Stewart, A. Keith

TPS8053 Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.

e19530 Background: Neuropathy is a universal symptom of patients with POEMS syndrome, which makes the use of bortezomib less appealing. However, proteasome inhibitors (PIs) can provide rapid and deep hematologic responses in plasma cell disorders. Because there is very little data regarding the use PIs in POEMS syndrome, we performed a study of patients with POEMS syndrome treated with PIs. Methods: Among the 167 patients with POEMS syndrome seen at our institution between 2001-2016, we identified 12 patients who received a PI. One patient receiving < 1 cycle of bortezomib because of worsening neuropathy was included but was excluded from response analyses. One patient received 2 different PIs at separate points during the disease course and each course was considered separately. Four response categories were considered: hematologic, PET, VEGF and clinical as previously described (Dispenzieri et. al AJH 2015). Results: Among the 12 patients who received 13 courses of therapy, the median age at PI initiation was 59; 8 patients were male. Median number of prior therapies was 1 (0-4) and median time from diagnosis to initiation of PI was 75 months. Excluding steroids, regimens were as follows: bortezomib, n=3; bortezomib and cyclophosphamide, n=4; carfilzomib, n=1; and ixazomib, n=1. With a median follow-up from PI initiation of 18 months, the median duration of treatment was 7 months (1-18). Three patients achieved a hematologic CR. Of 6 patients with an abnormal baseline VEGF, 3 achieved normalization VEGF levels. Of 5 patients with an abnormal baseline PET, 2 achieved normalization of their PET. Two patients had improvement of their neuropathy, with the rest having stable symptoms. Of 9 patients with fluid overload, 8 improved. Only 2 patients stopped therapy due to worsening neuropathy related to PIs. Median PFS and OS from initiation of PI were 50 months and 53 months, respectively. Conclusions: We show that PI use in patients with POEMS syndrome can be safe and effective. Nearly 75% of patients treated with bortezomib had no exacerbation of their neuropathy. Clinical improvement in severe fluid overload symptoms (edema, ascites, pleural effusions) is almost universal, making PI-based therapy an attractive potential option in these patients.

Abstract Introduction: Representing 10% of hematologic malignancies, multiple myeloma (MM) is typified by clonal plasma cell proliferation in the bone marrow (BM) and may progress to therapy-resistant plasma cell leukemia (PCL). Despite many novel therapies, relapse rates remain high as a result of malignant regeneration (self-renewal) of MM cells in inflammatory microenvironments. In addition to recurrent DNA mutations and epigenetic deregulation, inflammatory cytokine-responsive adenosine deaminase associated with RNA (ADAR1)-mediated adenosine to inosine (A-to-I) RNA editing has emerged as a key driver of cancer relapse and progression. In MM, copy number amplification of chromosome 1q21, which contains both ADAR1 and interleukin-6 receptor (IL-6R) gene loci, portends a poor prognosis. Thus, we hypothesized that ADAR1 copy number amplification combined with inflammatory cytokine activation of ADAR1 stimulates malignant regeneration of MM and therapeutic resistance. Methods and Results: Analysis of MMRF CoMMpass RNA sequencing (RNA-seq) data revealed that high ADAR1 expression (n=162 patients) correlated with significantly reduced progression-free and overall survival compared with a low ADAR1 subset (n=159 patients). In contrast to lentiviral ADAR1 shRNA knockdown and overexpression of an editase defective ADAR1 mutant (ADAR1E912A), lentiviral wild-type ADAR1 overexpression enhanced editing of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist. Editing of GLI1 transcripts enhanced GLI transcriptional activity in luciferase reporter assays, and promoted lenalidomide resistance in vitro. Finally, lentiviral shRNA ADAR1 knockdown reduced regeneration of high-risk MM in humanized serial transplantation mouse models, indicative of reduced malignant self-renewal capacity. Whole-transcriptome RNA-sequencing of primary samples after lentiviral shRNA knockdown of ADAR1 revealed specific modulation of extracellular and immune response genes, while overexpression of wild-type versus edited GLI1 elicited distinct gene expression changes in human myeloma cells analyzed using NanoString nCounter assays. These data demonstrate that ADAR1 promotes malignant self-renewal of MM and, if selectively inhibited, may prevent progression and relapse through modulation of extracellular and immune response genes. Conclusions: Deregulated RNA editing, driven by aberrant ADAR1 activation, represents a unique source of transcriptomic and proteomic diversity, resulting in self-renewal of MM cells in inflammatory microenvironments. In summary, both genetic (1q21 amplification) and microenvironmental factors (inflammatory cytokines, IMiDs) combine to drive GLI1-dependent malignant regeneration in MM. Thus, ADAR1 represents both a vital prognostic biomarker and therapeutic target in MM. Citation Format: Leslie A. Crews, Elisa Lazzari, Phoebe K. Mondala, Nathaniel Delos Santos, Amber Miller, Gabriel Pineda, Qingfei Jiang, Anusha-Preethi Ganesan, Christina Wu, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, A. Keith Stewart, Catriona H. M. Jamieson. Down-modulation of ADAR1-mediated GLI1 editing alters extracellular and immune response genes in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4437.

Key Points Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.