Citations

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.

BACKGROUNDNational Cancer Institute (NCI)/National Comprehensive Cancer Network (NCCN)–designated cancer centers (CCs) offer patients state‐of‐the‐art treatment, but their impact on multiple myeloma (MM) patient outcomes has not been evaluated.METHODSAdult MM patients diagnosed between 1973 and 2011 were identified from the Surveillance, Epidemiology, and End Results database and were stratified by the county of residence at the time of diagnosis and the year of CC designation. The influence of NCI/NCCN CC access, race, and the year of diagnosis on overall survival (OS) was evaluated with a Cox regression model.RESULTSA statistically significant OS improvement was noted in patients diagnosed after 1995 with access to 2 or more NCI CCs overall (P = .002 for 1996‐2002; P < .001 for 2003‐2011) and by race for whites (hazard ratio [HR] for 1996‐2002, 0.85; 95% confidence interval [CI], 0.78‐0.91; HR for 2003‐2011, 0.85; 95% CI, 0.79‐0.91) but not for nonwhites. For NCCN access, improvement was seen in 1996‐2002 (P = .003), in 2003‐2011 (P < .001), and by race for whites (HR, 0.917; 95% CI, 0.88‐0.95) and nonwhites (0.94; 95% CI, 0.89‐0.99), but within nonwhites, this was true only for African Americans (AAs; HR, 0.88; 95% CI, 0.81‐0.97) and not for Asians, Hispanics, or Native Americans.CONCLUSIONSImprovement in OS was seen in MM patients diagnosed after 1995 with access to 1 NCCN CC or 2 or more NCI CCs. NCI access benefited only whites, whereas NCCN access benefited only white and AA patients. No OS benefit was seen for any subgroup with access to only 1 NCI center. Eliminating racial disparities in health care access and utilization is needed to improve outcomes. Cancer 2016;122:618–625. © 2015 American Cancer Society.

Abstract Inhibitors of the proteasome-ubiquitin system have been found to be effective in the clinical management of multiple myeloma. We here describe the compound VLX1570, an optimized lead of the 19S deubiquitinase inhibitor b- AP15. VLX1570 was shown to inhibit the enzymatic activities of both USP14 and UCHL5 in vitro, and was shown to induce accumulation of high molecular weight polyubiquitinated proteins in multiple myeloma cells. The compound showed limited inhibitory activity of a panel of kinases. VLX1570 induces apoptosis and cell death of multiple myeloma cell lines at submicromolar concentrations. Importantly, a multiple myeloma cell line selected for bortezomib resistance was found to be sensitive to VLX1570. VLX1570 was found to be able to overcome apoptosis resistance by these cells. Induction of the phosphorylation of stress-activated kinases (JNK and p38) and inhibition of ERK phosphorylation was observed in multiple myeloma cells. We finally showed that VLX1570 confers antineoplastic activity in two different myeloma xenograft models and conclude that VLX1570 is a candidate agent for treatment of multiple myeloma. Citation Format: Xin Wang, Chitralehka Mohanty, Padraig D'Arcy, Maria Hägg Olofsson, Felicitas Bossler, Asher Chanan-Khan, Stig Linder. Development of the proteasome deubiquitinase inhibitor VLX1570 for treatment of multiple myeloma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4557A. doi:10.1158/1538-7445.AM2015-4557A

SummaryLong‐term outcomes and updated clinical efficacy and safety data were evaluated for newly‐diagnosed multiple myeloma patients treated on a phase II study of bortezomib and pegylated liposomal doxorubicin (PegLD). Out of 61 patients, the overall response rate was 57% and the near‐complete/complete response rate was 7%. Patients aged ≥65 years old had a higher incidence of treatment‐related ≥Grade 3 non‐haematological toxicity (80% vs. 51%, P = 0·020). Median overall survival was 5·6 years and negatively impacted by the presence of International Staging System stage III disease, underscoring the need for novel treatment strategies for this group of patients.

Key PointsIn a randomized phase 3 trial, overall response rates, PFS, and overall survival were similar between MPT-T and mPR-R. Toxicity with both regimens was common, but mPR-R was better tolerated, and patients on the mPR-R regimen reported better quality of life.

Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL.