Leukemia (2014) 28, 1902–1908 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu
ORIGINAL ARTICLE
Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma M Merz1,2, T Hielscher3, B Wagner2, S Sauer1, S Shah1, MS Raab1, A Jauch4, K Neben1, D Hose1, G Egerer1, M-A Weber5, S Delorme2, H Goldschmidt1,6 and J Hillengass1,2 Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wbMRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3–6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or X95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM. Leukemia (2014) 28, 1902–1908; doi:10.1038/leu.2014.75
INTRODUCTION Smoldering multiple myeloma (SMM) is a plasma cell disorder defined by a serum monoclonal protein (M-Protein)X30 g/l and/or bone marrow plasma cells (BMPC)X10% in the absence of secondary end-organ damage (hypercalcemia, renal insufficiency, anemia and osteolyses (CRAB criteria)).1 Previous studies from the Mayo Clinic showed that risk of progression into symptomatic multiple myeloma (MM) is linked to the size of serum M-Protein, the percentage of BMPCs2 and a pathological serum free light-chain (FLC) ratio.3 Data from the Programa Espan˜ol de Tratamientos en Hematologı´a demonstrated that a predominance of aberrant plasma cells (aPC) within the BMPC compartment (aPC/BMPC X95%) as detected by flow cytometry and immunoparesis are predictors for progression into MM.4,5 According to the International Myeloma Working Group, the appropriate follow-up of patients with SMM is performed every 2–3 months after diagnosis and should include serum and urine electrophoresis, blood counts as well as measurements of serum creatinine and calcium levels.6 As previous studies showed that the presence of focal lesions (FL) or a diffuse bone marrow infiltration in magnetic resonance imaging (MRI) is also associated with an increased risk of progression into MM,7–10 the guidelines recommend an MRI for the initial workup of patients with SMM. Further radiological evaluation with X-ray studies is only recommended if there is evidence for progressive disease from the routine workup.1,6 To our knowledge, so far, no study has been conducted to evaluate the prognostic significance of longitudinally performed whole-body MRI (wb-MRI) in patients with SMM. Therefore, we performed the current analysis under the
hypothesis that a progressive focal or diffuse bone marrow involvement detected by wb-MRI might predict a progression into symptomatic MM, requiring systemic therapy.
PATIENTS AND METHODS Patients We retrospectively analyzed 63 patients with SMM, diagnosed according to the criteria proposed by the International Myeloma Working Group.1 Between July 2004 and January 2013, all patients received at least two wb-MRIs for follow-up (3 MRIs: n ¼ 39, 4 MRIs: n ¼ 13, 5 MRIs: n ¼ 3, 6 MRIs: n ¼ 1; overall: 182 wb-MRIs; median of 346 days between MRIs). The median age at the first MRI was 55 years (range 29–76 years). Although patients with evidence for symptomatic disease requiring systemic therapy were excluded from the current analysis, 10 patients were included who had received local radiation therapy for a concomitant solitary plasma cell tumor. Patients with true solitary plasmocytoma (no sign for systemic disease, that is, no serum M-Protein or BMPC o10%) were also excluded. Retrospective data analysis had been approved by the institutional ethics review board.
Imaging protocol and analysis For wb-MRI, T1- and T2-weighted as well as T2-weighted short-tau inversion recovery sequences were used without application of contrast agent as described previously on one of two similar 1.5 Tesla MR scanners (both Magnetom Avanto, Siemens Healthcare, Erlangen, Germany).10,11 FL and diffuse infiltration were defined as described previously.10,11 Radiological progressive disease in longitudinally performed wb-MRIs (MRI-PD) was defined by the appearance of new FL or new diffuse infiltration of previously unaffected regions. Furthermore, the growth of
1 Department of Hematology and Oncology, University Hospital of Heidelberg, Heidelberg, Germany; 2Department of Radiology, German Cancer Research Center, Heidelberg, Germany; 3Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany; 4Department of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany; 5Department of Diagnostic and Interventional Radiology, University Hospital of Heidelberg, Heidelberg, Germany and 6National Center for Tumor Diseases, Heidelberg, Germany. Correspondence: M Merz, Department of Medicine V, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail:
[email protected] Previous presentations: Parts of this work were presented at the 2013 ASCO Annual Meeting. Received 7 January 2014; revised 8 February 2014; accepted 12 February 2014; accepted article preview online 18 February 2014; advance online publication, 14 March 2014
Longitudinal MRI in smoldering myeloma M Merz et al
1903 preexisting FL (X1 cm in diameter) or a progressive diffuse infiltration of already affected bones as indicated by further signal decay in T1-weighted images or increased bone marrow signal in T2-weighted images were classified as MRI-PD. Notably, MRI-PD would not necessarily indicate progression into symptomatic MM unless accompanied by alterations of mineralized bone, that is, lytic bone lesions or progressive osteoporosis that can only be reliably detected by X-ray or computed tomography. An unchanged bone marrow signal compared with the prior MRI was defined as radiological stable disease (MRI-SD).
