bortezomib

Moreover, Pin1 inhibition combined with Pyk2 inhibition decreases myeloma burden both in vitro and in vivo. Altogether, our findings reveal the tumor-promoting role of Pin1 in MM and provide evidence that targeting Pin1 could be a therapeutic strategy for MM.

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=50, Recruiting, The First Affiliated Hospital of Soochow University

P1/2, N=10, Recruiting, Northwell Health

After four cycles of cyclophosphamide, bortezomib, and dexamethasone therapy, he achieved a partial response, followed by complete hematologic response (CR) post eight cycles of lenalidomide, dexamethasone, and bortezomib therapy...Following failure of >4 lines of therapy, he received chimeric antigen receptor T (CAR-T) cell therapy (ciltacabtagene autoleucel) for salvage...This case report highlights MM management complexities in CHIP presence, suggesting potential utility of HSCT and CAR-T cell therapy. Prospective studies are necessary to evaluate the safety and efficacy of these therapies in myeloma patients with concurrent CHIP, aiming to optimize treatment strategies and improve outcomes in this challenging clinical context.

P4, N=8, Not yet recruiting, Alexion Pharmaceuticals, Inc. | Trial completion date: Sep 2028 --> Jan 2029 | Trial primary completion date: Sep 2028 --> Jan 2029

Background: Ciltacabtagene autoleucel (cilta-cel) demonstrated superior progression-free survival (PFS) and overall survival compared to standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone) in patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior lines of therapy (LOTs) in the phase 3 CARTITUDE-4 trial. The increase in the TTNT and sustained benefits in PROs, along with prolonged survival, support cilta-cel as a new SOC treatment for MM patients who are refractory to lenalidomide and have received 1-3 prior LOTs. Importantly, with ~3 years of follow-up, a single infusion of cilta-cel provided patients with a longer delay in worsening of MM related symptoms, functional impacts, and GHS/QoL. The totality of clinical and patient-reported evidence demonstrates the significant benefit of cilta-cel.

Background The only FDA-approved therapy for systemic light chain (AL) amyloidosis is daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD)...At the time of the MRD test, 30 (58.8%) patients were on active surveillance, 10 (19.6%) were on daratumumab and 9 (17.6%) on venetoclax...In patients with relapsed AL, MRD negativity is correlated with a better hematological response and could potentially play a role in clinical trial design. The impact of gender on MRD status remains an important area for further study.

We recently reported that increased expression of ST3GAL1 was associated with inferior PFS in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed MM patients treated with bortezomib, thalidomide, and dexamethasone (VTd) +/- Dara as induction and consolidation within the CASSIOPEIA study. Within part 2 of CASSIOPEIA, increased expression of ST3GAL1 is significantly associated with inferior PFS and predicts lack of sustained MRD and disease progression in patients MRD negative (10-5) prior to the onset of maintenance therapy or observation. Our preliminary data suggest that desialylation strategies, currently in clinical development, could help achieve deep and durable remissions in MM patients receiving current Dara based quadruplet treatment approaches.

D-VRd resulted in significantly higher rates of overall and sustained MRD negativity at both 10–5 and 10–6 sensitivity thresholds versus VRd at all timepoints in TIE and transplant-deferred patients with NDMM. This deeper response translated into significant improvements in overall PFS in the D-VRd group. Of patients who achieved MRD-negativity (10–5) with D-VRd, >80% were alive and progression-free at 54 months.

Pts received Isa (10 mg/kg IV) in the Isa-VRd arm and bortezomib (1.3 mg/m2 SC), lenalidomide (25 mg PO), and dexamethasone (20 mg IV/PO) in both arms. Isa-VRd followed by Isa-Rd led to greater depth of response of MRD-neg over time, with higher rates of MRD-neg at both the end of initiation and during maintenance compared with the control arm. Results from these analyses continue to demonstrate higher rates of sustMRD-neg over time at 10-5 and 10-6 sensitivity thresholds, and more pts retained MRD-neg status through maintenance phase. More pts had positive-to-negative conversions with Isa-VRd vs VRd, with conversion events increasing over the maintenance period.

