Myeloma Research Articles

Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed / refractory multiple myeloma.

Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors (PIs). Here, analysis of RNA sequencing data derived from 672 patients with newly diagnosed or relapsed/refractory disease identified the acid ceramidase, ASAH1, as a key regulator of PI resistance. Genetic or pharmacological blockade of ASAH1 remarkably restored PI sensitivity and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity thus facilitating the increased expression and activity of the pro-survival proteins, MCL-1, and BCL-2. We corroborated these findings in human MM datasets, and in ex vivo patient MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM (RRMM).

Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

Bone-independent extramedullary disease is associated with inferior overall survival in multiple myeloma patients: a single center, real-world experience.

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Targeting Caveolin-1 in Multiple Myeloma Cells Enhances Chemotherapy and Natural Killer Cell-Mediated Immunotherapy.

The cell membrane transport capacity and surface targets of multiple myeloma (MM) cells heavily influence chemotherapy and immunotherapy. Here, it is found that caveolin-1 (CAV1), a primary component of membrane lipid rafts and caveolae, is highly expressed in MM cells and is associated with MM progression and drug resistance. CAV1 knockdown decreases MM cell adhesion to stromal cells and attenuates cell adhesion-mediated drug resistance to bortezomib. CAV1 inhibition in MM cells enhances natural killer cell-mediated cytotoxicity through increasing CXCL10, SLAMF7, and CD112. CAV1 suppression reduces mitochondrial membrane potential, increases reactive oxygen species, and inhibits autophagosome-lysosome fusion, resulting in the disruption of redox homeostasis. Additionally, CAV1 knockdown enhances glutamine addiction by increasing ASCT2 and LAT1 and dysregulates glutathione metabolism. As a result of CAV1 inhibition, MM cells are more sensitive to starvation, glutamine depletion, and glutamine transporter inhibition, and grow more slowly in vivo in a mouse model treated with bortezomib. The observation that CAV1 inhibition modulated by 6-mercaptopurine, daidzin, and statins enhances the efficacy of bortezomib in vitro and in vivo highlights the translational significance of these FDA-approved drugs in improving MM outcomes. These data demonstrate that CAV1 serves as a potent therapeutic target for enhancing chemotherapy and immunotherapy for MM.

Trajectory, interactions, and predictors of higher symptom burden during induction therapy for multiple myeloma

BackgroundPatients with multiple myeloma (MM) experience disabling symptoms that are difficult to manage and may persist after induction therapy. Monitoring disease-related and induction therapy–induced symptoms and identifying patients at greater risk for high symptom burden are unmet clinical needs. The objective of this study was to examine the trajectories of symptom severity over time and identify predictors of high symptom burden during MM induction therapy.MethodologyEligible patients with MM rated their symptoms by completing the MD Anderson Symptom Inventory MM module repeatedly during 16 weeks of induction therapy. Group-based trajectory modeling identified patient groups with persistently high-severity (versus low-severity) symptom trajectories over time. Quality of life (QOL) and affective and physical functioning status were assessed. Predictors of high symptom burden were examined by regression analysis.ResultsSixty-four MM patients participated. Most patients (89%) received bortezomib-based therapy. The five most-severe symptom trajectory groups were pain (59%), muscle weakness (46%), numbness (42%), disturbed sleep (41%), and fatigue (31%). Patients in the high-severity trajectory group for the five most-severe symptoms (31% of the sample) were more likely to have high-severity cognitive and affective symptoms. Patients in the high-severity trajectory groups for fatigue, muscle weakness, disturbed sleep, and bone aches were more likely to have high pain scores (all p < 0.05). Significant increases over time were observed in scores for pain (estimate: 0.026), numbness (0.051), muscle weakness (0.020), physical items (0.028), and affective items (0.014) (all p < 0.05). A higher baseline composite score of the five most-severe symptoms predicted worse QOL (− 6.24), and poor affective (0.80) and physical (1.10) statuses (all p < 0.01). Female sex predicted higher risk for being in the high-severity trajectory group for muscle weakness.ConclusionAlmost one-third of MM patients suffer from up to 5 moderate to severe symptoms persistently, including pain, muscle weakness, numbness, disturbed sleep, and fatigue. Importantly, these results identify a group of symptoms that should be monitored and managed as part of routine patient care during MM induction therapy and suggest that pre-therapy pain management is necessary for better symptom control.

Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.

Multiple myeloma (MM) is an incurable blood malignancy characterized by the clonal expansion of plasma cells and the secretion of monoclonal immunoglobulins. High-risk MM, defined by specific cytogenetic abnormalities, poses significant therapeutic challenges and is associated with inferior survival outcomes compared to standard-risk disease. Although molecularly targeted therapies have shown efficacy in other hematologic malignancies, currently venetoclax is the only targeted therapy approved for MM (t(11;14)). However, chromosome 1q gains, amplifications, and 1p deletions are frequently observed in MM, and have been linked to drug resistance and poor patient prognosis. Accordingly, this review focuses on emerging MM precision therapies capable of targeting dysregulated genes within these regions. It addresses gene therapies, small molecule inhibitors and monoclonal antibodies currently under investigation to antagonize oncogenic drivers including MCL-1, BCL9, F11R, and CKS1B, all of which are implicated in cell survival, proliferation or drug resistance. In conclusion, the link between chromosome 1 abnormalities and high-risk disease in MM patients offers a compelling rationale to identify and explore therapeutic targeting of chromosome 1 gene products as a novel precision medicine approach for a poorly served patient population.

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

Interferon-alpha has activity against multiple myeloma. Modakafusp alfa is an immunocytokine comprising two attenuated interferon-alpha2b molecules and an anti-CD38 IgG4 antibody, targeting delivery of interferon-alpha to CD38+ immune and myeloma cells. This phase I/II trial (NCT03215030) 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. During dose escalation, modakafusp alfa was administered at ten doses in four schedules across 13 cohorts. The primary endpoint was safety for dose escalation, and overall response rate for dose expansion. We enrolled 106 patients who had received a median of 6.5 lines of prior therapy; 84% of patients had myeloma previously refractory to an anti-CD38 antibody. The most feasible dosing schedule was every 4 weeks (Q4W), at which the maximum tolerated dose was 3 mg/kg. Among 30 patients treated at 1.5 mg/kg Q4W, the overall response rate was 43.3%, with a median duration of response of 15.1 months (95% CI, 7.1-26.1); median progression-free survival was 5.7 months (95% CI, 1.2-14.0). Grade ≥3 adverse events occurred in 28 (93.3%) patients, the most common were neutropenia (66.7%) and thrombocytopenia (46.7%); infections were reported in 8 (26.7%) patients (including grade 3 in 4 [16.7%]). Modakafusp alfa therapy induced upregulation of the type I interferon gene signature score, increased CD38 receptor density in CD38+ cells, and innate and adaptive immune cell activation. Modakafusp alfa resulted in anti-tumor activity and immune activation in patients with multiple myeloma. Adverse events were primarily hematologic.

Minimal Residual Disease as an Early Endpoint for Accelerated Drug Approval in Myeloma: A Roadmap.

Improvements in multiple myeloma (MM) treatments have extended patient survival to a decade or more. Treatment response rates >90% have introduced new challenges for drug development, including a need for early endpoints with greater sensitivity. The FDA, based on data from two academic research groups and industry, evaluated minimal residual disease (MRD) negativity as an intermediate endpoint for progression-free and overall survival, culminating in a unanimous vote by the Oncology Drugs Advisory Committee in April 2024 supporting MRD-negative complete response as an early endpoint reasonably likely to predict clinical benefit in MM that may be used to support accelerated approval.

Phase I Trial of MCARH109, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma: An Updated Analysis.

MCARH109 is a first-in-class G protein-coupled receptor, class C, group 5, member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma. This phase I clinical trial included 17 patients and determined that MCARH109 is safe at a maximum tolerated dose of 150 × 106 CAR T cells. In this updated analysis, no new serious adverse events were reported at a median follow-up of 37 months. Overall, 12 (71%) of 17 patients responded, including seven (70%) of 10 patients previously treated with B-cell maturation antigen-targeted therapy. The median duration of response was 8.6 months (95% CI, 5.7 to not reached [NR]) with two patients sustaining a stringent complete response at the time of last follow-up, 32 months and 41 months, respectively. The median overall survival (OS) was NR and the 3-year OS estimate was 59% (95% CI, 40 to 88). Possible GPRC5D loss via immunohistochemistry was observed in 6 (60%) of 10 patients at relapse. High-dimensional spectral cytometry-based immune profiling associated an activated T-cell phenotype at apheresis with a response to MCARH109.

