1 Department of Radiology and 2 Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 3 Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
* Correspondence to: Prof. M. A. Dimopoulos, 227 Kifissias Avenue, Kifissia, Athens 14561, Greece. Tel: +30-210-3381541; Fax: +30-210-8131383; E-mail: mdimop{at}med.uoa.gr
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival.
Results: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation.
Conclusion: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management.
Key words: MRI, multiple myeloma, prognosis
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Magnetic resonance imaging (MRI) is a non-invasive technique which can sample a large volume of bone marrow. This modality depicts bone marrow abnormalities in multiple myeloma with greater sensitivity than conventional radiographs and CT [4]. In our current study we evaluated the correlation of different MRI patterns with the ISS and with the outcome of patients with previously untreated symptomatic multiple myeloma.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
These patients were classified according to the recently proposed International Staging System (ISS) for multiple myeloma: stage I, serum ß2-microglobulin <3.5 mg/l and serum albumin 3.5 g/dl; stage II, neither stage I nor III; stage III, serum ß2 microglobulin
5.5 mg/l. All patients received primary treatment with high-dose dexamethasone-containing regimens such as vincristine and doxorubicin administered as a 4 day continuous infusion with dexamethasone pulses (VAD), melphalandexamethasone, VAD bolus or VAD with liposomal doxorubicin and the hyper-CVAD regimen [5
7
]. High-dose therapy (HDT) with autologous stem cell transplantation was administered to 61 patients. These patients received HDT during various phases of their disease, and 90% were aged <65 years at the time of administration. The conditioning regimen consisted of high-dose melphalan 200 mg/m2 i.v. in 80% of patients, while the remaining patients received high-dose melphalan with total body irradiation or a combination of thiotepa, busulfan and cyclophosphamide as previously described [8
10
].
MRI patterns were defined as described previously [4, 11
]. Briefly, four patterns were identified. A normal pattern required no evidence of abnormal signal. The focal pattern consisted of localized areas of abnormal marrow. On T1-weighted images, focal lesions are darker than yellow marrow and slightly darker than or isointense with red marrow. On T2-weighted images they are brighter than both red and yellow marrow, and on enhanced T1-weighted images they enhance to various degrees depending on the vascularity of the underlying pathologic process. In the diffuse MRI pattern of abnormal marrow, the normal bone marrow is completely replaced by the abnormal process. The intervertebral disks appear brighter than or are isointense with the diseased marrow. On T1-weighted images, there is a diffuse decrease in the signal intensity of the marrow. On T2-weighted images a variable increase in the signal intensity of the abnormal marrow is observed. After the administration of intravenous contrast, the abnormal marrow enhances. The intervertebral disks appear darker than the enhanced spine. The variegated pattern consists of innumerable small foci of disease on a background of intact marrow. The small lesions of the variegated pattern are dark on T1-weighted images and bright on T2-weighted images, and they enhance after the administration of intravenous contrast.
Response to treatment was assessed according to the EBMT criteria [12]. Survival was calculated from the start of treatment to death from any cause or the last follow-up visit, whichever occurred first.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An MRI protocol for the study of bone marrow consists of T1-weighted images, short inversion recovery or fast spin echo T2-weighted images with fat saturation and contrast-enhanced T1-weighted images. MRI is a qualitative measure, i.e. the degree of marrow infiltration by bone marrow biopsy and the degree of hyperintensity on STIR sequence may be difficult to correlate. T1-weighted MR images are most sensitive in depicting abnormal bone marrow. In patients with focal bone marrow patterns, MRI may reveal lesions as small as 5 mm but it may not show microscopic disease. In patients with the diffuse MRI pattern the change in signal intensity depends on the percentage of neoplastic cells in the bone marrow, i.e. bone marrow plasmacytosis below 10% may be associated with a false-negative MRI study.
We evaluated a large number of patients with previously untreated symptomatic multiple myeloma who had undergone MRI of the spine before initiation of antimyeloma therapy in order to assess the prognostic significance of this imaging modality. Furthermore, with a minimum follow-up of 3 years we are able to provide mature survival data for our patients. Over 90% of our patients had an abnormal MRI examination and the focal pattern was the most common pattern. Approximately a quarter of our patients had a diffuse pattern of marrow replacement which was associated with features of more advanced disease such as severe anemia, extensive bone marrow plasmacytosis, hypercalcemia and elevated serum LDH. These findings expand our preliminary observation and the findings of other series [11, 18
20
]. Moreover, a diffuse MRI pattern was more frequently associated with ISS III disease than the other MRI patterns. Half of patients with the diffuse pattern were stage III whereas half of patients with the focal pattern were stage I. The diffuse pattern was also associated with a significantly inferior survival when compared with the other abnormal MRI patterns or a normal MRI study. We believe that this is a consequence of the more advanced disease associated with this MRI pattern. Similar findings have also been reported by others [18
, 19
]. However, Lecouvet et al. [20
] did not observe inferior survival of their patients with the diffuse pattern when compared with those with a focal pattern despite the fact that the former patients had features of more advanced disease. This discrepancy might have been due to the small number of patients included in their series. More recently, Baur et al. [21
] performed MRI studies of 77 patients with multiple myeloma and observed that patients with the normal or variegated pattern had a significantly better survival than patients with the diffuse or focal pattern.
