Faculty Bibliography

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

The introduction of bortezomib, a novel first-in-class proteasome inhibitor, has been a major break through in the treatment of multiple myeloma. It is currently approved for the treatment of myeloma in the relapsed setting post transplant or as a second line treatment in patients unsuitable for transplantation. In pre-clinical studies bortezomib showed a number of different anti-myeloma effects including disruption of the cell cycle and induction of apoptosis, alteration of the bone marrow microenvironment and inhibition of nuclear factor kappa B (NFkappaB). Due to its novel mechanism of action, bortezomib has been shown to induce responses in previously refractory patients (including those with poor risk cytogenetics), and results in an increased progression free and overall survival in relapsed patients when compared with dexamethasone treatment alone. It is well tolerated and can be administered in the outpatient setting with manageable toxicities. Peripheral neuropathy is the most common dose limiting toxicity and thrombocytopenia can generally be managed with platelet transfusions without reducing or omitting doses. Bortezomib shows a synergistic effect in combination with dexamethasone and also sensitises myeloma cells to the effects of other chemotherapeutic agents with major response rates of over 50% being shown in the relapsed setting. Initial data from ongoing trials in front line therapy are encouraging with response rates of 80%-90% when bortezomib is given in combination with other agents and importantly, the ability to mobilize peripheral blood stem cells is not impaired.

Conventional intravenous chemotherapy regimens are toxic, cumbersome, and negatively affect patients' quality of life, with oral treatment preferable to most patients with cancer. Multiple myeloma is the second most common haematological malignant disease, but cannot be cured with conventional and high-dose chemotherapy. New oral treatments that target myeloma cells or bone marrow are being developed that are highly effective yet have low toxic effects, such as the immunomodulatory drugs thalidomide and lenalidomide. Several treatments in early development have shown antimyeloma activity, including: CHIR-258, which inhibits fibroblast growth factor receptor 3; NVP-ADW742, which inhibits insulin-like growth factor receptor 1; and PTK787, which inhibits vascular endothelial growth factor. Additional drugs aimed at switching off silenced genes include histone deacetylase inhibitors. The availability of these various oral treatments is hoped to improve regimens that, if used sequentially or in combination, offer the potential of making multiple myeloma a chronic disease, thereby extending patients' lifespans and improving quality of life.

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.

We report an analysis of the value of a second high-dose melphalan autograft, performed at relapse, on a series of newly diagnosed myeloma patients entered into the high-dose program at our center. We conclude that relapse-free survival after the first autograft is a major prognostic factor in determining outcome.

PURPOSE/OBJECTIVE:Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency. PATIENTS AND METHODS/METHODS:A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed. RESULTS:Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002. CONCLUSION/CONCLUSIONS:A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.

Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.

This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions -1031, -863, -857, -308 and -238 of the 5' promoter region of TNF-alpha gene, and 252 in the LT-alpha gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF-alpha-308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF-alpha-308 variant allele A, odds ratio, 0.57; 95% confidence interval, 0.38-0.86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.