Faculty Bibliography

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.

INTRODUCTION/BACKGROUND:Pomalidomide, a derivative of thalidomide and member of the immunomodulatory drugs is licenced for use in relapsed and refractory multiple myeloma (RRMM) in Europe, USA, Canada and Japan. AREAS COVERED/METHODS:This review details all published trials in which pomalidomide has been used in the treatment of myeloma including phase I, II and III studies via PubMed searches for randomised control trials, observational cohort, case reports, meta-analysis and reviews. In addition abstract searches from the 2015 IMW and ASH conferences have been included. Drug safety has been a main focus with additional detail outlining the current clinical experience and treatment efficacy. Drug related toxicities and management of such events are covered in detail. EXPERT OPINION/CONCLUSIONS:Pomalidomide is well tolerated and has been demonstrated to prolong progression free survival and overall survival in RRMM patients in comparison to other agents commonly used later in the disease. Treatment related toxicities are usually easily managed using treatment interruption, dose modification, prophylactic therapies and blood/platelet transfusions. There is scope for the drug to be used in combination with newer agents at disease presentation, relapse and as a long-term maintenance option. At present trials assessing its use in early disease and maintenance are lacking.

Multiple myeloma is a plasma cell malignancy that is characterized by refractory and relapsing course of disease. Despite the introduction of high-dose chemotherapy in combination with autologous stem cell transplantation and innovative agents such as proteasome inhibitors and immunomodulatory drugs, achieving cure in multiple myeloma is a challenging endeavor. In the last couple of years, enormous advances were made in implementing monoclonal antibody therapy in multiple myeloma. A large number of preclinical and clinical studies have been introduced successfully, demonstrating a safe and efficient administration of monoclonal antibodies in multiple myeloma. In particular, the application of monoclonal antibodies in combination with immunomodulatory drugs, proteasome inhibitors, corticosteroids or conventional chemotherapy seem to be promising and will expand the treatment arsenal for patients with multiple myeloma.

PURPOSE/OBJECTIVE:At the molecular level, myeloma is characterized by copy number abnormalities and recurrent translocations into the immunoglobulin heavy chain locus. Novel methods, such as massively parallel sequencing, have begun to describe the pattern of tumor-acquired mutations, but their clinical relevance has yet to be established. METHODS:We performed whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial, for whom complete molecular cytogenetic and clinical outcome data were available. RESULTS:We identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3. The mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor-κB (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically. Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) are associated with a negative impact on survival. In contrast, those in IRF4 and EGR1 are associated with a favorable overall survival. We combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score that can identify a high-risk population of patients who experience relapse and die prematurely. CONCLUSION/CONCLUSIONS:We have refined our understanding of genetic events in myeloma and identified clinically relevant mutations that may be used to better stratify patients at presentation.

As part of Total Therapy (TT) 3b, baseline marrow aspirates were subjected to two-color flow cytometry of nuclear DNA content and cytoplasmic immunoglobulin (DNA/CIG) as well as plasma cell gene expression profiling (GEP). DNA/CIG-derived parameters, GEP and standard clinical variables were examined for their effects on overall survival (OS) and progression-free survival (PFS). Among DNA/CIG parameters, the percentage of the light chain-restricted (LCR) cells and their cytoplasmic immunoglobulin index (CIg) were linked to poor outcome. In the absence of GEP data, low CIg <2.8, albumin <3.5 g/dl and age ⩾65 years were significantly associated with inferior OS and PFS. When GEP information was included, low CIg survived the model along with GEP70-defined high risk and low albumin. Low CIg was linked to beta-2-microglobulin >5.5 mg/l, a percentage of LCR cells exceeding 50%, C-reactive protein ⩾8 mg/l and GEP-derived high centrosome index. Further analysis revealed an association of low CIg with 12 gene probes implicated in cell cycle regulation, differentiation and drug transportation from which a risk score was developed in TT3b that held prognostic significance also in TT3a, TT2 and HOVON trials, thus validating its general applicability. Low CIg is a powerful new prognostic variable and has identified potentially drug-able targets.