The role of the unfolded protein response pathway in bone homeostasis and potential therapeutic target in cancer-associated bone disease.

The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade, essential for cell function and survival. Unfolded protein response signaling is tightly integrated with bone cell differentiation and function, and chronic unfolded protein response activation has been identified in bone disease. The unfolded protein response has been found to promote oncogenesis and drug resistance, raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.

A Phase II Trial of Geriatric Assessment-Guided Selection of Treatment Intensity in Older Adults With AML.

How to select the appropriate intensity of chemotherapy in older adults with acute myeloid leukemia (AML) remains an unanswered question. In a phase II trial of older adults ≥ 60 years with AML (n = 73), we used geriatric assessment (measures of comorbidity burden, physical and cognitive function) to determine fitness for intensive chemotherapy. We integrated the geriatric assessment and genetic test results to personalize the selection of chemotherapy intensity with a goal to reduce early mortality (NCT03226418).

A phase 2 randomized study of modakafusp alfa as a single agent for patients with relapsed/refractory multiple myeloma.

Modakafusp alfa is a first-in-class immunocytokine-directing interferon alfa to CD38+ cells. Our previous phase 1/2 trial identified 2 potential phase 2 doses of modakafusp alfa for patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks.

Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.

Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure-activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels.

Structure-activity relationship of isoprenoid triazole bisphosphonate-based geranylgeranyl diphosphate synthase inhibitors: Effects on pharmacokinetics, biodistribution, and hepatic transporters.

Geranylgeranyl diphosphate synthase produces the isoprenoid geranylgeranyl diphosphate, which is used in protein geranylgeranylation. Our previous work illustrates that geranylgeranyl diphosphate synthase inhibitors (GGSIs) disrupt Rab-mediated protein trafficking in cells, inducing the unfolded protein response pathway and apoptosis. Structure-function studies of our GGSIs, which are isoprenoid triazole bisphosphonates, have revealed a complex relationship between GGSI structure and enzymatic, cellular, and in vivo activities.

Neurotoxicity and Rare Adverse Events in BCMA-Directed CAR T Cell Therapy: A Comprehensive Analysis of Real-World FAERS Data.

Chimeric antigen receptor T (CAR T) cell therapies have emerged as a valuable treatment modality for patients with plasma cell disorders. As the population of patients receiving CAR T therapies grows, the identification and management of associated rare toxicities become increasingly crucial. This study aims to identify safety signals associated with commercial anti-B-cell maturation antigen (BCMA) CAR T therapies using the Food and Drug Administration Adverse Event Reporting System (FAERS).

Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma.

Interferon alfa has activity against multiple myeloma (MM). Modakafusp alfa is an immunocytokine comprising 2 attenuated interferon alfa-2b molecules and an anti-CD38 immunoglobulin G4 antibody, targeting delivery of interferon alfa to CD38-expressing (CD38+) immune and myeloma cells. This phase 1/2 trial enrolled patients with relapsed/refractory multiple myeloma with ≥3 prior lines of treatment and refractory to, or intolerant of, ≥1 proteasome inhibitor and ≥1 immunomodulatory drug.

Development and Validation of an LC-MS/MS Assay for the Quantitation of MO-OH-Nap Tropolone in Mouse Plasma: Application to In Vitro and In Vivo Pharmacokinetic Studies.

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of MO-OH-Nap tropolone (MO-OH-Nap) in mouse plasma. MO-OH-Nap is an α-substituted tropolone with anti-proliferative properties in various cancer cell lines. Detection and separation of analytes was achieved on an ACE Excel C18 (1.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]).

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]).

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy.

Post hoc analysis of daratumumab plus lenalidomide, bortezomib and dexamethasone in Black patients from final data of the GRIFFIN study.

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events.

α-Amino bisphosphonate triazoles serve as GGDPS inhibitors.

Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and in vivo activities.

Longitudinal changes in cognitive and physical function and health-related quality of life in older adults with acute myeloid leukemia.

Introduction: Many older adults with acute myeloid leukemia (AML) do not receive chemotherapy because of physicians' and patients' concern for toxicities and functional decline. This highlights the critical and urgent need to generate knowledge of functional changes following new treatments.

Materials And Methods: As a part of a pragmatic single-center trial, 59 older adults ≥60 years with AML completed geriatric assessment and health-related quality of life measures before treatment and at one month and three months after chemotherapy initiation.

Investigation of the activity of a novel tropolone in osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types.

Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy.

Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential.

Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.

Background: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.

Methods: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA.

Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future.

Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States.

Ciltacabtagene autoleucel for the treatment of multiple myeloma.

While treatment options for multiple myeloma (MM) are continuing to expand, this disease remains one characterized by requiring multiple lines of therapy, with generally decreasing effectiveness of each subsequent line. The development of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has proven an exception to this rule. In the trial that led to approval of the BCMA CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) by the U.

A plain language summary of daratumumab plus lenalidomide/bortezomib/dexamethasone in transplant-eligible Black patients with newly diagnosed multiple myeloma in the GRIFFIN study.

What Is This Summary About?: This is a summary of a publication about Black participants of the GRIFFIN clinical study that was published in in April 2022. The GRIFFIN clinical study looked at the treatment combination of daratumumab plus a standard therapy for multiple myeloma (called RVd therapy, which stands for lenalidomide, bortezomib, and dexamethasone) in adult patients who had not been treated before for multiple myeloma and so were considered to have newly diagnosed multiply myeloma. Multiple myeloma is a blood cancer of plasma cells.