictor of progression (hazard ratio, 3.30; P¼.002). Serum B2M was

combined with sMC, uMC, and BMPC to create a risk-stratification model based on 4 groups with different risk of pro-

gression: very low (5-year risk, 0%), low-intermediate (5-year risk, 19.6%), high-intermediate (5-year risk, 60.7%), and

high (5-year risk, 80.7%). The model that included serum B2M along with sMC, uMC, and BMPC was able to predict

disease progression better than the model that was based on sMC, uMC, and BMPC without serum B2M (C statistics,

0.760 vs 0.726). CONCLUSIONS: The current results indicated that 1) serum B2M is an independent predictor of

asymptomatic MM progression, and 2) serum B2M adds prognostic information when combined with the most widely

used prognosticators of asymptomatic MM progression. Cancer 2010;116:2188–200. VC 2010 American Cancer Society.

KEYWORDS: multiple myeloma, asymptomatic, beta-2 microglobulin, progression, prognosis.

Asymptomatic multiple myeloma (MM) is a plasma cell-proliferative disorder characterized by a bone marrowplasma cell (BMPC) percentage �10% and/or a serum monoclonal component (sMC) �3 g/dL and by the absence ofend organ damage.1,2 Although it is projected that up to 80% of patients with asymptomatic MMwill progress to sympto-matic disease and require treatment, the risk of progression is not uniform across patients. In fact, the category that is rec-ognized as asymptomatic MM includes both patients who harbor an indolent disease similar to monoclonal gammopathyof undetermined significance (MGUS) and patients who have a rapidly progressive disease and might benefit from veryclose follow-up.3-15

To date, few clinical predictors of asymptomatic MM progression have been identified, including BMPC percent-age, sMC level, and serum free light chain (FLC) burden measured either by the serum FLC ratio or by Bence-Jones (BJ)proteinuria.3-15 At least 3 predictive models have been derived from the combination of these variables, allowing the strati-fication of patients with asymptomatic MM into groups with a distinct risk of progression.8,12,15

Beta-2 microglobulin (B2M) is a serum marker of tumor burden in lymphoid malignancies, including MM.16-23

Although B2M represents a key variable of the International Staging System (ISS) for symptomatic MM,22 its role inasymptomatic MM has not been explored in detail. In fact, the ISS database did not include patients with asymptomatic

DOI: 10.1002/cncr.24959, Received: May 26, 2009; Revised: July 14, 2009; Accepted: August 17, 2009, Published online March 2, 2010 in Wiley InterScience

(www.interscience.wiley.com)

Corresponding author: Davide Rossi, MD, Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern

Piedmont, Via Solaroli 17, 28100 Novara, Italy; Fax: (011) 39-0321-620421; rossidav@med.unipmn.it

1Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont and Maggiore della Carita Hospi-

tal, Novara, Italy; 2Division of Pathology, Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont and Maggiore della Carita Hospital,

Novara, Italy

The first author designed the study, interpreted data, performed statistical analysis, and drafted the article; the last author supervised the study design and data

interpretation and drafted the article; the second author contributed to data collection and statistical analysis; the third, fourth, fifth, sixth, and seventh authors

collected and revised clinical data; and the eighth and ninth authors collected and revised pathologic data. All authors read and approved the article.

2188 Cancer May 1, 2010

Original Article

MM,22 and none of the studies on the prognosis forpatients with asymptomatic MM focused on B2M.3-15

Therefore, in the current study, we investigated a cohortof patients who had asymptomatic MM to verify 1)whether B2M levels predict progression to symptomaticMM and 2) how B2M interacts with currently knownpredictors of progression to symptomatic MM.

MATERIALS AND METHODS

Patients

This study was based on a consecutive series of 148 patientswith asymptomatic MM. All patients were referred to ourcenter for the screening of monoclonal gammopathy fromJune 1998 through June 2008. The database was updatedfor the analysis in February 2009. The median follow-up ofpatients who remained alive was 48 months. No patientwas lost at follow-up. All patients provided informed con-sent in accordance with local institutional review boardrequirements and the Declaration of Helsinki. The diagno-sis of asymptomatic MM was according to the InternationalMyeloma Working Group criteria1 and required BMPCs�10% and/or an sMC level �3 g/dL in the absence of endorgan damage defined according to calcium elevation, renalfailure, bone disease and anemia (CRAB) criteria; amyloi-dosis; hyperviscosity; or recurrent infections.

The following clinical variables were recorded atpresentation: age, sex, percentage of BMPCs on bonemarrow biopsy, sMC type, sMC size, type of light chain,urinary immunofixation, urinary monoclonal component(uMC), polyclonal immunoglobulin (Ig) reduction, aprevious history of MGUS, complete blood count, serumalbumin, C-reactive protein, serum B2M, serum creati-nine, creatinine clearance calculated with the Cockcroft-Gault formula, serum calcium, and skeleton x-ray. All148 patients were complete for the data listed above.

