Comparison of 18F-sodium fluoride uptake in the whole bone, pelvis, and femoral neck of multiple myeloma patients before and after high-dose therapy and conventional-dose chemotherapy.

AIM: To compare the effects of high-dose therapy (HDT consisting of high-dose chemotherapy followed by autologous stem cell transplantation) and conventional-dose chemotherapy (non-HDT) on the uptake of 18F-sodium fluoride (NaF) in the whole bone, pelvis, and femoral neck of multiple myeloma (MM) patients. METHOD: The data of 19 MM patients who received HDT (61.5 (SD 5.6) years) and 11 MM patients who received conventional-dose chemotherapy (70.9 (SD 7.2) years) were collected in a prospective study. NaF PET/CT imaging was performed at baseline, and 8 weeks and 2 weeks after treatment for the HDT group and the non-HDT group, respectively. A CT-based algorithm was applied to segment the bones, and the global mean SUV (GSUVmean) of the whole bone and pelvis was calculated (OsiriX MD v.9.0, Pixmeo SARL; Bernex, Switzerland). In addition, regions of interest for the whole, medial, and lateral femoral neck were delineated bilaterally. Whole bone and pelvis measurements were replicated by two observers. RESULTS: The average GSUVmean in the whole bone and pelvis of the patients who underwent HDT significantly decreased from before to after treatment (- 16.27%, p = 0.02 and - 16.54%, p = 0.01, respectively). A significant decrease in the whole and lateral femoral neck was also observed bilaterally in the HDT group. No significant decrease in average GSUVmean was observed in the non-HDT group. A high level of inter-observer reliability was found in intra-class correlation (ICC for pre-treatment whole bone 0.983, post-treatment whole bone 0.989, pre-treatment whole pelvis 0.998, post-treatment whole pelvis 0.996). CONCLUSION: NaF uptake significantly decreased after treatment in patients who received high-dose therapy. A high level of agreement was observed between two operators for whole bone and pelvis measurements.

Guidelines for Acquisition, Interpretation, and Reporting of Whole-Body MRI in Myeloma: Myeloma Response Assessment and Diagnosis System (MY-RADS).

Acknowledging the increasingly important role of whole-body MRI for directing patient care in myeloma, a multidisciplinary, international, and expert panel of radiologists, medical physicists, and hematologists with specific expertise in whole-body MRI in myeloma convened to discuss the technical performance standards, merits, and limitations of currently available imaging methods. Following guidance from the International Myeloma Working Group and the National Institute for Clinical Excellence in the United Kingdom, the Myeloma Response Assessment and Diagnosis System (or MY-RADS) imaging recommendations are designed to promote standardization and diminish variations in the acquisition, interpretation, and reporting of whole-body MRI in myeloma and allow response assessment. This consensus proposes a core clinical protocol for whole-body MRI and an extended protocol for advanced assessments. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Myc protein overexpression is a feature of progression and adverse prognosis in multiple myeloma.

OBJECTIVE: Prognostic and predictive markers in multiple myeloma are continuously explored because of the heterogeneity of the tumor biology. Myc protein is the final product from activating MYC oncogene, but the prognostic impact in multiple myeloma is not well described. METHODS: In a population-based cohort of 194 untreated, newly diagnosed patients with multiple myeloma, we assessed myc protein expression using CD138/myc immunohistochemical double stain and collected clinicopathological data. RESULTS: Cases with myc protein expression ≥40% (mycHIGH ) had a median overall survival of 11 months compared to 48 months in cases of myc protein expression <40% (mycLOW ) (P < 0.01). MycHIGH was significantly correlated to R-ISS, high proliferation index, high percentage of plasma cell in bone marrow, plasmablastic morphology, high calcium level, and abnormal karyotype. In multivariate survival analyses, mycHIGH was independently associated with inferior overall survival with a hazard ratio of 2.5. CONCLUSION: Our results indicate myc protein overexpression to be associated with advanced multiple myeloma and poor prognosis.

Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study.

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.

Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21.

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population-based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow-up of patients still alive at analysis was 40 months for the high-dose (HDT)-treated ones and 29 months for the whole population. Three hundred forty-seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14;16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3-yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P < 0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3-yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3-yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P < 0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted.

Prognostic significance of 18F-sodium fluoride in newly diagnosed multiple myeloma patients.