Pts were assigned 1:1 to cilta-cel or SoC (pomalidomide, bortezomib, and dexamethasone [PVd]/daratumumab, pomalidomide, and dexamethasone [DPd]). At 33.6-mo median follow-up in CARTITUDE-4, cilta-cel vs SoC significantly increased overall MRD-negativity rates >3-fold in the ITT set, with pts achieving MRD negativity rapidly post cilta-cel. The prognostic value of MRD-negative ≥CR at mo 12 was shown, as median PFS was >3 years in pts with MRD-negative ≥CR at mo 12, regardless of tx. These data further underscore the benefit of cilta-cel, which led to significant >3-fold increases vs SoC in rates of MRD-negative ≥CR at any time and at mo 12, and sustained MRD negativity.

The presence of both high CTC and HRCA identifies a group of patients with an overall dismal outcome. The addition of daratumumab to VRd induction/consolidation and R maintenance improves outcome in NDMM patients with high-risk disease defined by high CTC, leading to higher rates of deep and sustained MRD-neg and better PFS.

The prediction model based on bone marrow MVD and vasogenesis factors (VEGF, HGF, bFGF) in MM patients has higher clinical evaluation performance and predictive value.

P=N/A, N=50, Recruiting, Peking University People's Hospital | Not yet recruiting --> Recruiting

Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.

P3, N=650, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Oct 2025 --> Feb 2026

P1/2, N=265, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1, N=80, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2024 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2026

Case presentation: Herein, we present the case of a 23-month-old girl with high-risk B-ALL who experienced very early isolated medullary relapse; following the failure of conventional chemotherapy according to the ALL-IC REL 2016 protocol, she went on to receive the bispecific T-cell engager (BiTE) blinatumomab and subsequently, due to refractory disease, the combination of fludarabine, cytarabine, and the proteasome inhibitor bortezomib without achieving remission. The minimal residual disease (MRD) was 0.08% on day 28, and InO was continued, thus achieving MRD negativity; the patient successfully underwent an allogeneic stem cell transplantation from a matched family donor. Our case highlights the efficacy and safety of InO as a salvage treatment in the setting of relapsed B-ALL refractory not only to conventional chemotherapy but also to novel treatments, such as blinatumomab and bortezomib.

P2, N=29, Not yet recruiting, Ruijin Hospital

P2, N=130, Recruiting, University of Heidelberg Medical Center | N=70 --> 130 | Trial completion date: Oct 2027 --> Aug 2028 | Trial primary completion date: Oct 2026 --> Feb 2027

Notably, our study identified eight drugs-Bortezomib, Midostaurin, CHIR.99021, JNK.Inhibitor.VIII, Lenalidomide, Sunitinib, GDC0941, and GW.441756-as exhibiting sensitivity toward OS. The outcomes of this investigation present an opportunity to predict the survival outcomes among individuals diagnosed with OS. Furthermore, these findings hold promise for progressing research endeavors focused on prognostic evaluation and therapeutic interventions pertaining to this particular ailment.

Identifying the key gene MDK and its associated signaling pathways extends our understanding of the molecular processes that underlie resistance to BTZ in MCL. This discovery establishes a theoretical framework for future investigations of targeted therapy in clinical settings.

Despite application of several new drugs, such as daratumumab, bortezomib/lenalidomide/dexamethasone, in combination with hematopoietic stem cell transplantation, overall prognosis remains poor and the pathological mechanism of MM is still unknown. The present findings suggested that miR-1343-3p may regulate ATG7 and autophagy by directly targeting the 3'UTR of ATG7. To the best of our knowledge, there are no direct data showing the roles of miR-1343-3p in development of MM; however, miR-1343-3p may be considered a potential target for MM treatment.

