Imaging in monoclonal plasma cell disorders

• Research Focus
• Systematic comparison of RSS and WBCT
• Tumor heterogeneity
• Prediction of bone destruction from bone marrow lesions
• Monitoring of allogenic stem cell transplantation for MM
• Future challenges
• Figures
• Current members of the working group
• Current Cooperations

Multiple myeloma (MM) and its precursors, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), are characterized by a clonal proliferation of abnormal, monoclonal plasma cells that may cause an elevation of serum calcium, renal insufficiency, anemia, and damage to mineralized bone. Typical paraproteins can be found in serum and sometimes urine. MGUS and SMM are termed asymptomatic, since they have not or not yet caused any end organ damage as described above, and are discriminated by the paraprotein levels in serum and the degree of plasma cell infiltration in the bone marrow sample obtained from the iliac crest. MGUS is common in the population, increases with age, and in only 1 % of affected persons per year will it progress into symptomatic MM. For SMM, however, the progression rate is 10 % per year. Treatment is warranted only once the disease has become or is very likely to become symptomatic, bone damage being the leading symptom: At first diagnosis of symptomatic MM, 80 % of patients have bone damage, and half of the remaining will eventually be diagnosed with bone destructions during the further course of the disease.

As a consequence, imaging plays an important role for the diagnosis of plasma cell disorders. Staging and indication for treatment largely depend on the proof or exclusion of damage to mineralized bone. Traditionally, the modality used has been radiological skeletal survey (RSS), i.e., a series of plain x-ray films of almost the entire skeleton. Recently, whole-body computed tomography (WBCT) and whole-body magnetic resonance imaging (WB-MRI) have gained increasing importance. WBCT can be performed without intravenous contrast agents. Its radiation dose can be held reasonably low, slightly above that of an RSS, but its sensitivity and specificity for bone destructions is significantly higher (Figure 1). Furthermore, ease and comfort is higher for the patient. With WB-MRI (Figure 2, Figure 3), changes to the bone marrow itself, that have not yet caused alterations to the mineralized bone, are visible, and so are lesions outside the skeleton, that are invisible with RSS and in instances hard to detect with CT. MRI also includes functional imaging studies, e.g., to measure tissue perfusion in the bone marrow or in suspicious lesions (that is typically increased in myeloma infiltrates), or to use diffusion-weighted imaging (DWI) to detect areas where cells are particularly densely packed - as is the case in MM lesions, in an either focal or diffuse fashion (Figure 4). Another important imaging modality is positron emission tomography (usually with PET/CT hybrid scanners, most recently also PET/MR combinations) to find particularly active myeloma lesions. Since in Germany the reimbursement for PET studies in the outpatient sector is restricted to extremely few indications, the experience here with PET for MM is limited mainly to academic medicine. In other countries including USA, PET/CT is being routinely used for MM.

The division of Radiology at the German Cancer Research Center (DKFZ) cooperates closely with the Department of Internal Medicine V (Hematology and Oncology) at the Heidelberg University Hospital since more than 15 years. The cooperation is not only academic but also clinical: Patients with plasma cell disorders receive imaging studies at the DKFZ, and our scientists routinely participate in weekly tumor boards. Our cooperation has been fruitful and led to numerous important results. It was found, e.g., that the presence of more than one focal bone marrow lesion in the MRI of a patient who according to standard criteria would have MGUS or SMM, indicates a significantly shortened time to progression into a symptomatic stage. Based on these results, the criteria of the International Myeloma Working Group (IMWG) for symptomatic MM warranting treatment have been updated and now also include the presence of more than one focal bone marrow lesion in MRI - even in absence of frank destruction to mineralized bone. Currently there are several ongoing reserach projects.

