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Keywords:

  • multiple myeloma;
  • bone marrow;
  • bone marrow neoplasms;
  • magnetic resonance;
  • medical imaging

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

In an attempt to compare the sensitivity of bone radiographs and bone marrow magnetic resonance (MR) imaging for bone lesion detection in patients with stage III multiple myeloma (MM) and to evaluate the possible consequences of the replacement of the conventional radiographic skeletal survey (RSS) by an MR survey of the spinal and pelvic bone marrow in these patients, we obtained MR studies of the thoracic and lumbar spine, pelvis and proximal femurs in addition to the conventional RSS (including radiographs of the skull, entire spine, pelvis, ribs, humerus and femurs) in 80 consecutive patients with newly diagnosed stage III MM according to the Durie and Salmon staging system (based on blood tests and on the RSS). The performance of MR and radiographic studies to detect bone lesions in given anatomic areas and in given patients were compared. The consequences on MM staging following the substitution of the RSS by the MR survey were assessed.

MR imaging was superior to radiographs for lesion detection in the spine (76% v 42% of patients) and pelvis (75% v 46% of patients). The RSS was superior to the limited MR imaging survey for the detection of bone involvement in the patient population (87.5% v 79% of patients). If the RSS had been replaced by the MR imaging survey for patient staging, 7/80 patients would have been categorized as stage I and one as stage II MM on the basis of normal MR findings and biological findings consistent with these stages.

Substitution of the RSS by a limited spinal and pelvic marrow MR survey would lead to ‘understaging’ of 10% of patients with otherwise stage III MM on the basis of blood tests and the conventional RSS.

Multiple myeloma (MM) is a malignant disorder of plasma cells that seed throughout the bone marrow, usually produce a monoclonal immunoglobulin in the blood, urine, or both, and cause lytic bone lesions (Malpas & Caroll, 1995; Salmon & Cassady, 1995). The variability in individual symptoms and rate of disease progression, as well as the necessity to optimize therapy regimens, have raised the need for staging of the disease (Boccadoro & Pileri, 1997). Durie & Salmon (1975) showed that lytic bone lesions, haemoglobin, serum calcium and monoclonal component blood levels were significantly correlated with tumour mass and patient eventual survival. Their clinical staging system (Table I) based on these four parameters is still used for therapeutic management because of its easy application. Radiologists are routinely involved in patient staging, and discovery of at least two unequivocal rounded, punched-out lytic bone lesions indicates stage III MM for which immediate treatment is indicated (Durie & Salmon, 1975; Healy & Armstrong, 1994; Boccadoro & Pileri, 1995; Salmon & Cassady, 1995).

The superiority of MR imaging over plain radiographs for the detection of spinal bone lesions has been repeatedly demonstrated (Daffner et al, 1986; Ludwig et al, 1987; Fruehwald et al, 1988; Moulopoulos et al, 1994; Carlson et  al, 1995; Tertti et al, 1995). The prognostic significance of bone marrow MR imaging has been demonstrated in early and advanced MM (Moulopoulos et al, 1995; Vande Berg et  al, 1996; Weber et al, 1997; Zagdanski et al, 1997; Lecouvet et al, 1998). Several authors have suggested that MR imaging could play a role in the staging of the disease (Carlson et al, 1995; Stabler et al, 1996), but this issue has not been properly addressed.

The present study aimed to determine whether the conventional RSS could be replaced by an MR imaging survey limited to the spinal and pelvic marrow in the staging of advanced MM. We also determined the real importance of the conventional RSS in the staging of stage III MM, and compared the respective sensitivity of radiographs and MR imaging to detect bone lesions in well-defined anatomic areas.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Patient characteristics

The study population consisted of 80 consecutive patients (48 men, 32 women; age range 28–79 years, median 59 years) with untreated newly diagnosed stage III MM according to the criteria defined by Durie & Salmon (1975). These criteria are summarized in Table I. 48 patients had immunoglobulin (Ig) G myeloma, 16 had Ig A myeloma, 14 had light chain myeloma, and two had nonsecretory myeloma.

