TKI discontinuation in CML: how do we make more patients eligible? How do we increase the chances of a successful treatment-free remission?

Treatment-free remission (TFR) is a new and significant goal of chronic myeloid leukemia management. TFR should be considered for patients in stable deep molecular response (DMR) after careful discussion in the shared decision-making process. Second-generation tyrosine kinase inhibitors (TKIs) improve the speed of response and the incidence of DMR. Treatment may be changed to a more active TKI to improve the depth of response in selected patients who have not reached DMR. Stem cell persistence is associated with active immune surveillance and activation of BCR-ABL1-independent pathways, eg, STAT3, JAK1/2, and BCL2. Ongoing studies aim to prove the efficacy of maintenance therapies targeting these pathways after TKI discontinuation.

Early Dynamics and Depth of Response in Multiple Myeloma Patients Treated With BCMA CAR-T Cells

Chimeric antigen receptor T-cell (CAR-T) therapy targeted against B-cell maturation antigen (BCMA) in multiple myeloma (MM) has produced rapid responses but many eventually relapse. In light of this new treatment, novel predictors of progression-free survival (PFS) are needed. We performed a single institution analysis of 54 BCMA-CAR-T patients. We analyzed patient’s overall response rate (ORR) by the IMWG criteria, involved serum-free light chains (iFLC), and minimal residual disease testing by next-generation sequencing (MRD-NGS). Between patients who achieved a ≤SD and those who achieved a ≥PR, PFS differed significantly (p < 0.0001); though there was no difference between patients who achieved a ≥CR vs. VGPR/PR (p = 0.2). In contrast, patients who achieved a nonelevated iFLC at 15 days (p < 0.0001, HR = 6.8; 95% CI, 2.7–17.3) or 30 days (p < 0.001, HR = 16.7; 95% CI, 3.9–71.7) had a prolonged PFS compared with those with an elevated iFLC. Patients achieving MRD-NGS less than the detectable limit at a sensitivity of 10−6 had a better PFS than those with detectable disease at 1 month (p = 0.02) and 3 months (p = 0.02). In conclusion, achieving a nonelevated iFLC and an undetectable MRD-NGS quickly were factors that were strongly associated with improved PFS. Further studies are needed to confirm the role of these markers in MM patients receiving CAR-T therapies.

Minimal residual disease in multiple myeloma: an important tool in clinical trials

: Minimal residual disease (MRD) detection represents a great advancement in multiple myeloma. New drugs are now available that increase depth of response. The International Myeloma Working Group recommends the use of next-generation flow cytometry (NGF) or next-generation sequencing (NGS) to search for MRD in clinical trials. Best sensitivity thresholds have to be confirmed, as well as timing to detect it. MRD has proven as the best prognosticator in many trials and promises to enter also in clinical practice to guide future therapy.

Autologous Haematopoietic Stem Cell Transplantation in Waldenström Macroglobulinemia: A Single-Centre 18-Year Experience

