Jeff Haessler

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study

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.

Magnetic Resonance Imaging in Multiple Myeloma: Diagnostic and Clinical Implications

PURPOSE 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). PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma

F18-fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful tool to investigate the role of tumor metabolic activity and its suppression by therapy for cancer survival. As part of Total Therapy 3 for newly diagnosed multiple myeloma, metastatic bone survey, magnetic resonance imaging, and FDG-PET scanning were evaluated in 239 untreated patients. All 3 imaging techniques showed correlations with prognostically relevant baseline parameters: the number of focal lesions (FLs), especially when FDG-avid by PET-computed tomography, was positively linked to high levels of beta-2-microglobulin, C-reactive protein, and lactate dehydrogenase; among gene expression profiling parameters, high-risk and proliferation-related parameters were positively and low-bone-disease molecular subtype inversely correlated with FL. The presence of more than 3 FDG-avid FLs, related to fundamental features of myeloma biology and genomics, was the leading independent parameter associated with inferior overall and event-free survival. Complete FDG suppression in FL before first transplantation conferred significantly better outcomes and was only opposed by gene expression profiling-defined high-risk status, which together accounted for approximately 50% of survival variability (R(2) test). Our results provide a rationale for testing the hypothesis that myeloma survival can be improved by altering treatment in patients in whom FDG suppression cannot be achieved after induction therapy.

Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.

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 × 106 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.

Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities.

Total Therapy 2 examined the clinical benefit of adding thalidomide up-front to a tandem transplant regimen for newly diagnosed patients with multiple myeloma. When initially reported with a median follow-up of 42 months, complete response rate and event-free survival were superior among the 323 patients randomized to thalidomide, whereas overall survival was indistinguishable from that of the 345 patients treated on the control arm. With further follow-up currently at a median of 72 months, survival plots segregated 5 years after initiation of therapy in favor of thalidomide (P = .09), reaching statistical significance for the one third of patients exhibiting cytogenetic abnormalities (CAs; P = .02), a well-recognized adverse prognostic feature. The duration of complete remission was also superior in the cohort presenting with CAs such that, at 7 years from onset of complete remission, 45% remained relapse-free as opposed to 20% on the control arm (P = .05). These observations were confirmed when examined by multivariate analysis demonstrating that thalidomide reduced the hazard of death by 41% among patients with CA-positive disease (P = .008). Because two thirds of patients without CAs have remained alive at 7 years, the presently emerging separation in favor of thalidomide may eventually reach statistical significance as well.

Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2

Total therapy 3 (TT3), incorporating bortezomib up‐front into a tandem transplant regimen for newly diagnosed multiple myeloma (MM), effected 2‐year complete response (CR) estimates >90%, which appeared superior to results reported for total therapy 2 (TT2). With median follow‐up times of 2 years with TT3 and 5 years with TT2, the clinical outcomes of 303 patients in the former and 668 in the latter trial were compared, including the subset of 607 patients with gene expression profiling (GEP) data. With similar baseline prognostic factors, event‐free survival (EFS) (P = 0·0002) and CR duration (P = 0·003) were superior with TT3 vs. TT2 with a strong trend noted also for improved overall survival (OS) (P = 0·16). In the GEP‐defined FGFR3 subgroup, TT3 imparted significantly superior OS, EFS and CR duration vis‐à‐vis TT2. Matching 300 patients each by standard prognostic factors, TT3 yielded superior EFS and CR duration and borderline superior OS. The advantage of TT3 still pertained when the comparison was limited to patients who completed TT2 consolidation rapidly within 24 months. Our data strongly suggest that the addition of bortezomib in TT3 was accountable for its superior performance rather than greater compliance with protocol completion as a result of greater dose‐density in TT3 vs. TT2.

Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project

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.

Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Complete Remission Sustained 3 Years From Treatment Initiation Is a Powerful Surrogate for Extended Survival in Multiple Myeloma

Complete response (CR) has been considered a necessary although not sufficient early clinical endpoint for extended survival in multiple myeloma.

An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma

TP53 is a tumor suppressor gene that functions as transcriptional regulator influencing cellular responses to DNA damage. Here we explored the clinical and transcriptional effects of TP53 expression in multiple myeloma (MM). We found that low expression of TP53, seen in approximately 10% of newly diagnosed patients, is highly correlated with TP53 deletion, an inferior clinical outcome, and represents an independent risk factor. Analysis of the expression of 122 known TP53 target genes in TP53-high vs -low MM cells from 351 newly diagnosed cases, revealed that only a few were highly correlated with TP53 expression. To elucidate TP53 regulatory networks in MM, we overexpressed TP53 in 4 MM cell lines. Gene expression profiling of these cell lines detected 85 significantly differentially expressed genes, with 50 up-regulated and 35 down-regulated. Unsupervised hierarchical clustering of myeloma samples from 351 newly diagnosed and 90 relapsed patients using the 85 putative TP53 target genes revealed 2 major subgroups showing a strong correlation with TP53 expression and survival. These data suggest that loss of TP53 expression in MM confers high risk and probably results in the deregulation of a novel set of MM-specific TP53-target genes. TP53 target gene specificity may be unique to different cell lineages.