In each patient, serum immunoglobulin, haemoglobin, creatinine, calcium, β2-microglobulin and C-reactive protein (CRP) levels were determined at diagnosis. The presence of urinary Bence-Jones protein was assessed and quantified in 64 patients by protein electrophoresis using 24 h concentrate. Bone marrow cellularity, plasmacyte percentage, and the histologic patterns of marrow infiltration by myeloma cells were determined in all patients on unilateral bone marrow aspirates and biopsies obtained blindly from the posterior iliac crest.

Conventional skeletal surveys

Every patient with monoclonal gammopathy and suspected MM underwent conventional radiographic skeletal surveys, including plain radiographs of the skull (anterior-posterior (AP) and lateral), ribs (AP global, AP on the lower thoracic grid, two oblique views), spine (AP and lateral of the cervical, thoracic and lumbar areas), pelvis (AP), femurs (AP and lateral) and humerus (AP and lateral). The RSSs obtained at diagnosis in the 80 patients were prospectively reviewed by two musculoskeletal radiologists who determined by consensus the presence of unequivocal lytic lesions. The RSS was considered positive in terms of osteolytic lesion detection if at least two unequivocal bone lesions were identified. The distribution of the lesions in the different anatomical areas was recorded.

MR images acquisition and analysis

All patients underwent MRI investigation of the thoraco-lumbar and pelvic bone marrow within 1 week after diagnosis, before the start of treatment.

In the thoracic spine, T1-weighted spin-echo MR images were obtained in the sagittal plane with use of a 40 × 20 cm rectangular surface coil in the receive-only mode (350/20; repetition time 350 ms/echo time 20 ms; 192 × 256 matrix; four signals averaged; 6-mm-thick sections; 0.6 mm intergap; 400 mm field of view). T2*-weighted gradient-echo MR images were also obtained in the sagittal plane (500/27; flip angle, 30°; 192 × 256 matrix; four signals averaged; 6-mm-thick sections; 0.6 mm intergap; 400 mm field of view). Short inversion time inversion recovery (STIR) MR images were also obtained in the sagittal plane (2000/25; inversion time 120 ms; 192 × 256 matrix; two signals averaged; 6-mm- thick section ; 1.2 mm intergap; 400 mm field of view). In the lumbar spine, T1-weighted spin-echo, T2*-weighted gradient-echo and STIR sagittal MR images were obtained with use of a 18 cm circular surface coil and with identical technical parameters except for a field of view of 300 mm.

In the pelvic region, coronal T1-weighted spin echo (600/20) and T2*-weighted gradient-echo (725/27 ; flip angle 30°) MR images were obtained by using a body coil (192 × 256 matrix, two signals acquired, 6-mm-thick sections, 2 mm intersection gap, 400 mm field of view).

In patients with bone marrow abnormalities, T1-weighted spin-echo MR images of the thoracic and lumbar spine and pelvis were obtained immediately after intravenous administration of 0.1 mmol/kg of gadoterate meglumine (Dotarem; Guerbet, Aulnay-sous-Bois, France). Patients with unequivocal normal bone marrow status at MRI did not receive contrast material injection.

All MRI studies of the spine and of the pelvic marrow were reviewed by two radiologists. The patients were classified into three categories according to the previously described MR patterns of spinal bone marrow involvement. The three MR patterns were the normal pattern, the focal pattern and the diffuse pattern, which have been described in the literature (Moulopoulos et al, 1992, 1994; Lecouvet et al, 1997a; Moulopoulos & Dimopoulos, 1997).

Data analysis

To assess the impact of the radiographic skeletal survey on staging, we determined the proportion of patients for whom the RSS was the only parameter leading to the categorization of stage III.

