Faculty Bibliography

BACKGROUND:Respiratory viral infections are a significant problem in patients with hematologic malignancies. We report a cluster of HPIV 3 infections in our myeloma patients, and describe the utility of next generation sequencing (NGS) to identify transmission linkages which can assist in infection prevention. OBJECTIVES:To evaluate the utility of NGS to track respiratory viral infection outbreaks and delineate between community acquired and nosocomial infections in our cancer units. STUDY DESIGN:Retrospective chart review conducted at a single site. All patients diagnosed with multiple myeloma who developed symptoms suggestive of upper respiratory tract infection (URTI) or lower respiratory tract infection (LRTI) along with a respiratory viral panel (RVP) test positive for HPIV 3 between April 1, 2016, to June 30, 2016, were included. Sequencing was performed on the Illumina MiSeqâ„¢. To gain understanding regarding community strains of HPIV 3 during the same season, we also performed NGS on HPIV3 strains isolated from pediatric cases. RESULTS:We saw a cluster of 13 cases of HPIV3 infections in the myeloma unit. Using standard epidemiologic criteria, 3 cases were considered community acquired, 7 cases developed infection during treatment in the cancer infusion center, while an additional 3 developed infections during hospital stay. Seven patients required hospitalization for a median duration of 20days. NGS enabled sensitive discrimination of the relatedness of the isolates obtained during the outbreak and provided evidence for source of transmission. Two hospital onset infections could be tracked to an index case; the genome sequences of HPIV 3 strains from these 3 patients only differed by a single nucleotide. CONCLUSIONS:NGS offers a significantly higher discriminatory value as an epidemiologic tool, and can be used to gather real-time information and identification of transmission linkages to assist in infection prevention in immunocompromised patients.

JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.

INTRODUCTION/BACKGROUND:Multiple myeloma is a malignant neoplasm characterized by plasma cell proliferation in blood and bone marrow. Approximately two-thirds of the patients with multiple myeloma are >65 years at the time of diagnosis. Patients in this age group often have co-existing cardiovascular diseases. Areas covered: The presence of multiple myeloma adds to the malady by direct deposition of amyloid protein in the heart or via toxicity of chemotherapeutic agents. Cardiac contractile dysfunction, arrhythmias and thromboembolic disorders are the main issues in the management of elderly patients with multiple myeloma. Expert commentary: Assessment of cardiac risk and functional status requires careful evaluation by history, physical examination and imaging studies such as echocardiography and magnetic resonance imaging. The management of cardiovascular disorders in the presence of multiple myeloma is difficult and poses a challenge for the internist, the oncologist, and the cardiologist alike. This review is an overview of the problem of cardiovascular risk in and management of elderly patients with multiple myeloma.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

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.