Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Daratumumab, Elotuzumab, and the Development of Therapeutic Monoclonal Antibodies in Multiple Myeloma.

There has been substantial progress in clinical outcomes for patients with multiple myeloma (MM). This encouraging trend derives in large part from the increasing number of effective therapeutic options and the ability because of this to achieve higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with lenalidomide and dexamethasone, in late 2015, was a notable achievement in the field, as daratumumab and elotuzumab represent the first monoclonal antibodies available for use in MM. Given their unique mechanisms of action and favorable side effect profiles, daratumumab and elotuzumab have considerable potential as therapeutic partners with agents in other drug classes and in different clinical settings ranging from newly diagnosed to relapsed disease. This review discusses the development of daratumumab and elotuzumab as well as other monoclonal antibodies currently being evaluated for use in MM.

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Development of a conceptual model to illustrate the impact of multiple myeloma and its treatment on health-related quality of life.

PURPOSE: Little qualitative research exploring the impact of multiple myeloma (MM) and its treatment on the health-related quality of life (HRQL) of patients has been published. This study aimed to explore the burden of MM symptoms and treatment and the impact of these on HRQL. A model was developed to illustrate key concepts and their interrelationships. METHODS: Patients with MM were recruited to this cross-sectional, qualitative study through a patient panel and at two clinical sites in the USA. An interview discussion guide was developed using a review of published literature and interviews with experienced MM clinicians. In-depth, semistructured telephone interviews with MM patients were conducted to explore their experiences of the disease and its treatment. Data were analyzed using a thematic analysis approach. RESULTS: Twenty MM patients at various stages of treatment participated in open-ended, semistructured interviews. Patients reported both current and previous MM symptoms; most had experienced fatigue and pain. Other commonly reported symptoms were fractures, anemia, neuropathy, aches, and infections. MM treatment was found to have a negative impact on patients' HRQL; treatment-related adverse events included fatigue, neuropathy, insomnia, and gastrointestinal symptoms. MM treatment placed a substantial psychological and physical burden on patients, disrupting social activities, decreasing independence, and impacting on relationships. A model was developed to illustrate the relationship between these concepts. CONCLUSION: The conceptual model developed in this study illustrates the many aspects of MM and its treatment and how they can have a negative impact on patients' HRQL.

The use of novel agents in the treatment of relapsed and refractory multiple myeloma.

Although outcomes for patients with multiple myeloma (MM) have improved over the past decade, the disease remains incurable and even patients who respond well to induction therapy ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose therapy with stem cell transplantation (SCT) have historically been utilized in the management of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, have assumed a primary role in this setting. This review focuses on the role of thalidomide, lenalidomide and bortezomib in relapsed and refractory MM, with additional discussion dedicated to emerging drugs in relapsed MM that may prove beneficial to patients with this disease.

S1 screw bending moment with posterior spinal instrumentation across the lumbosacral junction after unilateral iliac crest harvest.

STUDY DESIGN: A biomechanical study comparing fixation across the lumbosacral junction. OBJECTIVES: To determine which long posterior construct across the lumbosacral junction produces the least bending moment on the S1 screw when only one ilium is available for fixation. SUMMARY OF BACKGROUND DATA: Recent in vitro studies have demonstrated the benefit of anterior support and fixation into the ilium when instrumenting a long posterior construct across the lumbosacral junction. METHODS: Four L2-sacrum constructs were tested on six synthetic models of the lumbar spine and pelvis simulating that the right ilium had been harvested. Construct 1: L2-S1 bilateral screws. Construct 2: L2-S1 + left iliac bolt. Construct 3: L2-S1 + left iliac bolt + right S2 screw. Construct 4: L2-S1 + bilateral S2 screws. The four constructs were then retested with an anterior L5-S1 strut. A flexion-extension moment was applied across each construct, and the moment at the left and right S1 pedicle screw was measured with internal strain gauges. RESULTS: Iliac bolt fixation was found to significantly decrease the flexion-extension moment on the ipsilateral S1 screw by 70% and the contralateral screw by 26%. An anterior L5-S1 strut significantly decreased the S1 screw flexion-extension moment by 33%. Anterior support at L5-S1 provided no statistical decrease in the flexion-extension moment when bilateral posterior fixation beyond S1 was present with either a unilateral iliac bolt and contralateral S2 screw, or bilateral S2 screws. CONCLUSIONS: There is a significant decrease in the flexion-extension moment on the S1 screw when extending long posterior constructs to either the ilium or S2 sacral screw. There is no biomechanical advantage of the iliac bolt over the S2 screw in decreasing the moment on the S1 screw in flexion and extension. Adding anterior support to long posterior constructs significantly decreases the moment on the S1 screw. Adding distal posterior fixation to either the ilium or S2 decreases the moment on S1 screws more than adding anterior support. Further, adding anterior support when bilateral distal fixation past S1 is already present does not significantly decrease the moment on the S1 screws in flexion and extension.