From 8 international centers, RSS and WBCT studies that had been obtained within one month were collected together with clinical data and read by 3 radiologists experienced in multiple myeloma to determine to which degree CT is more sensitive than plain films to bone destructions and whether among patients without lesions in the RSS those with lesions seen in WBCT would have a worse prognosis than those without. This retrospective study in more than 200 patients, supported by the International Myeloma Foundation (IMF), revealed not only that CT was significantly more sensitive for bone destructions than the RSS, but also that patients with lesions in WBCT but not in the RSS had a significantly shorter time to clinical progression than those in whom the bones were intact in both RSS and WBCT. As a consequence, replacing the RSS by WBCT for staging and follow-up for patients with plasma cell disorders will identify patients with symptomatic MM who would otherwise be understaged, and concerns that this would induce overtreatment appear so far unjustified.  

Malignant tumors are genetically unstable, and genetically different lesions will evolve in various locations during the course of the disease. This is a potential cause for the long-term treatment resistance and incurability of MM. In an ongoing prospective study supported by the International Myeloma Foundation (IMF), patients with MM lesions in different locations are examined in MRI, including functional measurements, and FDG-PET, and biopsies are taken from one or more lesions, in addition to the routine biopsy from the iliac crest. The specimens are being examined for their genetic profile, and the study intends to reveal whether there are associations with the phenotype, such as diffuse or nodular growth, or osteodestructive properties, and with the treatment response and the duration of a treatment-induced remission.

Within the framework of a three-institution research network (Transregio-Sonderforschungsbereich) supported by the German Research Foundation (DFG), devoted to developing novel osteosynthetic materials for bone regeneration in systemic bone disorders, we are conducting a project with the intention to learn whether functional imaging is able to predict whether a so far non-destructive MM lesion in the bone marrow will or will not progress to a frank bone destruction. Patients with SMM are examined with MRI including DWI and contrast-enhanced MRI. The rationale is that within the research framework materials are developed that are enriched with antitumor drugs (e.g. Bortezomib). They might be applied locally to prevent a future destructive behavior of a lesion and thereby delay the need for systemic treatment.

Autologous stem cell transplantation (ASCT) is a routine procedure for MM and is even performed repeatedly. Allogenic stem cell transplantation (AlloSCT), however, is only performed in rare cases, owing to its high toxicity, and because it is not yet clear which patients will benefit from it. In a current retrospective study, we are examining whether the number of bone marrow lesions before AlloSCT will predict the treatment success, and whether the number of persisting lesions after AlloSCT is a predictor of early relapse.

Our imaging projects will continue to address major clinical challenges, which are asymptomatic stages of the disease, eligibility for local or aggressive treatment in symptomatic stages, and the detection of minimal residual disease (MRD). It has become evident that a part of patients with MGUS in fact have early MM and will soon become symptomatic, while some with SMM will never progress, although their paraprotein levels in serum and plasma cell counts in bone marrow are higher than in MGUS. The prediction of the behavior of focal lesions and local treatment options beyond surgery and radiotherapy are still in their infancy, and so is the identification of patients who will benefit from aggressive systemic treatment such as AlloSCT or novel agents. The diagnosis of MRD based on iliac crest biopsies is notoriously hampered by the multifocal distribution of MM and will need support by imaging studies.

Prof. Dr. med. Stefan Delorme, radiologist

Prof. Dr. med. Jens Hillengaß, hematologist and oncologist

Dr. med. Jennifer Mosebach, resident in radiology

Dr. med. Bettina Beuthien-Baumann, nuclear medicine physician

Dr. med. Dorde Komljenovic, animal researcher (E020)

Prof. Dr. Hartmut Goldschmidt, University Hospital Heidelberg, Department of Hematology and Oncology

Prof. Dr. Lia-Angela Moulopoulos, Radiologist, University of Athens

Dr. Vassilis Koutelidis, Radiologist, University of Athens

Prof. Dr. Ola Landgren, Hematologist and Oncologist, Memorial Sloan Kettering Hospital, New York

1.    Moehler TM, Hawighorst H, Neben K, Egerer G, Benner A, Hillengass J, Max R, Ho AD, Goldschmidt H, van Kaick G (2000) Funktionelle Magnetresonanztomographie in Diagnostik und Therapiemonitoring beim Multiplen Myelom. Radiologe 40:723-740