BACKGROUND The role of autologous stem cell transplantation (ASCT) in Waldenström Macroglobulinaemia (WM) is not well established, largely due to the paucity of evidence. It remains unclear where ASCT should be placed in the sequence of treatment lines. The debate is stronger in the era of targeted therapies that can achieve prolonged progression free survival (PFS) intervals and expected treatment-free intervals of approximately 4 to 8 years. The goal of this real world analysis was to review response and survival outcomes, and relapse risk factors in WM patients who underwent ASCT in a single WM referral centre. METHODS A retrospective cohort analysis was undertaken of consecutive WM patients treated with ASCT at a single specialist centre between 2003 and 2020. Baseline demographic/biological data, number/types of prior therapies, and pre- and post-ASCT depth of response, were collected from patient records and the WMUK Rory Morrison Registry. The primary aims were to determine depth of response, overall survival (OS), progression free survival (PFS), transplant related mortality (TRM) and relapse-associated mortality. RESULTS A total of 32 patients received ASCT, with a median age at time of ASCT of 57 years (range 40-68 years) and median interval from diagnosis to ASCT of 2.3 years (range 0.5-16.8 years); 14 (43.7%) were male. Prior to ASCT, 11 patients (34%) had received one therapy, 11 patients had 2 lines of treatment (excluding mobilisation), and 10 patients (31%) had received 3 or more therapies. The disease status pre-ASCT was complete remission (CR)/very good partial response (VGPR) in 14 patients (43.7%) and partial response (PR) in 18 patients (56.2%). Conditioning therapy comprised LEAM (Lomustine, Etoposide, Cytarabine, Melphalan; 18 patients, 56.2%), BEAM (Carmustine substituted for Lomustine; 12 patients, 37.5%), or Melphalan only (2, 6.2%). All patients had successful engraftment. Median time from stem cell reinfusion to hospital discharge was 15.5 days (range 13-187 days) in the 24 patients for whom these data were available; 5/24 patients (21%) were discharged >25 days after stem cell reinfusion. Restaging at 100 days post-ASCT showed deepening of response by ASCT in 17 patients (53.1%). CR/VGPR was achieved by 26 patients (81.2%) and PR by 4 patients (12.5%). Two patients (6.2%) experienced disease progression before day 100 post-ASCT (both receiving ASCT in second remission/PR2). At a median follow up of 8.9 years (range 0.1-18 years), the estimated median PFS was 4.5 years (95% confidence interval [CI] 3.2-5.7 years), with estimated 2-year and 5-year PFS rates of 75% and 35.9%, respectively (Figure 1A). In this small cohort, there was no significant difference in PFS based on age, number of prior lines of treatment, pre-ASCT remission status (CR/VGPR vs PR) or post-ASCT response achieved. At time of analysis, 14/32 patients (43.7%) had died: TRM rate was 6.2% (2 patients died during inpatient admission of ASCT complications), 4 patients (12.5%) died of PD, and 1 patient died of unknown causes. Another 7 patients (21.9%) died of infective causes after the immediate post-ASCT period: the median time from ASCT to death among these patients was 5.5 years (range 0.8-10.8 years). Estimated median OS for the unstratified cohort was 10.8 years (95% CI 7.3-14.3 years), with estimated 2- and 5-year OS rates of 87.5% and 77.5%, respectively (Figure 1B). Overall survival did not differ significantly based on age at time of ASCT, number of therapy lines prior to ASCT, pre-ASCT remission status (CR/VGPR vs PR) or post-ASCT response achieved. One patient (3.1%) underwent ASCT after BTK inhibitor therapy, achieving deepening of response (PR to VGPR) with ASCT and progression free interval of 11 months. CONCLUSION ASCT is a feasible treatment option for patients with relapsed WM, producing deeper responses following salvage therapy and resulting in PFS intervals comparable to other currently available therapeutic options. With the benefit of a long follow up period, performing ASCT at later stages in the treatment course (i.e. following 3 or more prior therapy lines) did not appear to result in inferior survival outcomes; timing of ASCT should therefore be considered on an individual patient basis and in light of other available therapy options for relapsed disease. Figure 1 Figure 1. Disclosures Yong: Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria; Autolus: Research Funding; BMS: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Wechalekar: Amgen: Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Caelum Biosciences: Other: Clinical Trial Funding; Takeda: Honoraria; Celgene: Honoraria; Janssen: Consultancy. D'Sa: Sanofi: Honoraria; Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding.

