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- PATIENTS AND METHODS
We assessed the role of spinal magnetic resonance imaging (MRI) and bone densitometry as prognostic factors in patients with asymptomatic stage I multiple myeloma (MM) and negative skeletal survey. 55 consecutive patients underwent spinal MRI and 41 of them underwent bone densitometry by dual-energy X-ray absorptiometry (DEXA).
Spinal MRI studies showed evidence of bone marrow involvement in 17/55 patients (31%). A diffuse pattern was present in three patients and a focal pattern in 14 patients, nine of them with only one nodular lesion. During a median follow-up of 25 months, 10 patients had disease progression, 8/17 patients with abnormal MRI and 2/38 patients with normal MRI. Median time to disease progression was not reached in both groups but was significantly different for patients with normal and those with abnormal patterns on MRI (P < 0.0001). Lumbar BMD was only slightly decreased compared with normal people (median lumbar Z score − 0.43) and was not of prognostic value. Using a multivariate analysis the only two independent significant prognostic parameters were abnormal MRI (P < 0.001, HR 30.4, 95% CI 4.3–213) and bone marrow plasmacytosis > 20% (P = 0.004, HR 16.4, 95% CI 2.6–104).
Thus, spinal MRI but not bone densitometry, appeared to be justified in patients with stage I asymptomatic MM and negative skeletal survey.
Various criteria have been proposed to distinguish patients who are likely to remain stable without therapy for a long period from those who are at high risk for a serious complication and might benefit from early chemotherapy. They include the presence of one lytic bone lesion on skeletal survey, a high level of serum myeloma protein or urinary Bence-Jones protein, the degree of bone marrow plasmacytosis, anaemia and the IgA isotype of the monoclonal component (Dimopoulos et al, 1993; Facon et al, 1995; Kyle & Greipp, 1980; Weber et al, 1997; Wisloff et al, 1991). Since the presence of a lytic bone lesion on skeletal survey is constantly associated with a median time to progression of about 8–10 months, such patients should be treated soon after diagnosis.
In patients without any lytic bone lesions on skeletal survey, two sensitive techniques may disclose bone abnormalities related to MM: spinal magnetic resonance imaging (MRI) and bone densitometry. One group assessed the value of spinal MRI in 47 patients with asymptomatic MM and concluded that MRI appeared to be justified only for patients at intermediate risk defined by one of the three following features: serum peak level > 30 g/l, IgA myeloma, Bence-Jones protein excretion > 50 mg/d (Moulopoulos et al, 1995; Weber et al, 1997). The prognostic value of bone densitometry in patients with asymptomatic MM has never been studied, although its value as a marker of treatment response has been established in patients with advanced MM (Mariette et al, 1992, 1995).
In this study concerning 55 patients we assessed the role of spinal MRI and bone densitometry as prognostic factors in patients with asymptomatic stage I MM without any lytic bone lesions on skeletal survey.
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- PATIENTS AND METHODS
Most patients with MM are diagnosed with one or more symptoms which require immediate treatment. In recent years the increased frequency of multichemical blood screening has led to the incidental diagnosis of many patients in early phase of the disease and who are free of symptoms. These patients with asymptomatic MM do not require chemotherapy until disease progression, because there is no evidence that prompt treatment provides any survival benefit (Hjorth et al, 1993). However, a subgroup of these asymptomatic patients is at high risk for a serious complication and therefore might benefit from early chemotherapy. Several studies have defined criteria that distinguish patients with early disease progression from those with disease that may remain stable for many years (Dimopoulos et al, 1993; Facon et al, 1995; Kyle & Greipp, 1980; Weber et al, 1997; Wisloff et al, 1991). In most of them the presence of a lytic bone lesion was associated with early progression, usually within a year. In this report we show that, in patients without any lytic bone lesion on skeletal survey, abnormal spinal MRI was an independent prognostic feature of disease progression, whereas decreased lumbar bone mineral density assessed by dual-energy X-ray absorptiometry did not carry any adverse prognosis.
The presence of an abnormal MRI pattern was not correlated with the degree of osteoporosis, evaluated by a very sensitive method: lumbar and total body bone densitometry. We confirmed that, in contrast to patients with stage III MM, patients with asymptomatic stage I MM have a roughly normal bone density (median lumbar Z score − 0.43) whatever their MRI pattern (Abildgaard et al, 1996). Moreover, bone density had no prognostic value in these patients. Thus, bone densitometry, which might be useful in some stage III MM patients, showing decreased lumbar BMD which may improve with effective chemotherapy (Mariette et al, 1992, 1995), appears to have, in most cases, no indication in patients with asymptomatic stage I MM.
