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18F-FDG-PET/CT in relapsed multiple myeloma: Are prognostic thresholds different from first-line therapy?

18F-FDG-PET/CT in relapsed multiple myeloma: Are prognostic thresholds different from first-line... Purpose: While F‑FDG PET/CT yields valuable prognostic information for patients in first ‑line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first ‑line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first ‑line setting. Methods: Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG‑PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET‑positive extramedullary lesions (EMD) were analysed. Results: For the number of FLs, the prognostic value was demonstrated with a cut‑ off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above‑mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001). Conclusion: The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first ‑line setting but also in relapsed MM. Keywords: Multiple myeloma, Relapse, Prognostic factors, 18FDG PET‑ CT improved the progression-free and overall survival, but Background the vast majority of patients will eventually experience Multiple myeloma (MM) is a malignant plasma cell dis- disease progression [1, 2]. The multifaceted presenta - order that is currently incurable in most cases. The tion and progressive nature of MM require complex introduction of novel therapeutic agents significantly assessment including detailed radiological examination. Whole-body computed tomography (CT), magnetic res- *Correspondence: Romans.Zukovs@med.uni‑ duesseldorf.de onance imaging (MRI), and positron emission tomogra- Department for Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich Heine University Dusseldorf, Moorenstr. 5, phy—computed tomography (PET/CT) are the methods 40225 Dusseldorf, Germany Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 2 of 10 of choice, depending on the clinical setting and their FDG-avid focal intramedullary lesions (FL) as well as the availability [3]. presence of extramedullary disease (EMD) [4, 8–16]. Pro- 18 18 The F-fluorodesoxyglucose ( F-FDG) PET/CT is spective studies during first line therapy identified cut-off particularly useful for differentiating between active and values for PET/CT parameters with minor variability [8, smoldering myeloma, assessing residual disease after 11, 12, 15]. These prognostically significant thresholds therapy, or detecting extramedullary involvement [4, 5]. were reproduced in multiple smaller retrospective stud- Disease activity assessed by PET/CT at diagnosis, after ies (Table  1). A maximal SUV (SUVmax) above 3.9–4.2, induction therapy, and after high-dose therapy is a useful more than 3 FLs, and the presence of PET-positive EMD predictor of progression-free survival (PFS) and overall were repeatedly demonstrated to be negative predictors survival (OS), as shown by multiple prospective and ret- for OS and/or PFS [8–10, 14, 15, 17]. rospective studies (Table  1). Moreover, comparative pre- The role of PET/CT in relapsed or refractory MM is and post-therapeutic PET/CT for evaluation of therapy less clear, particularly in the post-transplantation setting response yields important prognostic information, too [6, [4]. The parameters and thresholds used in relapse stud - 7]. The IMWG consensus statement on radiologic diag - ies are heterogeneous, which hampers the evaluation of nostics in MM recommends the use of PET/CT at diag- the prognostic role of PET/CT. The prognostic thresh - nosis when available, especially in studies, followed by olds proposed for SUVmax and number of focal lesions st PET/CT re-evaluation after 1 line treatment for assess- in patients with relapsed MM are 3–4 times higher and ment of residual disease [3]. more variable than those identified in the first-line set - Most studies on the prognostic role of PET/CT in MM ting [18, 19] (Table 1). measured metabolic disease activity using standard- In our retrospective single center study, we analyzed ized uptake values (SUV) and evaluated the number of patients with MM who underwent at least one HDT with Table 1 Overview of studies evaluating prognostic role of variable PET‑ CT parameters in multiple myeloma Study Study design Number Time of PET/CT Thresholds for PET-CT parameters of (relevant survival parameter) patients Bartel et al. [15] Prospective 239 At diagnosis and before autologous SCT nFL > 3 (OS and EFS), SUVmax > 3.9 (EFS*), EMD‑positivity (OS* and EFS*) Zamagni et al. [8] Prospective 192 At diagnosis SUVmax > 4.2 (OS and PFS), EMD‑positivity (OS and PFS), nFLs > 3 (PFS*) Fonti et al. [21] Retrospective 47 At diagnosis, with subpopulation in relapse MTV (OS and PFS) Usmani et al. [11] Prospective 302 At diagnosis and at induction day 7 nFL > 3 on day 7 (OS and PFS) Zamagni et al. [9] Retrospective 282 After first line SUVmax > 4.2 (PFS and OS), nFL > 3 (OS* and PFS*), EMD‑positivity (OS* and PFS*) Patriarca et al. [10] Retrospective 67 Before allogeneic SCT SUVmax > 4.2 (OS and PFS*), EMD‑positivity (OS* and PFS), nFL > 1 (OS* and PFS*), Beksac et al. [12] Prospective 139 Before and after autologous SCT SUVmax > 3.35 (OS), SUVmax > 4.2 (PFS) Moreau et al. [22] Prospective 134 After first line compared to PET at diagnosis PET‑positive versus PET ‑normalization (PFS and OS) Davies et al. [14] Retrospective (based 596 At diagnosis, during and after induction nFL > 3 (OS, PFS) at diagnosis. Suppression of on population of TT4‑6 FL‑signal beneficial trials) Wang et al. [16] Retrospective 123 At diagnosis SUVmax > 5.7 (OS*), EMD‑positivity (OS and PFS) Moon et al. [17] Retrospective 76 At diagnosis nFL > 3 (OS and PFS), EMD‑positivity (OS and PFS) Fonti et al. [23] Retrospective 47 At diagnosis MVT (OS and PFS), TLG (OS* and PFS*), SUV‑ max (OS*), nFL (OS* and PFS*) Lapa et al. [18] Retrospective 37 At relapse nFL > 10 ( TTP and OS), EMD ( TTP and OS), SUVmax (ROC) > 18.5 ( T TP) Jamet et al. [19] Retrospective 40 At relapse nFL (appendicular skeleton) > 6 (OS, PFS), TLG (OS), SUVmax (ROC) > 15.9 (PFS), nFLs > 13 (PFS*) SCT stem cell transplantation, OS overall survival, EFS event free survival, PFS progression free survival, CRD complete response duration, TTP time to progression, nFL number of focal lesions, EMD extramedullary disease, SUV-standardized uptake value, MTV metabolic tumor volume, TLG total lesion glycolysis. *Parameter was significant only on univariate analysis Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 3 of 10 autologous or allogeneic SCT and experienced disease Table 2 Overview of patient’s data relapse. We evaluated the prognostic role of F-FDG- Parameter Number (%) PET-CT for OS and PFS, focusing on prognostic param- Patients, total 36 eters that were mostly identified in larger prospective Age, years, median 60 studies looking at baseline parameters and/or response to Age, years, range 44–76 therapy. Sex, male 20 (55.5%) Sex, female 16 (44.5%) Methods MM subtype We retrospectively evaluated patients with MM who IgG Kappa/Lambda 12 (33.3%)/7 (19.4%) underwent F-FDG-PET/CT in our center between 2012 IgA Kappa/Lambda 3 (8.3%)/2 (5.6%) and 2019. In this population, 36 pre-treated patients, who IgM Lambda 1 (2.8%) had received at least one autologous or allogeneic SCT Light chain only, Kappa 5 (13.9%) and experienced