LAGlambda-1: a clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma.

We set out to generate new human myeloma tumors that grow in immunodeficient mice and can be used for pathophysiological studies and rapid evaluation of new therapies. Fresh whole core bone marrow (BM) biopsies taken from 33 myeloma patients were engrafted into the hind limb muscle of severe combined immunodeficient (SCID) mice. Human Ig was detected in 28/33 mice and three grew palpable tumors displaying many features of human myeloma including morphology, immunophenotype and BM plasmacytosis. Following intramuscular passage, we generated large numbers of mice with predictable increases in tumor growth and human paraprotein levels. We further characterized the model generated from an IgGlambda-producing tumor known as LAGlambda-1 and determined the effects of the proteasome inhibitor bortezomib, the alkylating agent melphalan, and the DNA damaging agent liposomal doxorubicin, on the growth of this tumor. LAGlambda-1-bearing mice receiving higher doses of bortezomib showed reduced tumor growth whereas a lower dose had no effect. In contrast, melphalan did not significantly alter tumor growth, except minimally at high doses, reflecting the resistance of this patient's tumor to this drug. We also used our intramuscular (i.m.) LAGlambda-1 model to optimize the dosing schedule of liposomal doxorubicin. Low doses administered once daily three days per week decreased tumor growth and human paraprotein levels whereas much higher doses given once weekly had no anti-myeloma effects. Furthermore, LAGlambda-1 cells produce local tumors when injected subcutaneously and lytic lesions when injected intravenously allowing for multiple methods of evaluating the anti-myeloma effects of a variety of agents. Our new clinically relevant SCID models of human myeloma should greatly facilitate drug development and enable novel therapies to quickly move from the laboratory to the clinic.

Pleiotrophin is highly expressed by myeloma cells and promotes myeloma tumor growth.

Pleiotrophin (PTN) is an important developmental cytokine that is highly expressed during embryogenesis but shows very limited expression in adult tissues, where it is largely restricted to the brain. High PTN serum levels are associated with a variety of solid tumors. We recently showed that patients with multiple myeloma (MM) also have elevated serum levels of this protein and the amount of PTN correlated with the patients' disease status and response to treatment. In this study, we demonstrate that MM cell lines and the malignant cells from MM patients' bone marrow produced PTN and secreted PTN protein into the supernatants during short-term culture. Moreover, Ptn gene expression correlated with the patients' disease status. Inhibition of PTN with a polyclonal anti-PTN antibody reduced growth and enhanced apoptosis of MM cell lines and freshly isolated bone marrow tumor cells from MM patients in vitro. Importantly, this antibody also markedly suppressed the growth of MM in vivo using a severe combined immunodeficiency (SCID)-hu murine model. This represents the first study showing the importance of PTN in the growth of any hematological disorder. Because the expression of this protein is very limited in normal adult tissues, PTN may represent a new target for the treatment of MM.

Serum pleiotrophin levels are elevated in multiple myeloma patients and correlate with disease status.

Pleiotrophin (PTN), a tightly regulated angiogenic and mitogenic heparin-binding protein, is markedly elevated in a variety of aggressive solid tumours. The role of PTN in haematological malignancies, however, has not been previously evaluated. This study demonstrated that PTN serum levels were elevated in multiple myeloma (MM) patients when compared with healthy subjects (P < 0.0001). Serum levels of this protein significantly increased during progression of disease, and decreased during response to anti-MM therapy (P < 0.001). These results suggest that serum PTN may be a new biomarker for monitoring the disease status and therapeutic response of MM patients.