The Role of CD-19 Targeting Chimeric Antigen Receptor (CAR) T-cell Therapy in Non-Hodgkin Lymphoma

Chimeric Antigen Receptor (CAR) T-cell therapy has improved outcomes in multiple hematological malignancies, such as multiple myeloma and non-Hodgkin lymphoma. CD-19 targeting CAR T-cells have improved outcomes in both aggressive and indolent types of non-Hodgkin lymphoma. Four CAR T-cell products have been approved by the United States (U.S.) Food and Drug Administration (FDA) for the management of non-Hodgkin lymphoma. This article reviews the currently available commercial CAR T-cells products' role in managing diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. We summarize pivotal clinical trials and real-world data on their efficacy and safety.

Doxorubicin synergizes bortezomib-induced multiple myeloma cell death by inhibiting aggresome formation and augmenting endoplasmic reticulum/Golgi stress and apoptosis

BackgroundBortezomib is a standard treatment for multiple myeloma (MM), working by the accumulation of toxic misfolded proteins in cancer cells. However, a significant clinical challenge arises from the development of resistance to bortezomib in MM treatment. Aggresome, a subcellular structure enclosed within Vimentin, forms in response to proteasome inhibitors and sequesters misfolded proteins that are transported by histone deacetylase 6 (HDAC6) and Dynein for degradation via autophagy, thereby reducing bortezomib’s cytotoxic effects. Therefore, in this study, we screened several anticancer agents to identify those that could synergize with bortezomib to enhance cell death and block aggresome formation in the MM cell line U266B1.MethodsTo enhance bortezomib’s efficacy, we screened a range of anticancer compounds for their potential to promote cell death and inhibit aggresome formation in U266B1 MM cells. We utilized the trypan blue exclusion assay and immunofluorescence for evaluation, and explored the underlying mechanisms through Western blot analysis.ResultsDoxorubicin enhanced bortezomib-induced cytotoxicity while inhibiting aggresome formation. Mechanistic studies revealed that doxorubicin downregulated key aggresome components, including Vimentin, HDAC6, and Dynein, leading to accumulation of misfolded proteins and augmentation of proapoptotic and necroptotic pathways by intensifying endoplasmic reticulum (ER) and Golgi stress responses. Notably, doxorubicin did not enhance cell death triggered by proteasome inhibitors that do not induce aggresome formation. Furthermore, the combination of bortezomib and doxorubicin failed to produce synergy in the killing of MM cell lines that lacked aggresome-forming ability.ConclusionsDoxorubicin enhances bortezomib-induced cell death in MM by inhibiting aggresome formation and amplifying ER/Golgi stress and apoptosis. This study highlights the potential therapeutic benefits of combining bortezomib with doxorubicin for MM treatment.Graphical

Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. We therefore studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28 day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide was on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. The trial completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80) and the median number of prior lines was 3 (range 1-9); 25% had high risk FISH. Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%). Best ORR was 56.3% and median PFS was 10 months. In patients with 1 prior line of therapy, ORR was 73.7% and median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

CAR T-cell therapy to treat multiple myeloma: current state and future directions.

Chimeric antigen receptor (CAR) T-cell therapy represents a transformative advancement in treating relapsed or refractory multiple myeloma (MM) in both early- and late-line settings. MM, a plasma cell malignancy, traditionally requires ongoing complex drug regimens, posing significant burdens on patients. In contrast, CAR T-cell therapy offers a one-time treatment option without the need for continuous maintenance therapy. CAR T-cell therapy leverages engineered T-cells to target specific antigens on tumor cells, leading to their elimination. Current approved therapies target B-cell maturation antigen (BCMA); new targets are under investigation, such as G-protein-coupled receptor class C group 5 member D (GPRC5D). Despite its efficacy, CAR T-cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS), necessitating careful management. The review will provide an overview of the design and manufacturing of CAR T-cells and current FDA indications, as well as challenges and future directions of CAR-T therapy for MM treatment.

The Undetermined Significance of Screening for Monoclonal Gammopathy of Undetermined Significance

AbstractThe identification of premalignant lesions in solid tumors such as colorectal and cervical cancer has led to the development of highly effective population-wide screening programs for these malignancies. Although precursor clinical states are not well-established for most hematologic malignancies, multiple myeloma is a notable exception. Virtually all patients with multiple myeloma first develop monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic but easily detectable condition. However, broad screening for MGUS has not been adopted primarily because there is no proven intervention to delay or prevent the progression of MGUS to multiple myeloma. Furthermore, the incidence of MGUS is poorly understood; a better understanding of its epidemiology will be critical in designing appropriate screening guidelines once an effective treatment has been developed. In the current issue of Cancer Epidemiology, Biomarkers &amp; Prevention, Ji and colleagues provide important epidemiologic insights on MGUS, including a critical discussion on how its incidence and preclinical duration vary by age and race, acknowledging that both MGUS and multiple myeloma are more common in Black than White populations.See related article by Ji et al., p. 1690

Guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)

Multiple myeloma (MM), an incurable clonal plasma cell dysplasia, is the second most common hematological malignancy in many countries, mainly developing in the elderly population. With the emergence of novel agents and laboratory methods, the diagnosis and treatment of MM have been significantly improved. In this version of the "Guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)", several examination items have been updated in the diagnostic section; the definition of ultra high-risk MM has been proposed in the risk stratification section; for patients with equal or more than second-line relapse, chimeric antigen receptor T cell therapy and a bispecific T-cell engager have been added; and the treatment recommendations have been listed at different levels based on the best available evidence.

Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma.

Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.

Advances for treatment of relapsed or refractory multiple myeloma: interpretation of guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)

Advances for treatment of relapsed or refractory multiple myeloma: interpretation of guidelines for the diagnosis and management of multiple myeloma in China (2024 revision)

Anti-Tumor Activity of Indole: A Review

: Generally, heterocyclic compounds are included in a large class of pharmacologically active compounds. The indole scaffold in this category is widely distributed in nature and present in many active compounds, especially anti-cancer agents. Due to its unique physicochemical and biological properties, the indole platform has been considered a favorable scaffold in anti-cancer drug design and development. Various indole compounds (synthetic, semisynthetic, and natural) show remarkable anti-proliferative activity. According to the recent literature, this review describes the role of indole scaffolds as anti-cancer agents. Indole was reported to induce anti-tumor activity through multiple mechanisms, for example, Epidermal Growth Factor Receptors (EGFR), histone deacetylase (HDAC), kinase, DNA-topoisomerases, and tubulin inhibition. The current review focuses on some indole compounds with amazing effects against different types of cancers as there are too many FDA-approved drugs, for example, osimertinib, alectinib, and anlotinib in NSCLC treatment, panobinostat in multiple myeloma, midostaurin in acute myeloid leukemia treatment, etc. Moreover, several compounds are still in clinical trials to treat different cancer types. Additionally, there are some oxindole derivatives with potent inhibition against different types of tumors, such as ovarian cancer, colorectal cancer, and prostate cancer. Different series of oxindoles are promising and recommended for further studies due to their remarkable inhibition of tumor cells. Accordingly, the collection of data on a pharmacologically significant motif might aid researchers in further employing indoles in developing novel anti-cancer drugs with potentially fewer side effects and higher potency against this rapidly spreading disease.

Severe Immune Effector Cell-Associated Neurotoxicity Syndrome in a Patient With Multiple Myeloma Treated With Elranatamab

Severe Immune Effector Cell-Associated Neurotoxicity Syndrome in a Patient With Multiple Myeloma Treated With Elranatamab

Does immunohistochemical staining predict mobilization success in multiple myeloma patients?

BackgroundSo many risk factors for mobilization failure have been described so far. We aimed to identify the risk factors and search the possible effects of bone marrow fibrosis (BMF), CD56, c-myc, and cyclinD1 expression on mobilization. MethodsWe evaluated 189 patients with MM who were admitted for stem cell mobilization before autologous stem cell transplantation (ASCT) between 2015 and June 2021. Clinical, laboratory, treatment features, and survival outcomes were compared in patients who were successfully mobilized and who were not. ResultsMobilization failure rate was 11.1% (21) in our study group. Male gender, mobilization with only G-CSF, history of previous ASCT, lenalidomide exposure, and 2 lines of chemotherapy before stem cell mobilization were observed more commonly in mobilization failure group. There is no relationship between mobilization failure and BMF, CD56, c-myc, and cyclin D1 expression status in patients who received either only G-CSF or G-CSF+ chemotherapy for mobilization. Overall survival (OS) was not different in groups of patients who were successfully mobilized and who were not. Neutrophil engraftment was faster in patients who were transfused > 5 × 106/kg stem cells (p=0.015). ECOG performance status (p=0.004), c-myc expression (p=0.005), lenalidomide therapy before mobilization (p=0.032), and mobilization with G-CSF+chemotherapy was found to be predictive factors for OS. ConclusionEven though we could not find any predictive value of CD56, c-myc, and cyclin D1 expression on mobilization, c-myc was found to be associated with low OS. Further studies with large and homogenous study population would be more informative.