Spinal MRI is a sensitive technique to detect focal or diffuse bone marrow involvement in patients with MM (Bellaiche et al, 1997; Fruehwald et al, 1988; Kusumoto et al, 1997; Ludwig et al, 1987; Moulopoulos et al, 1994; Tertti et al, 1995). This procedure has been shown to be useful in cases where epiduritis was suspected and to define the staging and treatment of patients with solitary plasmacytoma of bone (Moulopoulos et al, 1993). In patients with stage III symptomatic myeloma, spinal MR imaging is abnormal in > 80% of the cases but does not provide information which could modify the treatment (Bellaiche et al, 1997; Kusumoto et al, 1997; Tertti et al, 1995). Changes in MRI seem to be fairly well correlated with response to chemotherapy (Moulopoulos et al, 1994) and therefore sequential MRI might be useful in some patients without any biological markers to assess the response to treatment, although this remains to be definitely established. In patients with stage I asymptomatic MM and one lytic bone lesion on skeletal survey, spinal MR imaging is abnormal in most cases: during the period of the present study it was performed in eight patients with a single lytic bone lesion and was abnormal in seven cases (data not shown). In these patients, spinal MR imaging patterns did not yield to changes in treatment which was required soon after diagnosis. In patients with stage I asymptomatic MM and negative skeletal survey, we detected an abnormal spinal MRI pattern in 31% (17/55) of the patients, which is in accordance with two other studies of the literature which included enough patients with asymptomatic stage I MM patients: 17/47 (36%) in the study by Weber et al (1997) and 7/24 (29%) in the study by Van de Berg et al (1996). The pattern of bone marrow involvement was focal in 14 patients (a single nodular lesion in nine patients and multiple nodular lesions in five patients) and diffuse in three patients. In our study, MRI of the lumbar spine and of the last three dorsal vertebras was performed in all patients but 19 patients also underwent thoracic examination. However, the latter could not detect lesions in patients whose lower spine examination (including T10, T11, T12, lumbar spine and sacrum) was normal. Contrary to Weber et al (1997), we did not detect any patients with a variegated pattern which, in any case, appears rare.
An abnormal MRI pattern, when it is present, might be an additive tool to differentiate asymptomatic MM from MGUS. Indeed, in patients with MGUS, MRI is always normal (Bellaiche et al, 1997). The distinction between asymptomatic MM and MGUS is difficult and is based on bone marrow examination (Greipp & Kyle, 1983). Some authors take into account only the percentage of bone marrow plasma cells to diagnose MM. However, marrow infiltration is frequently uneven in MM and the failure to demonstrate plasma cells in excess of 10%, even on several marrow specimens, does not rule out the possibility of MM. Other cytologists take into account not only the percentage of bone marrow plasma cells but also the presence of plasma cell nuclear abnormalities to diagnose MM. Like Weber et al (1997), which included 12/47 patients with < 10% bone marrow plasma cells, we considered this latter definition of MM in our study. Interestingly, the incidence of patients with abnormal spinal MR imaging was the same in patients with < 10% bone marrow plasma cells (33%) and in those with > 10% (28%). Likewise, the risk of progression to symptomatic MM was not different in patients with more or less than 10% bone marrow plasma cells: 5/28 and 5/27 (17%), respectively. These data confirm that we dealt with patients with asymptomatic stage I MM and not with MGUS.
The most interesting finding of the current study is the multivariate analysis of all prognostic features which points to the value of two independent parameters: an abnormal MRI pattern and marrow plasmacytosis. Marrow plasmacytosis had been already mentioned in a multivariate regression analysis as an independent prognostic feature in stage I asymptomatic MM (Facon et al, 1995). In another report evaluating spinal MRI in patients with asymptomatic MM, marrow plasmacytosis appeared as a prognostic factor in a univariate regression analysis (Weber et al, 1997; Moulopoulos et al, 1995). In our study, as in the study by Weber et al (1997), spinal MRI appeared to be of important prognostic value. Because the number of patients with different abnormal MRI patterns was small, we could not determine if one of the three observed patterns may also have prognostic value. The two patients with both bone marrow plasmacytosis > 20% and an abnormal pattern on MRI progressed within only 2 months. On the other hand, only one of the 33 patients with normal spinal MRI and marrow plasmacytosis < 20% had disease progression within a median follow-up of 25 months. Therefore spinal MR imaging appeared to be justified in stage I asymptomatic MM patients with negative skeletal survey, which must remain under close supervision when MRI is shown to be abnormal. Median time to progression in patients with abnormal spinal MRI seems to be in the order of 2 years. Whether or not the presence of abnormal MRI findings must lead to initiation of treatment, either with chemotherapy or bisphosphanates, needs further evaluation.