4th Heidelberg Myeloma Workshop · Kaplan-Meier plots of survival from initiation of therapy according to magnetic resonance imaging–deﬁned focal lesions (MRI-FL). Survival was

4th Heidelberg Myeloma Workshop

Bildgebung beim Multiplen MyelomDr. Jens Hillengaß

Sektion Multiples MyelomMedizinische Universitätsklinik Heidelberg

Arbeitsgruppe E013 Hämato-onkologische BildgebungDeutsches Krebsforschungszentrum

• konventionelles Röntgen

• Computertomographie (CT)

• Positronen Emissions-Tomographie mit/ohne CT (PET/CT)

• Magnet-Resonanz-Tomographie (MRT) Knochenmark

Bildgebungsmodalitäten beim Multiplen Myelom

Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G

Knochen

Röntgen-Skelettstatus


• konventionelles Röntgen

• Computertomographie (CT)

• Magnet-Resonanz-Tomographie (MRT)

• Positron Emission Tomography w/o CT (PET/CT)



Vorteile• Flächendeckende Verfügbarkeit• billig• International anerkannter Standard*• niedrige Strahlenbelastung (im Vergleich zur CT ca. 1/4-1/2)

*Dimopoulos et al. 2011 Blood



Nachteile• niedrige Sensitivität: Nachweisbarkeit erst bei mindestens 50%igem Verlust von Knochen*

*Edelstyn et al. 1965 Clin. Radiol.


Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G*Edelstyn et al. 1965 Clin. Radiol.



Nachteile• niedrige Sensitivität: Nachweisbarkeit erst bei mindestens 50%igem Verlust von Knochen*

*Edelstyn et al. 1965 Clin. Radiol.

• niedrige Spezifität - insbesondere bei Osteopenie• Sternum/ Rippen/ Schulter nur schlecht darstellbar• Verlaufsbeurteilung nur bei Verschlechterung verwertbar• lange Untersuchungszeit


Computertomographie


ComputertomographieVorteile• höchste Sensitivität für die Detektion von Osteolysen

• zuverlässige Stabilitätsbeurteilung der Wirbelsäule

• Bedingte Detektion von Weichteil- und Knochenmarkläsionen

• „Patientenkomfort“

• Planung von Radiatio und Chirurgie


Computertomographie

Horger et al. 2007 Cancer

VerlaufsbeurteilungInitial

bei Therapieansprechen

im Progress


ComputertomographieNachteile• höhere Strahlenbelastung selbst in „low dose“-Technik (4,1 mSv => ca. 2x Röntgen-Skelettstatus)• niedrigere Sensitivität als MRT*

*Baur-Melnyk et al. 2008 AJR

Vorteile• Darstellung einer Infiltration vor Knochendestruktion• Keine Strahlenbelastung• Darstellung der Weichteile mit höchster Auflösung• bedingte Unterscheidung von benignen und malignen Kompressionsfrakturen • Verlaufsbeurteilung in beide Richtungen relevant=> inbesondere bei hypo-/ asekretorischem MM

Magnetresonanztomographie


Magnetresonanztomographie


0

1-10

>2011-20

Prognostische Bedeutung residueller Befunde nach Therapie

Hillengass et al. 2012 Haematologica

MagnetresonanztomographieNachteile• nicht anwendbar bei klaustrophobischen Patienten• nicht anwendbar bei metallischen Fremdkörpern• Unterlegenheit bei der Stabilitätsbeurteilung des Knochens• Bedeutung der Veränderungen für die Therapieentscheidung noch nicht ausreichend untersucht


Magnetresonanztomographieprognostische Bedeutung

Walker et al. 2006 JCO, Hillengass et al. 2010 JCO,Hillengass submitted


MRI-FLs, present in 27 of 30 patients with nonsecretory MM,provided a valuable tool for assessing response, traditionally relyingonly on serial bone marrow examinations. Thus, bone marrow–defined CR occurred in 22 (81%) of these 27 patients, and MRI-CRwas documented in 41% of patients at 36 months.

