Faculty Bibliography

PURPOSE/OBJECTIVE:The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY/METHODS:An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS/CONCLUSIONS:Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Percutaneous transcatheter device closure for post-myocardial infarction ventricular septal defect is a feasible alternative to open surgical patch repair. Patient selection, imaging, timing of intervention, technique, and results are discussed.

Inositol-requiring enzyme 1 alpha (IRE1α) is a transmembrane sensor protein with both kinase and ribonuclease activity, which plays a crucial role in the unfolded protein response (UPR). Protein misfolding in the endoplasmic reticulum (ER) lumen triggers dimerization and subsequent trans-autophosphorylation of IRE1α. This leads to the activation of its endoribonuclease (RNase) domain and splicing of the mRNA of the transcriptional activator XBP1, ultimately generating an active XBP1 (XBP1s) implicated in multiple myeloma survival. Previously, we have identified human IRE1α as a target for the development of kinase inhibitors that could modulate the UPR in human cells, which has particular relevance for multiple myeloma and other secretory malignancies. Here we describe the development and validation of a 384-well high-throughput screening assay using DELFIA technology that is specific for IRE1α autophosphorylation. Using this format, a focused library of 2312 potential kinase inhibitors was screened, and several novel IRE1α kinase inhibitor scaffolds were identified that could potentially be developed toward new therapies to treat multiple myeloma.

Maintenance therapy is an attractive strategy for patients with multiple myeloma. However, the impact of maintenance thalidomide according to the underlying biology of the disease is still a matter of debate, with some studies suggesting that thalidomide is more beneficial in high risk disease, whilst others show the opposite. Biological risk groups defined by interphase fluorescence in situ hybridization (FISH) are powerful predictors of outcome. In this report we investigated the effect of maintenance thalidomide in different biological risk groups defined by different FISH categories. Our data show that maintenance thalidomide improves outcome in patients with biologically low risk disease, defined by the absence of adverse cytogenetic lesion or by the presence of hyperdiploidy alone. Conversely, thalidomide maintenance is detrimental for the overall survival of patients with biological high risk. We conclude that it is important to identify biologically low risk patients who will benefit from a maintenance strategy with thalidomide.

Graft-versus-host disease (GvHD) is a common complication following haematopoietic stem cell transplant but little is published about the impact of this condition on hospital readmission rates. We report a retrospective analysis of readmission rates and associated costs in 187 consecutive allogeneic transplant patients to assess the impact of GvHD. The overall readmission rate was higher in patients with GvHD (86% (101/118) vs. 59% (41/69), p < 0.001). The readmission rate was higher both in the first 100 d from transplant (p = 0.02) and in the first year following transplant (p < 0.001). 151/455 (33%) of all readmission episodes occurred within 100 d of transplant. The mean number of inpatient days was significantly higher in patients with grade III/IV acute GvHD (101 d) compared with those with grade I/II GvHD (70 d; p = 0.003). The mean cost of readmission was higher in patients with GvHD (£28 860) than in non-GvHD patients (£13 405; p = 0.002) and in patients with grade III/IV GvHD (£40 012) compared with those patients with grade I/II GvHD (£24 560; p = 0.038). Survival was higher in those with grade I/II GvHD (55%) compared to grade III/IV GvHD (14%; p < 0.001). This study shows the high economic burden and poor overall survival associated with grade III/IV GvHD.

Loeys-Dietz is a multisystem congenital syndrome that comprises craniofacial and cutaneous abnormalities as well as structural cardiac defects. One of its key pathological features is an aggressive widespread vasculopathy that can manifest as aortic or cerebral aneurysms, which is prone to dissection and rupture. We report a case of a large aneurysm of the ductus arteriosus in a patient with Loeys-Dietz syndrome, successfully occluded by interventional catheterization.

The first of the so-called "novel agents" (thalidomide, lenalidomide, and bortezomib), thalidomide has demonstrated activity as a single agent and in combination with other agents in patients with relapsed and/or refractory MM. The combination of melphalan, prednisone, and thalidomide (MPT) has become a standard treatment option for newly diagnosed patients who are ineligible for high-dose chemotherapy with autologous stem cell transplantation (ASCT). For patients intending to undergo ASCT, the combination of thalidomide, dexamethasone and cyclophosphamide can be used as a non-myelosuppressive induction regimen. Treatment with thalidomide is associated with an increased risk of developing peripheral neuropathy, which can be managed with dose reductions and discontinuation, and venous thromboembolism, which warrants thromboprophylaxis. While its adverse event profile may preclude prolonged use as maintenance therapy, thalidomide is an effective and well-tolerated salvage therapy option. Ongoing trials continue to evaluate novel thalidomide-based regimens to further optimize the use of thalidomide in the management of MM.