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Multiple myeloma (MM), is a heterogeneous disease in which chromosomal abnormalities are important for prognostic risk stratification. Cytogenetic profiling with FISH on plasma cells from bone marrow samples (BM-PCs) is the current gold standard, but variable infiltration of plasma cells or failed aspiration can hamper this process. Ultra-low coverage sequencing (ULCS) of circulating cell-free DNA (ccfDNA) may offer a minimally invasive alternative for the work-up of these cases. We compared ULCS, aCGH and FISH on selected BM-PCs in a routine setting with ULCS of ccfDNA for the detection of somatic copy number aberrations (CNAs) in MM., Methods: Purified CD138+ BM-PCs of 23 MM patients at initiation of their treatment were subjected to aCGH, FISH and ULCS. Paired samples of peripheral blood-ccfDNA obtained at diagnosis were analyzed by ULCS and compared to the results found in BM-PCs., Results: Using ULCS of ccfDNA, cytogenetic markers were identified in 18 out of 23 patients; five cases could not be analyzed due to low (≤3%) tumor fraction (TF). High similarity between CNA profiles of BM-PCs and ccfDNA was found. Moreover, 78% of the ccfDNA profiles resulted in the same risk classification as the routine FISH and/or BM-PCs ULCS and aCGH. Chromothripsis was detected in five patients; these had the highest TF values (range 7.1% to 42%) in our series and their profiles showed other high-risk anomalies., Conclusion: This proof-of-principle study indicates that ULCS of ccfDNA can reveal CNAs in MM and should be explored further as a cost-efficient alternative, especially in cases where BM-PC purification fails., (Copyright © 2021. Published by Elsevier Ltd.)