Serum B2M levels were quantified by nephelometry(Siemens Healthcare Diagnostics, Milan, Italy; referencerange, 1.8-2.3 mg/L). By using the 2.3 mg/L upper limitof normal (ULN) of our laboratory, 55 of 148 patients(37.2%) with asymptomaticMMhad abnormal B2M lev-els. Quantification of serum M-protein was performed bydensitometry of the monoclonal peak on electrophoresisfor IgG monoclonal proteins. Immunochemical measure-ment of the total Ig isotype level was used for IgA mono-clonal proteins migrating in the beta band on serumelectrophoresis. Quantification of urinary light chainexcretion was performed directly on a 24-hour urine col-lection. The proportion of BMPCs was estimated onbone marrow biopsy as reported previously.1,12 BMPC

percentage was assessed on bone marrow aspirates and onparaffin-embedded bone marrow biopsy specimens thatwere stained by hematoxylin and eosin with a differentialcount of 500 cells. In addition, immunohistochemistrywas applied to paraffin sections of the bone marrow bi-opsy specimens with the use of antibodies directed againstCD138. The bone marrow aspirate, biopsy, and immu-nohistochemistry stains were reviewed independently by 1hematopathologist (A.R.) and by 1 hematologist (D.R.).BMPC percentage estimates from all 3 methods werecombined to provide the final proportion of BMPCs.12

All patients underwent regular follow-up every 3 to4 months. During follow-up, the following variables wererecorded: 1) the date of progression to symptomatic MM,2) the date of last follow-up, and 3) the date of death.

Statistical Analysis

The primary endpoint of the study was progression tosymptomatic MM, which was defined according to Inter-national Myeloma Working Group criteria.1 The time toprogression was measured from the date of asymptomaticMMdiagnosis to either the date of progression to sympto-matic MM, or the date of last follow-up, or the date ofdeath. The cumulative probability of progression tosymptomatic MM was calculated by using Kaplan-Meieranalyses in which data from patients who had died werecensored.24 Kaplan-Meier curves were compared with theuse of log-rank statistics. The cumulative incidence ofprogression to symptomatic MM was calculated byaccounting for death as a competing risk25 and was com-pared across groups with the Gray test for equality.26 Coxproportional hazards regression was used to build a multi-variate model.27 Because the hazard ratio derived fromCox analysis measures the magnitude of risk rather than amodel’s ability to accurately classify patients, the HarrellC statistic was used to further evaluate the discriminatoryvalue of the prognostic models in terms of progression tosymptomatic MM.28 The C statistic estimates the propor-tion of correct prediction of the model (a C statistic of 1indicates perfect discrimination, and a C statistic of 0.5 isequivalent to chance).28 The standard error of the C statis-tic was calculated based on 3000 bootstrap samples. Thestratification of continuous clinical variables was based onthe best predictive cutoff value or an usual limit of nor-mal. The best cutoff values for B2M, BMPC percentage,sMC, uMC, hemoglobin, calcium, creatinine, creatinineclearance, and C-reactive protein were selected accordingto receiver operating curve (ROC) analysis using diseaseprogression as a state variable and according to the

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Cancer May 1, 2010 2189

Youden index, which was calculated using the sensitivityand specificity derived from ROC analysis.29 Categoricalvariables were compared by using chi-square tests orFisher exact tests, as appropriate. Continuous variableswere compared by using the Mann-Whitney test or theKruskal-Wallis test, as appropriate. All statistical testswere 2-sided, and statistical significance was defined as a Pvalue <.05. The analysis was performed with StatisticalPackage for the Social Sciences (SPSS) software (version16.0; SPSS, Inc., Chicago, Ill) and, in the competing risk

analysis, with the R statistical package (available at: http://www.r-project.org/ accessedMay 25, 2009).

RESULTS

Characterization of the AsymptomaticMultiple Myeloma Cohort

Clinical features at diagnosis of the patients with asymp-tomatic MM (n¼ 148) are reported in Table 1. The me-dian age at diagnosis was 67 years. In total, 75 patientswere men, and 73 patients were women. Of 148 patients,

Table 1. Clinical Characteristics of Patients With Asymptomatic Multiple Myelomaa

Variable No. of Patients/Total No. (%)

Median[Range]a

Median age [range], y 67 [57-73]

Men:women 75:73

Type of monoclonal componentIgG 113/148 (76.4)

IgA 32/148 (21.6)

Light chain 3/148 (2)

j 85/148 (57.4)

k 63/148 (42.6)

Serum monoclonal component, g/dL 1.1 [0.8-1.7]

IgG, g/dL 1.2 [0.8-1.8]

IgA, g/dL 0.9 [0.6-1.5]

Positive urinary immunofixation 27/148 (18.2)

Urinary monoclonal component, mg/24 hb 98 [44.525]

Polyclonal immunoglobulin reduction 114/148 (77)

Bone marrow plasma cells, % 15 [12-20]

Albumin, g/dL 4.3 [4-4.5]

Beta-2-microglobulin, mg/L 2.0 [1.5-2.5]

C-reactive protein, mg/L 0.3 [0.1-0.4]

Hemoglobin, g/dL 13.8 [12.7-14.5]

Platelet count, �109/L 220 [178-283]

White blood cells, �109/L 6.0 [4.9-7.2]

Absolute neutrophil count, �109/L 3.3 [2.5-4.5]

Absolute lymphocyte count, �109/L 1.9 [1.5-2.4]

Calcium, mg/dL 9.4 [9-9.7]

Creatinine, mg/dL 1.0 [0.9-1.1]

Creatinine clearance, mL/min 72 [58-97]

Previous MGUS 32/148 (21.6)

ISSI 128/148 (86.5)

II 18/148 (12.2)

III 2/148 (1.4)

Progression to symptomatic disease 29/148 (19.5)

Symptoms at progressionCalcium elevation 4/29 (13.8)

Renal failure 5/29 (17.2)

Anemia 14/29 (48.3)

Bone lesion 13/29 (44.8)

IgG indicates immunoglobulin G; IgA, immunoglobulin A; MGUS, monoclonal gammopathy of undetermined significance;

ISS, International Staging System.aRanges (in square brackets) indicate the 25th through 75th percentiles for continuous variables.b This was calculated only for patients who had positive urinary immunofixation results.

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113 (76.4%) had IgG, 32 patients had (21.6%) IgA, and 3patients had light chain sMC (2%). The light chain typewas j in 85 patients (57.4%) and k in 63 patients(42.6%). The median sMC levels was 1.1 g/dL. Concen-trations of uninvolved Igs were reduced in 114 of 148patients (77%). Positive urinary immunofixation wasdocumented in 27 of 148 patients (18.2%). Among thepatients who had positive urinary immunofixation, the me-dian uMC level was 98 mg per 24 hours. The median he-moglobin concentration was 13.8 g/dL, the median serumB2M level was 2.0 mg/L, the median serum albumin levelwas 4.3 g/dL, and the median serum C-reactive proteinlevel was 0.3 mg/L. On bone marrow biopsy, the medianBMPC percentage was 15%. A previous history of MGUSwas recorded in 32 of 148 patients (21.6%). According toISS criteria, 128 of 148 patients (86.5%) patients had stageI disease, 18 of 148 patients (12.2%) had stage II disease,and 2 of 148 patients (1.4%) had stage III disease.

During 484 cumulative person-years of follow-up(range, 0.5-10.1 person-years), 4 of 148 patients died(median follow-up of patients who remained alive, 4years). During this period, 29 of 148 patients progressedto symptomatic MM, accounting for a 5-year probabilityof progression of 29.5% (95% confidence interval, [CI],19.6%-39.4%).

Serum Beta-2-Microglobulin Is anIndependent Predictor of AsymptomaticMultiple Myeloma Progression

Clinical features at diagnosis were evaluated for theirimpact on the risk of progression to symptomatic MM.According to the Youden index, the best cutoff valueswere 2.5 mg/L for B2M, 1.5 g/dL for sMC, 500 mg per24 hours for uMC, 20% for BMPC percentage, 13.5 g/dLfor hemoglobin, 10.0 mg/dL for calcium, 0.9 mg/dL forcreatinine, 70 mL per minute for creatinine clearance, and1.0 mg/L for C-reactive protein. On the basis of these cut-off values, at diagnosis, 40 of 148 patients (27%) patientshad B2M >2.5 mg/dL, 57 of 148 patients (38.5%) hadsMC >1.5 g/dL, 8 of 148 patients (5.4%) had uMC>500 mg per 24 hours, 46 of 148 patients (31.1%) had aBMPC percentage �20%, 63 of 148 patients (42.5%)had hemoglobin �13.5 g/dL, 19 of 148 patients (12.8%)had calcium >10 mg/dL, 98 of 148 patients (66.2%) hadcreatinine >0.9 mg/dL, 71 of 148 patients (48%) had acreatinine clearance <70 mL per minute, and 11 of 148patients (7.4%) had C-reactive protein>1.0 mg/L.

Among the clinical features at diagnosis, univariateanalysis identified B2M>2.5 mg/L as a risk factor of pro-

gression to symptomatic MM (cumulative probability at5 years, 64.5%; hazard ratio [HR], 3.85; 95% CI, 1.85-8.01; P < .001) (Table 2, Fig. 1A). Other variables thatwere associated with a significantly increased risk of pro-gression to symptomatic MM included sMC >1.5 g/dL(cumulative probability at 5 years, 49.1%; HR, 5.76; P<

.001), uMC>500 mg per 24 hours (cumulative probabil-ity at 5 years, 68.7%; HR, 6.60; P < .001), a BMPC per-centage�20% (cumulative probability at 5 years, 50.2%;HR, 5.77; P < .001), hemoglobin �13.5 g/dL (cumula-tive probability at 5 years, 43.5%; HR, 2.24; P¼ .035),and creatinine >0.9 mg/dL (cumulative probability at 5years, 36.3%; HR, 2.89; P¼ .031) (Table 2; Figs. 1B-D,2).These associations also remained significant after cor-recting for death as a competing risk (Table 2).

Clinical variables that were not associated with pro-gression to symptomatic MM (P � .05 in all analyses)were age, sex, sMC type, type of light chain, polyclonal Igreduction, albumin, C-reactive protein, platelets, whiteblood cell count, absolute neutrophil count, absolute lym-phocyte count, calcium, creatinine clearance, and a previ-ous history of MGUS (Table 2). The independentpredictive value of B2M for the risk of progression tosymptomaticMMwas assessed in a Cox multivariate anal-ysis. Variables that were entered into the multivariateanalysis along with B2M were sMC and BMPC percent-age. Multivariate analysis selected B2M >2.5 mg/L (HR,3.30; 95% CI, 1.57-6.91; P¼ .002) as an independentpredictor of progression to symptomatic MM along withsMC >1.5 g/dL (HR, 3.71; 95% CI, 1.46-9.39;P¼ .006) and a BMPC percentage �20% (HR, 3.96;95%CI, 1.75-8.97; P¼ .001) (Table 3).

