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

Abstract

Abstract. 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 IgGÏ-producing tumor known as LAGÏ-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. LAGÏ-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.) LAGÏ-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, LAGÏ-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.

A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma

“…In our preclinical in vivo studies using our severe combined immunodeficiency --hu myeloma models, we showed that administration of low-dose PLD administered on a daily basis produced more marked anti-myeloma effects and was better tolerated compared to administering PLD at a higher dose once weekly. 32 Clinical data has shown that increasing the length of each cycle while reducing the dose of bortezomib and the dose and schedule of PLD can result in similar efficacy and improved tolerability for relapsed/refractory (R/R) 13 and untreated 33 MM patients receiving these two agents with intravenously administered dexamethasone. In both of these studies, the traditional dosing of bortezomib at 1.3 mg/m 2 and oral dexamethasone 40 mg both on days 1, 4, 8 and 11 with PLD at 30 mg/m 2 on day 4 on a 3-week cycle 12,15 was modified to a longer 4-week cycle in which PLD at 5 mg/m 2 , bortezomib at a lower dose (1 mg/m 2 ) and dexamethasone administered intravenously (IV) at 40 mg were all given on days 1, 4, 8 and 11.…”

Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis

“…THP-1 cells that express GFP (THP-1/GFP) were mixed with human MM LAG-1 40 cells that express PTN 21 and were injected into C.B-17 SCID mice. The animals were killed at 6 weeks and the tumors were analyzed by fluorescence microscopy and scanned using confocal microscopy.…”

“…40 The LAG-1 tumor was established from serial intramuscular passages of BM derived from an IgG-producing MM patient and has been maintained for more than 5 years. 40 Animal studies were conducted according to protocols approved by the Animal Research Committee at the Institute for Myeloma & Bone Cancer Research. We injected subcutaneously 10 6 LAG-1 cells, 10 6 THP-1 monocytes, or coinjected both cell types into SCID mice.…”

Anti-Myeloma Effects of the Novel Anthracycline Derivative INNO-206

“…This led to a high response rate but was associated with significant toxicity. We have showed using our multiple myeloma xenograft models that more frequent dosing of PLD at lower doses is more effective and better tolerated than higher doses administered less often (13). We have used this approach for treating patients with multiple myeloma (14,15) by combining PLD with bortezomib and i.v.…”