Focal bone lesions and fractures due to weakened bone are associated with higher morbidity and mortality of multiple myeloma (MM) patients. 18F-sodium fluoride (18F-NaF) is a sensitive PET radiotracer for detection of abnormal bone metabolism and, therefore, is particularly suited to assess the degree of bone involvement in MM patients. We aimed to investigate the prognostic significance of metabolic active volume (MAV) of 18F-NaF-avid lesions in MM patients. In addition to MAV, conventional methods of PET quantification, namely SUVmean and SUVmax, were measured in each patient for the purpose of comparison. Thirty-seven newly diagnosed MM patients were included. PET imaging was performed after intravenous administration of 200 MBq NaF. Active bone lesions and fractures on whole-body 18F-NaF-PET/CT scans were identified. An adaptive thresholding algorithm automatically calculated the total MAV, SUVmean and SUVmax for each patient (ROVER, ABX, Radeberg, Germany). The patients were followed for a median of 39.8 months after treatment (range: 17.8-55.4). The overall survival (OS) of patients with 18F-NaF-MAV value > 38.65 (36.36% [N of Events/Total N: 4/11]) was significantly shorter than that of patients with 18F-NaF-MAV value < 38.65 (3.85% [1/26]; P = 0.002). In multivariate forward stepwise (conditional LR) Cox regression analysis of prognostic factors of OS (including 18F-NaF-MAV (> 38.65 or < 38.65), age, gender, beta-2 microglobulin, and revised international staging system), 18F-NaF-MAV remained the only significant factor (HR: 14.39, P = 0.02). The results for PFS were not significant. Moreover, Kaplan-Meier analyses of conventional methods of PET quantification did not reveal any statistically significant log-rank p-values. MM patients with high 18F-NaF-MAV had shorter overall survival, compared to those with low 18F-NaF-MAV levels (NCT02187731).

Correlation of whole-bone marrow dual-time-point 18F-FDG, as measured by a CT-based method of PET/CT quantification, with response to treatment in newly diagnosed multiple myeloma patients.

The practical application of dual-time-point-imaging (DTPI) technique still remains controversial. One of the issues is that current parameters of DTPI quantification suffer from some deficiencies, mainly limited sampling of the diseased sites by confining measurements to specific locations. We aimed to examine the correlation between the percent change from early to delayed scans in whole-bone marrow (WBM) 18F-FDG uptake, as measured by a CT-based method of PET/CT quantification, and response to treatment in multiple myeloma (MM) patients. Pre-treatment 18F-FDG-PET/CT scans of 36 newly diagnosed MM patients were collected in a prospective study at 1 h and 3 h post tracer injection (NCT02187731). A threshold algorithm based on bone Hounsfield units on CT was applied to segment and quantify WBM 18F-FDG uptake. Patients were separated into two treatment groups: high-dose therapy with autologous stem cell transplant (HDT) and non-high dose therapy (non-HDT). The International Response Criteria for MM patients was used to determine each patient's response to treatment. In the HDT group, WBM 18F-FDG uptake increased significantly in patients that had a poor response to treatment, from a median of 1.31 (IQR: 1.13-1.64) at 1 h to a median of 1.85 (1.45-2.10) at 3 h. The median percent change was 37.77% (IQR: 23.47-46.4), with a range of 6.10-50.73 (P = 0.003). However, no significant change in uptake was observed in patients with a complete response (P = 0.24). The same trend was observed for the non-HDT group. WBM uptake of 18F-FDG assessed with dual-time-point imaging may have a role in predicting treatment response in MM.

Brain glucose metabolism in patients with newly diagnosed multiple myeloma significantly decreases after high-dose chemotherapy followed by autologous stem cell transplantation.

PURPOSE: The aim of this study was to compare the effect of intensive therapy [consisting of high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT)] and conventional standard-dose chemotherapy (CDC) on brain FDG uptake, as an indicator of glucose metabolism, in multiple myeloma patients. MATERIALS AND METHODS: Twenty-four patients with newly diagnosed multiple myeloma were included. Sixteen patients received HDC/ASCT, including bortezomib-based induction therapy, and eight patients received CDC. F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) was performed 1 and 3 hours following tracer administration before and after the treatment. The manual segmentation of supratentorial and cerebellum of each patient was performed by two independent observers. The data were expressed as global mean standardized uptake values (GSUVmean). Wilcoxon signed-rank test was used to compare changes from before to after treatment. RESULTS: A significant decrease in the GSUVmean of supratentorial brain and cerebellum was observed after treatment in the patients who received HDC/ASCT (1 hour scans: 7.03 ± 1.18 vs. 6.56 ± 0.94; P = 0.03 and 7.01 ± 1.08 vs. 6.34 ± 0.93; P = 0.01, respectively). GSUVmean changes in the patients who received CDC were not significantly different after treatment (1 hour scans: 6.47 ± 1.16 vs. 6.21 ± 0.91; P = 0.40 and 6.30 ± 1.21 vs. 6.09 ± 0.86; P = 0.62, respectively). The same findings were observed for 3 hours scans. A high level of agreement was observed between two operators. CONCLUSION: Multiple myeloma patients who received HDC/ASCT demonstrated a significant decrease in FDG uptake in the supratentorial brain and cerebellum, while patients who received CDC did not demonstrate significant changes in the brain FDG uptake.

Identification of Heterotopic Ossification Using 18F-NaF PET/CT.

Heterotopic ossification (HO) is a benign condition characterized by the abnormal formation of mature lamellar bone in extraskeletal soft tissues. Most frequently, HO is observed around the hip joint after fractures or surgical procedures such as open reduction internal fixation or total hip arthroplasties. We are presenting a case of HO as detected by F-NaF PET/CT in a 68-year-old woman with multiple myeloma and a history of internal fixation of the right hip. Many previous publications have reported F-NaF uptake portraying calcification in soft tissue; the present report demonstrates the feasibility of F-NaF PET/CT to assess extraosseous calcification.