Beta-2-Microglobulin Synergizes With OtherRisk Factors in Predicting AsymptomaticMultiple Myeloma Progression

When treated as a categorical variable, B2M >2.5 mg/dLwas not associated with any 1 of the variables correlatedmost significantly with progression by univariate analysis,including sMC >1.5 g/dL (P¼ .324), uMC >500 mgper 24 hours (P¼ .034), or BMPC percentage �20%(P¼ .068). This observation documents the finding thatB2M >2.5 mg/dL did not have colinearity with sMC,uMC, or BMPC percentage and, thus, that B2M did notbehave as a reciprocal surrogate of sMC, uMC, or BMPCpercentage.

On this basis, we used bivariate log-rank analysisto test how B2M >2.5 mg/L interacted with sMC >1.5g/dL, uMC >500 mg per 24 hours, and BMPC

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Table 2. Clinical Variables at Asymptomatic Multiple Myeloma (MM) Diagnosis That Predicted Progression to Symptomatic MM inUnivariate Analysis

Variable No. of Events/No. of Patients

CumulativeProbabilityat 5 years6 SE, %a

HR 95% CI Cox Pb Gray Pc

Age <60 y 5/41 15.6 � 8.4 — — .088

Age �60 y 24/107 34.3 � 6.3 2.31 0.88-6.08

Women 12/73 28.9 � 8.2 — — .286

Men 17/75 28.7 � 6.0 1.49 0.71-3.13

Type of serum monoclonal componentIgG 18/113 24.3 � 5.6 — — .076

IgA 9/32 35.6 � 10.2 2.07 0.92-4.65

Type of light chainj 19/85 35.5 � 7.5 — — .325

k 10/63 19.6 � 6.2 1.47 0.68-3.16

Serum monoclonal component �.5 g/dL 6/91 11.1 � 6 — — <.001d <.001d

Serum monoclonal component >1.5 g/dL 23/57 49.1 � 7.6 5.76 2.34-14.18

Urinary monoclonal component �500 mg/24 h 24/140 26.2 � 5.2 — — <.001d <.001d

Urinary monoclonal component >500 mg/24 h 5/8 68.7 � 17.8 6.60 2.49-17.49

No polyclonal immunoglobulin reduction 2/34 36.2 � 26 — — .155

Polyclonal immunoglobulin reduction 27/114 30 � 5.2 2.84 0.67-12.03

Bone marrow plasma cells <20% 9/102 17.7 � 5.9 — — <.001d <.001d

Bone marrow plasma cells �20% 20/46 50.2 � 8.7 5.77 2.62-12.69

Albumin >3.5 g/dL 27/140 27.6 � 5.1 — — .257

Albumin �3.5 g/dL 2/8 60 � 29.7 2.30 0.54-9.78

Beta-2-microglobulin �2.5 mg/L 14/108 16.7 � 4.5 — — <.001d <.001d

Beta-2-microglobulin >2.5 mg/L 15/40 64.5 � 12.1 3.85 1.85-8.01

C-reactive protein �1.0 mg/L 25/137 24.9 � 4.8 — — .303

C-reactive protein >1.0 mg/L 4/11 53.3 � 19 1.74 0.60-5.02

Hemoglobin >13.5 g/dL 12/85 19.4 � 5.3 — — .035d .036d

Hemoglobin �13.5 g/dL 17/63 43.5 � 9.6 2.24 1.05-4.66

Platelets >150�109/L 26/131 29.7 � 5.6 — — .838

Platelets �150�109/L 3/17 20.7 � 10.7 0.88 0.26-2.92

White blood cells >4�109/L 25/134 28.2 � 5.4 — — .366

White blood cells �4�109/L 4/14 41.8 � 13.4 1.63 0.56-4.70

Absolute neutrophil count >2�109/L 26/131 30.5 � 5.7 — — .721

Absolute neutrophil count �2�109/L 3/17 17.6 � 9.2 0.80 0.24-2.66

Absolute lymphocyte count >2�109/L 12/58 32.3 � 8.4 — — .959

Absolute lymphocyte count �2�109/L 17/90 25.7 � 6.2 0.98 0.46-2.05

Calcium �10 mg/dL 24/129 27.3 � 5.4 — — .226

Calcium >10 mg/dL 5/19 32.4 � 12.2 1.82 0.69-4.80

Creatinine �0.9 mg/dL 5/50 13.4 � 7.3 — — .031d .023d

Creatinine >0.9 mg/dL 24/98 36.3 � 6.5 2.89 1.10-7.58

Creatinine clearance �70 mL/min 14/77 25.4 � 6.5 — — .406

Creatinine clearance <70 mL/min 15/71 32.8 � 8.2 1.36 0.65-2.82

No previous MGUS 21/116 27.5 � 5.8 — — .407

Previous MGUS 8/32 33.8 � 11.5 1.41 0.62-3.19

ISSI 24/128 26.9 � 5.3 — — .187

II-III 5/20 41 � 15.6 1.91 0.72-5.03

SE indicates standard error; HR, hazard ratio; CI, confidence interval; IgG indicates immunoglobulin G; IgA, immunoglobulin A; MGUS, monoclonal gammop-

athy of undetermined significance; ISS, International Staging System.a Calculated by using the Kaplan-Meier method.bCalculated by using Cox analysis.c Calculated by using the Gray test after adjusting for death as a competing risk.d Statistically significant P value.