Our analysis indicated that the presence of a diffuse MRI pattern could separate patients with ISS I or II into two subgroups with different survival times. Thus the median survival of 28 months for patients with ISS I or II and a diffuse MRI was similar to the median survival of 24 months for patients with ISS III. The presence or absence of a diffuse MRI pattern was less significant in patients with ISS III, and this was more likely to be due to the small number of patients. Based on our data, we believe that an MRI study may be of particular value in patients with low- or intermediate-stage multiple myeloma (ISS I or II). There is limited information regarding the prognostic significance of different MRI patterns in patients treated with high-dose therapy and autologous stem cell transplantation. Lecouvet et al. [22] evaluated 25 patients and observed that individual MRI parameters did not correlate with response duration and survival. Our data indicated that the negative impact of a diffuse MRI pattern was present in both patients who received conventional chemotherapy only and patients who received high-dose therapy. Further studies on the role of MRI in patients undergoing high-dose therapy are needed. Recent evidence suggests that the diffuse MRI pattern is associated with increased neovascularization of the bone marrow [23
]. This observation may also explain the impaired prognosis of patients with the diffuse MRI pattern.
Recent studies have used oligonucleotide microarray profiling and biochemical and immunohistochemical analyses to identify molecular determinants of bone lesions in patients with multiple myeloma. It was found that overexpression of the dickkopf1 gene and overproduction of its corresponding protein DKK1 was associated with the presence of focal lesions on MRI studies [24]. Similar analyses may identify differences in the activation of genes in patients with diffuse MRI compared with other MRI patterns. We conclude that MRI pattern of involvement has prognostic significance in patients with multiple myeloma who require treatment; diffuse marrow involvement by MRI adds to the evaluation of patients with multiple myeloma and their management.
Received for publication April 19, 2005. Revision received June 27, 2005. Accepted for publication June 28, 2005.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Smith DB, Scarffe JH, Eddleston B. The prognostic significance of X-ray changes at presentation and reassessment in patients with multiple myeloma. Hematol Oncol 1988; 6: 16.[ISI][Medline]
3. Greipp PR, San Miguel JF, Durie BG et al. International Staging System for Multiple Myeloma. J Clin Oncol 2005; 23: 34123420.
4. Dimopoulos MA, Moulopoulos LA, Datseris I et al. Imaging of myeloma bone diseaseimplications for staging, prognosis and follow-up. Acta Oncol 2000; 39: 823827.[CrossRef][ISI][Medline]
5. Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 1990; 33: 8689.[ISI][Medline]
6. Dimopoulos MA, Pouli A, Zervas K et al. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 2003; 14: 10391044.
7. Dimopoulos MA, Weber D, Kantarjian H et al. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol 1996; 52: 7781.[CrossRef][ISI][Medline]
8. Alexanian R, Dimopoulos M, Smith T et al. Limited value of myeloablative therapy for late multiple myeloma. Blood 1994; 83: 512516.
9. Alexanian R, Dimopoulos MA, Hester J et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84: 42784282.
10. Dimopoulos MA, Alexanian R, Przepiorka D et al. Thiotepa, busulfan, and cyclophosphamide: a new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma. Blood 1993; 82: 23242328.[Abstract]
11. Moulopoulos LA, Varma DG, Dimopoulos MA et al. Multiple myeloma: spinal MR imaging in patients with untreated newly diagnosed disease. Radiology 1992; 185: 833840.[Abstract]
12. Blade J, Samson D, Reece D et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 11151123.[CrossRef][ISI][Medline]
13. Moulopoulos LA, Dimopoulos MA, Weber D et al. Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol 1993; 11: 13111315.
14. Van de Berg BC, Lecouvet FE, Michaux L et al. Stage I multiple myeloma: value of MR imaging of the bone marrow in the determination of prognosis. Radiology 1996; 201: 243246.[Abstract]
15. Mariette X, Zagdanski AM, Guermazi A et al. Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma. Br J Haematol 1999; 104: 723729.[CrossRef][ISI][Medline]
16. Weber DM, Dimopoulos MA, Moulopoulos LA et al. Prognostic features of asymptomatic multiple myeloma. Br J Haematol 1997; 97: 810814.[ISI][Medline]
17. Moulopoulos LA, Dimopoulos MA, Alexanian R, Leeds NE, Libshitz HI. Multiple myeloma: MR patterns of response to treatment. Radiology 1994; 193: 441446.[Abstract]
18. Kusumoto S, Jinnai I, Itoh K et al. Magnetic resonance imaging patterns in patients with multiple myeloma. Br J Haematol 1997; 99: 649655.[CrossRef][ISI][Medline]
19. Stabler A, Baur A, Bartl R et al. Contrast enhancement and quantitative signal analysis in MR imaging of multiple myeloma: assessment of focal and diffuse growth patterns in marrow correlated with biopsies and survival rates. Am J Roentgenol 1996; 167: 10291036.[Abstract]
20. Lecouvet FE, Vande Berg BC, Michaux L et al. Stage III multiple myeloma: clinical and prognostic value of spinal bone marrow MR imaging. Radiology 1998; 209: 653660.[Abstract]
21. Baur A, Stabler A, Nagel D et al. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon? Cancer 2002; 95: 13341345.[CrossRef][ISI][Medline]
22. Lecouvet FE, Dechambre S, Malghem J et al. Bone marrow transplantation in patients with multiple myeloma: prognostic significance of MR imaging. Am J Roentgenol 2001; 176: 9196.
23. Baur A, Bartl R, Pellengahr C et al. Neovascularization of bone marrow in patients with diffuse multiple myeloma: a correlative study of magnetic resonance imaging and histopathologic findings. Cancer 2004; 101: 25992604.[CrossRef][ISI][Medline]
24. Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 24832494.
|