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The treatment of relapse or refractory multiple myeloma (RRMM) is still a big challenge in clinic. Recently, several clinical trials indicated that the XPO1 inhibitor, selinexor could significantly improve the remission rate in MM patients. However, the heterogeneous genetic background greatly influenced the efficiency of selinexor among MM. Here, we tried to characterized the biomarkers associated with selinexor sensitivity by analyzing gene expression data in MM patients. We found the cytogenetic background of selinexor sensitive MM patients was not limited to specific cytogenetic subtypes. In addition, by weighted gene co-expression network analysis (WGCNA), we obtained 10 key genes which showed a strong correlation with the selinexor sensitivity in MM patients. Notably, ABCC4 (MRP4) was the only gene which was both differentially expressed and proved to be clinical prognostic valuable (both for event-free survival and overall survival) in MM patients. We further validated the heterogenous expression of ABCC4 in MM cell lines and its value as a novel indicator for selinexor sensitivity. Moreover, immune infiltration analysis showed that ABCC4 expression had a significantly positive correlation with NK infiltration as well as immunotherapy target TIM-3 (HAVCR2) expression. Collectively, our findings indicated that ABCC4 might be a predictive biomarker of selinexor sensitivity in MM patients, which could be enhanced if combined with immunotherapy drugs such as TIM-3 inhibitor.

Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2 nd-generation TKIs. Cells with BCR-ABL1 T315I mutations are insensitive to 1 st- and 2 nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3 rd-generation ponatinib). Olverembatinib is a novel, potent, 3 rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile. Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1 T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs). Results: Baseline characteristics Study CC201 （CML-CP ） On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12. Study CC202 （CML-AP ） On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12. Efficacy Study CC201 （CML-CP ） After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%). Study CC202 （CML-AP ） After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%). Safety Study CC201 （CML-CP ） Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred. Study CC202 （CML-AP ） Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2). Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1 T315Imutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Multiple myeloma (MM) is a malignant hematological cancer of plasma cells origin. However, MM with/without t(11;14) exists a huge therapeutic venetoclax response gap. To explore the clinical and genetic characteristics of MM patients, we divided the patients into two groups according to the t(11;14) translocation status. A total of 110 patients were enrolled in this analysis and 28 of them had t(11;14) translocation, of which 24 cases were MM patients and 4 cases were smoldering myeloma (SMM) patients. Compared to those t(11;14) counterparts, patients without t(11;14) has a higher ratio of early/later relapse, double/triple hit risk, higher mutation count as well as more hyper-karyotypes and other chromosome alterations (Figure 1A). Circos diagram analysis indicated the correlation between t(11;14) and most of cytogenetic alterations except del IGH, del 13q, t(6;14) and t(4;14),. To be specific, the strong connection between t(11;14) and Cyclin D was also in consistent with other reports (Figure 1B). With the normalized data of area under the curve (AUC), we further analyzed the drug sensitivity of patients with/without t(11;14) and 6 out of 76 drugs were identified to be significantly different. Compared to non-t(11;14), t(11;14) patients were significantly more sensitive to venetoclax as the lower AUC suggests. However, no significant difference in AUC of other potential myeloma drugs was found between the two groups (Figure 1C). In order to identify the critical genes associated with venetoclax sensitivity, we screened out the differentially expressed genes (DEGs) and applied weighted gene co-expression network analysis as previously described (Figure 1D and E). We combined clinical phenotype with the significant modules, and the key genes were screened based on the thresholds with cor. gene module membership > 0.5 and cor. gene significance > 0.3. Five modules were identified and of them brown and yellow modules showed significant negative correlations with AUC, with correlations being -0.4 and -0.31(p=0.01 and 0.07), respectively (Figure 1F). Furthermore, we analyzed these two modules in detail and finally screened 29 key genes associated with venetoclax sensitivity (Figure 1G), which were enriched in regulation of immune effector process pathway by Metascape, suggesting the immune dysfunction in these patients (Figure 1H). To identify the critical molecules affected by venetoclax, we analyzed the DEGs between the two groups divided by the median AUC value . In total, 143 genes were significantly upregulated and 38 genes downregulated in the high AUC group (i.e. low sensitivity to venetoclax) group . Next, we systematically analyzed the DEGs in brown module, AUC of venetoclax and of t(11;14). Notably, only NRG2 was identified to be involved in all these three aspects. NRG2, which presented a high sensitivity of venetoclax, was also validated to be more expressed in non-t(11;14) patients. Moreover, we could observe a trend of the expression of NRG2 increasing with the progression of myeloma, especially the significantly higher expression in disease stage of MM (P=0.0245) compared to sMM. In addition, NRG2 expression in myeloma is rather high compared to most hematological malignancies, while the extremely low expression was observed in AML which might correspond to its better reactivity to venetoclax. The expression of NRG2 in non-t(11;14) MM cells such as NCIH929, U266B1 and MM.1S was much higher than that in KMS12. BCL-2 expression was an important biomarker of venetoclax sensitivity. We found that NRG2 and BCL-2 had a strong positive correlation in non-t(11;14) MM patients (R 2=0.5016, P Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.