Elevation of baseline parameters and follow-up Patients were serologically and clinically examined at the 1st wb-MRI and every 3–6 months after the initial wb-MRI in our outpatient clinic. BMPCs at the time of the 1st wb-MRI were determined on bone marrow aspirates or CD138-stained trephine biopsies, if available. Interphase fluorescence in situ hybridization on CD138-purified plasma cells was performed to identify high-risk aberrations (del17, t(4;14), þ 1q21) and to quantify the proportion of aPC in the BMPC compartment as described previously.12 aPC were measured as the number of cells carrying a specific aberration divided by the number of all purified mononuclear cells in a total minimum of 700 counted cells.12 In patients with progression into symptomatic MM, X-ray (until 2008) or CT (since 2009) studies were performed to identify lytic bone lesions. The time from initial MRI to the point of fulfillment of CRAB criteria1 requiring a start of systemic therapy defined the event for evaluation of time to progression into MM.
Statistical analysis Distribution of time to progression was estimated using Kaplan–Meier method and group comparisons were analyzed with the log-rank test. Hazard ratios (HR) and 95% confidence intervals from univariate Cox proportional hazard model were used to assess the prognostic significance of patient characteristics, laboratory and imaging parameters evaluated at the 1st MRI. The onset of the first MRI-PD during follow-up MRIs no. 2 to no. 6 was determined and included into the Cox model as time-dependent covariate, that is, intervening event. The Simon–Makuch method13 was used to estimate time to progression probability for time-dependent MRI-PD. In a separate multivariate Cox proportional hazard analysis, the influence of the initial M-Protein and aPC/BMPC X95% in combination with bone marrow signal from the 1st MRI and the occurrence of first MRI-PD was analyzed using multiple imputations for missing M-Protein. Predictive mean matching with 200 runs after a burn-in period of five runs was used to impute missing values based on available lab parameters and patient characteristics. In addition, a separate landmark analysis with landmark date of the 2nd MRI was used to assess the impact of MRI-PD detected at the 2nd MRI on time to progression. For the landmark analysis, MRI-PD at 2nd MRI was treated as baseline factor in Cox regression and for Kaplan–Meier estimates. The association between changes in MRI pattern (MRI-PD yes/no) and change in lab values for subsequent MRIs was assessed. For a patient with n MRIs, there were n-1 MRI episodes with subsequent measurements. As patient episodes from the same patient are not independent, we used a linear mixed effect model with a random patient effect to assess the impact of MRI-PD on change in lab values. We corrected for the effect of initial MRI pattern and lab values at 1st MRI by including them into the model. The model was fitted with R package lme4 and Satterthwaite’s approximation of degrees of freedom as implemented in R package lmerTest was used to assess significance of predictors. All P-values were two-sided. P-values o0.05 were considered statistically significant. No correction for multiple testing was performed. All analyses were carried out with software R (R Foundation, Vienna, Austria).