Of 57 patients with MRI-FL, random bone marrow examina-tion from the posterior iliac crest revealed less than 10% monoclonalplasma cells; 43 (75%) fulfilled diagnostic criteria of MM due toM-protein levels and/or osteolytic lesions, whereas the remaining14 patients would have been considered as having MGUS. CT-FNAand biopsy of MRI-FLs showed unequivocal involvement withMM. In these 14 patients, MRI-FL number averaged 14 FLs (range,two to 40 FLs).

MRI-CR and CCRTime-dependent cumulative proportions of patients achieving

MRI-CR revealed significant gradations when considering baselineMRI-FL features: the 76 patients without FL had the steepest onset andhighest level of MR-CR, followed by the group of 185 with up to sevenFLs; the slowest onset and lowest MRI-CR frequency was in the groupof 196 patients with more than seven MRI-FLs (Fig 4A). The time to

CCR was similar for the three MRI-FL subgroups (data not shown)and mirrored the time to MRI-CR only for patients with seven orfewer MRI-FLs. Among the patients achieving MRI-CR, significantproportions remained without CCR at 48 months, indicating thepersistence of M-protein producing tumor clones in the absence ofimaging abnormalities (Fig 4B). According to a landmark analysis of319 patients surviving at least 36 months, MRI-CR status conferredsuperior survival (Fig A1A, online only). Further examination in thecontext of MRI-FL baseline status revealed that MRI-CR status was

Table 3. Correlation of MRI- and MBS-Defined FLs With Prognostically Relevant Standard Parameters

Clinical Parameter

MRI-FL MBS-FL

%

P

%

P! 7 (n ! 393) " 7 (n ! 218) ! 5 (n ! 456) " 5 (n ! 155)

CRP " 8.0 mg/L 32 52 # .001 34 54 # .001Albumin # 3.5 g/dL 13 24 # .001 16 22 .092LDH " ULN 23 33 .009 24 36 .004Creatinine " 2.0 mg/dL 7 13 .022 8 14 .013

Abbreviations: MRI, magnetic resonance imaging; MBS, metastatic bone survey; FL, focal lesion; CRP, C-reactive protein; LDH, lactate dehydrogenase; ULN, upperlimit of normal.

0

Over

all S

urvi

val (

%)

Time From TT2 Enrollment (years)

100

80

60

40

20

2 4 6 8 10

MRI-FL normal

MRI-FL > 7

Deaths / N48 / 191

95 / 218

5 YearsEstimated % Alive

73

55

95% CI66 to 80

48 to 63MRI-FL between 1-7 63 / 202 68 61 to 75

Fig 3. Kaplan-Meier plots of survival from initiation of therapy according tomagnetic resonance imaging–defined focal lesions (MRI-FL). Survival was signif-icantly longer among patients without and with up to seven FLs than in the thosepresenting with more than seven FLs. P value: Overall # .0001; MRI-FL normalversus MRI-FL normal between 1 and 7, .28; MRI-FL normal versus MRI-FL " 7,.0001; MRI-FL normal between 1 and 7 versus MRI-FL " 7, .0001

A

B

0

Inci

denc

e (%

)

Time After Starting VAD (months)

100

80

60

40

20

24 48 72 96

MRI-FL normalMRI-FL between 1-7MRI-FL > 7

Also achieved CCRAlso achieved CCRAlso achieved CCR

No.

of P

atie

nts

Time From Start of Therapy (months)

0

20

40

60

80

100

120

140

12 24 36 48

Events / N Median (months)MRI-CR and MRI-FL > 7 77 / 196 67MRI-CR and MRI-FL between 1-7 107 / 185 26CCR 264 / 457 22MRI-CR and MRI-FL normal 60 / 76 9

Fig 4. Clinical complete response (CCR) and magnetic resonance imaging–defined complete response (MRI-CR). (A) Cumulative proportions of patientsachieving CCR and MRI-CR according to the presence and number of MRI-defined focal lesions (MRI-FLs). (B) Number of patients achieving MRI-CR andCCR at 12, 24, and 36 months after initiation of therapy, according to number ofMRI-FLs at baseline.

Walker et al

6 JOURNAL OF CLINICAL ONCOLOGY

Copyright © 2007 by the American Society of Clinical Oncology. All rights reserved. from 129.206.90.2.

