Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma.

Introduction: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Patients And Methods: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON).

Proceedings from the Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune and Cellular Therapy in Multiple Myeloma.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma.

Patient perspectives on symptoms, health-related quality of life, and treatment experience associated with relapsed/refractory multiple myeloma.

Purpose: This study aimed to better understand the patient perspective and treatment experience of relapsed and/or refractory multiple myeloma (RRMM).

Methods: This qualitative study enrolled adult RRMM patients from 6 US clinics who had ≥ 3 months of life expectancy, ≤ 6 prior lines of therapy, and ≥ 1 treatment regimen with a proteasome inhibitor and immunomodulator, or a CD38 monoclonal antibody or an alkylating agent, and a steroid. In-person semi-structured qualitative interviews were conducted to capture concepts that were relevant and important to patients.

SUMOylation inhibition enhances multiple myeloma sensitivity to lenalidomide.

Despite the potent effect of lenalidomide (Len) in multiple myeloma (MM) treatment, patients develop Len resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms mediating Len resistance. Our study identified SUMOylation as a potential mechanism regulating Len resistance in MM. Len-resistant MM cell line MMR10R presented much higher SUMO E1 (SAE2) expression and more global SUMOylation than Len-sensitive MM1S cell line.

Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires.

i-Motif formation and spontaneous deletions in human cells.

Concatemers of d(TCCC) that were first detected through their association with deletions at the RACK7 locus, are widespread throughout the human genome. Circular dichroism spectra show that d(GGGA)n sequences form G-quadruplexes when n > 3, while i-motif structures form at d(TCCC)n sequences at neutral pH when n ≥ 7 in vitro. In the PC3 cell line, deletions are observed only when the d(TCCC)n variant is long enough to form significant levels of unresolved i-motif structure at neutral pH.

What Do the Elevated Protein Levels Mean in My Patients with Myeloma, Amyloidosis, and Related Disorders?

Multiple myeloma, light chain amyloidosis, and other plasma cell dyscrasias are characterized, in part, by abnormal production of paraproteins that are often responsible for the sequelae of those diseases. These paraproteins are whole or fragmented immunoglobulins produced by clonal antibody-secreting cells (usually plasma cells, but occasionally, B lymphocytes). Significant heterogeneity exists in the presentation of these diseases, ranging from incidental detection of a monoclonal protein in an asymptomatic patient, to life-threatening manifestations that require urgent diagnostic confirmation and intervention.

SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma.

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM.

MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in -Mutated Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs).

Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma.

Background And Objective: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted.

Methods: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1.

Isatuximab for the treatment of multiple myeloma.

Isatuximab is an IgG1 monoclonal antibody targeting CD38 that has received regulatory approval in combination regimens for patients with relapsed/refractory multiple myeloma. CD38 is an antigen with high surface expression on multiple myeloma cells. While daratumumab holds most of the market share for this drug class, isatuximab offers several unique aspects including a mechanism of action that may involve more direct myeloma-cell inhibition and killing and less reliance on cross-linking and immune effector cells, as well as subgroup data from pivotal trials showing notable efficacy in populations with renal impairment, high-risk cytogenetics and the elderly.

Daratumumab for the treatment of multiple myeloma.

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens.

Targeting SUMOylation in cancer.

Purpose Of Review: In the article, we focus on the role of SUMOylation in tumorigenesis and cancer-related processes, including Epithelial-mesenchymal transition (EMT), metastasis, resistance to cancer therapies, and antitumor immunity. Clinical perspective on small ubiquitin-like modifier (SUMO) inhibitors will be discussed.

Recent Findings: SUMOylation regulates multiple important biologic functions including gene transcription, DNA damage repair, cell cycle, and innate immunity.

The Emerging Role of Extracellular Vesicle-Associated RNAs in the Multiple Myeloma Microenvironment.

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells (PCs) that develop at multiple sites within the bone marrow (BM). MM is treatable but rarely curable because of the frequent emergence of drug resistance and relapse. Increasing evidence indicates that the BM microenvironment plays a major role in supporting MM-PC survival and resistance to therapy.

When and How to Treat Relapsed Multiple Myeloma.

The treatment landscape for relapsed multiple myeloma has expanded considerably in recent years, as numerous agents with new mechanisms of action have been introduced, increasing responses even in advanced disease and prolonging survival. The wealth of novel regimens comes with the challenges of balancing toxicities and aligning a regimen with the biology of the myeloma and the nature of the relapse in conjunction with patient treatment history and personal preference. Herein, we provide an overview of treatment options for both early and late relapsing disease as well as a discussion of the role of emerging immune-based therapies.

Oncolytic herpes simplex virus infects myeloma cells and .

Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM.

Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.

CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma.

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the BM. The BM microenvironment supports survival of the malignant cells and is composed of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects.

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis.

Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown.

Extracellular Vesicles in Hematological Malignancies: From Biomarkers to Therapeutic Tools.

Small extracellular vesicles (EVs) are a heterogenous group of lipid particles released by all cell types in physiological and pathological states. In hematological malignancies, tumor-derived EVs are critical players in mediating intercellular communications through the transfer of genetic materials and proteins between neoplastic cells themselves and to several components of the bone marrow microenvironment, rendering the latter a "stronger" niche supporting cancer cell proliferation, drug resistance, and escape from immune surveillance. In this context, the molecular cargoes of tumor-derived EVs reflect the nature and status of the cells of origin, making them specific therapeutic targets.

Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG.

The role of myeloid-derived suppressor cells in hematologic malignancies.

Purpose Of Review: This article focuses on the immunosuppressive impact of myeloid-derived suppressor cells (MDSCs) and the potential clinical implications in hematological malignancies.

Recent Findings: MDSCs play a critical role in the regulation of the immune response in cancer. They inhibit activation of adaptive immune response and as a result foster the growth of the malignancy.