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Background: Almost two thirds of transplant-ineligible, treatment naïve multiple myeloma (NDMM, TNE) patients (pts) do not proceed to second line anti-MM therapy. Given depth of response to initial therapy correlates to overall survival (OS), a deep remission should also be the target for this cohort of generally elderly and frail patients. However, this should not come at the expense of either treatment-related or fiscal toxicity. IRIL is a phase II, multicentre, response-adapted study examining treatment intensification with isatuximab (Isa; supported by Sanofi/Genzyme), an anti-CD38 monoclonal antibody, for pts not achieving pre-defined target responses to lenalidomide and dexamethasone (Rd). Method: TNE NDMM pts meeting IMWG criteria for treatment are eligible for enrolment. Pts commence treatment with lenalidomide [25mg D1-D21 of a 28-day cycle (C)] and dexamethasone [40mg (20mg for those aged ³75 years) PO weekly]. Failure to achieve pre-defined target response [<PR after 4 cycles, <VGPR after 6, or <CR after 9 cycles of Rd] or progressive disease (PD) within the first 9 cycles of Rd leads to addition of Isa (10mg/kg IV weekly for cycle 1, then fortnightly) until PD or adverse events (AEs) that warrant treatment cessation. The primary endpoint is to evaluate the rate of achievement of ³PR following completion of 6 cycles Isa-Rd in those who failed to achieve <PR after C4 Rd. The secondary endpoints are to evaluate overall improvement in depth of response to Isa-Rd, progression free survival (PFS), OS, and safety. Results: From June 2019 to June 2021, 42 pts [52.3% male, median age 77.7 yrs (range 68.5-86.0), R-ISS Stage I (n=8), Stage II (n=23) and Stage III (n=7)] were accrued. 30 pts have completed at least C4 Rd and were deemed evaluable (12 non-evaluable; 5 only recently recruited, 5 withdrew consent (WD) due to logistic reasons, 2 PD pre-C4 and were taken of study at investigator discretion). Of the 30 evaluable pts (see Figure 1), 25 remain on study with 2 further WD (logistic reasons) and 3 deaths. In total, 25pts have had treatment intensification with Isa [9pts (5<PR and 4 PD) prior to C4 Rd, 11/13 eligible < VGPR after C6 Rd (1 omission in error, 1 pt WD consent), 4/5 eligible pts < CR after C9 Rd (1 omission in error) and 1 PD at C6]. 18/25 patients have had at least 6 months of Isa intensification with increased depth of response in 12 (66.7%) pts. Of the 9 pts rescued with Isa after not reaching target response post C4 Rd, 7 have completed 6 Isa-Rd cycles with 100% deepening of response (5 PR, 4 VGPR). The overall response rate in the cohort of evaluable patients is 100% (16 PR, 14 VGPR). The median (±SD) follow-up time of the evaluable cohort was 9.96 ± 6.24 months with med OS not reached. Thirty-one (73.8%) pts experienced any grade AE (median = 6; range 1-21). Grade 3 or 4 AEs were reported in 16 pts (34 events in total; median per pt = 2; range 1-5). Most common ³ Grade 3 events include infection (10), neutropenia (7) and insomnia and mood disorder (3 each). Neutropenia was the single grade 4 AE in a patient on Rd. Fewer of the reported grade 3 or 4 AEs occurred while on Isa-Rd (16) than while on Rd alone (n=18) with causality was less frequently attributed to Isa (n=4) than R (n=17) or d (n=14). Conclusion: A response-adapted approach for TNE NDMM pts with isatuximab intensification upon inadequate response to standard-of-care lenalidomide-dexamethasone is both safe and effective. Isa-Rd leads to universal deepening of response in patients failing to achieve a PR or better after 4 months of Rd, while the overall response rate in evaluable patients, irrespective of initial response to Rd, is 100%. Isa-Rd is well tolerated in this elderly patient cohort. The safety profile for the combination Isa-Rd is similar to previous reports. Patient accrual is ongoing. Figure 1: Swimmer's plot highlighting patient response after C4 Rd, timepoints of isatuximab intensification (*Isa) and subsequent depth and duration of response. Figure 1 Figure 1. Disclosures Janowski: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Quach: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Selinexor acts by inhibiting the nuclear export protein XPO1; however, its mRNA expression does not correlate with response, and the biological mechanisms underlying treatment response for different patients remain unclear. There is a critically unmet need for validated genomic biomarkers