Information downloaded from www.jco.org and provided by Med. Klinik d. Universitaet Heidelberg on February 28, 2007

Symptomatisches Myelom

PATIENTS AND METHODS

PatientsFrom November 2003 to April 2008, a total of 149 individuals with aMM

(73 women and 76 men) were examined with wb-MRI. The median age was 58years (range, 25 to 81 years). Staging followed the classification proposed bythe International Myeloma Working Group, but this classification did notinclude MRI findings.1 In 16 patients, a localized plasma cell tumor plusevidence of systemic disease according to other factors, such as elevated mono-clonal protein or percentage of plasma cells in bone marrow, were present.None of the patients had signs of bone disease besides one with osteolysiscaused by the plasma cell tumor, and none of the patients were treated system-ically until sMM occurred later. The only therapy was local irradiation with adose of 25 to 50 Gy in 14 patients and a tumor extirpation in two patients. Likethe other patients in this study, those patients would not have had an indica-tion for a systemic treatment after definitive local therapy, such as irradiationand/or surgery; hence, we decided to include them into this analysis. Patientswith true solitary plasmacytoma were excluded from this analysis, becauseother survival rates and prognostic factors for this entity have been described inthe literature.

The median time of follow-up for the whole patient group was 23.7months, and information about patients was last updated in January 2009.Retrospective evaluation of wb-MRI data of patients with MM in our clinichad been approved by the institutional ethics review board.

MRI ProtocolWb-MRI was performed with two 1.5-Tesla, whole-body systems (Mag-

netom Avanto, Siemens Medical Solutions, Erlangen, Germany) with phased-array, body-matrix surface coils (Siemens Medical Solutions, Erlangen,Germany) that had the following parameters: T1-weighted turbo-spin echosequence (TR ! 627 milliseconds [ms]; TE ! 11 ms) of the head (voxel size,1.25 " 1.25 " 5 mm3; scan time, 2 minutes 4 seconds), thorax and abdomen(voxel size, 1.25 " 1.25 " 5 mm3; scan time, 2 minutes 4 seconds), pelvis(1.25 " 1.25 " 5 mm3; scan time, 2 minutes 4 seconds), and leg (voxel size,1.25 " 1.25 " 5 mm3; scan time, 2 minutes 4 seconds), all in coronal orienta-tion; T2-weighted short-! inversion recovery (STIR) sequence (TR ! 3,340ms; TE ! 109 ms; TI ! 160 ms) of the head (voxel size, 1.25 " 1.25 " 5 mm3;scan time, 1 minute 20 seconds), thorax and abdomen (voxel size, 1.25 "1.25 " 5 mm3; scan time, 1 minute 20 seconds), and pelvis (voxel size, 1.25 "1.25 " 5 mm3; scan time, 1 minute 20 seconds), all in coronal orientation;T1-weighted turbo spin echo sequence (TR ! 400 ms; TE ! 11 ms) of thespine in sagittal orientation (voxel size, 1.836 " 1.836 " 3.5 mm3; scan time, 1minute 16 seconds); T2-weighted FLASH 2D sequence (TR ! 402 ms; TE !12 ms) of the spine in sagittal orientation (voxel size, 0.84 " 0.84 " 5 mm3;scan time, 1 minute 38 seconds). The patients were positioned with arms alongtheir bodies, and the series covered the region between the skull vertex and themidcalf. Depending on the body height of the patient, the distal calves and thefeet were not included.

Image AnalysisAll MRI scans were read by two experienced radiologists (K.F., M.A.W.)

in consensus who were blinded to the diagnosis of the patients and whocounted the number of FLs in the axial skeleton (ie, spine and sacral bone), theextra-axial skeleton (ie, all other parts of the skeleton), and in soft tissueseparately. Furthermore, diffuse bone marrow infiltration in the axial skeletonwas recorded according to the criteria proposed by Staebler and Baur.10,11 FLspresented with decreased signal intensity in T1-weighted images and withincreased signal intensity in T2-weighted images. Diffuse infiltration was char-acterized as homogeneous signal decrease in T1- and increase in T2-weightedimages compared with the signal intensity of the vertebral disk. Lesions intypical locations for degenerative changes were not counted.

