Faculty Bibliography

Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (<55 years), β(2)MG <2.5 mg/L at diagnosis, a remission duration of >9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.

Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n = 238) and a validation set (HOVON65/GMMG-HD4 and a Czech dataset; n = 231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1. (IFM 2005-01 clinicaltrials.gov identifier: NCT00200681; HOVON-65/GMMG-HD4 isrctn.org identifier: ISRCTN64455289).

Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.

PURPOSE/OBJECTIVE:Myeloma bone disease impairs quality of life and is associated with impaired survival. Even with effective bisphosphonate treatment, a significant proportion of patients still develop skeletal-related events (SRE). Identifying such patients at presentation would allow treatment modification. EXPERIMENTAL DESIGN/METHODS:To investigate the molecular basis of bone disease at presentation and to develop a predictive signature for patients at high risk of developing SREs on bisphosphonates, 261 presenting myeloma samples were analyzed by global gene expression profiling. The derived "SRE gene signature" was complemented by the integration of associated clinical parameters to generate an optimal predictor. RESULTS:Fifty genes were significantly associated with presenting bone disease, including the WNT signaling antagonist DKK1 and genes involved in growth factor signaling and apoptosis. Higher serum calcium level and the presence of bone disease and hyperdiploidy at presentation were associated with high risk of SRE development. A gene signature derived from the fourteen genes overexpressed in the SRE group was able to identify patients at high risk of developing an SRE on treatment. These genes either belonged to the IFN-induced family or were involved in cell signaling and mitosis. Multivariate logistic model selection yielded an optimal SRE predictor comprising seven genes and calcium level, which was validated as an effective predictor in a further set of patients. CONCLUSIONS:The simple expression-based SRE predictor can effectively identify individuals at high risk of developing bone disease while being on bisphosphonates. This predictor could assist with developing future trials on novel therapies aimed at reducing myeloma bone disease.

Hemizygous deletion of 17p (del(17p)) has been identified as a variable associated with poor prognosis in myeloma, although its impact in the context of thalidomide therapy is not well described. The clinical outcome of 85 myeloma patients with del(17p) treated in a clinical trial incorporating both conventional and thalidomide-based induction therapies was examined. The clinical impact of deletion, low expression, and mutation of TP53 was also determined. Patients with del(17p) did not have inferior response rates compared to patients without del(17p), but, despite this, del(17p) was associated with impaired overall survival (OS) (median OS 26.6 vs. 48.5 months, P < 0.001). Within the del(17p) group, thalidomide induction therapy was associated with improved response rates compared to conventional therapy, but there was no impact on OS. Thalidomide maintenance was associated with impaired OS, although our analysis suggests that this effect may have been due to confounding variables. A minimally deleted region on 17p13.1 involving 17 genes was identified, of which only TP53 and SAT2 were underexpressed. TP53 was mutated in <1% in patients without del(17p) and in 27% of patients with del(17p). The higher TP53 mutation rate in samples with del(17p) suggests a role for TP53 in these clinical outcomes. In conclusion, del(17p) defined a patient group associated with short survival in myeloma, and although thalidomide induction therapy was associated with improved response rates, it did not impact OS, suggesting that alternative therapeutic strategies are required for this group.

Auto-SCT is the standard first-line consolidative therapy in patients with multiple myeloma (MM). We performed a national benchmarking outcome analysis for patients with MM who underwent a single auto-SCT in 1999 and 2005. They were identified from the British Society of Blood and Marrow Transplantation (BSBMT) (n=211 and n=453) and EBMT (n=1311 and n=1978) registries. An improvement in Day+100 and D+365 non-relapsed mortality (NRM) was shown between years 1999 and 2005 (P=0.0495). The 4-year relapse rate (RR) was significantly higher in 2005 (P=0.0003) and was associated with a shorter time to next treatment (TTNT) (P=0.025). The 4-year PFS was significantly lower in 2005 (P=0.0012), with the year of auto-SCT (P=0.001) and status at auto-SCT (P=0.02) being independently significant. The 4-year OS was similar between the year cohorts (P=0.266). In the 'benchmarking' comparison, the European Group for Blood and Marrow Transplantation (EBMT) 1999 cohort demonstrated the best PFS, although no year-of-transplant effect could be demonstrated on the 4-year OS rates (P=0.760). An improvement in supportive care resulting in reduced NRM is evident between the decades. The main cause of treatment failure remains disease progression. The similarity in OS between the years may reflect the introduction of novel agents in salvage therapy. The reduced PFS in 2005 is as yet not fully explained, but may represent recent disease response criterion standardization.

As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111.

The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.

BACKGROUND:Several cancer types have differences in incidence and clinical outcome dependent on gender, but these are not well described in myeloma. The aim of this study was to characterize gender disparities in myeloma. METHODS:We investigated the association of gender with the prevalence of tumor genetic lesions and the clinical outcome of 1,960 patients enrolled in the phase III clinical trial MRC Myeloma IX. Genetic lesions were characterized by FISH. RESULTS:Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001) and hyperdiploidy being more common in men (50% female vs. 62% male, P < 0.001). There were also differences in secondary genetic events with del(13q) (52% female vs. 41% male, P < 0.001) and +1q (43% female vs. 36% male, P = 0.042) being found more frequently in female myeloma patients. Female gender was associated with inferior overall survival (median: 44.8 months female vs. 49.9 months male, P = 0.020). CONCLUSIONS:We found gender-dependent differences in the prevalence of the primary genetic events of myeloma, with IGH translocations being more common in women and hyperdiploidy more common in men. This genetic background may impact subsequent genetic events such as +1q and del(13q), which were both more frequent in women. The higher prevalence of lesions associated with poor prognosis in the female myeloma population, such as t(4;14), t(14;16) and +1q, may adversely affect clinical outcome. IMPACT/CONCLUSIONS:These differences suggest that gender influences the primary genetic events of myeloma.