P2, N=40, Not yet recruiting, Goethe University

These findings are in line with the results of recent trials testing new agents on comparable patient cohorts and provide initial evidence of clinical benefit for patients with refractory/relapsed MM treated with MP0250 in combination with bortezomib/dexamethasone. Further clinical evaluation in the emerging MM treatment landscape would be required to confirm the clinical potential of MP0250.

Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer.

R A N D O M I Z A T I O N Arm 1: Lenalidomide VRd-Lite (Bortezomib + Lenalidomide + Dexamethasone) Arm 2: Arm 3: DRd (Daratumumab and hyaluronidase-fihj + Lenalidomide + Dexamethasone) DRd (Daratumumab and hyaluronidase-fihj + Lenalidomide + Dexamethasone) Lenalidomide Daratumumab and hyaluronidase-fihj + Lenalidomide FALL 2024 SWOG MYELOMA 23 S2209/III Secondary Endpoints: To compare PFS in Arm 1 versus Arm 3. Among the nine patients on the DRD-DR arm evaluated for adverse events, there has been one treatment-related death from heart failure. Two additional patients experienced a Grade 4 adverse event as maximum grade (both hematologic).

ADAM8 regulates intracellular STAT3 levels via miR-181a-5p and NEAT1 in pancreatic cancer.

Significantly, KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates significant tumor shrinkage in KS18-treated NSG mice without notable toxicity signs after 4 weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.

P2, N=39, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center | Initiation date: Sep 2024 --> Dec 2024

P2, N=36, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

P2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026

Our KCMC-PPB-1 is the first genuine, molecularly characterized PPB cell line. The cell line is transplantable to nu/nu mice; therefore, it is suitable for a preclinical model for new drug development. The cytotoxicity assay demonstrated that bortezomib is active in the current PPB model.

Methods Patients diagnosed with myeloma and concomitant dialysis-dependent renal dysfunction were admitted for ASCT after achieving at least partial response with bortezomib-based induction therapy. For both patients, mobilization consisted of granulocyte colony stimulating factor for 5 days and CD34 directed Plerixafor on Day 1...Use of reduced dose melphalan, pre-emptive dialysis after 24 hours and monitoring for acidosis and symptoms of uraemia to identify acidosis at an early stage allows safe administration of high dose chemotherapy. A major proportion of patients can potentially achieve reduction or freedom from dialysis support post-transplant.

Introduction: In the phase 3 PERSEUS study, subcutaneous (SC) DARA + VRd (D-VRd) induction/consolidation (ind/consol) and D-R maintenance (maint) increased PFS and depth of response (≥ complete response [CR] and MRD negativity [neg]) vs VRd ind/consol and R maint for TE NDMM. Higher rates of deep (10 –6 ) and sustained MRD neg with D-VRd ind/consol and D-R maint vs VRd ind/consol and R maint translated to improved PFS. These data support D-VRd and D-R maint as a new standard of care in TE NDMM and highlight the benefit of DARA SC in maint.

Introduction: In the phase 3 PERSEUS study, subcutaneous (SC) DARA + VRd induction/consolidation (ind/consol) and D-R maint improved progression-free survival (PFS) and rates of deep, durable responses, including minimal residual disease (MRD) negativity (neg) vs VRd ind/consol and R maint in TE NDMM, regardless of cytogenetic risk. Adding DARA SC to VRd ind/consol and R maint significantly improved PFS and sustained response rates, supporting D-VRd ind/consol and D-R maint as a new SOC for TE NDMM, regardless of cytogenetic risk status.

P3, N=395, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Aug 2025 --> May 2024

Co-administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines...Similar events occurred in highly bortezomib-resistant (PS-R) cells, in the presence of patient-derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors...Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib-resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.

P2; Trial completion date: Aug 2026 --> May 2026 | Trial primary completion date: Aug 2024 --> May 2024

P2, N=50, Active, not recruiting, University of Arkansas | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025