Evaluation of Progression-Free SurvivalFollow-up took place every 3 to 6 months and included clinical history

and examination as well as serum and urine markers. A radiologic skeletalsurvey (RSS) was obtained for occurrence of symptoms or an increase inmonoclonal protein levels; the average interval between x-ray studies was 2

years. The start of systemic therapy was defined as the date of event for theanalysis of progression-free survival.

Statistical AnalysisThe search for an optimal cutoff point in number of FLs with respect to

progression-free survival into symptomatic disease was performed by usingmaximally selected rank statistics.12-14

Univariate AnalysisThe significance of the number of focal FLs in wb-MRI greater than the

cutoff point, the presence of a diffuse infiltration pattern in MRI, and thepresence of established adverse prognostic markers for aMM for the progres-sion into sMM was analyzed. Time to progression into sMM was estimated byusing the Kaplan-Meier method. Group comparisons were made by using alog-rank test. The prognostic value of a number of FLs greater than the cutoffpoint for the probability of progression was analyzed in a Cox proportionalhazard regression model.

Multivariate AnalysisRisk factors analyzed in multivariate analysis were M protein concentra-

tion of " 40 g/L; presence of an IgA monoclonal protein; reduction of unin-volved Igs; presence of urinary Bence Jones Protein and a plasma cellinfiltration in bone marrow of " 20%.3-5 MRI-derived risk factors were thenumber of FLs greater than the cutoff point and the presence or absence ofdiffuse bone marrow involvement. Multivariate analysis was performed with aCox proportional hazards regression model.

Backward variable selection was performed for the multivariate modelwith a significance level for staying in the model of 0.2 to select the mostimportant risk factors for progression-free survival into symptomatic dis-ease.15 Correlation analysis between the different risk factors was done byusing the Kendall ! test.

RESULTS

Optimal Cutoff Point for the Number of FLsSearch for an optimal cutoff point of the number of FLs revealed

that patients with greater than one FL had significantly shorterprogression-free survival than those without or with only one FL(P # .001). The Kaplan-Meier plot for progression into symptomaticdisease is shown in Figure 1.

Log-rank P < .001

1.0

0.8

0.6

0.4

0.2

0

Time Since MRI Treatment (months)

0 or 1 FLMore than 1 FL

12623

10619

8110

645

493

362

20 11 3 1 1

Prog

ress

ion-

Free

Sur

viva

l 6 12 18 24 30 36 42 48 54 60

! 1> 1

Fig 1. Kaplan-Meier plots for progression into symptomatic myeloma of patientswho had no or one focal lesion (FL) compared with patients who had greater thanone FL. The median time to progression was not reached (last event at 43months) for the patient group with no or one FL and 13 months for the patientgroup with greater than one FL, respectively. MRI, magnetic resonance imaging.

Hillengass et al

2 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved. 129.206.90.2.

Information downloaded from jco.ascopubs.org and provided by Universitaet Heidelberg on February 23, 2010 from

asymptomatisches MyelomMGUS

Positronen-EmissionstomographiePET/CT

Dr. Jens Hillengass University Hospital Heidelberg, S.D.G

Vorteile• Darstellung des Metabolismus

• Prognostische Bedeutung sowohl initial als auch im Verlauf

• Darstellung von Krankheitsaktivität

Bartels Blood 2009Zamagni Blood 2011

Positronen-EmissionstomographiePET/CT

Dr. Jens Hillengass University Hospital Heidelberg, S.D.G

Nachteile• falsch positiv bei Entzündung

• teuer

• Strahlenbelastung

• keine flächendeckende Verbreitung

• Keine Kostendeckung durch die Krankenversicherungen

Neuerung:• n = 47• Messung des “Metabolic Tumor Volume”

PET/CT

Fonti et al. 2013 J Nucl Med

• Ganzkörper-MRT hat eine signifikant höhere Detektionsrate des Myelombefalls als Ganzkörper-CT

Intermodalitäten-Vergleich

Baur-Melnyk et al. 2008 AJR

1102 AJR:190, April 2008

Baur-Melnyk et al.

Fig. 5—61-year-old woman with lambda Bence Jones myeloma.A–E, Discordant findings on MRI and MDCT images show multifocal infiltrates in the spine. Note also pathologic fracture in L5. Sagittal MDCT reconstruction of spine in same patient showed large bone destruction in L5 with pathologic fracture and six other smaller osteolyses (not shown in this slice).