RESULTS Progression into MM The median follow-up was 5.4 years and patient information was last updated in April 2013. In the first 5 years after the initial MRI, 25 patients (40%) progressed into MM. According to CRAB criteria, the cause of progression into MM was the appearance of lytic bone lesions in 19 patients (76%); three patients (12%) developed anemia, one patient hypercalcemia and one patient renal failure. In another patient, treatment was initiated due to the risk of hyperviscosity syndrome. & 2014 Macmillan Publishers Limited
Findings at initial MRI Initial wb-MRI detected FL in 21 patients (33%; 1 FL n ¼ 12 (19%), X2 FL n ¼ 9 (14%)). Exclusively diffuse bone marrow involvement without FL was found in 19 patients (30%). In 23 patients (38%), no bone marrow involvement was detected by wb-MRI. Univariate analysis of baseline parameters Univariate Cox proportional hazard analysis showed that patients with X2 FL in the initial MRI exhibited a 6.6-fold risk of developing symptomatic MM compared with patients without pathological findings at the 1st MRI (Figure 1a). Although M-Protein levels X20 g/l were associated with a 4.4-fold risk of progression into MM (P ¼ 0.010), BMPC X10% orX20% were not linked to higher risk. According to the Mayo Clinic model, five patients were allocated to the high-risk group (M-Protein X30 g/l and BMPC X10%), which was associated with a 4.7-fold risk of progression into MM (P ¼ 0.036). Patients withX95% aPC/BMPC as detected by fluorescence in situ hybridization had a 5.3-fold risk of developing MM (P ¼ 0.010), whereas the presence of immunoparesis was not associated with adverse outcome. In addition, the concomitant presence of a solitary plasma cell tumor, elevated serum protein and beta2-microglobulin levels were associated with a higher risk of progression into MM. The summary of results from univariate analysis of baseline parameters can be found in Table 1. Changes in longitudinal wb-MRI and effect on progression into MM Patients with pathological 1st MRI were more likely to have their 2nd MRI performed within 1 year (53% vs 30%) but were not more likely to have MRI-PD at the 2nd (33% vs 30%) or any other time (50% vs 48%) compared with patients with normal 1st MRI. Overall, we found MRI-PD in 31 patients (49%). Twenty-one (33%) patients developed new FL or showed a progression of preexisting FL. Exclusively progressive diffuse bone marrow involvement was found in 10 patients (16%). MRI-PD was associated with a 16.5-fold risk of progression into symptomatic MM compared with patients with MRI-SD (Po0.0001), regardless of preexistence (HR 18.0; Po0.0001) or absence of bone marrow involvement (HR 12.0; P ¼ 0.0032) in the 1st MRI. Patients with focal or diffuse bone marrow involvement at the 1st MRI had no significantly higher risk of progression into MM, when they had MRI-SD in follow-up MRIs (Figure 1b). MRI-PD also remained a significant adverse factor when excluding the 10 patients with a concomitant plasma cell tumor (HR 13.7; Po0.0001) from the analysis. Landmark analysis at 2nd MRI Landmark analysis at the 2nd MRI (median of 388 days after 1st MRI) showed that MRI-PD was associated with a 7-fold risk of progression into MM (Po0.0001, Figure 1c) also when excluding the 10 patients with evidence for a plasma cell tumor (HR 6.8; P ¼ 0.0001). Landmark analysis at the 2nd MRI also confirmed that the risk of progression into MM was independent of diffuse or focal bone marrow involvement at the first MRI. Patients with MRI-SD at the 2nd MRI had no higher risk of progression into MM, even in the presence of focal/diffuse lesions at the 1st MRI (Figure 1c). MRI-PD at the 2nd MRI was of prognostic significance in both groups, patients who received the 2nd MRI within 1 year (HR 6.5; P ¼ 0.005) and patients with 2nd MRI after 1 year (HR 17.8; P ¼ 0.0007, see Supplementary Figure 1). Multivariate analysis Separate multivariate analyses were performed for established-risk factors that had a significant effect on progression into MM in our cohort (M-Protein and aPC/BMPC X95%) as well as FL at the 1st Leukemia (2014) 1902 – 1908
Longitudinal MRI in smoldering myeloma M Merz et al
1904 No infiltration
Proportion of progressive disease
100%
Diffuse infiltration 1 focal lesion ≥ 2 focal lesion
75%
p (log-rank) < 0.0001
50%
25%
0% 0
1
2
3 4 5 6 Years since first MRI
At risk 23 19 12 9
22 17 12 6
20 16 10 3
16 12 8 1
15 9 4 1
7
6 5 1 0
14 8 2 0
2 3 0 0
Proportion of progressive disease
1.0
MRI #1
0.8
Follow-up MRIs
normal
MRI-SD
normal
MRI-PD
pathologic
MRI-SD
pathologic
MRI-PD
0.6 0.4 0.2 0.0 0
1
2
3
4
5
6
7
8
9
10
Years since first MRI
Proportion of progressive disease
100%
MRI #1
MRI #2
normal
MRI-SD
normal
MRI-PD
pathologic MRI-SD pathologic MRI-PD
75%
p (log-rank) < 0.0001
50%
25%
0% 0
1
2
3
4
5
6
7
Years since first MRI At risk
Leukemia (2014) 1902 – 1908
16
14
10
8
3
2
0
0
7
2
2
2
1
1
0
0
27
22
17
12
9
4
3
0
13
6
3
1
1
1
1
1
& 2014 Macmillan Publishers Limited
Longitudinal MRI in smoldering myeloma M Merz et al
1905 MRI and MRI-PD (Table 2). In both analyses, the presence of X2 FL at the 1st MRI was no longer associated with a higher risk of progression into MM. MRI-PD remained an independent risk factor for progression into MM in the presence of initial M-Protein X20 g/l (HR 14.1; Po0.001) or aPC/BMPC X95% (HR 10.4; P ¼ 0.001). Multivariate analysis also confirmed that M-Protein X20 g/l and aPC/BMPC X95% were independent predictors for progression into MM in our cohort (Table 2). Correlation of MRI with clinical data Comparing baseline characteristics and risk factors from patients with or without pathological findings at the 1st MRI, we found no significant differences between both groups (see Supplementary Table 1). Patients with findings in the 1st MRI had same median M-Protein levels as patients with a normal 1st MRI (14.9 g/l). Analysis of the association between longitudinally assessed laboratory parameters and results from wb-MRI showed that patients with MRI-PD experienced a significant decrease of
Table 1.