Dorsal intercarpal ligament capsulodesis for scapholunate dissociation: biomechanical analysis in a cadaver model.

The purpose of this study was to evaluate in cadavers a new method for treating scapholunate dissociations, dorsal intercarpal ligament capsulodesis (DILC), and to compare its performance with that of a previously described soft tissue reconstruction, Blatt capsulodesis (BC). A cadaver model was used to simulate normal and abnormal wrist motions. The positions of the scaphoid and lunate and their changes with wrist motion and ligament condition were recorded using biplanar radiographs taken posteroanteriorly and laterally. The scapholunate gap was measured on the posteroanterior radiographs and the scapholunate angle was measured on the lateral view radiographs. Following scapholunate interosseous ligament sectioning, a diastasis developed between the scaphoid and lunate that was maximum in the clenched fist position 2.1 +/- 0.33 mm (mean +/- SEM) with the ligament intact versus 8.0 +/- 1.74 mm after the ligament was sectioned. Dorsal intercarpal ligament capsulodesis reduced gap formation more than BC, including when the specimens were in the clenched fist position: increased gap versus intact specimens equals 1.0 mm for DILC versus 3.7 mm for BC. The differences in diastasis were statistically significant between BC and DILC when the wrist was in extension, radial deviation, and clenched fist positions. After the scapholunate interosseous ligament was divided, the scaphoid flexed relative to the lunate. Both capsulodeses improved scapholunate alignment and there was a trend for DILC to correct the scapholunate angle more than BC. The results demonstrate that DILC is an attractive alternative to BC ex vivo. Because DILC does not tether the scaphoid to the distal radius, as BC does, improved wrist motion, especially flexion, might be possible in vivo. The use of DILC in the treatment of scapholunate dissociation warrants further investigation and clinical trials.

Cooperation between core binding factor and adjacent promoter elements contributes to the tissue-specific expression of interleukin-3.

Tissue-specific expression of interleukin-3 (IL-3) is mediated via cis-acting elements located within 315 base pairs of the transcription start. This is achieved in part through the positive activities of the AP-1 and Elf-1 sites in the IL-3 promoter. The contribution to T cell-specific expression by other promoter sites was assessed in a transient expression assay with IL-3 promoter constructs linked to a luciferase gene, focusing initially on the core binding factor (CBF) site, which is footprinted in vivo upon T cell activation. Activity of the CBF site is shown to be critically dependent on the adjacent activator site Act-1. Together the Act-1 and CBF sites form a functional unit (AC unit) with dual activity. The AC unit is demonstrated to enhance basal activity of promoters both in fibroblasts and T cells. This activity is further inducible in activated T cells, but not in fibroblasts. In addition to the already identified NIP repressor site, evidence is presented for a second repressor region that restricts promoter activity in fibroblasts. Finally, a novel positive regulatory element has been mapped in the IL-3 promoter between nucleotide -180 and -210 that leads to increased expression in T cells. Together these results demonstrate that T cell expression of IL-3 is not specified by the activity of a single tissue-specific element, but instead involves multiple interacting elements that provide both specific positive regulation in T cells and specific negative regulation in fibroblasts.