We previously showed that serum beta-2-microglobulin (beta2m)-free human leucocyte antigen (HLA) class I heavy chain (FHC) levels were increased in MM and correlate with disease activity. The present investigation, carried out in 124 multiple myeloma patients, studied the expression of the three size variants of FHC, namely the 42 kDa intact heavy chain (A variant, AV), released through a shedding process, and the truncated FHC (tFHC) 39 kDa (BV) and 36-35 kDa (CV) released by means of membrane-type metalloprotease activity. The increase in FHC correlated with a high expression percentage of BV (r = 0.32, P = 0.0002) and tFHC (r = 0.42, P < 0.0001), which could help to discriminate multiple myeloma from monoclonal gammopathy of undetermined significance (tFHC mean ratio = 3.2; Mann-Whitney U-test, P < 0.0001). tFHC levels highly correlated with other disease activity markers, namely haemoglobin (r = -0.35; Spearman's rank, P = 0.0001), percentage of bone marrow plasma cells (r = 0.4, P < 0.0001) and beta2m levels (r = 0.36, P < 0.0001), while only the last barely correlated (r = 0.2, P = 0.03) with AV. Finally, the 0.4, 0.57 and 0.71 mg/l BV, tFHC and (to a lesser extent) FHC cut-off values divided patients into two groups with different survival curves (P = 0.0005, P = 0.0025 and P = 0.04 respectively). These data are in favour of a correlation between disease aggressiveness and cleavage of these variants by membrane-type metalloprotease enzymes.