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percentage �20% in predicting progression of asymp-tomatic MM. B2M identified a subgroup of patients withasymptomatic MM who had a higher probability of pro-gression despite being characterized at diagnosis by favor-able predictors. This observation was reproducible in allfavorable risk categories. Within the stratum of asymp-tomatic MM that harbored favorable predictors, B2M>2.5 mg/L segregated a group of patients with asymp-tomatic MM who had higher cumulative probability ofprogression despite being characterized by sMC �1.5 g/dL (P¼ .010), uMC �500 mg per 24 hours (P¼ .003),or BMPC percentage <20% (P¼ .009) (Table 4, Fig. 3).In addition, B2M discriminated unfavorable risk catego-ries within the stratum of patients with asymptomaticMM who had poor prognosticators. Indeed, patients whohad the highest cumulative probability of progressionwere identified by the combination of B2M >2.5 mg/dLwith sMC >1.5 g/dL (P¼ .009) or a BMPC percentage�20% (P¼ .013) (Table 4, Fig. 3). These associations

Figure 2. These survival curves illustrate the cumulative prob-ability of asymptomatic multiple myeloma progression tosymptomatic disease according to serum creatinine.

Figure 1. These survival curves illustrate the cumulative probability of asymptomatic multiple myeloma (MM) progression tosymptomatic disease according to beta-2 microglobulin (BM2) and other clinical risk factors. The cumulative probability ofasymptomatic MM progression to symptomatic disease is illustrated according to levels of (A) B2M, (B) serum monoclonalcomponent (sMC), (C) urinary monoclonal component (uMC) and (D) the percentage of bone marrow plasma cells (BMPC).

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remained significant after correcting for death as a com-peting risk (Table 4). Because of the low number ofpatients, the stratum of patients with uMC >500 mg/dLwas not powered enough to detect a difference in the riskof progression according to B2M.

Beta-2-Microglobulin Improves the RiskStratification of Asymptomatic MultipleMyeloma

The burdens of sMC, BMPC and FLC measured in se-rum or estimated indirectly by BJ proteinuria are amongthe most widely recognized risk factors for asymptomatic

MM progression.8,12,15 Consistent with previous observa-tions, sMC, uMC, and BMPC percentage were selected aspredictors of progression in our asymptomatic MMcohort. When combined into a model, sMC, uMC, andBMPC percentage allowed us to stratify patients into 3risk categories (Fig. 4A).

B2M contributed toward segregating patients withasymptomatic MM who had no risk of progression andpatients with asymptomatic MM who were projected toprogress in virtually all cases. Three lines of evidence sug-gest that B2M may improve the risk stratification modeldefined by sMC, uMC, and BMPC percentage.

First, B2M >2.5 mg/L adds prognostic informationwithin the low-risk group characterized by sMC �1.5g/dL, uMC �500 mg per 24 hours, and BMPC percent-age <20% and within the high-risk group defined by sMC>1.5 g/dL, and/or uMC >500 mg per 24 hours, and/orBMPC percentage �20% (Table 5). Conversely, the prog-nosis of intermediate-risk patients who harbored sMC>1.5 g/dL, or uMC >500 mg per 24 hours, or BMPC�20% was not affected significantly by B2M (Table 5).

Second, the risk stratification model that includedB2M >2.5 mg/L along with sMC >1.5 g/dL, uMC

Table 4. Bivariate Analysis of the Interaction Between Beta-2-Microglobulin and Serum MonoclonalComponent, Urinary Monoclonal Component, and Bone Marrow Plasma Cell Percentage inPredicting the Progression of Asymptomatic Multiple Myeloma

Variable No. of Events/No. of Patients

Cumulative Probabilityat 5 Years 6 SE, %a

Log-RankPb

GrayPc

Serum monoclonal component �1.5 g/dLB2M £2.5 mg/L 2/69 1.7 � 1.7 .010 .011

B2M >2.5 mg/L 4/22 46.2 � 23

Serum monoclonal component >1.5 g/dLB2M £2.5 mg/L 12/39 36.4 � 8.6 .009 .020

B2M >2.5 mg/L 11/18 80.3 � 11.9

Urinary monoclonal component �500 mg/24 hB2M £2.5 mg/L 13/105 16.2 � 4.6 .003 .006

B2M >2.5 mg/L 11/35 60 � 13.5

Urinary monoclonal component >500 mg/24 hB2M £2.5 mg/L 1/3 32.3 � 27.2 .107 .128

B2M >2.5 mg/L 4/5 100 � 21.9

Bone marrow plasma cells <20%B2M £2.5 mg/L 4/79 8 � 4.2 .009 .012

B2M >2.5 mg/L 5/23 52.1 � 18.1

Bone marrow plasma cells �20%B2M £2.5 mg/L 10/29 36.7 � 10.2 .013 .028

B2M >2.5 mg/L 10/17 77.7 � 13.1

SE indicates standard error; B2M, beta-2-microglobulin.a Calculated by using the Kaplan-Meier method.bCalculated by using the log-rank test.c Calculated by using the Gray test after adjusting for death as a competing risk.

Table 3. Clinical Variables at Asymptomatic Multiple Myeloma(MM) Diagnosis That Predicted Progression to SymptomaticMM in Multivariate Analysis

Variable HR 95% CI Pa

Serum monoclonal component �1.5 g/dL — — .006

Serum monoclonal component >1.5 g/dL 3.71 1.46-9.39

Beta-2-microglobulin �2.5 mg/L — — .002

Beta-2-microglobulin >2.5 mg/L 3.30 1.57-6.91

Bone marrow plasma cells <20% — — .001

Bone marrow plasma cells �20% 3.96 1.75-8.97

HR indicates hazard ratio; CI, confidence interval.a Calculated by using Cox analysis.

