Developmental therapeutics for multiple myeloma—A road map for the future

Abstract

I N ADDRESSING state of the art therapeutics and recognizing the various clinical presentations and outcomes with both standard and high-dose therapies, it is imperative to identify opportunities for novel treatments. The leading principle in such endeavors should be to accomplish advances without compromising current achievements. This requires more accurate risk prediction, especially for newly diagnosed patients, recognizing that current predictors only account for 20% to 25% of the heterogeneity encountered. The most robust adverse prognostic parameter is the cytogenetically defined abnormality of chromosome 13 (including partial and complete deletions and 13q translocations), present in 18% of newly diagnosed patients.* Regardless of other risk factors such as &-microglobulin @2M), C-reactive protein (CRP), and duration of prior therapy, patients with chromosome 13 abnormalities have a dismal prognosis even with tandem autotransplants (Table 1). Fewer than 20%, even of newly diagnosed patients with chromosome 13 deletion receiving Total Therapy, remain event-free at 2 years.s In the current Total Therapy II program (see Barlogie et al3 in this issue), cytogenetically defined chromosome 13 abnormalities (present in 21 patients, 18%) were associated with inferior event-free survival (and overall survival, data not shown) compared to other cytogenetic abnormalities (26 patients) and normal diploid karyotypes (68 patients) (Fig l).s By contrast, fluorescence in situ hybridization (FISH) detected deletion 13 in 48% but was not yet associated with inferior clinical outcome. Thus, metaphase karyotyping must be considered an indispensable test for patients with multiple myeloma.5 We believe that a systematic investigation of myeloma gene expression with the use of high-density oligonucleotide microarray (HDA) is likely to accelerate therapeutic research, allow molecular classification of the disease, and identify new drugs that act on specific biochemical and genetic pathways. Gene expression profiling, conducted on more than 150 (64 extensively analyzed) patients with myeloma and interpreted in the context of normal donor bone marrow and tonsillar plasma cells, monoclonal gammopathy of undetermined significance (MGUS), and established human myeloma cell lines has helped identify three clusters using hierarchical clustering techniques that are statistically distinct.” One cluster, designated MMII, included 38 patients and all cell lines; MM1 comprised 11 patients, three of four MGUS cases, and all normal plasma cell cases; and MM111 contained 16 patients and a single case of MGUS. A comparison of clinical parameters across these groups demonstrated significant differences. In particular, we found that whereas MM1 and MM11 contained karyotypic abnormalities at 18% and 19%, respectively, more than 60% of the MM111 group had abnormal cytogenetics. Importantly, whereas the incidence of chromosome 13 abnormalities in MM111 was 37%, only 9% and 6% of karyotypes in MM11 and MM1 had this abnormality. The link of chromosome 13 deletion with MM111 suggests that molecular profiling of these particularly difficult to treat cases may shed light on the molecular mechanisms of this disease class. In addition, gene expression profiling will provide much needed information about the applicability of new drugs (see below). Based on these findings, a new therapy menu has been generated that will be applied early in the disease course of patients with high-risk myeloma, such as those presenting with chromosome 13 abnormalities and falling into our MM111 category. In the Arkansas program, HDA studies are performed on all newly diagnosed patients along with cytogenetics, interphase FISH, and plasma cell labeling index. Magnetic resonance imaging (MRI) studies of the axial bone marrow are also performed and help identify focal lesions that are accessible to computerized tomography (CT)guided fine-needle aspiration (FNA). Such studies have already revealed a higher incidence of chromosome 13 abnormalities, more proliferative activity, and a greater degree of genetic heterogeneity in such plasmacytoma lesions when compared with random iliac crest bone marrow examinations. Upon patients’ return after one cycle of dexamethasone or vincristine, doxorubicin, and dexamethasone (VAD), results of these laboratory tests are available. Those with chromosome 13 abnormalities judged to have no risk of impending clinical problems are candidates for new agents, selected on the basis of HDA results. For example, ST1571, currently undergoing investigation in advanced disease, is considered in patients with high expression of the ABL and KIT tyrosine kinases, which are observed in more than 50% of newly diagnosed patients. Similarly, the proteasome inhibitor PS341 is considered when appropriate genes associated with ubiquitination and proteosome activity are overexpressed. Other examples include retinoic acid compounds