Using SCID-Hu Models to Evaluate the Sequencing of Bortezomib Therapy for Multiple Myeloma (MM)

Although many previous studies from our laboratory and others have used mice bearing human MM to evaluate bortezomib (BORT) alone and in combination regimens, no data exist on the sequential treatment using BORT with conventional anti-MM agents in mice bearing human MM tumors who have progressed from their initial treatment with a variety of anti-MM agents including BORT. In this study, we treated severe combined immunodeficient (SCID) mice bearing one of our human MM tumors LAGκ-1A with single agent bortezomib BORT, melphalan (MEL), dexamethasone (DEX) or pegylated liposomal doxorubicin (PLD) until disease progression and then evaluated subsequent use of combination therapies. Progression was defined as an increase in paraprotein equal to or above 25% compared to the prior time point evaluated 1 week previously. Following progression, LAGκ-1A-bearing SCID mice were assigned to receive no treatment, continue the initial therapy, substitution of initial therapy by another conventional anti-MM agent BORT, MEL, DEX, or PLD, or continue the initial therapy in combination with another anti-MM agent. An untreated control group was also included in these studies.

Tumors were allowed to grow for 7 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into one of five treatment groups. Initial single agent therapy was administered as follows: BORT intravenously (i.v.) twice weekly at 0.5 mg/kg, DEX (1.25 mg/kg) daily by intraperitoneal (i.p.) injection, MEL i.p. weekly at 1.5 mg/kg, or PLD 0.2 mg/kg on three consecutive days weekly by i.p. injection. Following disease progression, mice were randomized into one of the above mentioned treatment groups. Tumor size and IgG levels were measured using calipers and a hIgG specific immune assay on a weekly basis. Results: Following progression from single-agent BORT, mice treated with the combination of BORT + DEX or DEX alone showed similar anti-MM effects. In contrast, after mice progressed from single-agent DEX, BORT alone did not show significant anti-MM effects compared to mice continued on DEX alone or who received no further treatment whereas the addition of BORT to DEX produced a marked anti-MM effect. Following disease progression from MEL treatment alone, treatment with BORT alone or in combination with MEL produced similar anti-MM activity. However, among mice progressing from single agent BORT, the addition or substitution with MEL showed no anti-MM effects; and in fact, reduced the efficacy of BORT when compared to mice remaining on the drug alone following disease progression. Following disease progression from single agent PLD treatment, BORT therapy alone showed anti-MM effects; however, the addition of BORT to PLD did not show any anti-MM activity. In addition, mice progressing from BORT treatment alone who then received either PLD alone or in combination with BORT actually showed enhanced tumor growth compared to continuing BORT alone. Conclusions: Results from these in vivo studies using our SCID-hu models of human MM suggest that the sequencing of drugs following progression from initial therapy has a dramatic impact on responsiveness of the human myeloma cells growing in SCID mice. These studies suggest that this approach can be used to optimize in what order and specific combinations of anti-MM drugs should be administered following disease progression which should improve outcomes for patients with MM.

Hilger:Millennium Pharmaceuticals, Inc.: Employment. Hibner:Millennium Pharmaceuticals, Inc.: Employment. Berenson:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.