2.    Moehler TM, Hawighorst H, Neben K, Egerer G, Hillengass J, Max R, Benner A, Ho AD, van Kaick G, Goldschmidt H (2001) Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging. International Journal of Cancer 93:862-868

3.    Wasser K, Moehler T, Neben K, Nosas S, Heiss J, Goldschmidt H, Hillengass J, Düber C, Kauczor HU, Delorme S (2004) Dynamische MRT des Knochenmarks zum Monitoring des Multiplen Myeloms unter Thalidomid-Monotherapie oder Kombination mit CED-Chemotherapie. Fortschritte auf dem Gebiet der Röntgenstrahlen und der neuen Bildgebenden Verfahren 176:1285-1295

4.    Nosas-Garcia S, Moehler T, Wasser K, Kiessling F, Bartl R, Zuna I, Hillengass J, Goldschmidt H, Kauczor HU, Delorme S (2005) Dynamic contrast-enhanced MRI for assessing the disease activity of multiple myeloma: A comparative study with histology and biochemical markers. Journal of Magnetic Resonance Imaging 22:154-162

5.    Hillengass J, Wasser K, Delorme S, Kiessling F, Zechmann C, Benner A, Kauczor HU, Ho AD, Goldschmidt H, Moehler TM (2007) Lumbar bone marrow microcirculation measurements from dynamic contrast-enhanced magnetic resonance imaging is a predictor of event-free survival in progressive multiple myeloma. Clinical cancer research: an official journal of the American Association for Cancer Research 13:475-481

6.    Zechmann CM, Giesel FL, Hillengass J, Mehndiratta A, Neben K, Delorme S, Moehler T (2007) Where is the primary tumour? Lancet 370:1800

7.    Hillengass J, Zechmann CM, Nadler A, Hose D, Cremer FW, Jauch A, Heiss C, Benner A, Ho AD, Bartram CR, Kauczor HU, Delorme S, Goldschmidt H, Moehler TM (2008) Gain of 1q21 and distinct adverse cytogenetic abnormalities correlate with increased microcirculation in multiple myeloma. International journal of cancer. Journal international du cancer 122:2871-2875

8.    Fechtner K, Hillengass J, Delorme S, Kauczor HU, Weber MA (2009) Current imaging concepts in multiple myeloma. European Medical Image Review 1:67-71

9.    Hillengass J, Zechmann C, Bauerle T, Wagner-Gund B, Heiss C, Benner A, Ho A, Neben K, Hose D, Kauczor HU, Goldschmidt H, Delorme S, Moehler T (2009) Dynamic contrast-enhanced magnetic resonance imaging identifies a subgroup of patients with asymptomatic monoclonal plasma cell disease and pathologic microcirculation. Clinical cancer research: an official journal of the American Association for Cancer Research 15:3118-3125

10.    Bäuerle T, Hillengass J, Fechtner K, Zechmann CM, Grenacher L, Moehler TM, Christiane H, Wagner-Gund B, Neben K, Kauczor HU, Goldschmidt H, Delorme S (2009) Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging. Radiology 252:477-485

11.    Hillengass J, Fechtner K, Weber MA, Bauerle T, Ayyaz S, Heiss C, Hielscher T, Moehler TM, Egerer G, Neben K, Ho AD, Kauczor HU, Delorme S, Goldschmidt H (2010) Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28:1606-1610

12.    Fechtner K, Hillengass J, Delorme S, Heiss C, Neben K, Goldschmidt H, Kauczor HU, Weber MA (2010) Staging monoclonal plasma cell disease: comparison of the Durie-Salmon and the Durie-Salmon PLUS staging systems. Radiology 257:195-204

13.    Hillengass J, Bauerle T, Bartl R, Andrulis M, McClanahan F, Laun FB, Zechmann CM, Shah R, Wagner-Gund B, Simon D, Heiss C, Neben K, Ho AD, Schlemmer HP, Goldschmidt H, Delorme S, Stieltjes B (2011) Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology. British Journal of Haematology 153:721-728