to help guide treatment recommendations to selinexor based therapy. Here, we characterized the transcriptomic correlates of response to selinexor in data from 189 patients from multiple studies of selinexor-based therapy and identified and validated a 3-gene expression signature predictive of treatment response. We performed RNA sequencing on CD138+ cells from 103 patients who participated in the BOSTON study, a phase III, open-label clinical trial of patients with multiple myeloma (MM) who were treated with selinexor, bortezomib and dexamethasone (XVd) after 1-3 lines of standard therapy versus a bortezomib and dexamethasone (Vd) regimen (Grosicki et al 2020 Lancet; Fig 1A-B). Then, we performed differential expression, followed by pathway analysis, to compare patients with long and short progression-free survival (PFS) in the XVd arm of the BOSTON dataset across various PFS and overall depth-of-response (OR) cutoffs. Here, we identified a total of 24 unique downregulated genes and 33 unique upregulated genes that were associated with longer PFS or better depth of response in the XVd arm (FDR < 0.05). Pathway analyses revealed downregulation of apoptosis and MYC targets in patients with selinexor-associated longer PFS or better depth of response (FDR < 0.05), consistent with the known relationship between depth and duration of response in MM. Using the differentially expressed genes, we employed time-to-event univariate Cox proportional hazard models (CPH) with repeated 4-fold cross validation, log-rank testing, and spearman correlations to identify a novel signature that predicts PFS in the BOSTON dataset. This analysis revealed a GSVA score composed of three genes, WNT10A, DUSP1, and ETV7, that were upregulated in XVd patients with PFS > 120 days. Further, this signature accurately distinguished patients with long term PFS in the XVd arm of the BOSTON study (Fig 1C; log rank P = 0.017; spearman Rho = 0.46, P = 0.0007; CPH, FDR=0.047, HR=0.36 [95% CI = 0.14-0.84]). We also found that the signature significantly tracks with a depth of response of VGPR or better (Fig 1D, Wilcoxon P = 0.025). Finally, we validated the accuracy of our signature using transcriptomic data from two external cohorts: the STORM trial of penta-refractory MM (N = 64; Chari et al., NEJM), and a cohort of patients treated with selinexor-based regimens at Mount Sinai who were not part of a clinical trial (N = 21). This signature validated successfully in the STORM study (Fig 1E, log-rank P = 0.02; spearman Rho = 0.18, P = 0.14; CPH P = 0.08, HR=0.63 [95% CI = 0.47-1.03 ]) and in the non-trial Mount Sinai cohort (Fig 1G, log-rank P = 0.0033; spearman Rho = 0.6, P = 0.0043; CPH P = 0.004, HR = 0.215 [95% = 0.15-0.72]). Additionally, the association of the signature expression with depth-of-response validated in the STORM cohort (Fig 1F; Wilcoxon P = 0.021), further supporting the robustness of our signature. We used the MMRF-COMMPASS dataset (N=700) as a negative control and found that the signature is not predictive of PFS in patients who were treated with non-selinexor based, standard of care therapies. Together, these results support the conclusion that our signature is specific to selinexor treatment response and is not reflective of overall prognosis. We are currently performing experimental validation of the three genes in cell line experiments to better understand the mechanisms underlying their predictive power. We are also evaluating the utility of augmenting gene-expression based biomarkers with an ex-vivo mass-based biomarker assay to more accurately predict response to selinexor. In summary, we report a novel gene expression signature for response to selinexor-based therapy in patients with MM. We have validated our findings in several external transcriptomic datasets of MM patients treated with selinexor-based regimens. This signature has important clinical significance as it could identify patients most likely to benefit from treatment with selinexor-based therapy, especially in earlier lines of therapy. Figure 1 Figure 1. Disclosures Stevens: Travera: Current Employment. Richter: Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Chari: Takeda: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Legend Biotech: Consultancy; Takeda: Consultancy. Walker: Karyopharm Therapeutics Inc.: Current Employment. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy - Final Analysis from the Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial

BACKGROUND Survival rates in multiple myeloma (MM) have significantly improved in recent decades with the advent of high-dose chemotherapy conditioned autologous stem cell transplantation (ASCT) and the availability of novel agents for induction therapy (Kumar SK et al. Blood 2008). Failure to respond to front-line bortezomib-based induction therapy remains a significant clinical challenge in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM), and is associated with poor outcomes with shortened progression free survival (PFS) and overall survival (OS) (Lee SE et al. Ann Hematol. 2014). In combination with immunomodulatory agents (IMiDs), carfilzomib, a second generation proteosome inhibitor, has been shown to be highly effective in the context of MM induction with high rates of negativity for minimal residual disease (MRD) and few dose limiting toxicities (Langren O et al. Leukemia 2019). The ALLG MM17 trial is a multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in TE NDMM patients refractory or with suboptimal response to bortezomib-based induction therapy, designed to evaluate the efficacy of early response adaption with a switch to an intensive salvage strategy. METHOD Eligible patients included those with TE NDMM, aged 18 years and older, demonstrating sub-optimal response to bortezomib-based induction therapy (failure to achieve a minimal response after 2 cycles, partial response [PR] after 4 cycles, or disease progression within 60 days of completing induction). Salvage therapy consisted of 100mg daily oral thalidomide, with 20 mg of oral dexamethasone and 20mg/56mg of IV carfilzomib on days 1, 2, 8, 9, 15, and 16, with of each 28-day cycle. Following 4 cycles, patients in stringent complete response (sCR) proceeded to melphalan conditioned ASCT whereas those in less than sCR received a further 2 cycles of KTd prior to ASCT. Consolidation therapy consisted of a further 2 cycles of KTd, followed by maintenance 100mg daily thalidomide and 40mg weekly dexamethasone (Td) continuing until progressive disease, unacceptable toxicity, or 12 months of therapy. Primary objectives were to determine the overall response rate (ORR) and safety profile of treatment with KTd salvage therapy, with secondary objectives to determine the maximal depth of response, progression free survival (PFS), and overall survival (OS) achieved with sequential treatment with KTd salvage, ASCT, post-ASCT consolidation, and maintenance Td therapy. Efficacy assessments were performed via serum protein electrophoresis, serum free light chain and bone marrow evaluation. Next generation flow (NGF) cytometry MRD evaluation of bone marrow aspirate was undertaken pre-ASCT, at day 100 post-ASCT, after 2 cycles of consolidation KTd, and following completion of Td using standardized 8-colour EuroFlow platform. RESULTS 50 patients were recruited across 6 Australian sites between September 2016 and April 2018. Overall response rate to KTd salvage was 78% (Credible Interval 95%: 64.4-87.1%), with dual proof of concept criteria met (observed ORR ≥ 50% and posterior probability that the true ORR exceeds 30% is ≥ 0.90). Response rates included 12% sCR, 6% CR, 38% VGPR, and 22% PR. Sixteen patients discontinued treatment (32%) including 10 cases (20%) of progressive disease, and 2 patient deaths without progression. NGF MRD negativity was found to be 32%, 36% and 55% at the pre-ASCT, post-ASCT and post-consolidation time-points. At the cut-off date, estimated median follow-up for disease status was 38.6 months and median PFS and OS had not been reached. At 36 months PFS and OS were 63.9% (95%CI: 49.0 - 75.5%) and 79.9% (95%CI: 65.8 - 88.6%) respectively (Figure 1). KTd was found to be well tolerated with 44% of patients experiencing a grade 3 of higher adverse event (AE). Most common AEs included upper respiratory infection (48%), peripheral neuropathy (36%), musculoskeletal pain (32%), dyspnoea (28%), fatigue or lethargy (28%), and constipation (28%). Significant cardiac toxicity was not observed at this higher dose level of carfilzomib. CONCLUSION Results demonstrate that response-adaptive utilisation of KTd salvage, ASCT, and consolidation therapy induces high response rates, improving depth of response with high levels of sequential MRD negativity, and durable responses with an acceptable toxicity profile in TE NDMM patients failing bortezomib-based induction therapy. Figure 1 Figure 1. Disclosures Quach: Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalff: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Roche: Honoraria; CSL: Honoraria; Sandoz: Honoraria. Bergin: Amgen: Other: Travel to workshop; Celgene: Consultancy. Reynolds: Novartis AG: Current equity holder in publicly-traded company; Alcon: Current equity holder in publicly-traded company; Abbvie: Research Funding. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria.

Priority directions of increasing the adaptivity of universities to the conditions of the digital economy

The digital economy forms a set of new challenges to the higher education system, namely: accelerating the pace of socio-economic transformations; transformation of information into a commodity and a productive force; large-scale digitalization of economic entities; virtualization of workplaces; active introduction of information and communication technologies; creation of a global information field; exacerbation of cybersecurity problems. In such conditions, the system of higher education and the activities of universities need to be adequately changed in order to ensure their competitiveness in the modern market of educational services. The article substantiates the need to increase the level of adaptability of higher education institutions to exogenous challenges. Under the category of adaptability, it is proposed to understand the desired property of the higher education system, which determines its ability to absorb shocks, adapt or reorganize in accordance with the challenges posed by the development of the digital economy. The main parameters of the adaptability of the higher education system to the digital economy are the degree of its resistance to external disturbances, the depth of response to them, the speed of recovery after crises, the degree of structural and functional reorganization, the possibility of continuing pre-board development trajectory. The purpose of the article is to formulate scientifically sound proposals to increase the level of adaptability of universities to the challenges of the digital economy. The authors of the set of such proposals are structured according to the selected types of adaptability: introversion and extraversion.