[Show abstract][Hide abstract] ABSTRACT: The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.Leukemia advance online publication, 26 October 2012; doi:10.1038/leu.2012.282.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; 27(3). DOI:10.1038/leu.2012.282 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T 0). The median age at diagnosis was 58 years, and time from diagnosis to T 0 was 3.3 years. Following T 0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T 0 in 94 patients (44%) including ≥partial response in 69 (32%). The median overall survival and event-free survival from T 0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2012; 26(5):1153. DOI:10.1038/leu.2012.15 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including partial response in 69 (32%). The median overall survival and event-free survival from T0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.Keywords: multiple myeloma; relapse; natural history; survival
[Show abstract][Hide abstract] ABSTRACT: Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P=0.0026); log(2) DKK-1 expression (P=0.0046); serum lactic dehydrogenase (LDH) (P=0.0074); Gsk3beta (P=0.02) and TNFSF8 (P=0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 23(10):1913-9. DOI:10.1038/leu.2009.129 · 9.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Complete response (CR) has been considered a necessary although not sufficient early clinical endpoint for extended survival in multiple myeloma.
By using Total Therapy 2 (TT2) clinical outcome data in 668 patients, whether sustained CR (SUS-CR) was potentially a superior surrogate for survival than attaining CR status per se was evaluated.
Compared with not achieving CR (NON-CR) and especially achieving and subsequently losing CR status (LOS-CR) within a 3-year landmark from treatment initiation, SUS-CR was associated with highly superior postlandmark survival (P < .0001). These results were validated in 231 untreated patients enrolled in the predecessor trial, TT1 (hazard ratio [HR] = 0.54, P = .013) and in 1103 previously treated patients on other transplant protocols (HR = 0.49; P < .001).
In all 3 trial settings the survival benefit of SUS-CR was independent of metaphase abnormalities as a dominant adverse parameter. Given its bleak prognosis despite high CR rates, SUS-CR should be evaluated as a primary trial endpoint in high-risk myeloma.
Cancer 07/2008; 113(2):355-9. DOI:10.1002/cncr.23546 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether the clinical benefit of complete remission (CR) may depend on prognostic subgroups of patients with multiple myeloma.
Newly diagnosed patients with myeloma received a tandem autotransplant regimen. Using multivariate regression analyses, we examined the prognostic implications of time-dependent onset of CR on overall survival and event-free survival in the context of standard prognostic factors (SPF) and gene expression profiling-derived data available for 326 patients.
CR benefited patients regardless of risk status when only SPFs were examined. With knowledge of gene array data, a survival (and event-free survival) benefit of CR only pertained to the small high-risk subgroup of 13% of patients (hazard ratio, 0.23; P = 0.001), whereas the majority of patients with low-risk disease had similar survival expectations whether or not CR was achieved (hazard ratio, 0.68; P = 0.128).
Access to gene expression information permitted the recognition of a small very high-risk subgroup of 13% of patients, in whom prolonged survival critically depended on achieving CR. Absence of such benefit in the remainder should lead to a reassessment of clinical trial designs that rely on this end point as a surrogate for long-term prognosis.
Clinical Cancer Research 01/2008; 13(23):7073-9. DOI:10.1158/1078-0432.CCR-07-0527 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Total therapy 3 incorporated bortezomib into a melphalan-based tandem transplant regimen for 303 newly diagnosed patients with myeloma. Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone and 4-d continuous infusions of cis-platin, doxorubicin, cyclophosphamide, etoposide); 3-year maintenance comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A minimum of 20 x 10(6) CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment-related death. At 24 months, 83% had achieved near-complete remission, which was sustained in 88% at 2 years from its onset. With a median follow-up of 20 months, 2-year estimates of event-free and overall survival were 84% and 86% respectively. The 44 patients who experienced an event more often had a high-risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase, beta-2-microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo-embolic events in 27% and peripheral neuropathy in 12%. Results of this phase-2 study demonstrated that bortezomib could be safely combined with multi-agent chemotherapy, effecting near-complete remission status and 2-year survival rates in more than 80% of patients.
British Journal of Haematology 07/2007; 138(2):176-85. DOI:10.1111/j.1365-2141.2007.06639.x · 4.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prognostic models for multiple myeloma have been fraught with tremendous heterogeneity in outcome among subgroups. In the context of Total Therapy 2, a tandem transplant trial for newly diagnosed myeloma, comprehensive information was available in 220 patients on standard prognostic factors (SPF), magnetic resonance imaging (MRI)-defined focal lesions, cytogenetic abnormalities (CA), fluorescence-in-situ-hybridisation (FISH)-derived amplification of chromosome 1q21 (amp1q21) and deletion of 13q14, as well as gene expression profiling (GEP). Five multivariate analysis-based survival models were derived, utilising SPF only (model 1), with progressive addition of CA (model 2), MRI (model 3), FISH (model 4) and GEP (model 5). The R(2) value, a measure of accounting for clinical outcome variability, increased progressively from 18% in model 1 to 38% in model 5. The hazard ratio for overall survival was highest for GEP (3.07, P < 0.001) followed by amp1q21 (1.71, P = 0.05). According to the presence of none (49%), one (35%) or both of these two risk features (16%), 3-year survival decreased progressively from 92% to 78% to 43% (P < 0.0001). Thus, the dominance over other prognostic parameters of molecular genetics justifies the generation of quantitative reverse transcription polymerase chain reaction methodology ('MM genetic kit') for the optimal risk stratification of patients participating in therapeutic trials.
British Journal of Haematology 06/2007; 137(6):530-6. DOI:10.1111/j.1365-2141.2007.06586.x · 4.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance imaging (MRI) permits the detection of diffuse and focal bone marrow infiltration in the absence of osteopenia or focal osteolysis on standard metastatic bone surveys (MBSs).
Both baseline MBS and MRI were available in 611 of 668 myeloma patients who were treated uniformly with a tandem autologous transplantation-based protocol and were evaluated to determine their respective merits for disease staging, response assessment, and outcome prediction.
MRI detected focal lesions (FLs) in 74% and MBS in 56% of imaged anatomic sites; 52% of 267 patients with normal MBS results and 20% of 160 with normal MRI results had FL on MRI and MBS, respectively. MRI- but not MBS-defined FL independently affected survival. Cytogenetic abnormalities (CAs) and more than seven FLs on MRI (MRI-FLs) distinguished three risk groups: 5-year survival was 76% in the absence of both more than seven MRI-FLs and CA (n = 276), 61% in the presence of one MRI-FL (n = 262), and 37% in the presence of both unfavorable parameters (n = 67). MRI-FL correlated with low albumin and elevated levels of C-reactive protein, lactate dehydrogenase, and creatinine, but did not correlate with age, beta-2-microglobulin, and CA. Resolution of MRI-FL, occurring in 60% of cases and not seen with MBS-defined FL, conferred superior survival.
MRI is a more powerful tool for detection of FLs than is MBS. MRI-FL number had independent prognostic implications; additionally, MRI-FL resolution identified a subgroup with superior survival. We therefore recommend that, in addition to MBS, MRI be used routinely for staging, prognosis, and response assessment in myeloma.