The Role of Low Dose Whole Body CT in the Detection of Progression of Patients with Smoldering Multiple Myeloma
Authors: Gavriatopoulou Maria , Boultadaki Andriani , Koutoulidis Vassilis , Ntanasis-Stathopoulos Ioannis , Bourgioti Charis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Kastritis Efstathios , Terpos Evangelos , Dimopoulos Meletios A. , Moulopoulos Lia A. 
Published: November 2020

Introduction: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by bone marrow infiltration of monoclonal plasma cells and end-organ involvement. Smoldering MM (SMM) is an intermediate clinical entity between MGUS and MM, with a risk of progression to symptomatic disease at 10% per year. Bone disease is the most frequent related symptom of MM, with approximately 90% of patients developing bone lesions throughout their disease course. Therefore, imaging plays a crucial role in diagnosis and management of these patients. Conventional radiography was traditionally considered as the standard of care, however the limited sensitivity in detecting osteolytic bone lesions has led to more advanced imaging modalities. Imaging also is of high importance to discriminate MM from smoldering disease, since the presence of bone lesions establishes the diagnosis of active disease and requires treatment initiation. Computed tomography (CT) was found to be the most sensitive modality in detecting small osteolytic bone lesions less than 5 mm. Ionizing radiation exposure was one of the main limitations of this technique. Technological advances have made possible low dose assessment of the entire skeleton with effective radiation doses comparable to those of a whole-body plain radiographic skeletal survey. Furthermore, the low dose CT is widely available and has a very short scan time. Therefore, whole-body low dose CT (WBLDCT) has been incorporated in the latest diagnostic criteria of the IMWG. The purpose of this study was to evaluate the role of WBLDCT in the early identification of patients with asymptomatic MM who progress with bone disease only and who require immediate antimyeloma treatment.
Patients and Methods: Our study was approved by the local IRB and all patients provided informed consent. All patients diagnosed with SMM based on the 2003 International Myeloma Working Group (IMWG) definition of SMM were serially assessed with WBLDCT from July 2013 until March 2020 as part of our institutional workup. The assessments were performed at baseline, 1-year post diagnosis and every 1 year thereafter. The patients enrolled in the study were those who had at least 2 consecutive CT assessments at the above described time points. All WBLDCT exams were performed with a 16-detector CT scanner. The CTs were evaluated by two experienced radiologists, blinded to the clinical and laboratory data.
RESULTS
We prospectively evaluated 100 patients with SMM (median age at diagnosis 61 years, range 40-86 years, 52 female /48 male) who underwent WBLDCT at the above described time points. Median number of WBLDCTs exams performed was 2.5 (range 2-5). Totally, 31 patients progressed (either with CRAB criteria and/or at least one myeloma defining event). During a median follow up of 57 months 31 patients have progressed (with either CRAB criteria and/or at least one myeloma defininf event). Importantly, 10 of 31 patients progressed only with bone lesions that were identified on the scheduled WBLDCT as per protocol. Median time to progression from asymptomatic to symptomatic disease for all patients has not been reached, while median time for those who actually progressed was 22 months (95% CI:15,6-28,4). For the subgroup of patients who progressed with bone lesions only the median time was also 22 months (95%CI:3,4-40,6). Median time to progression was not statistically different between the two progressor subgroups. All patients were initiated with antimyeloma treatment immediately post evolution to symptomatic disease. PFS for all 31 patients at first line treatment was 52 months (95%CI:34,5-69,5) and median PFS for bone progressors has not yet been reached. Among the patients who progressed 29 were alive at the time of the analysis. The 2 deaths that occurred were one related (progressive disease) and one unrelated to multiple myeloma (cardiovascular event). Neither had progressed with isolated bone involvement.
Conclusion: In conclusion, our strategy allowed early detection of bone lesions in 10% of our patients and these patients were immediately initiated with antimyeloma treatment to avoid further myeloma-related complications. Consecutive low-dose WBLDCT studies can identify early myeloma evolution to symptomatic disease and optimize the disease monitoring along with our therapeutic strategy.

Disclosures
Gavriatopoulou: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Terpos:Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria; Takeda: Honoraria.