C DB

Fig. 4—Discordant findings on MRI and MDCT in 68-year-old man with lambda Bence Jones myeloma.A and B, T1-weighted spin-echo (A) and STIR (B) images show high-grade diffuse infiltration of bone marrow by myeloma. Signal is diffusely reduced on T1-weighted spin-echo (A) images and increased on fat-saturated STIR (B) images because of increase in cells and reduction of fat. In addition, two circumscribed lesions are detectable in spine. One of them is displayed at ninth thoracic vertebral body (arrow, B).C, On MDCT image (sagittal reconstruction), only circumscribed tumor nodules were displayed as focal destructions. Arrow indicates circumscribed lesion.

CBDr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G

• Ganzkörper-CT und -MRT haben eine höhere Sensitivität als der konventionelle Röntgen-Skelettstatus• Ganzkörper-CT und -MRT ergänzen sich bei der Abschätzung der Tumormasse


Gleeson et al. 2009 Skeletal Radiol.Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G

• PET/CT und MRT zeigen eine vergleichbare Sensitivität


Fonti et al. 2008 J Nucl. Med.Dr. Jens Hillengass Universitätsklinik Heidelberg, S.D.G



Technik ungefähre Strahlendosis

Knochen-schädigung

Tumorlast Therapie-monitoring

Dauer

Röntgen-Skelettstatus 2-4 mSv + 0 0 30-45 min

low dose CT 4-7,5 mSv ++ + + 10 min

PET/ CT 17-25 mSv ++ + ++ 120 min

Ganzkörper-MRT no (+) ++ ++ 45 min

Consensus Guidelines 2011


doi:10.1182/blood-2010-10-299529 Prepublished online Feb 3, 2011;

Boccadoro, Shaji Kumar, Sergio Giralt, Nikhil C. Munshi and Sundar Jagannath Beksaç, Kenneth C. Anderson, Philippe Moreau, Seema Singhal, Hartmut Goldschmidt, MarioChanan-Khan, Heinz Ludwig, Douglas Joshua, Jayesh Mehta, Morie Gertz, Hervé Avet-Loiseau, Meral Meletios Dimopoulos, Robert Kyle, Jean-Paul Fermand, S. Vincent Rajkumar, Jesus San Miguel, Asher

Myeloma Workshop Consensus Panel 3Guidelines for standard investigative workup: report of the International

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. Hematology; all rights reservedCopyright 2011 by The American Society of 20036.the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by

For personal use only. at Universitaetsbibliothek Heidelberg on March 3, 2011. www.bloodjournal.orgFrom

• konventioneller Röntgen-Skelettstatus-weiterhin Goldstandard bei Erstuntersuchung und im Progress

• Computertomographie-bei klinischer Indikation (OP-/ Bestrahlungsplanung)-bei symptomatischen Patienten mit unauffälligem Skelettstatus

• Magnetresonanztomographie-bei klinischer Indikation (Myelonkompression)-als Ganzkörper-Protokoll bei unauffälligem Röntgen-Skelettstatus-als Wirbelsäulen-MRT bei solitärem Plasmozytom-isolierter Nachweis von ≥ 3 fokale Läsionen „Myelom-definierendes Ereignis“• Positronenemissionstomographie/ Tc-Sestamibi-Aufgrund aktueller Datenlage noch keine Routinediagnostik

Consensus Guidelines 2011


• Ganzkörper low dose CT ersetzt den konventionellen Röntgen-Skelettstatus (initial, und im Progress)• Ganzkörper-MRT-bei Erstdiagnose-nach Abschluss der Primärtherapie• Bei hypo-/ asekretorischem Multiplem Myelom-Verlaufskontrolle alle 6 Monate MRT• Bei klinischer Indikation• PET-CT/ PET-MRT im Rahmen von Studien

„Der Heidelberger Weg“



• PET-MRT: Vereint die Vorteile von PET und MRT

Zukunftsmusik

Vielen Dank


Documents

4th Heidelberg Myeloma Workshop · Kaplan-Meier plots of survival from initiation of therapy according to magnetic resonance imaging–deﬁned focal lesions (MRI-FL). Survival was