Malignant plasma cells (PC) in human multiple myeloma (MM) are retained in the bone marrow (BM) microenvironment. Using HUTS21 monoclonal antibody that reacts with active CD29 integrin, we demonstrate that this active form is tightly regulated by divalent cations and soluble CD106 (sCD106) contained in the BM plasma. Moreover, we also show that in vivo expression of the active CD29 on PC was clearly diminished in a minority of MM cases (HUTS21(-) patients). HUTS21(-) cells were refractory to the addition of either normal allogeneic BM plasma or optimal concentrations of exogenous divalent cations and recombinant sCD106. Furthermore, a lower binding to fibronectin was detected in comparison with HUTS21(+) PC. On the other hand, although HUTS21(-) PC showed a reduced amount of total (active+inactive) CD29, western-blot assays demonstrated that these clonal PC contained the two species of CD29, with molecular masses of 110 and 130 kDa, which were expressed on normal or HUTS21(+) PC. Finally, we detected a clear association between the presence of HUTS21(-) PC in the BM and an increased percentage of circulating PC with a high proliferative index, emphasizing the essential role of CD29 in the pathogenesis and progression of this disease.