hemoglobin levels during the observation period (P ¼ 0.02). No significant correlation of MRI-PD with serum M-Protein was found. Figure 2 gives an overview of the performed wb-MRIs and the occurrence of CRAB criteria for every patient with MRI-PD during the observation period. DISCUSSION MRI has evolved as a reliable technique for risk stratification at the initial workup for patients with SMM and symptomatic MM, as the presence of focal or diffuse marrow involvement is linked to adverse outcome in both patient groups.7–10,14,15 A recent study from our group revealed that findings from MRI before and after high-dose therapy are correlated with response and survival in symptomatic MM.16 However, to our knowledge, the current study is the first showing the prognostic significance of longitudinally performed wb-MRI in patients with SMM. With the current study, we demonstrate that longitudinally performed wb-MRIs contribute to the risk stratification in patients
Univariate analysis of baseline parameters and findings from the initial MRI
Variable Age (years) hemoglobin (g/dl) Platelets (per nl) Leukocytes (per nl) Creatinin (mg/dl) Calcium (mmol/l) Total Protein (g/l) LDH (U/l) CRP (mg/l) Albumin (g/l) beta 2-MG (mg/l) Variable M-ProteinX20 g/l M-ProteinX30 g/l BMPC X10% BMPC X20% Sex (male) Plasma cell tumor ISS II MRI diffuse MRI 1 FL MRI X2 FL Mayo high risk FLC ratio o0.125;48 Immunoparesis aPC/BMPC X95% High-risk cytogenetic
n/N
Median
Range
HR
95% CI
P-value
63/63 62/63 62/63 62/63 63/63 61/63 60/63 63/63 47/63 55/63 47/63
55 13.90 263 5.4 0.81 2.32 80.7 172 2 43.9 1.6
26–79 10.3–16.7 4–537 2.4–14.0 0.52–1.91 2.05–2.60 64.1–108.5 113–393 2–24 36.1–65.2 0.8–4.2
1.00 1.06 1.00 1.03 1.59 1.82 1.05 1.01 1.05 1.02 1.76
0.96–1.04 0.76–1.46 0.99–1.00 0.86–1.25 0.31–8.08 0.05–64.3 1.01–1.09 1.00–1.01 0.99–1.12 0.93–1.12 1.01–3.05
0.988 0.746 0.720 0.737 0.576 0.742 0.018 0.061 0.119 0.638 0.046
n/N
Median
Range
HR
95% CI
P-value
Progression 2 years (%)
14/46 5/46 34/51 15/51 39/63 10/63 2/42 19/63 12/63 9/63 5/36 11/25 18/57 5/27 10/27
14.9
0–40.1
13.0
0–46.0
4.39 3.64 0.74 0.93 0.42 4.52 2.37 0.56 1.21 6.60 4.69 3.15 1.32 5.30 1.74
1.43–13.5 0.96–13.8 0.29–1.87 0.33–2.61 0.17–1.05 1.82–11.19 0.30–18.5 0.17–1.82 0.36–4.04 2.29–19.0 1.11–19.8 0.61–16.4 0.45–3.89 1.50–18.7 0.53–5.71
0.010 0.057 0.520 0.888 0.062 0.001 0.410 0.334 0.753 0.001 0.036 0.172 0.610 0.010 0.363
29 40 24 27 28 40 50 16 8 67 40 34 28 80 50
Abbreviations: aPC, aberrant plasma cells; beta 2-MG, beta 2-microglobulin; BMPC, bone marrow plasma cells; CI, confidence interval; CRP, C-reactive protein; FL, focal lesions; FLC, free light-chain; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehyrogenase; MRI, magnetic resonance imaging. M-Protein levels X20 g/l and X30 g/l are shown as the optimal cut-off using a maximally selected log-rank test approach was 2.4 g/dl in our cohort. Bold and italic numbers represent significant findings.