14.    Hillengass J, Stieltjes B, Bauerle T, McClanahan F, Heiss C, Hielscher T, Wagner-Gund B, Habetler V, Goldschmidt H, Schlemmer HP, Delorme S, Zechmann CM (2011) Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging of bone marrow in healthy individuals. Acta Radiologica 52:324-330

15.    Hillengass J, Ayyaz S, Kilk K, Weber MA, Hielscher T, Shah R, Hose D, Delorme S, Goldschmidt H, Neben K (2012) Changes in magnetic resonance imaging before and after autologous stem cell transplantation correlate with response and survival in multiple myeloma. Haematologica 97:1757-1760

16.    Sumkauskaite M, Hillengass J, Heiss C, Dornisch B, Stieltjes B, Schlemmer HP, Goldschmidt H, Delorme S (2012) Diagnostic value of functional magnetic resonance imaging for differentiation of benign osteoporosis and multiple myeloma. European Congress of Radiology Insight into Imaging 3 Suppl. 1:336

17.    Hillengass J, Delorme S (2012) Multiples Myelom: Aktuelle Empfehlungen für die Bildgebung. Radiologe 52:360-365

18.    Zechmann CM, Traine L, Meissner T, Wagner-Gund B, Giesel FL, Goldschmidt H, Delorme S, Hillengass J (2012) Parametric histogram analysis of dynamic contrast-enhanced MRI in multiple myeloma: a technique to evaluate angiogenic response to therapy? Acad Radiol 19:100-108

19.    Shah R, Stieltjes B, Andrulis M, Pfeiffer R, Sumkauskaite M, Delorme S, Schlemmer HP, Goldschmidt H, Landgren O, Hillengass J (2013) Intravoxel incoherent motion imaging for assessment of bone marrow infiltration of monoclonal plasma cell diseases. Ann Hematol 92:1553-1557

20.    Liu Y, Cao L, Ray S, Thormann U, Hillengass J, Delorme S, Schnettler R, Alt V, Bauerle T (2013) Osteoporosis influences osteogenic but not angiogenic response during bone defect healing in a rat model. Journal of the care of the injured 44:923-929

21.    Liu Y, Cao L, Hillengass J, Delorme S, Schlewitz G, Govindarajan P, Schnettler R, Heiss C, Bauerle T (2013) Quantitative assessment of microcirculation and diffusion in the bone marrow of osteoporotic rats using VCT, DCE-MRI, DW-MRI, and histology. Acta Radiol 54:205-213

22.    Kloth JK, Hillengass J, Listl K, Kilk K, Hielscher T, Landgren O, Delorme S, Goldschmidt H, Kauczor HU, Weber MA (2014) Appearance of monoclonal plasma cell diseases in whole-body magnetic resonance imaging and correlation with parameters of disease activity. Int J Cancer 135:2380-2386

23.    Andrulis M, Bauerle T, Goldschmidt H, Delorme S, Landgren O, Schirmacher P, Hillengass J (2014) Infiltration patterns in monoclonal plasma cell disorders: correlation of magnetic resonance imaging with matched bone marrow histology. Eur J Radiol 83:970-974

24.    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538-48

25.    Merz M, Hielscher T, Wagner B, Sauer S, Shah S, Raab MS, Jauch A, Neben K, Hose D, Egerer G, Weber MA, Delorme S, Goldschmidt H, Hillengass J (2014) Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia 28:1902-1908

26.    Hillengass J, Weber MA, Kilk K, Listl K, Wagner-Gund B, Hillengass M, Hielscher T, Farid A, Neben K, Delorme S, Landgren O, Goldschmidt H (2014) Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia 28:174-178

27.    Wolf MB, Murray F, Kilk K, Hillengass J, Delorme S, Heiss C, Neben K, Goldschmidt H, Kauczor HU, Weber MA (2014) Sensitivity of whole-body CT and MRI versus projection radiography in the detection of osteolyses in patients with monoclonal plasma cell disease. Eur J Radiol 83:1222-1230

28.    Hillengass J, Stoll J, Zechmann CM, Kunz C, Wagner B, Heiss C, Sumkauskaite M, Moehler TM, Schlemmer HP, Goldschmidt H, Delorme S (2014) The application of Gadopentate-Dimeneglumin has no impact on progression free and overall survival as well as renal function in patients with monoclonal plasma cell disorders if general precautions are taken. Eur Radiol 25:745-750