We reviewed the MR charts and laboratory data of the 80 patients to assess the consequences of the hypothetical substitution of the RSS by MR imaging survey in the staging.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Radiographic studies

The RSS showed at least two focal lytic lesions and was considered as positive in 70 (87.5%) patients. The radiographic studies of the spine and pelvis were positive in 34 (42%) patients and in 37 (46%) patients, respectively. The prevalence of lytic lesions detected on plain radiographs in the different anatomical areas is illustrated in Fig 1.

MR imaging studies

MR images were abnormal in 63 (79%) patients. In the thoraco-lumbar spine, MR imaging showed a normal bone marrow appearance in 19 (24%) patients, and a focal or diffuse pattern of marrow involvement in 35 (44%) and 26 (32%) patients, respectively. In the pelvis and proximal femurs, MR imaging showed a normal marrow appearance in 20 (25%) patients, and a focal or diffuse pattern of marrow involvement in 43 (54%) and 17 (21%) patients, respectively.

Comparison of radiographic and MR findings

In separate anatomic areas, MR imaging was largely superior to the RSS for lesion detection either in the thoraco-lumbar spine and in the pelvis and proximal femurs (Table II).

In the whole patient population, the RSS detected bone involvement in more patients (70 (87.5%) patients with lytic bone lesions) than MR studies (63 (79%) patients with marrow involvement).

Role of the RSS in staging and evaluation of its hypothetical substitution by an MR imaging survey

In 53 patients, blood tests alone indicated stage III MM and medical imaging had no influence on staging. In the remaining 27 (34%) patients a positive RSS was the unique parameter for categorization as Durie and Salmon stage III MM, since biological findings were consistent with stage I or II. Among these 27 patients, MR imaging studies of the spinal and pelvic marrow were abnormal in 19 and normal in eight. In these eight patients with normal MR studies, biological findings indicated stage I MM in seven, and stage II MM in one (Fig 2). Review of the RSS of these eight patients showed unequivocal lytic bone lesions in the ribs in four patients, in the skull in three patients, in the humerus in two patients, and in the distal femurs in two patients.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

A relatively simple staging system based on blood tests and conventional radiographs of the skeleton was proposed by Salmon and Durie more than two decades ago, and is still currently used to guide therapeutic decision in patients with MM (Durie & Salmon, 1975). Stage I patients with limited alterations in blood parameters and fewer than two bone lesions on conventional radiographs are not treated and are followed-up clinically (Hjorth et al, 1993; Alexanian & Dimopoulos, 1995). Stage II or III patients with more severe blood changes and/or multiple bone lesions on conventional radiographs require immediate initiation of chemotherapy (Boccadoro & Pileri, 1995).

Development of MR imaging as a tool to investigate bone marrow has raised the hope that it could also be used in MM staging (Carlson et al, 1995; Stabler et al, 1996). The results of the current study, based on the combined investigation of a series of 80 stage III MM patients by using conventional radiographs and MR imaging, confirm the important role of medical imaging in MM staging and the superiority of MR imaging over radiographs for lesion detection in given skeletal areas. However, this study reveals that substitution of the RSS by an MR imaging survey limited to the spine and pelvis would have caused understaging of eight patients, with a possible negative impact on patient management.

To the best of our knowledge, since Durie & Salmon (1975) emphasized the prognostic significance of bone radiographs in MM and incorporated the RSS in their staging system, the exact contribution of this radiological survey to patient categorization and therapeutic decision has never been quantitatively determined. Herein, we demonstrated that this survey played a decisive role for clinical management in 34% of patients with stage III disease.

The superiority of MR imaging over plain radiographs for lesion detection in the thoraco-lumbar spine has been repeatedly demonstrated (Daffner et al, 1986; Ludwig et al, 1987; Fruehwald et al, 1988; Moulopoulos et al, 1994; Carlson et al, 1995; Tertti et al, 1995) and was confirmed in our study. Moreover, our results showed that the superiority of MR imaging over plain radiographs for lesion detection also applied to the pelvic girdle.