Figure 1. Effects of baseline and follow-up findings from wb-MRI on progression into symptomatic MM. (a) Kaplan–Meier plots for patients with different infiltration patterns in initial MRI. The presence of X2 FL at initial MRI was linked to a significantly shorter time to progression into MM. P-value is derived from log-rank test. (b) Simon–Makuch curves showing the proportion of patients with progressive disease in dependency of bone marrow infiltration at initial MRI (MRI no. 1) and MRI-PD/ MRI-SD from follow-up MRIs as time-dependent variable. (c) Kaplan–Meier plots for progression into MM according to the pattern of bone marrow infiltration at the initially performed MRI (MRI no. 1) and the occurrence of MRI-PD or MRI-SD at the 2nd MRI (MRI no. 2). Patients with MRI-PD exhibited a significant shorter time to progression into MM in case of prior pathological or normal bone marrow signal. Patients with pathological bone marrow signal at the 1st MRI and MRI-SD did not have a shorter time to progression into MM than patients with no bone marrow infiltration in both, the 1st and 2nd MRI. P-values are derived from log-rank test. & 2014 Macmillan Publishers Limited
Leukemia (2014) 1902 – 1908
Longitudinal MRI in smoldering myeloma M Merz et al
1906 with SMM and MRI-PD defines a subgroup with high risk of progression into MM, regardless if FL were present at the initial MRI. Beyond initial and longitudinal assessment with wb-MRI, we included in our analysis established baseline risk factors: The size of serum M-Protein and aPC/BMPC X95% were also significant predictors for adverse outcome in our cohort. In multivariate analysis, both parameters and MRI-PD from longitudinal wb-MRI were independent risk factors for progression into MM. Table 2.
Multivariate analysis HR
95% CI
P-value
1st MRI X2 FL MRI-PD M-Protein X20 g/l
2.24 14.1 1.05
0.84–5.98 5.06–39.3 1.01–1.09
0.108 o0.001 0.022
1st MRI X2 FL MRI-PD aPC/BMPCX95%
2.90 10.4 6.40
0.45–18.6 2.57–42.0 1.36–30.2
0.260 0.001 0.020
Variable
Abbreviations: aPC, aberrant plasma cells; BMPC, bone marrow plasma cells; CI, confidence intervals; FL, focal lesions; HR, hazard ratio; MRI, magnetic resonance imaging; MRI-PD, radiological progressive disease. Multivariate analysis for serum M-Protein and aPC/BMPC X95% at initial MRI as well as radiological progressive disease (MRI-PD) for progression into symptomatic MM. P-values are derived from Wald-test in Cox proportional hazard analysis. Bold and italic numbers represent significant findings.
Month
0
3
6
9
12
15
18
21
24
27
30
33
36
This underlines that longitudinally performed wb-MRI provides additional information, beyond the risk assessment of baseline parameters only. However, effects of abnormal serum free lightchain ratio3 or cytogenetic aberrations12,17 did not reach statistical significance due to the limited available data and the small number of events observed in our population. Although we confirmed that aPC/BMPC X95% detected by the largest fluorescence in situ hybridization abnormality is a factor for adverse outcome, further studies need to clarify the role of aberrations, which are present only in subclones and account for the clonal heterogeneity of the disease. Also, BMPC had no impact on progression into MM. This might be explained by the fact that BMPC are not homogeneously distributed in the bone marrow of patients and aspirates as well as biopsies only encompass a small region. Here, follow-up MRIs allowed non-invasive insight into the distribution of myeloma cells in the bone marrow overtime. Patients with MRI-PD showed a significant decrease in hemoglobin levels during the observation period. This is in line with the results from the natural history study of SMM patients performed by Rosin˜ol et al.,18 which showed a decrease in hemoglobin levels for patients with progression into MM compared with baseline parameters. In their analysis and more recently in a study by Kastritis et al. the most frequent cause of progression into MM was anemia.18,19 In our study, the development of lytic bone lesions was the primary cause of progression into MM. A possible explanation for this might be that in our patients with MRI-PD (31 patients), mostly progressive focal
39
42
45
48
51
54
57
60
63
66
69
72
75
78
81
Patient 1 2
B
3 A
4 5
A
6
B
7 8 9 10
B
11 12 13 14 B
15 16 17
B
18
B B
19 20
B B
21
23
B
24
A
25
B
26
B
27
B
29
B
30
Figure 2.