disease relapse at the time of PET/CT Light chain only, Lambda 3 (8.3%) investigation, were identified and included in the study. Non‑secretory 3 (8.3%) Relapse was defined according to IMWG-criteria [20]. High‑ dose therapies with SCTs Patients with relapse who had already started new ther- One autologous SCT 17 (47.2%) apy prior to the PET/CT were excluded. Clinical findings Two autologous SCT 12 (33.3%) and laboratory results were integrated into our analysis Three autologous SCT 1 (2.8%) (Table 2). Allogeneic SCT (following autologous) 6 (16.7%) [5(13.9%)] Therapy lines before current progress PET-CT Scans First line 13 (36.1%) All scans were performed as a non-contrast low-dose Second line 9 (25%) PET/CT (mCT, 128 slices, Siemens Healthineers). Scan Third line 8 (22.2%) range included whole body from the top of the head Fourth line 4 (11.1%) through the feet. The F-FDG-tracer dosing was adapted Fifth line 2 (5.6%) for body weight (3MBq F-FDG/kg). The visual evalua - Median 2 tion of the PET was carried out using the Ultra-HD-3D ISS stage at current progress mode reconstruction and the iterative 3D-mode recon- I 19 (52.8%) structions. The SUV measurements were conducted II 13 (36.1%) using the iterative 3D-mode reconstructions. The SUV - III 4 (11.1%) max was defined as maximal measured SUV value of Cytogenetics on FISH the single most active intramedullary or extramedullary High‑ eisk 6 (16.6%) lesion on each scan using manually placed volumes of Non‑high‑risk 15 (41.7%) interest (VOI). Focal bone lesions were defined as FDG- Cytogenetics not available 15 (41.7%) avid focal areas within bone structure with tracer uptake LDH intensity above median bone marrow activity (based on Elevated (> 250 U/l) 20 (55.5%) the prospective study by Bartel et  al. [15]). The thresh - Normal (≤ 250 U/l) 16 (44.5%) old of more than 3 focal lesions and the SUVmax cut-off Best response after last therapy line value of 4 for survival analysis were based on prospec- CR 10 (27.7%) tive and larger retrospective studies of F-FDG-PET/CT vgPR 5 (13.9%) prognostic role in first-line therapy (Table  1) and IMWG PR 19 (52.8%) 2017 consensus statement [4]. The presence of PET-posi - SD 2 (5.6%) tive EMD was also evaluated. EMD was defined as FDG- avid lesion that was not contiguous to bone on CT-scan SCT stem cell transplantation, ISS international staging system, FISH fluorescence in situ hybridization, CR complete remission, vgPR very good partial remission, and arose in soft tissue. PR partial remission, SD stable disease Statistics We used commercial software (SPSS ver. 23 by IBM was defined as death of any reason for OS, and as next Statistics) for statistical analysis. Kaplan–Meier sur- disease relapse or death for PFS. Log-rank tests were vival analysis was performed to assess the time of OS used to assess statistical significance. A significance and PFS with start-point at the moment of the PET/CT level of p-value was set at 0.05. Besides PET parame- investigation. Survivors were censored at the time of ters, clinical findings and laboratory results, as well as the last clinical contact. In survival analysis, an event Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 4 of 10 number of prior treatment lines, were evaluated as risk statistical significance as a negative predictor of OS or factors. PFS (Table 3). Extramedullary disease Results FDG-avid EMD was present in 12/36 (33.3%) of our Patient characteristics patients. In patients with EMD the median OS was 3.63 Among 36 relapsed patients, 20 were male and 16 female (SE 2.2) months, compared to not reached in patients (Table  2). Median age was 60  years (range 44–76). Sev- with no EMD on PET/CT (p = 0.004, Fig. 1c). In patients enteen patients previously underwent single autolo- with EMD the median PFS was 3.5 (SE 0.4) months, com- gous SCT, 12 patients received two autologous SCTs, pared to 11 (SE 1.8) months in patients with no EMD and 1 patient had three autologous SCTs. Six patients on PET-CT (p = 0.006, Fig.  2c). In 9/12 cases the SUV- underwent allogeneic SCT, five of them after previ - max was located in the extramedullary lesion and in 8 of ous autologous transplantation. Thirteen (36%) patients those 9 cases it exceeded the threshold of 4. In 8 of 12 experienced first disease relapse, 9 (25%) had a second, 8 patients radiation therapy of PET-positive extramedul- (22%) had a third, and 6 (17%) patients suffered a fourth lary lesions was initiated, demonstrating relevance for or fifth relapse. With a median follow-up of 37.9 months, therapy planning. the median OS in the entire study population was 16.3 (SE 17.7) months. Median time of PFS of was 6.0 (SE 3.6) Laboratory and clinical parameters months. Five of 36 patients (14%) were lost to follow-up Laboratory parameters were assessed at the time of before reaching next progress or death. PET/CT investigation (Table  3). Thirteen patients had ISS stage II and four had stage III. The OS was signifi - PET parameters cantly shorter in patients with higher ISS stage (3.9 and At the time of relapse, 26/36 (72.2%) of our patients had a 13.6  months vs. not reached, p = 0.016, Fig.  3a). The ISS positive PET scan. Among those, 14/26 patients had only stage had somewhat weaker, but still significant nega - intramedullary disease, while 10/26 had both intra- and tive predictive value for PFS as well (p = 0.046, Fig.  3b). extramedullary FDG-avid lesions. Two patients had EMD In 15/36 patients cytogenetic analysis was not available, only. Ten patients had a negative PET scan with no FDG- precluding determination of disease stage according to avid lesions detectable. the revised ISS (R-ISS). The role of elevated LDH (> 250 U/l), as an element of R-ISS, was assessed separately. Maximal SUV LDH was elevated in 20/36 patients and was predictive The median OS of the 16 patients with an SUVmax < 4 of significantly shorter OS (6  months vs. not reached, was not reached, while in the 20 patients with an SUV- p = 0.006, Fig.  3c) and PFS (4 vs. 15  months, p = 0.003, max > 4 the estimated median survival was 3.9 (SE 8.01) Fig.  3d). Patients relapsing after third-line or later line months (p = 0.014, Fig.  1a). Using established first- of therapy had significantly shorter PFS (p = 0.001) and line parameters, a significantly shorter time of PFS was showed a strong trend to lower OS (p = 0.069). observed in 20 patients with SUVmax > 4 (median of 4 (SE 0.17) vs. 15 (SE 4) months, p = 0.002) as well (Fig. 2a). Combining PET and ISS To identify the patients with the highest risk, we evalu- Focal bone lesions ated the combined value of PET and ISS. We selected The presence of a single PET-positive focal lesion failed the cases in which both higher ISS stage (II or III) and to achieve significance for OS in our population (p = 0.1). at least one of the predictive PET parameters (EMD, Looking at the established number of FL in first-line nFL > 3, or SUVmax > 4) was present. These “high- patients, the median survival of the 15 patients with risk” patients (n = 11) had significantly shorter OS than more than 3 FLs was significantly shorter (3.8 months, SE the rest of the population (3.7 (SE 0.2) months vs. not 4.7) than in 21 patients with 3 or less FLs (median not reached, p < 0.001), with minimal variability. The PFS was reached, p = 0.003, Fig. 1b). significantly shorter in these patients, too (3.63 (SE 0.14) Similarly, the presence of a single PET-positive vs. 11.7 (SE 2.2), p < 0.001). In contrast, the “low-risk” focal lesion was not a significant predictor for shorter patients with ISS stage I and none of the predictive PET PFS (p = 0.08), while the threshold of > 3 focal lesions parameters survived significantly longer (OS: not reached achieved significance as negative predictor for PFS (3.5 vs. 13.6  months, p = 0.028; PFS: 20.7 vs. 5.9  months, (SE 0.14) vs. 15 (SE 3.8) months, p < 0.001) (Fig.  2b). p = 0.007). The comparison of “high-risk” versus “low- Interestingly, the presence of > 3 focal bone lesions on CT risk” patients versus others in a single model is demon- alone, without PET assessment of lesion activity, had no strated in Fig. 4. Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 5 of 10 Fig. 1 Kaplan–Meier analysis of prognostic impact of PET‑ CT parameters for overall survival. a According to maximum SUV over 4. b According to number of focal lesions, threshold over 3. c According to presence of EMD the presence of FDG-avid EMD and a SUVmax > 3.9 Discussion were significant on monovariate analysis. These findings Evaluation of the prognostic role of PET/CT in the were confirmed in a prospective study of 192 patients by first line setting of myeloma treatment identified use - Zamagni et  al. in 2011. Presence of FDG-avid EMD and ful thresholds for certain parameters. For instance, Bar- SUVmax > 4.2 at baseline were identified as independent tel et  al. [15] showed in a large prospective study of 239 negative prognostic factors for OS and PFS [8]. The pres - patients that the presence of more than 3 FDG-avid ence of more than 3 PET-positive FLs at day 7 of induc- focal bone lesions at baseline was an independent prog- tion therapy was an independent negative prognostic nostic factor for OS and event-free survival (EFS), while Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 6 of 10 Fig. 2 Kaplan–Meier analysis of prognostic impact of PET‑ CT parameters for progression free survival. a According to maximum SUV over 4. b According to number of focal lesions, threshold over 3. c According to presence of EMD parameter for OS and PFS in the large prospective study FLs at baseline as a negative prognostic parameter for of 302 patients by Usmani et  al. [11]. In 2015, Zamagni OS and PFS in a retrospective evaluation of 596 cases. et al. demonstrated the negative prognostic role of base- Wang et  al. [16] demonstrated the negative prognostic line SUVmax > 4.2 for PFS and OS in a retrospective role of EMD present at baseline for both OS and PFS. The evaluation of 282 patients [9]. Patriarca et  al. [10] dem- IMWG 2017 consensus statement proposed a threshold onstrated the negative prognostic role of SUVmax > 4.2 of SUV > 4 for defining significant PET-positivity [4]. in 67 patients prior to autologous SCT. Davies et al. [14] In comparison, retrospective analyses in patients corroborated the presence of more than 3 PET-positive with relapse after SCT identified significantly higher Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 7 of 10 Table 3 The results of statistical analysis Parameter Patients, n For OS For PFS p-value, log-rank Hazard ratio (CI 95%) p-value, log-rank Hazard ratio (CI 95%) PET/CT-parameters SUVmax > 4 20/36 0.014 3.19 (1.2–8.48) 0.002 3.01 (1.39–6.51) n, FLs ≥ 1 23/36 0.10 2.29 (0.83–6.32) 0.08 1.86 (0.88–3.93) n, FLs > 3 15/36 0.003 3.7 (1.48–9.27) < 0.001 5.54 (2.25–13.6) EMD Present versus not present 12/36 0.004 3.40 (1.39–8.30) 0.006 2.67 (1.23–5.83) n, FLs > 3 on CT only* 28/36 0.74 1.19 (0.39–3.59) 0.54 1.31 (0.53–3.22) Remission status PR or worse versus at least vgPR 21/36 0.327 1.58 (0.63–3.97) 0.376 1.38 (0.67–2.83) Prior therapy lines ≥ 2 23/36 0.265 1.76 (0.64–4.87) 0.128 1.84 (0.83–4.07) ≥ 3 14/36 0.72 2.2 (0.91–5.4) 0.001 3.6 (1.59–8.13) Clinical parameters Age (≥ 65 years) 11/36 0.169 1.86 (0.75–4.58) 0.082 1.87 (0.86–4.07) Elevated LDH (> 250 U/l) 20/36 0.006 3.86 (1.38–10.77) 0.003 2.89 (1.35–6.17) ISS‑Stage (I vs. II vs. III) 19/13/4 0.016 2.37 (1.26–4.44) 0.046 1.88 (1.09–3.24) The statistically significant results with p-value below 0.05 are highlighted in bold OS overall survival, PFS progression free survival, SUV standardized uptake value, FLs focal (bone) lesions, EMD extramedullary disease, PR partial remission, vgPR very good partial remission, FLC free light chains. *Over 3 bone lesions on CT without PET-positivity prognostic thresholds. A study of 40 patients by Jamet with the results of multiple first line studies, and as dem - et  al. selected relapsed patients after high-dose chemo- onstrated by Lapa et al. [18] for relapsed myeloma. therapy and SCT. A SUVmax > 15.9 and more than 13 While the comparison with previous relapse studies is FLs (or > 6 FLs in appendicular skeleton) were identified hampered by small study populations and variability of as negative prognostic predictors for PFS [19]. Earlier, pretreatment intensity, our findings still provide a basis Lapa et al. [18] had performed a retrospective analysis of for comparing prognostic thresholds of PET/CT param- 37 patients suffering relapse after at least one autologous eters in the first-line and relapse settings. and/or allogeneic SCT. A SUVmax > 18.57 was predictive ISS stage is the most widely used tool for prognostic of shorter time to progression (TTP), while more than assessment and demonstrated prognostic significance 10 FLs and the presence of EMD predicted both shorter for OS and PFS in our patient population. Combining TTP and OS. In both studies, patients were heavily pre- ISS and PET-parameters allowed us to reliably identify treated prior to relapse, which is true for our study as patients with particularly short survival. We demon- well. strated that PET is an independent prognostic parameter, We used a lower threshold of SUVmax > 4, based on the adding prognostic information to ISS stage. The com - results of larger first line studies. In our relapse popula - bined use of PET thresholds and clinical parameters may tion, the SUVmax > 4 had a negative prognostic impact enhance PET-based prognostic evaluation in the first-line on both OS and PFS. A similar trend was seen regard- and relapse setting. ing cut-offs for active FLs. Multiple pre-SCT studies Our analysis has certain limitations. Similar to other of patients in first-line therapy identified a threshold of studies of PET/CT in MM relapse after SCT, patients in more than 3 FLs as a negative predictor for OS and/or our study were heterogeneous regarding their pretreat- PFS [8, 9, 14, 15, 17]. Similar to SUVmax, the threshold ment history. 