29.    Delorme S, Hillengass J (2014) Multiples Myelom. Radiologe 54:536-537

30.    Mai EK, Hielscher T, Kloth JK, Merz M, Shah S, Raab MS, Hillengass M, Wagner B, Jauch A, Hose D, Weber MA, Delorme S, Goldschmidt H, Hillengass J (2015) A magnetic resonance imaging-based prognostic scoring system to predict outcome in transplant-eligible patients with multiple myeloma. Haematologica 100:818-825

31.    Merz M, Ritsch J, Kunz C, Wagner B, Sauer S, Hose D, Mohler T, Delorme S, Goldschmidt H, Zechmann C, Hillengass J (2015) Dynamic contrast-enhanced magnetic resonance imaging for assessment of anti-angiogenic treatment effects in multiple myeloma. Clin Cancer Res 21:106-112

32.    Merz M, Moehler TM, Ritsch J, Bäuerle T, Zechmann CM, Wagner B, Jauch A, Hose D, Kunz C, Hielscher T, Laue H, Goldschmidt H, Delorme S, Hillengass J (2015) Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study. Eur Radiol

33.    Mai EK, Hielscher T, Kloth JK, Merz M, Shah S, Hillengass M, Wagner B, Hose D, Raab MS, Jauch A, Delorme S, Goldschmidt H, Weber MA, Hillengass J (2016) Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology. Eur Radiol 26:3939-3948

34.    Hillengass J, Ritsch J, Merz M, Wagner B, Kunz C, Hielscher T, Laue H, Bäuerle T, Zechmann CM, Ho AD, Schlemmer HP, Goldschmidt H, Moehler TM, Delorme S (2016) Increased microcirculation detected by dynamic contrast-enhanced magnetic resonance imaging is of prognostic significance in asymptomatic myeloma. Br J Haematol 174:127-135

35.    Kumar S, Paiva B, Anderson KC, Durie B, Moreau P, Munshi N, Lonial S, Bladé J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng W,J, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harouisseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Liseau H (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17:e328-46

International Myeloma Foundation

1.    Determination of inter- and intraclonal heterogeneity of multiple myeloma by the combination of imaging-guided biopsies and molecular characterization.

2.    Retrospective analysis of the results of computed tomography and conventional skeletal survey in patients with monoclonal plasma cell diseases.

3.    Development of computer-assisted image analysis in monoclonal plasma cell diseases

 German Research Foundation (DFG)

4.    Transregio-SFB 79 “Werkstoffe für die Geweberegeneration am systemisch erkrankten Knochen”: Project B8: Investigation of bone defects and microcirculation with volume computed tomography and dynamic contrast-enhanced magnetic resonance

(Source: Standard Operating Procedures of the National Center of Tumor Diseases (NCT) and the University Hospital Heidelberg)

Symptomatic MM

1. Before treatment: WB-MRI and WBCT
2. Day 100 after ASCT: WB-MRI and WBCT
3. At first relapse: WB-MRI and WBCT
4. During further course: WBCT upon clinical indication or serologic progression

Low-risk MGUS

1. At first presentation: WBCT
2. During further course: WBCT upon clinical indication or serologic progression

SMM, high-risk MGUS, solitary plasmacytoma

1. At first presentation:  WB-MRI including WB-DWI and WBCT
2. During further course for 5years: WB-MRI including WB-DWI annually, if no progression                        
3. At progression into symptomatic MM: WB-MRI and WBCT

Non-secretory MM or MM with soft-tissue lesions

1. At first presentation and every 6 months thereafter: WB-MRI
2. Upon clinical indication or progression in WB-MRI: WBCT

Abbreviations:

MM               (Symptomatic) multiple myeloma

MGUS           Monoclonal gammopathy of unclear significance

SMM             Smoldering multiple myeloma

WB-MRI        Whole-body magnetic resonance imaging

WBCT           Whole-body computed tomography