st No findnigs at 1 MRI
Follow-up MRI with MRI-SD Follow-up MRI with MRI-PD Follow-up without CRAB
R
28
31
Figure legend st Focal / diffuse lesionsat 1 MRI
22
Follow-up with occurence of CRAB
C
R
A
B
C B
Overview of the performed wb-MRIs and the course of disease for every patient with MRI-PD during the observation period.
Leukemia (2014) 1902 – 1908
& 2014 Macmillan Publishers Limited
Longitudinal MRI in smoldering myeloma M Merz et al
1907 bone marrow involvement was found (21 patients), whereas only 10 patients showed exclusively a progressive diffuse pattern. Moulopoulos and colleagues showed for patients with symptomatic MM that diffuse bone marrow involvement was more often associated with anemia (51%) compared with patients with focal (26%) or normal (34%) MRI.20 In agreement with our study, they also demonstrated that the skeletal survey showed more often osteolytic lesions in patients with FL in the MRI (91%) than in patients with diffuse (75%) or absent (49%) bone marrow involvement. From our study, we cannot exclude if every new focal lesion might have caused a corresponding osteolysis on CT, as CT was not performed routinely on the same day as wb-MRI. Further prospective studies will have to clarify the pathophysiological connection between focal bone marrow lesions as detected by MRI and focal osteolyses as detected by X-ray or CT. In addition to the identification of a high-risk group for progression into MM, we were able to demonstrate in our current analysis that patients with MRI-SD had no higher risk of progression into MM, even if FL were found in the initial MRI. This underlines the importance of longitudinal imaging in patients with SMM. The International Myeloma Working Group guidelines currently recommend a skeletal survey for follow-up only if there is evidence for progressive disease.1 However, X-ray studies require the induction of damage to mineralized bone for the detection of myeloma bone disease and are relatively insensitive to diffuse infiltration in cancellous bone compared with MRI21,22 excluding a predictive information because bone destruction already has to have taken place if X-ray detects any changes. As MRI enables the detection of bone marrow infiltration before the destruction of cortical bone becomes evident,23 we conclude that MRI is the best imaging method for longitudinal follow-up of SMM patients. Major downside of the current study is its retrospective character and the small number of patients included in the analysis. The decisions for follow-up MRIs were made by the treating physicians and not based on predefined schedules like in a prospective trial. As a result from that, patients with pathological findings in the 1st MRI were more likely to have their 2nd MRI within 1 year compared with patients with a normal 1st MRI. However, patients with findings in the 1st MRI were not more likely to have MRI-PD at the 2nd or any following MRI. Furthermore, there were no other differences in baseline characteristics for patients with or without findings in the 1st MRI. As we found that MRI-PD was associated with adverse outcome in patients with or without a pathological 1st MRI and was not affected by early (o1year) or late (41year) reassessment, we conclude that the selection did not affect our analysis. Because of these results, we postulate that wb-MRI independently contributes to risk stratification of patients with SMM. Therefore, we currently do not decide whether a patient has to be followed-up closely with wb-MRI based on findings from the initial assessment, but perform annual wb-MRI in all patients with SMM for the first 5 years after primary diagnosis. CT was only performed either if MRI-PD was observed or if there was evidence for progressive disease from clinical follow-up according to International Myeloma Working Group guidelines.1 Although according to current guidelines, systemic treatment is not indicated before CRAB criteria are fulfilled, the study published by Mateos et al.24 recently demonstrated a significant positive effect of a systemic treatment with lenalidomide on overall survival in patients with high-risk SMM. Therefore, the identification of a progressive, advanced or evolving type of SMM by follow-up examination with MRI in our study is even more important as there is an urgent need to identify those SMM patients with a high risk of progression who might benefit from early treatment. In this setting, some authors even speak of an ‘early myeloma’ rather than just high-risk SMM.25 & 2014 Macmillan Publishers Limited
In conclusion, we showed that longitudinally performed wb-MRIs contribute to the risk stratification, regardless of pathological findings at the initial MRI and are correlated with clinical parameters in patients with SMM. Our findings emphasize the role of longitudinal imaging in patients with SMM and might contribute to the developing role of treatment strategies24 for patients with ‘early’ or ‘evolving’ myeloma’.18,25 CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank the Dietmar-Hopp-Stiftung and the Deutsche Forschungsgemeinschaft (SFB Transregio 79) for research funding.