23 of 36 patients (63.8%) had received at number of FLs with negative prognostic power was much least 2 lines of therapy before current relapse, and 18 of higher (6 or 10 FLs) in retrospective studies of relapsed 36 (50%) had received more than one SCT. Since patient MM [18, 19]. However, the results of our analysis support selection for our retrospective analysis covered a 7-year the prognostic significance of the lower cut-off value of period (2012–2019), treatment protocols varied substan- FL > 3 for OS and PFS in patients with relapsed MM. Fur- tially. In addition, small patient numbers render multi- thermore, the presence of PET-positive EMD was a sig- variate models less informative and put more emphasis nificant negative predictor of OS and PFS, in accordance on univariate analysis. Still, the established clinical prog- nostic parameters, including elevated LDH and higher Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 8 of 10 Fig. 3 Kaplan–Meier analysis of prognostic impact of serum LDH levels and ISS‑Stage for OS and PFS. a According to ISS—Stage (OS), b according to ISS—Stage (PFS), c according to LDH, threshold > 250 U/l (OS), d according to LDH, threshold > 250 U/l (PFS) ISS proved themselves as significant negative predictors Our results could contribute to the management of for both OS and PFS in our relatively small study popu- MM at relapse after SCT. Data up to now only showed lation. The applicability of established clinical prognostic that very high thresholds for PET-parameters, such as parameters suggests that our patient cohort is represent- SUVmax of over 15 or 18 and nFLs of over 6 or 10 are ative of a wider population of patients with MM and sup- prognostically relevant in relapse setting [18, 19]. We ports the conclusions drawn from this study population. show that lower thresholds of FLs > 3 or SUVmax > 4 already identify patients with high risk and therefore should lead physicists to treat these patients more Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 9 of 10 Fig. 4 Kaplan–Meier analysis of combined prognostic impact of ISS and PET‑Parameters. a according to OS, b according to PFS. *negative PET— none of established predictive PET‑parameters (SUVmax > 4, nFLs > 3, EMD) present. **positive PET—at least one of predictive PET‑parameters (SUVmax > 4, nFLs > 3, EMD) present computed tomography; PFS: Progression‑free survival; PR: Partial remission; aggressively. The presence of extramedullary disease vgPR: Very good Partial Remission; R‑ISS: Revised (multiple myeloma) Interna‑ was a significant negative prognostic parameter both tional Staging System; SCT: Stem cell transplantation; SE: Standard error; SD: in our population and in previous studies. Stable disease; SUV: Standardised uptake value; SUVmax: Maximal standard‑ ised uptake value; TTP: Time to progression; VOI: Volume of interest. Conclusions Acknowledgements We show that the same PET/CT parameter thresholds Not applicable. that are used in the first-line setting can also stratify Author contributions patients with relapsed MM and identify those with par- Conceptualization, RH, RZ and CA; methodology, RZ, AM and CA.; software, ticularly poor prognosis. Our findings demonstrate the RZ and EM; validation, CA, RF and RH; formal analysis and investigation, all.; resources, CA and RH; data curation, RZ, EM and AM; writing—original draft prognostic yield of PET/CT in MM relapse independent preparation, RZ, RF.; writing—review and editing, all; visualization, RZ and EM; of ISS stage and suggest that the same thresholds for PET supervision, RH and CA; project administration, RZ.; funding acquisition, not prognostic parameters can be used at baseline and at later applicable. All authors read and approved the final manuscript. stages in the course of disease.Patients with relapsed MM Funding who show unfavourable prognostic PET/CT parameters Open Access funding enabled and organized by Projekt DEAL. This research may survive only few months. The use of F-FDG-PET/ received no external funding. CT, especially in combination with established clinical Availability of data and materials parameters, may thus help to select high-risk patients The anonymised dataset generated and analysed during the current study is with MM relapse who may benefit from aggressive treat - available from the corresponding author on reasonable request. ment approaches. Declarations Abbreviations Ethics approval and consent to participate F‑FDG: Fluorodeoxyglucose F18; CRD: Complete response duration; CR: Authors declare that the investigations were carried out following the rules Complete remission; EFS: Event‑free survival; EMD: Extramedullary dis‑ of the Declaration of Helsinki of 1975, revised in 2013. According to point 23 ease, Extramedullary Lesions; FISH: Fluorescence in situ hybridization; FL: of this declaration, approval of an ethics committee was sought prior to the Focal (bone) Lesion; nFLs: Number of focal (bone) Lesions; HDT: High‑ dose study. The approval was provided by the Ethics Committee of the Medical chemotherapy; IMWG: International Myeloma Working Group; ISS: (Multiple Faculty of Heinrich Heine University Dusseldorf, Germany (vote nr. 2020‑906). myeloma) International Staging System; LDH: Lactate dehydrogenase; MM: Patient consent was waived due to the monocentric and retrospective nature Multiple myeloma; OS: Overall survival; PET/CT: Positron emission tomography of the study and due to the following considerations: many patients were Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 10 of 10 already deceased at the time of data collection. Furthermore, all diagnostic treated with total therapy 3. Blood. 2013;121(10):1819–23. https:// doi. org/ procedures were performed as part of routine medical care. The monocentric 10. 1182/ blood‑ 2012‑ 08‑ 451690. study was conducted by the physicians at the University Hospital Dusseldorf, 12. Beksac M, Gunduz M, Ozen M, Bakanay Ozturk S, Kucuk O, Ozkan E. and no data were shared with or analysed by external parties. All data was Impact of PET‑ CT response on survival parameters following autologous anonymized prior to analysis. No data that could directly or indirectly identify stem cell transplantation among patients with multiple myeloma: com‑ the patients is included for publication. These aspects were specifically parison of two cut‑ off values. Blood. 2014;124(21):3983–4083. https:// doi. considered by the Ethics Committee of the Medical Faculty of Heinrich Heine org/ 10. 1182/ blood. V124. 21. 3983. 3983. University Dusseldorf, Germany, in vote nr. 2020‑906. 13. Jung SH, Kwon SY, Min JJ, et al. 18F‑FDG PET/CT is useful for determining survival outcomes of patients with multiple myeloma classified as stage II Consent for publication and III with the Revised International Staging System. Eur J Nucl Med Mol Not applicable. Imaging. 2019;46(1):107–15. https:// doi. org/ 10. 1007/ s00259‑ 018‑ 4114‑0. 14. Davies FE, Rosenthal A, Rasche L, et al. Treatment to suppression of focal Competing interests lesions on positron emission tomography‑ computed tomography is a Authors declare that they have no competing interests. therapeutic goal in newly diagnosed multiple myeloma. Haematologica. 2018;103(6):1047–53. https:// doi. org/ 10. 3324/ haema tol. 2017. 177139. Author details 15. Bartel TB, Haessler J, Brown TLY, et al. F18‑fluorodeoxyglucose positron Department for Hematology, Oncology and Clinical Immunology, Medical emission tomography in the context of other imaging techniques and Faculty, Heinrich Heine University Dusseldorf, Moorenstr. 5, 40225 Dussel‑ prognostic factors in multiple myeloma. Blood. 2009;114(10):2068–76. dorf, Germany. Clinic for Nuclear Medicine, Medical Faculty, Heinrich Heine https:// doi. org/ 10. 