Most of all, the current study demonstrated limitations in the value of MR imaging of the spine and pelvis for the detection of marrow involvement in a population of stage III MM patients despite its superiority over plain radiographs in defined skeletal areas. Actually, in this series of 80 patients with biopsy-proven marrow infiltration by neoplastic plasma cells, MR imaging failed to detect marrow involvement in 17 (21%) patients, whereas the RSS was normal in only 10 (12.5%) patients. Furthermore, replacement of the RSS by an MR imaging study of spinal and pelvic bones would have caused ‘understaging’ in eight patients. In addition, seven out of these eight patients would have been considered as stage I patients on the basis of minor blood tests alterations and normal MR studies. Treatment could have been unnecessarily delayed in these seven patients.

The limited sensitivity of MR imaging for the detection of marrow involvement has already been observed in previous studies of haematological malignancies and could be tentatively explained by either the limited sensitivity of the performed sequences or the limited proportion of bone marrow spaces that were investigated. First, the limited sensitivity of T1- and T2*-weighted MR images to diffuse marrow infiltration has been previously demonstrated in MM and several other haematological malignancies (Baur et  al, 1997; Lecouvet et al, 1997b, 1998). Libshitz et al (1992) reported normal MR findings in 7/23 patients with stage III MM. An insufficient alteration in the fat/non-fat marrow balance could explain the relatively low sensitivity (Baur et al, 1997). Second, an insufficient volume of bone marrow could have been explored in the limited MR surveys, because the thoraco-lumbar spine and the pelvis only contain approximately 70% of the haemopoietic marrow of the whole skeleton, 30% was not therefore investigated (Cristy, 1981).

Several options can be proposed to overcome these limitations. On the one hand, to improve the sensitivity of conventional MR images to marrow infiltration, the performance of other sequences such as opposed phase gradient echo technique should be further evaluated (Stabler et al, 1996) and the role of quantitative MR imaging methods, dynamic studies of contrast enhancement, diffusion MR imaging, and MR spectroscopic studies of the bone marrow should be assessed. On the other hand, to increase the proportion of investigated marrow spaces, whole body MR imaging for marrow lesion detection should be evaluated. The feasibility of this technique has been suggested in recent studies of secondary bone lesions in non-haematological malignancies (Eustace et al, 1997; Steinborn et al, 1997). An alternative approach for myeloma staging could be a combination of an MR study of the spine and pelvis with a radiographic assessment limited to the peripheral skeleton. Review of the most commonly involved sites on plain radiographs in the total patient population and in those with normal MRI findings and biological findings consistent with stage I or II MM shows that the skull and ribs were by far the areas in which lytic lesions were the most frequently detected. Radiographs of the skull and ribs could be the more fruitful adjunct to MR images of the spine and pelvis that provide a limited view of marrow spaces.

Two points must be stressed. First, the study population consisted of patients with stage III MM. The observation that MR imaging is inferior to plain radiographs for lesion detection in a patient population only applies to stage III patients. It has been demonstrated that in patients with low tumour burden, MR imaging — even if limited to the spine and pelvis — was superior to RSS for detection of marrow involvement in a patient population (Moulopoulos et al, 1995; Vande Berg et al, 1996; Zagdanski et al, 1997). Second, according to our results, determination of stage III MM relied on blood tests in two-thirds of patients and the RSS was the determinant in one third of cases. It should not be concluded that conventional radiographs were unnecessary in two-thirds of patients. Initial radiographic findings are essential for the assessment of fracture risk and as a baseline evaluation for subsequent follow-up during treatment.

In conclusion, MR imaging of the spinal and pelvic bone marrow, despite its superiority over radiographs for lesion detection in well-defined skeletal areas, appears insufficient for the staging of MM patients with advanced disease. Further work is warranted to improve the sensitivity of MR imaging before its hypothetical use in the staging of MM.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

This work was supported by grant Télévie no. 7.4555.95 from the Fonds National de la Recherche Scientifique (Brussels, Belgium).

