Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma.

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients.

The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti-MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty-five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m(2) and PLD 5 mg/m(2) were administered on days 1, 4, 8 and 11 of a 4-week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3-week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.

Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid.

Few studies have evaluated prognostic factors among patients with multiple myeloma (MM) since new therapies have become available. Monthly zoledronic acid (ZOL) has been incorporated into many treatment regimens to reduce skeletal-related events (SREs), but outcomes among patients receiving this bisphosphonate have not been well-defined. The aim of this retrospective study was to determine baseline and on-treatment prognostic factors in these patients. Data were collected from the date of diagnosis on 300 consecutive MM patients treated with ZOL. Median duration of ZOL was 18 months (range 1-121 months). The skeletal morbidity rate was 0.116 events per patient year. Five-year overall survival (OS) was 69%. Risk factors for shortened OS included SREs, increased serum creatinine, and International Staging System (ISS) Stage II or III. Thirty-four (11%) patients showed worsening renal function. In 28 of these patients, ZOL was discontinued and restarted in half of these patients following a brief delay. Only 5 of the 34 patients showed worsening of their renal function. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ). All patients with ONJ are in remission or with stable disease except one patient who died of a myocardial infarction while in remission. Only two patients showed some worsening of ONJ despite of ongoing monthly ZOL. Overall, these results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ and renal deterioration may infrequently occur with ZOL, most patients do not experience worsening of these conditions with ongoing treatment with this bisphosphonate.

A unified model of illusory and occluded contour interpolation.

Models of contour interpolation have been proposed for illusory contour interpolation but seldom for interpolation of occluded contours. The identity hypothesis (Kellman & Loukides, 1987; Kellman & Shipley, 1991) posits that an early interpolation mechanism is shared by interpolated contours that are ultimately perceived as either illusory or occluded. Here we propose a model of such a unified interpolation mechanism for illusory and occluded contours, building on the framework established in Heitger, von der Heydt, Peterhans, Rosenthaler, and Kubler (1998). We show that a single, neurally plausible mechanism that is consistent with the identity hypothesis also generates contour interpolations in agreement with perception for cases of transparency, self-splitting objects, interpolation with mixed boundary assignment, and "quasimodal" interpolations. Limiting cases for this local, feed-forward approach are presented, demonstrating that both early, local interpolation mechanisms and non-local scene constraints are necessary for describing the perception of interpolated contours.

Surface interpolation and 3D relatability.

Although the role of surface-level processes has been demonstrated, visual interpolation models often emphasize contour relationships. We report two experiments on geometric constraints governing 3D interpolation between surface patches without visible edges. Observers were asked to classify pairs of planar patches specified by random dot disparities and visible through circular apertures (aligned or misaligned) in a frontoparallel occluder. On each trial, surfaces appeared in parallel or converging planes with vertical (in Experiment 1) or horizontal (in Experiment 2) tilt and variable amounts of slant. We expected the classification task to be facilitated when patches were perceived as connected. We found enhanced sensitivity and speed for 3D relatable vs. nonrelatable patches. Here 3D relatability does not involve oriented edges but rather inducing patches' orientations computed from stereoscopic information. Performance was markedly affected by slant anisotropy: both sensitivity and speed were worse for patches with horizontal tilt. We found nearly identical advantages of 3D relatability on performance, suggesting an isotropic unit formation process. Results are interpreted as evidence that inducing slant constrains surface interpolation in the absence of explicit edge information: 3D contour and surface interpolation processes share common geometric constraints as formalized by 3D relatability.