Myeloma: targeted therapies march on

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS / NEOPLASIA

Over the past decade, considerable progress in the treatment of multiple myeloma (MM) has improved patient outcomes and expanded options in up-front and salvage therapy. Currently, myeloma treatment advances along 2 lines. One direction is building on the proven superiority of high-dose melphalan with autologous hematopoietic stem cell support and pursuing treatment intensification such as tandem autotransplants or a sequential approach of auto- and “mini-allo” transplantation. The second area of treatment innovation comprises a novel generation of therapeutic agents more specifically targeting the myeloma cell and its interactions with the bone marrow microenvironment. These agents not only have marked antimyeloma activity, but they also appear suited to overcome classical drug resistance. Active prototypes of these drugs include thalidomide, its immunomodulatory derivative CC-5013, and the proteasome inhibitor bortezomib (Velcade, formerly PS-341). In this issue of Blood, 2 papers address current progress in the expanding field of biologically targeted myeloma therapy.

Alsina and colleagues (page 3271) report the results of a phase 2 trial evaluating the activity and tolerability of the farnesyltransferase (FTase) inhibitor Zarnestra (tipifarnib, formerly R115777) at a dose of 300 mg orally twice a day in 43 patients with advanced MM. Although no complete or partial remissions were observed at this dose level, 23 of 36 evaluable patients (64%) had disease stabilization lasting between 2 and 26 months. The efficacy of this single-agent therapy is remarkable considering the favorable toxicity profile and the fact that more than half of the patients enrolled were refractory to prior therapy, had undergone stem cell transplantation, and/or had thalidomide pretreatment. If additional preclinical data can provide a rationale, further clinical evaluation of Zarnestra in combination with established antimyeloma agents would seem promising.

Zarnestra belongs to a class of drugs developed as inhibitors of the Ras oncoprotein. Their mechanism of action is considered to reside in the inhibition of Ras farnesylation that is required for its membrane association and signaling activity. Indeed, selective inhibition of FTase enzymatic activity and protein farnesylation by Zarnestra was shown in this study using patient peripheral blood and bone marrow samples. However, neither inhibition of FTase nor N-Ras and K-Ras mutation status of the myeloma cells correlated with response to treatment. These findings suggest that, even in Ras-mutated MM, deregulation of the Ras signaling cascade may be either a dominant transforming pathway or just one among redundant oncogenic events ensuring tumor growth and survival. Another likely explanation is that the biologic activity of FTase inhibitors is in fact more complex and involves proteins unrelated to Ras.^1,2 

Podar and colleagues (page 3474) provide the preclinical rationale for evaluation of the small molecule tyrosine kinase inhibitor GW654652 as novel antimyeloma agent. This indazolylpyrimidine inhibits vascular endothelial growth factor (VEGF) receptors 1 through 3. VEGF is known to be produced by both MM and bone marrow stroma cells and has been shown to optimize the micromilieu for MM tumors via autocrine and paracrine stimulatory loops. As a potent angiogenic cytokine, VEGF may also contribute to myeloma-associated marrow neoangiogenesis. The results of the in vitro studies reported demonstrate that GW654652 blocks VEGF-induced tyrosine phosphorylation of VEGF receptor-1 (Flt-1) and related downstream signaling in MM cells and inhibits MM cell migration, proliferation, and survival. It also acts on myeloma-stroma interactions, as shown by inhibition of VEGF and interleukin-6 production in a coculture model. Secondary to the interference with the production of the MM survival factor interleukin-6, GW654652 may also offer the potential to overcome drug resistance in MM. These findings are in line with and extend previous reports on in vitro activities of other VEGF receptor tyrosine kinase inhibitors.^3,4  Based on the promising preclinical data, first results of clinical evaluation of this novel class of drugs are eagerly awaited.