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References
  • 1
    Alexanian, R. & Dimopoulos, M.A. (1995) Management of multiple myeloma. Seminars in Hematology, 32, 20 30.
  • 2
    Baur, A., Stabler, A., Bartl, R., Lamerz, R., Scheidler, J., Reiser, M. (1997) MRI gadolinium enhancement of bone marrow: age-related changes in normals and in diffuse neoplastic infiltration. Skeletal Radiology, 26, 414 418.
  • 3
    Boccadoro, M. & Pileri, A. (1995) Prognostic factors in multiple myeloma. Myeloma: Biology and Management (ed. by J. S. Malpas, D. E. Bergsagel and R. A. Kyle), p. 251. Oxford University Press, New York.
  • 4
    Boccadoro, M. & Pileri, A. (1997) Diagnosis, prognosis, and standard treatment of multiple myeloma. Hematology/Oncology Clinics of North America, 11, 111 131.
  • 5
    Carlson, K., Astrom, G., Nyman, R., Ahlstrom, H., Simonsson, B. (1995) MR imaging of multiple myeloma in tumour mass measurement at diagnosis and during treatment. Acta Radiologica, 36, 9 14.
  • 6
    Cristy, M. (1981) Active bone marrow distribution as a function of age in humans. Physics in Medicine and Biology, 26, 389 400.
  • 7
    Daffner, R.H., Lupetin, A.R., Dash, N., Deeb, Z.L., Sefczek, R.J., Schapiro, R.L. (1986) MRI in the detection of malignant infiltration of bone marrow. American Journal of Roentgenology, 146, 353 358.
  • 8
    Durie, B.G. & Salmon, S.E. (1975) A clinical staging system for multiple myeloma: correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer, 36, 842 854.
  • 9
    Eustace, S., Tello, R., DeCarvalho, V., Carey, J., Wroblicka, J.T., Melhem, E.R., Yucel, E.K. (1997) A comparison of whole-body turboSTIR MR imaging and planar 99mTc-methylene diphosphonate scintigraphy in the examination of patients with suspected skeletal metastases. American Journal of Roentgenology, 169, 1655 1661.
  • 10
    Fruehwald, F.X., Tscholakoff, D., Schwaighofer, B., Wicke, L., Neuhold, A., Ludwig, H., Hajek, P.C. (1988) Magnetic resonance imaging of the lower vertebral column in patients with multiple myeloma. Investigative Radiology, 23, 193 199.
  • 11
    Healy, J.C. & Armstrong, P. (1994) Radiology of myeloma. Myeloma: Biology and Management (ed. by J. S. Malpas, D. E. Bergsagel and R. A. Kyle), p. 222. Oxford Medical Publications, New York.
  • 12
    Hjorth, M., Hellquist, L., Holmberg, E., Magnusson, B., Rodjer, S., Westin, J. (1993) Initial versus deferred melphalan–prednisone therapy for asymptomatic multiple myeloma stage I: a randomized study. Myeloma Group of Western Sweden. European Journal of Haematology, 50, 95 102.
  • 13
    Lecouvet, F.E., Malghem, J., Michaux, L., Michaux, J.L., Lehmann, F., Maldague, B.E., Jamart, J., Ferrant, A., Vande Berg, B.C. (1997 a) Vertebral compression fractures in multiple myeloma. Part II. Assessment of fracture risk with MR imaging of spinal bone marrow. Radiology, 204, 201 205.
  • 14
    Lecouvet, F.E., Vande Berg, B.C., Michaux, L., Malghem, J., Maldague, B.E., Jamart, J., Ferrant, A., Michaux, J.L. (1998) Spinal bone marrow MR imaging in stage III multiple myeloma: clinical and prognostic significance. Radiology, 205, 653 660.