1182/ blood‑ 2009‑ 03‑ 213280. University Dusseldorf, 40225 Dusseldorf, Germany. Department of Diagnostic 16. Wang C, Wu L, Sun C, Zhang Y. Clinical relevance of PET/CT in patients and Interventional Radiology, Medical Faculty, Heinrich Heine University Dus‑ with newly diagnosed multiple myeloma. Int J Clin Exp Pathol. seldorf, 40225 Dusseldorf, Germany. Department for Oncology and Hematol‑ 2019;12(2):619–27. ogy, St. Lukas Clinic Solingen, 42697 Solingen, Germany. 17. Moon SH, Choi WH, Yoo IR, et al. Prognostic value of baseline18F‑fluoro ‑ deoxyglucose PET/CT in patients with multiple myeloma: a multicenter Received: 21 November 2021 Accepted: 25 March 2022 cohort study. Korean J Radiol. 2018;19(3):481–8. https:// doi. org/ 10. 3348/ kjr. 2018. 19.3. 481. 18. Lapa C, Lückerath K, Malzahn U, et al. 18FDG‑PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation. Oncotarget. 2014;5(17):7381–91. https:// doi. org/ 10. 18632/ oncot arget. 2290. References 19. Jamet B, Bailly C, Carlier T, et al. 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Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 8. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18‑F FDG lished maps and institutional affiliations. PET/CT in newly diagnosed multiple myeloma patients treated with up‑ front autologous transplantation. Blood. 2011;118(23):5989–95. https:// doi. org/ 10. 1182/ blood‑ 2011‑ 06‑ 361386. 9. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res. 2015;21(19):4384–90. https:// doi. org/ 10. 1158/ 1078‑ 0432. CCR‑ 15‑ 0396. 10. Patriarca F, Carobolante F, Zamagni E, et al. The role of positron emission tomography with 18F‑fluorodeoxyglucose integrated with computed tomography in the evaluation of patients with multiple myeloma under‑ going allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(6):1068–73. https:// doi. org/ 10. 1016/j. bbmt. 2015. 03. 001. 11. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18‑fluoro ‑ deoxyglucose emission tomography in multiple myeloma http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medical Imaging Springer Journals

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Abstract

Purpose: While F‑FDG PET/CT yields valuable prognostic information for patients in first ‑line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first ‑line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first ‑line setting. Methods: Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG‑PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET‑positive extramedullary lesions (EMD) were analysed. Results: For the number of FLs, the prognostic value was demonstrated with a cut‑ off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above‑mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001). Conclusion: The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first ‑line setting but also in relapsed MM. Keywords: Multiple myeloma, Relapse, Prognostic factors, 18FDG PET‑ CT improved the progression-free and overall survival, but Background the vast majority of patients will eventually experience Multiple myeloma (MM) is a malignant plasma cell dis- disease progression [1, 2]. The multifaceted presenta - order that is currently incurable in most cases. The tion and progressive nature of MM require complex introduction of novel therapeutic agents significantly assessment including detailed radiological examination. Whole-body computed tomography (CT), magnetic res- *Correspondence: Romans.Zukovs@med.uni‑ duesseldorf.de onance imaging (MRI), and positron emission tomogra- Department for Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich Heine University Dusseldorf, Moorenstr. 5, phy—computed tomography (PET/CT) are the methods 40225 Dusseldorf, Germany Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 2 of 10 of choice, depending on the clinical setting and their FDG-avid focal intramedullary lesions (FL) as well as the availability [3]. presence of extramedullary disease (EMD) [4, 8–16]. Pro- 18 18 The F-fluorodesoxyglucose ( F-FDG) PET/CT is spective studies during first line therapy identified cut-off particularly useful for differentiating between active and values for PET/CT parameters with minor variability [8, smoldering myeloma, assessing residual disease after 11, 12, 15]. These prognostically significant thresholds therapy, or detecting extramedullary involvement [4, 5]. were reproduced in multiple smaller retrospective stud- Disease activity assessed by PET/CT at diagnosis, after ies (Table  1). A maximal SUV (SUVmax) above 3.9–4.2, induction therapy, and after high-dose therapy is a useful more than 3 FLs, and the presence of PET-positive EMD predictor of progression-free survival (PFS) and overall were repeatedly demonstrated to be negative predictors survival (OS), as shown by multiple prospective and ret- for OS and/or PFS [8–10, 14, 15, 17]. rospective studies (Table  1). Moreover, comparative pre- The role of PET/CT in relapsed or refractory MM is and post-therapeutic PET/CT for evaluation of therapy less clear, particularly in the post-transplantation setting response yields important prognostic information, too [6, [4]. The parameters and thresholds used in relapse stud - 7]. The IMWG consensus statement on radiologic diag - ies are heterogeneous, which hampers the evaluation of nostics in MM recommends the use of PET/CT at diag- the prognostic role of PET/CT. The prognostic thresh - nosis when available, especially in studies, followed by olds proposed for SUVmax and number of focal lesions st PET/CT re-evaluation after 1 line treatment for assess- in patients with relapsed MM are 3–4 times higher and ment of residual disease [3]. more variable than those identified in the first-line set - Most studies on the prognostic role of PET/CT in MM ting [18, 19] (Table 1). measured metabolic disease activity using standard- In our retrospective single center study, we analyzed ized uptake values (SUV) and evaluated the number of patients with MM who underwent at least one HDT with Table 1 Overview of studies evaluating prognostic role of variable PET‑ CT parameters in multiple myeloma Study Study design Number Time of PET/CT Thresholds for PET-CT parameters of (relevant survival parameter) patients Bartel et al. [15] Prospective 239 At diagnosis and before autologous SCT nFL > 3 (OS and EFS), SUVmax > 3.9 (EFS*), EMD‑positivity (OS* and EFS*) Zamagni et al. [8] Prospective 192 At diagnosis SUVmax > 4.2 (OS and PFS), EMD‑positivity (OS and PFS), nFLs > 3 (PFS*) Fonti et al. [21] Retrospective 47 At diagnosis, with subpopulation in relapse MTV (OS and PFS) Usmani et al. [11] Prospective 302 At diagnosis and at induction day 7 nFL > 3 on day 7 (OS and PFS) Zamagni et al. [9] Retrospective 282 After first line SUVmax > 4.2 (PFS and OS), nFL > 3 (OS* and PFS*), EMD‑positivity (OS* and PFS*) Patriarca et al. [10] Retrospective 67 Before allogeneic SCT SUVmax > 4.2 (OS and PFS*), EMD‑positivity (OS* and PFS), nFL > 1 (OS* and PFS*), Beksac et al. [12] Prospective 139 Before and after autologous SCT SUVmax > 3.35 (OS), SUVmax > 4.2 (PFS) Moreau et al. [22] Prospective 134 After first line compared to PET at diagnosis PET‑positive versus PET ‑normalization (PFS and OS) Davies et al. [14] Retrospective (based 596 At diagnosis, during and after induction nFL > 3 (OS, PFS) at diagnosis. Suppression of on population of TT4‑6 FL‑signal beneficial trials) Wang et al. [16] Retrospective 123 At diagnosis SUVmax > 5.7 (OS*), EMD‑positivity (OS and PFS) Moon et al. [17] Retrospective 76 At diagnosis nFL > 3 (OS and PFS), EMD‑positivity (OS and PFS) Fonti et al. [23] Retrospective 47 At diagnosis MVT (OS and PFS), TLG (OS* and PFS*), SUV‑ max (OS*), nFL (OS* and PFS*) Lapa et al. [18] Retrospective 37 At relapse nFL > 10 ( TTP and OS), EMD ( TTP and OS), SUVmax (ROC) > 18.5 ( T TP) Jamet et al. [19] Retrospective 40 At relapse nFL (appendicular skeleton) > 6 (OS, PFS), TLG (OS), SUVmax (ROC) > 15.9 (PFS), nFLs > 13 (PFS*) SCT stem cell transplantation, OS overall survival, EFS event free survival, PFS progression free survival, CRD complete response duration, TTP time to progression, nFL number of focal lesions, EMD extramedullary disease, SUV-standardized uptake value, MTV metabolic tumor volume, TLG total lesion glycolysis. *Parameter was significant only on univariate analysis Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 3 of 10 autologous or allogeneic SCT and experienced disease Table 2 Overview of patient’s data relapse. We evaluated the prognostic role of F-FDG- Parameter Number (%) PET-CT for OS and PFS, focusing on prognostic param- Patients, total 36 eters that were mostly identified in larger prospective Age, years, median 60 studies looking at baseline parameters and/or response to Age, years, range 44–76 therapy. Sex, male 20 (55.5%) Sex, female 16 (44.5%) Methods MM subtype We retrospectively evaluated patients with MM who IgG Kappa/Lambda 12 (33.3%)/7 (19.4%) underwent F-FDG-PET/CT in our center between 2012 IgA Kappa/Lambda 3 (8.3%)/2 (5.6%) and 2019. In this population, 36 pre-treated patients, who IgM Lambda 1 (2.8%) had received at least one autologous or allogeneic SCT Light chain only, Kappa 5 (13.9%) and experienced disease relapse at the time of PET/CT Light chain only, Lambda 3 (8.3%) investigation, were identified and included in the study. Non‑secretory 3 (8.3%) Relapse was defined according to IMWG-criteria [20]. High‑ dose therapies with SCTs Patients with relapse who had already started new ther- One autologous SCT 17 (47.2%) apy prior to the PET/CT were excluded. Clinical findings Two autologous SCT 12 (33.3%) and laboratory results were integrated into our analysis Three autologous SCT 1 (2.8%) (Table 2). Allogeneic SCT (following autologous) 6 (16.7%) [5(13.9%)] Therapy lines before current progress PET-CT Scans First line 13 (36.1%) All scans were performed as a non-contrast low-dose Second line 9 (25%) PET/CT (mCT, 128 slices, Siemens Healthineers). Scan Third line 8 (22.2%) range included whole body from the top of the head Fourth line 4 (11.1%) through the feet. The F-FDG-tracer dosing was adapted Fifth line 2 (5.6%) for body weight (3MBq F-FDG/kg). The visual evalua - Median 2 tion of the PET was carried out using the Ultra-HD-3D ISS stage at current progress mode reconstruction and the iterative 3D-mode recon- I 19 (52.8%) structions. The SUV measurements were conducted II 13 (36.1%) using the iterative 3D-mode reconstructions. The SUV - III 4 (11.1%) max was defined as maximal measured SUV value of Cytogenetics on FISH the single most active intramedullary or extramedullary High‑ eisk 6 (16.6%) lesion on each scan using manually placed volumes of Non‑high‑risk 15 (41.7%) interest (VOI). Focal bone lesions were defined as FDG- Cytogenetics not available 15 (41.7%) avid focal areas within bone structure with tracer uptake LDH intensity above median bone marrow activity (based on Elevated (> 250 U/l) 20 (55.5%) the prospective study by Bartel et  al. [15]). The thresh - Normal (≤ 250 U/l) 16 (44.5%) old of more than 3 focal lesions and the SUVmax cut-off Best response after last therapy line value of 4 for survival analysis were based on prospec- CR 10 (27.7%) tive and larger retrospective studies of F-FDG-PET/CT vgPR 5 (13.9%) prognostic role in first-line therapy (Table  1) and IMWG PR 19 (52.8%) 2017 consensus statement [4]. The presence of PET-posi - SD 2 (5.6%) tive EMD was also evaluated. EMD was defined as FDG- avid lesion that was not contiguous to bone on CT-scan SCT stem cell transplantation, ISS international staging system, FISH fluorescence in situ hybridization, CR complete remission, vgPR very good partial remission, and arose in soft tissue. PR partial remission, SD stable disease Statistics We used commercial software (SPSS ver. 23 by IBM was defined as death of any reason for OS, and as next Statistics) for statistical analysis. Kaplan–Meier sur- disease relapse or death for PFS. Log-rank tests were vival analysis was performed to assess the time of OS used to assess statistical significance. A significance and PFS with start-point at the moment of the PET/CT level of p-value was set at 0.05. Besides PET parame- investigation. Survivors were censored at the time of ters, clinical findings and laboratory results, as well as the last clinical contact. In survival analysis, an event Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 4 of 10 number of prior treatment lines, were evaluated as risk statistical significance as a negative predictor of OS or factors. PFS (Table 3). Extramedullary disease Results FDG-avid EMD was present in 12/36 (33.3%) of our Patient characteristics patients. In patients with EMD the median OS was 3.63 Among 36 relapsed patients, 20 were male and 16 female (SE 2.2) months, compared to not reached in patients (Table  2). Median age was 60  years (range 44–76). Sev- with no EMD on PET/CT (p = 0.004, Fig. 1c). In patients enteen patients previously underwent single autolo- with EMD the median PFS was 3.5 (SE 0.4) months, com- gous SCT, 12 patients received two autologous SCTs, pared to 11 (SE 1.8) months in patients with no EMD and 1 patient had three autologous SCTs. Six patients on PET-CT (p = 0.006, Fig.  2c). In 9/12 cases the SUV- underwent allogeneic SCT, five of them after previ - max was located in the extramedullary lesion and in 8 of ous autologous transplantation. Thirteen (36%) patients those 9 cases it exceeded the threshold of 4. In 8 of 12 experienced first disease relapse, 9 (25%) had a second, 8 patients radiation therapy of PET-positive extramedul- (22%) had a third, and 6 (17%) patients suffered a fourth lary lesions was initiated, demonstrating relevance for or fifth relapse. With a median follow-up of 37.9 months, therapy planning. the median OS in the entire study population was 16.3 (SE 17.7) months. Median time of PFS of was 6.0 (SE 3.6) Laboratory and clinical parameters months. Five of 36 patients (14%) were lost to follow-up Laboratory parameters were assessed at the time of before reaching next progress or death. PET/CT investigation (Table  3). Thirteen patients had ISS stage II and four had stage III. The OS was signifi - PET parameters cantly shorter in patients with higher ISS stage (3.9 and At the time of relapse, 26/36 (72.2%) of our patients had a 13.6  months vs. not reached, p = 0.016, Fig.  3a). The ISS positive PET scan. Among those, 14/26 patients had only stage had somewhat weaker, but still significant nega - intramedullary disease, while 10/26 had both intra- and tive predictive value for PFS as well (p = 0.046, Fig.  3b). extramedullary FDG-avid lesions. Two patients had EMD In 15/36 patients cytogenetic analysis was not available, only. Ten patients had a negative PET scan with no