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Figure 3. These survival curves illustrate the interaction between beta-2 microglobulin (B2M) and other clinical risk factors on thecumulative probability of asymptomatic multiple myeloma (MM) progression to symptomatic disease. A B2M level >2.5 mg/Lsegregated a group with asymptomatic MM that had a higher cumulative probability of progression within the strata of patientscharacterized by (A) a serum monoclonal component (sMC) �1.5 g/dL (P¼ .010; pairwise comparison) and sMC >1.5 g/dL(P¼.009; pairwise comparison), (B) a urinary monoclonal component (uMC) �500 mg per 24 per hours (P¼ .003; pairwise com-parison), and (C) bone marrow plasma cells (BMPC) <20% (P¼.009; pairwise comparison) and BMPC �20% (P¼.013; pairwisecomparison).

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Cancer May 1, 2010 2195

>500 mg per 24 hours, and BMPC percentage �20%allowed us to segregate 4 groups of patients with asymp-tomatic MM who had different risks of progressing tosymptomatic disease (Fig. 4B, Table 6). The cumulativeprobability of progressing to symptomatic MM at 5 years

was 0% for the very low risk group (0 risk factors), 19.6%for the low-intermediate risk group (1 risk factor), 60.7%for the high-intermediate risk group (2 risk factors), and80.7% for the high-risk group (3 or 4 risk factors; P <

.001) (Fig. 4B). After correcting for death as a competing

Figure 4. Risk stratification models were based on serum monoclonal component, urinary monoclonal component, and bonemarrow plasma cells with or without beta-2 microglobulin. (A) Patients were assigned 1 point for meeting each of the followingcriteria: serum monoclonal component <1.5 mg/L, urinary monoclonal component >500 mg per 24 hours, and bone marrowplasma cells �20%. The cumulative probability of asymptomatic multiple myeloma (MM) progression to symptomatic disease isrepresented for patients who had 0 (low risk), 1 (intermediate risk), or >1 (high risk) risk factors. (B) Patients were assigned 1point for meeting each of the following criteria: beta-2 microglobulin >2.5 mg/L, serum monoclonal component <1.5 mg/L, uri-nary monoclonal component >500 mg per 24 hours, and bone marrow plasma cells �20%. The cumulative probability of asymp-tomatic MM progression to symptomatic disease is represented for patients who had 0 (low risk), 1 (low-intermediate risk), 2(high-intermediate risk), or >2 (high risk) risk factors.

Table 5. The Addition of Beta-2-Microglobulin to Prognostic Categories Defined According toSerum Monoclonal Component, Urinary Monoclonal Component, and Bone Marrow Plasma Cells

Prognostic Category No. ofEvents/No. ofPatients

CumulativeProbabilityat 5 Years6 SE, %a

Log-RankPb

GrayPc

Low-risk (sMC �1.5 g/dL, and uMC �500 mg/24 h, and BMPC <20%)Beta-2-microglobulin £2.5 mg/L 0/57 0 .005 .005

Beta-2-microglobulin >2.5 mg/L 2/16 40 � 25.3

Intermediate-risk (sMC >1.5 g/dL, or uMC >500 mg/24 h, or BMPC �20%)Beta-2-microglobulin £2.5 mg/L 5/32 5.4 � 7.3 .091 .096

Beta-2-microglobulin >2.5 mg/L 3/10 70.8 � 24.1

High-risk (sMC >1.5 g/dL, and/or uMC >500 mg/24 h, and/or BMPC �20%)Beta-2-microglobulin £2.5 mg/L 9/19 55 � 13 .034 .076

Beta-2-microglobulin >2.5 mg/L 10/14 89 � 10.2

SE indicates standard error; sMC, serum monoclonal component, uMC, urinary monoclonal component; BMPC, bone

marrow plasma cells; NA, not assessable.aCalculated by using the Kaplan-Meier method.bCalculated by using the log-rank test.c Calculated by using the Gray test after adjusting for death as a competing risk.

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risk, the 5-year cumulative incidence of progression tosymptomatic MM for the very low risk, low-intermediaterisk, high intermediate risk, and high-risk groups was 0%,19.6%, 60.7%, and 75.3%, respectively (P < .001).Third, based on the C statistic, the model that includedB2M along with sMC, uMC, and BMPC percentage (Cstatistic, 0.760; standard error [SE], 0.045) allowed us topredict asymptomatic MM progression better than themodel that was based on sMC, uMC, and BMPC per-centage without B2M (C statistics, 0.726; SE, 0.049).

DISCUSSIONIn this report, we document our findings that 1) B2M isan independent predictor of asymptomatic MM progres-sion, and 2) B2M adds prognostic information whencombined with the most widely used prognosticators ofasymptomatic MM progression. Although B2M is a well

established prognostic factor in symptomatic MM,22 itsrole in asymptomatic disease is poorly characterized. Ourdata demonstrate that B2M is an independent predictorof asymptomatic MM progression and that patients whopresent with a B2M level >2.5 mg/L have an adjusted3.3-fold increase in the risk of progression to symptomaticdisease.

