Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma.

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

Clinical value of molecular subtyping multiple myeloma using gene expression profiling.

Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.

Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia.

Collection of hematopoietic progenitor cells (HPC) after previous autologous hematopoietic progenitor cell transplant (aHCT) was studied in 221 patients with multiple myeloma (MM). With a total of 333 collections, the median number of CD34+ cells collected was 4.7 × 10(6) CD34+ cells/kg, and 74% of the patients collected ≥ 2.5 × 10(6) CD34+ cells/kg. Among 26 variables examined, the strongest predictor for poor collection was a platelet count <100 × 10(6)/l before mobilization (P<0.001). A subsequent aHCT was performed in 154 of the 221 patients. Sole use of HPC procured after aHCT in 86 patients was associated with delayed platelet recovery (P<0.001) and linked to development of myelodysplastic syndrome (MDS)-associated cytogenetic abnormalities (MDS-CA; P=0.027, odds ratio (OR) 10.34) and a tendency towards clinical MDS/acute myeloid leukemia (AML; P=0.091, OR 3.57). However, treatment-related mortality (P=0.766) and time to absolute neutrophil count recovery ≥0.5 × 10(9)/l (P=0.879) were similar to when a pre-aHCT graft was used. Indeed, adding HPC collected before any aHCT neutralized the risk of MDS-CA or MDS/AML. Therefore, we advise generous initial HPC collection to broaden the salvage armamentarium for patients with MM.

Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling and clinical outcome with Total Therapy protocols.

To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene-expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.

mTOR-inhibition in metastatic renal cell carcinoma. Focus on temsirolimus: a review.

The potent inhibitor of the mammalian target of rapamycin, temsirolimus, comprises for cell cycle, angiogenesis and proliferation and has proven beneficial in the treatment of advanced renal cell carcinoma (RCC). Temsirolimus is officially approved for first line therapy in high risk previously untreated mRCC patients. This review summarizes the current clinical role of temsirolimus in the treatment of advanced renal cell carcinoma with regard to pharmacological features, toxicity and tolerability. It particularily discusses quality of life issues as important outcome parameters in palliative treatment of patients with mRCC and gives an outlook on current clinical developments regarding possible future combining/ sequencing strategies of temsirolimus.