  • 15
    Lecouvet, F.E., Vande Berg, B.C., Michaux, L., Schmitz, P.J., Malghem, J., Jamart, J., Maldague, B.E., Ferrant, A., Michaux, J.L. (1997 b) Early chronic lymphocytic leukemia: prognostic value of quantitative bone marrow MR imaging findings and correlation with hematologic variables. Radiology, 204, 813 818.
  • 16
    Libshitz, H.I., Malthouse, S.R., Cunningham, D., MacVicar, A.D., Husband, J.E. (1992) Multiple myeloma: appearance at MR imaging. Radiology, 182, 833 837.
  • 17
    Ludwig, H., Fruhwald, F., Tscholakoff, D., Rasoul, S., Neuhold, A., Fritz, E. (1987) Magnetic resonance imaging of the spine in multiple myeloma. Lancet, ii, 364 366.
  • 18
    Malpas, J.S. & Caroll, J.J. (1995) Myeloma: clinical presentation and diagnosis. Myeloma: biology and Management (ed. by J. S. Malpas, D. E. Bergsagel and R. A. Kyle), p. 169. Oxford University Press, New York.
  • 19
    Moulopoulos, L.A. & Dimopoulos, M.A. (1997) Magnetic resonance imaging of the bone marrow in hematologic malignancies. Blood, 90, 2127 2147.
  • 20
    Moulopoulos, L.A., Dimopoulos, M.A., Alexanian, R., Leeds, N.E., Libshitz, H.I. (1994) Multiple myeloma: MR patterns of response to treatment. Radiology, 193, 441 446.
  • 21
    Moulopoulos, L.A., Dimopoulos, M.A., Smith, T.L., Weber, D.M., Delasalle, K.B., Libshitz, H.I., Alexanian, R. (1995) Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. Journal of Clinical Oncology, 13, 251 256.
  • 22
    Moulopoulos, L.A., Varma, D.G., Dimopoulos, M.A., Leeds, N.E., Kim, E.E., Johnston, D.A., Alexanian, R., Libshitz, H.I. (1992) Multiple myeloma: spinal MR imaging in patients with untreated newly diagnosed disease. Radiology, 185, 833 840.
  • 23
    Salmon, S.E. & Cassady, J.R. (1995) Plasma cell neoplasms. Cancer: Principles and Practice of Oncology (ed. by V. T. De Vita, S. Hellman and S. A. Rosenberg), p. 1984. Lippincott, Philadelphia.
  • 24
    Stabler, A., Baur, A., Bartl, R., Munker, R., Lamerz, R., Reiser, M.F. (1996) 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. American Journal of Roentgenology, 167, 1029 1036.
  • 25
    Steinborn, M., Heuck, A.F., Tilling, R., Baur, A., Reiser, M.F. (1997) Whole body bone marrow MR imaging in metastatic disease: preliminary results. (Abstract). Radiology, 205, 448.
  • 26
    Tertti, R., Alanen, A., Remes, K. (1995) The value of magnetic resonance imaging in screening myeloma lesions of the lumbar spine. British Journal of Haematology, 91, 658 660.
  • 27
    Vande Berg, B.C., Lecouvet, F.E., Michaux, L., Labaisse, M., Malghem, J., Jamart, J., Maldague, B.E., Ferrant, A., Michaux, J.L. (1996) Stage I multiple myeloma: value of MR imaging of the bone marrow in the determination of prognosis. Radiology, 201, 243 246.
  • 28
    Weber, D.M., Dimopoulos, M.A., Moulopoulos, L.A., Delasalle, K.B., Smith, T., Alexanian, R. (1997) Prognostic features of asymptomatic multiple myeloma. British Journal of Haematology, 97, 810 814.
  • 29
    Zagdanski, A.M., Mariette, X., Guermazi, A. (1997) Intérêt pronostique de l'IRM du rachis dans le myélome multiple de stade I. (Abstract). Journal of Radiology, 78, 757.