To date, none of the previous studies on asymptom-atic MM focused on B2M,3-15 and only 2 reportsincluded B2M among baseline variables.7,10 In the studyby Moulopoulos et al,7 patients with asymptomatic MMwho presented with B2M >2.5 mg/L had a short time toprogression to symptomatic disease. However, because ofthe low numbers of patients (n¼ 38) in that study, theincreased risk of progression indicated by B2M elevationdid not reach statistical significance.7 In the study byCesana et al10 that included both MGUS and asymptom-atic MM, B2M elevation did not emerge as a risk factor

Table 6. Clinical Characteristics of Patients With Asymptomatic Multiple Myeloma According to Risk Category

Variable No. of Patients/Total No. (%) or Median [Range]a Pb

Very Low Risk:0 Risk Factors

Low-Intermediate:1 Risk Factor

High-Intermediate:2 Risk Factors

High Risk:3-4 Risk Factors

Age [range], y 64 [52-71] 67 [53-74] 68 [62-72] 72 [66-79] .031c

Men 24/57 (42.1) 24/48 (50) 16/28 (57.1) 11/15 (73.3) .156

Type of monoclonal componentIgG 41/57 (71.9) 41/48 (85.4) 22/28 (78.6) 9/15 (60) .327

IgA 15/57 (26.3) 7/48 (14.6) 5/28 (17.9) 5/15 (33.3)

Light chain 1/57 (1.8) 0 1/28 (3.6) 1/15 (6.7)

j 34/57 (59.6) 23/48 (47.9) 19/28 (67.9) 9/15 (60) .365

K 23/57 (40.4) 25/48 (52.1) 9/28 (32.1) 6/15 (40)

Serum monoclonal component, g/dL 0.8 [0.6-1.0] 1.3 [0.8-1.7] 1.8 [1.5-2.1] 1.9 [1.5-2.6] <.001c

Serum monoclonal component, >1.5 g/dL 0 (0) 22/48 (45.8) 22/28 (78.6) 13/15 (86.7) <.001c

Positive urinary immunofixation 6/57 (10.5) 5/48 (10.4) 9/28 (32.1) 7/15 (46.7) .001c

Median urinary monoclonal component, mg/24 h 0 [0-0] 0 [0-0] 0 [0-39] 0 [0-525] .001c

Urinary monoclonal component >500 mg/24 h 0 (0) 0 (0) 3/28 (10.7) 5/15 (33.3) <.001c

Polyclonal immunoglobulin reduction 40/57 (70.2) 36/48 (75) 25/28 (89.3) 13/15 (86.7) .118

Bone marrow plasma cells, % 13 [12-15] 15 [13-18] 25 [17-34] 35 [22-50] <.001c

Bone marrow plasma cells �20% 0 (0) 10/48 (20.8) 21/28 (75) 15/15 (100) <.001c

Albumin, g/dL 4.3 [4.1-4.5] 4.2 [4.0-4.4] 4.3 [4.0-4.5] 4.1 [3.6-4.4] .202

Beta-2-microglobulin, mg/L 1.7 [1.4-2.0] 2.0 [1.4-2.7] 2.3 [2.0-2.7] 3.1 [2.7-3.9] <.001c

Beta-2-microglobulin >2.5 mg/L 0 (0) 16/48 (33.3) 10/28 (35.7) 14/15 (93.3) <.001c

C-reactive protein, mg/L 0.2 [0.1-0.4] 0.3 [0.1-0.5] 0.2 [0.1-0.4] 0.3 [0.1-0.5] .155

Hemoglobin, g/dL 14.1 [13.1-14.8] 13.5 [12.7-14.3] 14.0 [12.4-14.5] 13.0 [11.8-13.8] .025c

Platelets, �109/L 222 [187-287] 209 [169-280] 231 [178-293] 182 [130-289] .339

White blood cells, �109/L 6.0 [4.7-7.1] 6.0 [4.9-7.2] 5.9 [4.9-8.4] 5.8 [3.9-6.3] .552

Absolute neutrophil count, �109/L 3.2 [2.3-4.7] 3.5 [2.6-4.5] 3.2 [2.9-4.4] 2.9 [2.6-3.8] .682

Absolute lymphocyte count, �109/L 1.9 [1.4-2.4] 1.9 [1.5-2.2] 2.0 [1.6-2.8] 1.8 [1.2-2.4] .401

Calcium, mg/dL 9.5 [9.1-9.7[ 9.4 [9.0-9.8] 9.3 [9.1-9.9] 9.3 [8.9-9.4] .311

Creatinine, mg/dL 1.0 [0.9-1.1] 1.0 [0.9-1.1] 1.0 [0.9-1.1] 1.2 [1.1-1.4] .003c

Previous MGUS 10/57 (17.5) 10/48 (20.8) 9/28 (32.1) 3/15 (20) .488

ISS II-III 1/57 (1.8) 9/48 (18.8) 4/28 (14.3) 6/15 (40) .001c

IgG indicates immunoglobulin G; IgA, immunoglobulin A; MGUS, monoclonal gammopathy of undetermined significance; ISS, International Staging System.a Ranges (in square brackets) indicate the 25th through 75th percentiles for continuous variables.bP values were calculated using the chi-square test for categorical variables and the Kruskal-Wallis test for continuous variables.c Statistically significant P value.