REFERENCES 1 Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010; 24: 1121–1127. 2 Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007; 356: 2582–2590. 3 Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson D, Benson J et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008; 111: 785–789. 4 Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV, de Coca AG et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007; 110: 2586–2592. 5 Blade J, Dimopoulos M, Rosinol L, Rajkumar SV, Kyle RA. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol 2010; 28: 690–697. 6 Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117: 5573–5581. 7 Mariette X, Zagdanski AM, Guermazi A, Bergot C, Arnould A, Frija J et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma. Br J Haematol 1999; 104: 723–729. 8 Moulopoulos LA, Dimopoulos MA, Smith TL, Weber DM, Delasalle KB, Libshitz HI et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995; 13: 251–256. 9 Baur-Melnyk A, Buhmann S, Durr HR, Reiser M. Role of MRI for the diagnosis and prognosis of multiple myeloma. Eur J Radiol 2005; 55: 56–63. 10 Hillengass J, Fechtner K, Weber MA, Bauerle T, Ayyaz S, Heiss C et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010; 28: 1606–1610. 11 Bauerle T, Hillengass J, Fechtner K, Zechmann CM, Grenacher L, Moehler TM et al. Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging. Radiology 2009; 252: 477–485. 12 Neben K, Jauch A, Hielscher T, Hillengass J, Lehners N, Seckinger A et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol 2013; 31: 4325–4332. 13 Simon R, Makuch RW. A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Stat Med 1984; 3: 35–44. 14 Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia 2009; 23: 1545–1556. 15 Walker R, Barlogie B, Haessler J, Tricot G, Anaissie E, Shaughnessy Jr. JD et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007; 25: 1121–1128.
Leukemia (2014) 1902 – 1908
Longitudinal MRI in smoldering myeloma M Merz et al
1908 16 Hillengass J, Ayyaz S, Kilk K, Weber MA, Hielscher T, Shah R et al. Changes in magnetic resonance imaging before and after autologous stem cell transplantation correlate with response and survival in multiple myeloma. Haematologica 2012; 97: 1757–1760. 17 Rajkumar SV, Gupta V, Fonseca R, Dispenzieri A, Gonsalves WI, Larson D et al. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia 2013; 27: 1738–1744. 18 Rosinol L, Blade J, Esteve J, Aymerich M, Rozman M, Montoto S et al. Smoldering multiple myeloma: natural history and recognition of an evolving type. Br J Haematol 2003; 123: 631–636. 19 Kastritis E, Terpos E, Moulopoulos L, Spyropoulou-Vlachou M, Kanellias N, Eleftherakis-Papaiakovou E et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia 2013; 27: 947–953. 20 Moulopoulos LA, Dimopoulos MA, Kastritis E, Christoulas D, Gkotzamanidou M, Roussou M et al. Diffuse pattern of bone marrow involvement on
21 22 23
24
25
magnetic resonance imaging is associated with high risk cytogenetics and poor outcome in newly diagnosed, symptomatic patients with multiple myeloma: a single center experience on 228 patients. Am J Hematol 2012; 87: 861–864. Zamagni E, Cavo M. The role of imaging techniques in the management of multiple myeloma. Br J Haematol 2012; 159: 499–513. Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol 2011; 29: 1907–1915. Tan E, Weiss BM, Mena E, Korde N, Choyke PL, Landgren O. Current and future imaging modalities for multiple myeloma and its precursor states. Leuk Lymphoma 2011; 52: 1630–1640. Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F, Lopez Corral L et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013; 369: 438–447. Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging ‘early myeloma’. Leuk Lymphoma 2013; 54: 1355–1363.
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
Leukemia (2014) 1902 – 1908
& 2014 Macmillan Publishers Limited