FDG- precluding determination of disease stage according to avid lesions detectable. the revised ISS (R-ISS). The role of elevated LDH (> 250 U/l), as an element of R-ISS, was assessed separately. Maximal SUV LDH was elevated in 20/36 patients and was predictive The median OS of the 16 patients with an SUVmax < 4 of significantly shorter OS (6  months vs. not reached, was not reached, while in the 20 patients with an SUV- p = 0.006, Fig.  3c) and PFS (4 vs. 15  months, p = 0.003, max > 4 the estimated median survival was 3.9 (SE 8.01) Fig.  3d). Patients relapsing after third-line or later line months (p = 0.014, Fig.  1a). Using established first- of therapy had significantly shorter PFS (p = 0.001) and line parameters, a significantly shorter time of PFS was showed a strong trend to lower OS (p = 0.069). observed in 20 patients with SUVmax > 4 (median of 4 (SE 0.17) vs. 15 (SE 4) months, p = 0.002) as well (Fig. 2a). Combining PET and ISS To identify the patients with the highest risk, we evalu- Focal bone lesions ated the combined value of PET and ISS. We selected The presence of a single PET-positive focal lesion failed the cases in which both higher ISS stage (II or III) and to achieve significance for OS in our population (p = 0.1). at least one of the predictive PET parameters (EMD, Looking at the established number of FL in first-line nFL > 3, or SUVmax > 4) was present. These “high- patients, the median survival of the 15 patients with risk” patients (n = 11) had significantly shorter OS than more than 3 FLs was significantly shorter (3.8 months, SE the rest of the population (3.7 (SE 0.2) months vs. not 4.7) than in 21 patients with 3 or less FLs (median not reached, p < 0.001), with minimal variability. The PFS was reached, p = 0.003, Fig. 1b). significantly shorter in these patients, too (3.63 (SE 0.14) Similarly, the presence of a single PET-positive vs. 11.7 (SE 2.2), p < 0.001). In contrast, the “low-risk” focal lesion was not a significant predictor for shorter patients with ISS stage I and none of the predictive PET PFS (p = 0.08), while the threshold of > 3 focal lesions parameters survived significantly longer (OS: not reached achieved significance as negative predictor for PFS (3.5 vs. 13.6  months, p = 0.028; PFS: 20.7 vs. 5.9  months, (SE 0.14) vs. 15 (SE 3.8) months, p < 0.001) (Fig.  2b). p = 0.007). The comparison of “high-risk” versus “low- Interestingly, the presence of > 3 focal bone lesions on CT risk” patients versus others in a single model is demon- alone, without PET assessment of lesion activity, had no strated in Fig. 4. Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 5 of 10 Fig. 1 Kaplan–Meier analysis of prognostic impact of PET‑ CT parameters for overall survival. a According to maximum SUV over 4. b According to number of focal lesions, threshold over 3. c According to presence of EMD the presence of FDG-avid EMD and a SUVmax > 3.9 Discussion were significant on monovariate analysis. These findings Evaluation of the prognostic role of PET/CT in the were confirmed in a prospective study of 192 patients by first line setting of myeloma treatment identified use - Zamagni et  al. in 2011. Presence of FDG-avid EMD and ful thresholds for certain parameters. For instance, Bar- SUVmax > 4.2 at baseline were identified as independent tel et  al. [15] showed in a large prospective study of 239 negative prognostic factors for OS and PFS [8]. The pres - patients that the presence of more than 3 FDG-avid ence of more than 3 PET-positive FLs at day 7 of induc- focal bone lesions at baseline was an independent prog- tion therapy was an independent negative prognostic nostic factor for OS and event-free survival (EFS), while Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 6 of 10 Fig. 2 Kaplan–Meier analysis of prognostic impact of PET‑ CT parameters for progression free survival. a According to maximum SUV over 4. b According to number of focal lesions, threshold over 3. c According to presence of EMD parameter for OS and PFS in the large prospective study FLs at baseline as a negative prognostic parameter for of 302 patients by Usmani et  al. [11]. In 2015, Zamagni OS and PFS in a retrospective evaluation of 596 cases. et al. demonstrated the negative prognostic role of base- Wang et  al. [16] demonstrated the negative prognostic line SUVmax > 4.2 for PFS and OS in a retrospective role of EMD present at baseline for both OS and PFS. The evaluation of 282 patients [9]. Patriarca et  al. [10] dem- IMWG 2017 consensus statement proposed a threshold onstrated the negative prognostic role of SUVmax > 4.2 of SUV > 4 for defining significant PET-positivity [4]. in 67 patients prior to autologous SCT. Davies et al. [14] In comparison, retrospective analyses in patients corroborated the presence of more than 3 PET-positive with relapse after SCT identified significantly higher Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 7 of 10 Table 3 The results of statistical analysis Parameter Patients, n For OS For PFS p-value, log-rank Hazard ratio (CI 95%) p-value, log-rank Hazard ratio (CI 95%) PET/CT-parameters SUVmax > 4 20/36 0.014 3.19 (1.2–8.48) 0.002 3.01 (1.39–6.51) n, FLs ≥ 1 23/36 0.10 2.29 (0.83–6.32) 0.08 1.86 (0.88–3.93) n, FLs > 3 15/36 0.003 3.7 (1.48–9.27) < 0.001 5.54 (2.25–13.6) EMD Present versus not present 12/36 0.004 3.40 (1.39–8.30) 0.006 2.67 (1.23–5.83) n, FLs > 3 on CT only* 28/36 0.74 1.19 (0.39–3.59) 0.54 1.31 (0.53–3.22) Remission status PR or worse versus at least vgPR 21/36 0.327 1.58 (0.63–3.97) 0.376 1.38 (0.67–2.83) Prior therapy lines ≥ 2 23/36 0.265 1.76 (0.64–4.87) 0.128 1.84 (0.83–4.07) ≥ 3 14/36 0.72 2.2 (0.91–5.4) 0.001 3.6 (1.59–8.13) Clinical parameters Age (≥ 65 years) 11/36 0.169 1.86 (0.75–4.58) 0.082 1.87 (0.86–4.07) Elevated LDH (> 250 U/l) 20/36 0.006 3.86 (1.38–10.77) 0.003 2.89 (1.35–6.17) ISS‑Stage (I vs. II vs. III) 19/13/4 0.016 2.37 (1.26–4.44) 0.046 1.88 (1.09–3.24) The statistically significant results with p-value below 0.05 are highlighted in bold OS overall survival, PFS progression free survival, SUV standardized uptake value, FLs focal (bone) lesions, EMD extramedullary disease, PR partial remission, vgPR very good partial remission, FLC free light chains. *Over 3 bone lesions on CT without PET-positivity prognostic thresholds. A study of 40 patients by Jamet with the results of multiple first line studies, and as dem - et  al. selected relapsed patients after high-dose chemo- onstrated by Lapa et al. [18] for relapsed myeloma. therapy and SCT. A SUVmax > 15.9 and more than 13 While the comparison with previous relapse studies is FLs (or > 6 FLs in appendicular skeleton) were identified hampered by small study populations and variability of as negative prognostic predictors for PFS [19]. Earlier, pretreatment intensity, our findings still provide a basis Lapa et al. [18] had performed a retrospective analysis of for comparing prognostic thresholds of PET/CT param- 37 patients suffering relapse after at least one autologous eters in the first-line and relapse settings. and/or allogeneic SCT. A SUVmax > 18.57 was predictive ISS stage is the most widely used tool for prognostic of shorter time to progression (TTP), while more than assessment and demonstrated prognostic significance 10 FLs and the presence of EMD predicted