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for progression to symptomatic disease. However, itshould be underscored that the criteria for the definitionof asymptomatic MM and for progression to sympto-matic disease used by Cesana et al10 did not fulfill cur-rently accepted criteria for these conditions.1 In addition,data on baseline B2M were lacking in a significant pro-portion of patients.10

Along with tumor mass, B2M also reflects renalfunction. In our cohort, as expected, B2M displayed astrong correlation with serum creatinine (Spearmanq¼ 0.529; P < .001) and creatinine clearance (Spearmanq¼ 0.404; P < .001). Despite this strong association, wecould exclude the possibility that the prognostic value ofB2M is led by renal function, because: 1) creatinine clear-ance, which is the standard measure of renal function inadults, was not associated with asymptomatic MM pro-gression when treated either as a categorical variable (Ta-ble 2) or as a continuous variable (HR, 0.99; 95% CI,0.98-1.01; P¼ .404); 2) in a multivariate analysis thatincluded sMC, BMPC percentage, and creatinine ratherthat B2M, creatinine was not selected as an independentpredictor of progression (P¼ .327); 3) based on C statis-tics, the model that included B2M along with sMC,uMC, and BMPC percentage (C statistic, 0.760; SE,0.045) allowed us to predict asymptomatic MM progres-sion better than the model that was based on creatininealong with sMC, uMC, and BMPC percentage withoutB2M (C statistic, 0.735; SE, 0.049).

sMC, BMPC percentage, and FLC burden, meas-ured in serum or estimated by BJ proteinuria, are amongthe most widely recognized risk factors of asymptomaticMM progression.8,12,15 Our results document that B2Mimproves the risk stratification model defined by sMC,uMC, and BMPC percentage by adding informationboth in the low-risk stratum and in the high-risk stratumof patients with asymptomatic MM. In fact, B2M con-tributes to identifying a group of patients who haveasymptomatic MM with a very favorable prognosis whoare not expected to progress and a group of high-riskpatients with asymptomatic MM virtually all of whom areprojected to progress.

Different technical methods for measuring B2M aswell different reference ranges exist across laboratories.The application of a standardized value of B2M wouldallow use of a 2.5 mg/L cutoff in other asymptomaticMM series that used different technical methods for meas-uring B2M. The standardized value of B2M could beobtained by dividing the original value expressed in mg/Lby the ULN of the laboratory. Accordingly, the 2.5 mg/L

cutoff value for B2M in our series corresponds to a stand-ardized cutoff value of 1.1-fold of the ULN.

The prognostic role of unbalanced light chain pro-duction in asymptomatic MM has been described at theurinary level and, more recently, at the serum level.8,15

Because serum FLC levels have entered the routine clinicalpractice only recently, this information was not availablefor the current analysis. On this basis, in our cohort, thebaseline serum FLC burden was estimated indirectly bymeasuring BJ proteinuria. Our data confirmed that anexcess of light chains is a risk factor for asymptomaticMM progression.

In MM, magnetic resonance imaging (MRI) allowsthe characterization of patterns of bone marrow involve-ment by tumor plasma cells and allows the observation ofchanges in the pattern of microcirculation within thebone.7-9,30 Abnormal bone marrow appearance on anMRI can be detected in a fraction of patients with asymp-tomatic MM and reportedly can predict an increased riskof progression to symptomatic disease.7-9,30 In our sur-vival analysis, the presence ofMRI abnormalities was asso-ciated with a higher (although not significant) probabilityof progression (cumulative probability of progression at 5years, 50.1% vs 23.9%; P¼ .110).

IgA isotype has been suggested as another possibleparameter that correlates with a higher risk of progressionto asymptomatic MM.8,10-12 In our study, similar to whatwas reported by Kyle et al,12 the IgA isotype in asymptom-atic MM indicated a 15% higher cumulative probabilityof progression compared with the IgG isotype in asymp-tomatic MM. This difference was at the limit of signifi-cance (P¼ .076). The finding that this value does notreach statistical significance may be because of the statisti-cal power allowed by our sample size.

Cytogenetics, either conventional or molecular, is 1of the strongest prognostic factors in patients with symp-tomatic MM.31 In the context of asymptomatic MM, theprognostic role of cytogenetics remains to be establishedand is suggested by: 1) the higher risk of progressionamong patients with asymptomatic MM who have cyto-genetic abnormalities32; 2) the higher prevalence of 13qdeletion and 1q gain among patients who have progres-sive, asymptomatic MM33; and 3) clonal evolution uponprogression.34

The current standard of care for asymptomatic MMis observation without therapy until the patient developsdisease progression or symptoms.1 Although it is pro-jected that most patients with asymptomatic MM willprogress to symptomatic disease, the risk of progression is

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2198 Cancer May 1, 2010

not uniform across patients. Prognostic models for pre-dicting asymptomatic MM progression,8,12,15 includingthe model described in the current study, would allow theidentification of low-risk patients who harbor a very indo-lent disease similar to MGUS and high-risk patients whomight benefit from close follow-up and who may be opti-mal candidates for experimental therapies aimed at delay-ing the progression of MM.35-41

CONFLICT OF INTEREST DISCLOSURESThe authors declare no competing financial interests. This studywas supported by Progetto Integrato Oncologia 2006, Ministerodella Salute, Rome, Italy; Ricerca Sanitaria Finalizzata, RegionePiemonte, Torino, Italy; Progetto Alfieri, Fondazione CRT, Tor-ino, Italy; and Novara-AIL Onlus, Novara, Italy.

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