both shorter for OS and PFS in our patient population. Combining TTP and OS. In both studies, patients were heavily pre- ISS and PET-parameters allowed us to reliably identify treated prior to relapse, which is true for our study as patients with particularly short survival. We demon- well. strated that PET is an independent prognostic parameter, We used a lower threshold of SUVmax > 4, based on the adding prognostic information to ISS stage. The com - results of larger first line studies. In our relapse popula - bined use of PET thresholds and clinical parameters may tion, the SUVmax > 4 had a negative prognostic impact enhance PET-based prognostic evaluation in the first-line on both OS and PFS. A similar trend was seen regard- and relapse setting. ing cut-offs for active FLs. Multiple pre-SCT studies Our analysis has certain limitations. Similar to other of patients in first-line therapy identified a threshold of studies of PET/CT in MM relapse after SCT, patients in more than 3 FLs as a negative predictor for OS and/or our study were heterogeneous regarding their pretreat- PFS [8, 9, 14, 15, 17]. Similar to SUVmax, the threshold ment history. 23 of 36 patients (63.8%) had received at number of FLs with negative prognostic power was much least 2 lines of therapy before current relapse, and 18 of higher (6 or 10 FLs) in retrospective studies of relapsed 36 (50%) had received more than one SCT. Since patient MM [18, 19]. However, the results of our analysis support selection for our retrospective analysis covered a 7-year the prognostic significance of the lower cut-off value of period (2012–2019), treatment protocols varied substan- FL > 3 for OS and PFS in patients with relapsed MM. Fur- tially. In addition, small patient numbers render multi- thermore, the presence of PET-positive EMD was a sig- variate models less informative and put more emphasis nificant negative predictor of OS and PFS, in accordance on univariate analysis. Still, the established clinical prog- nostic parameters, including elevated LDH and higher Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 8 of 10 Fig. 3 Kaplan–Meier analysis of prognostic impact of serum LDH levels and ISS‑Stage for OS and PFS. a According to ISS—Stage (OS), b according to ISS—Stage (PFS), c according to LDH, threshold > 250 U/l (OS), d according to LDH, threshold > 250 U/l (PFS) ISS proved themselves as significant negative predictors Our results could contribute to the management of for both OS and PFS in our relatively small study popu- MM at relapse after SCT. Data up to now only showed lation. The applicability of established clinical prognostic that very high thresholds for PET-parameters, such as parameters suggests that our patient cohort is represent- SUVmax of over 15 or 18 and nFLs of over 6 or 10 are ative of a wider population of patients with MM and sup- prognostically relevant in relapse setting [18, 19]. We ports the conclusions drawn from this study population. show that lower thresholds of FLs > 3 or SUVmax > 4 already identify patients with high risk and therefore should lead physicists to treat these patients more Z ukovs et al. BMC Medical Imaging (2022) 22:63 Page 9 of 10 Fig. 4 Kaplan–Meier analysis of combined prognostic impact of ISS and PET‑Parameters. a according to OS, b according to PFS. *negative PET— none of established predictive PET‑parameters (SUVmax > 4, nFLs > 3, EMD) present. **positive PET—at least one of predictive PET‑parameters (SUVmax > 4, nFLs > 3, EMD) present computed tomography; PFS: Progression‑free survival; PR: Partial remission; aggressively. The presence of extramedullary disease vgPR: Very good Partial Remission; R‑ISS: Revised (multiple myeloma) Interna‑ was a significant negative prognostic parameter both tional Staging System; SCT: Stem cell transplantation; SE: Standard error; SD: in our population and in previous studies. Stable disease; SUV: Standardised uptake value; SUVmax: Maximal standard‑ ised uptake value; TTP: Time to progression; VOI: Volume of interest. Conclusions Acknowledgements We show that the same PET/CT parameter thresholds Not applicable. that are used in the first-line setting can also stratify Author contributions patients with relapsed MM and identify those with par- Conceptualization, RH, RZ and CA; methodology, RZ, AM and CA.; software, ticularly poor prognosis. Our findings demonstrate the RZ and EM; validation, CA, RF and RH; formal analysis and investigation, all.; resources, CA and RH; data curation, RZ, EM and AM; writing—original draft prognostic yield of PET/CT in MM relapse independent preparation, RZ, RF.; writing—review and editing, all; visualization, RZ and EM; of ISS stage and suggest that the same thresholds for PET supervision, RH and CA; project administration, RZ.; funding acquisition, not prognostic parameters can be used at baseline and at later applicable. All authors read and approved the final manuscript. stages in the course of disease.Patients with relapsed MM Funding who show unfavourable prognostic PET/CT parameters Open Access funding enabled and organized by Projekt DEAL. This research may survive only few months. The use of F-FDG-PET/ received no external funding. CT, especially in combination with established clinical Availability of data and materials parameters, may thus help to select high-risk patients The anonymised dataset generated and analysed during the current study is with MM relapse who may benefit from aggressive treat - available from the corresponding author on reasonable request. ment approaches. Declarations Abbreviations Ethics approval and consent to participate F‑FDG: Fluorodeoxyglucose F18; CRD: Complete response duration; CR: Authors declare that the investigations were carried out following the rules Complete remission; EFS: Event‑free survival; EMD: Extramedullary dis‑ of the Declaration of Helsinki of 1975, revised in 2013. According to point 23 ease, Extramedullary Lesions; FISH: Fluorescence in situ hybridization; FL: of this declaration, approval of an ethics committee was sought prior to the Focal (bone) Lesion; nFLs: Number of focal (bone) Lesions; HDT: High‑ dose study. The approval was provided by the Ethics Committee of the Medical chemotherapy; IMWG: International Myeloma Working Group; ISS: (Multiple Faculty of Heinrich Heine University Dusseldorf, Germany (vote nr. 2020‑906). myeloma) International Staging System; LDH: Lactate dehydrogenase; MM: Patient consent was waived due to the monocentric and retrospective nature Multiple myeloma; OS: Overall survival; PET/CT: Positron emission tomography of the study and due to the following considerations: many patients were Zukovs et al. BMC Medical Imaging (2022) 22:63 Page 10 of 10 already deceased at the time of data collection. Furthermore, all diagnostic treated with total therapy 3. Blood. 2013;121(10):1819–23. https:// doi. org/ procedures were performed as part of routine medical care. The monocentric 10. 1182/ blood‑ 2012‑ 08‑ 451690. study was conducted by the physicians at the University Hospital Dusseldorf, 12. 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Journal

BMC Medical ImagingSpringer Journals

Published: Apr 4, 2022

Keywords: Multiple myeloma; Relapse; Prognostic factors; 18FDG PET-CT

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