Treatment Of Multiple Myeloma Research Articles

Identification of potential immune-related mechanisms related to the development of multiple myeloma.

Although significant advances have been made in the treatment of multiple myeloma (MM), leading to unprecedented response and survival rates among patients, the majority eventually relapse, and a cure remains elusive. This situation is closely related to an incomplete understanding of the immune microenvironment, especially monocytes/macrophages in patients with treatment-naïve MM. The aim of this study was to provide insight into the immune microenvironment, especially monocytes/macrophages, in patients with treatment-naïve MM. This study used the single-cell RNA sequencing (scRNA-seq) data of both patients with MM and heathy donors to identify immune cells, including natural killer (NK) cells, T cells, dendritic cells (DCs), and monocytes/macrophages. Transcriptomic data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM patients. A significant difference was observed between the bone marrow (BM) immune cells of the healthy controls and treatment-naïve MM patients through scRNA-seq. It is noteworthy that, through an scRNA-seq data analysis, this study found that interferon (IFN)-induced NK/T cells, terminally differentiated effector memory (TEMRA) cells, T-helper cells characterized by expression of IFN-stimulated genes (ISG + Th cells), IFN-responding exhausted T cells, mannose receptor C-type 1 (MRC1) + DCs, IFN-responding DCs, MHCII + DCs, and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve MM. Significantly, transcriptomic data of monocytes/macrophages demonstrated that "don't eat me"-related genes and IFN-induced genes increase in treatment-naïve MM patients. Furthermore, scRNA-seq, transcriptomic data, and flow cytometry also showed an increased proportion of CD16 + monocytes/macrophages and expression level of CD16. Cell-cell communication analysis indicated that monocytes/macrophages, whose related important signaling pathways include migration inhibitory factor (MIF) and interleukin 16 (IL-16) signaling pathway, are key players in treatment-naïve MM patients. Our findings provide a comprehensive and in-depth molecular characterization of BM immune cell census in MM patients, especially for monocytes/macrophages. Targeting macrophages may be a novel treatment strategy for patients with MM.

Acute hypoxic respiratory failure due to Lenalidomide-induced interstitial pneumonitis in a patient with multiple myeloma

BackgroundPatients with multiple myeloma are immunosuppressed due to both the disease itself and immunosuppressive therapies. Thus, when presenting with respiratory failure and pulmonary opacities, pneumonia must be considered. However, while rare, immunomodulating medications used in the treatment of multiple myeloma can also cause potentially life-threatening respiratory failure, a distinction which has important treatment implications.Case presentationAn 80-year-old male with recently diagnosed multiple myeloma undergoing treatment with lenalidomide and daratumumab presented with acute, rapidly progressive hypoxic respiratory failure ultimately requiring intubation and mechanical ventilatory support. Imaging revealed bilateral pulmonary opacities, however infectious workup was negative, and he was ultimately diagnosed with lenalidomide-induced interstitial pneumonitis, a rare but serious adverse effect of this medication. He was treated with drug discontinuation and methylprednisolone, and quickly recovered.ConclusionLenalidomide is an immunomodulating medication used in the treatment of multiple myeloma, and is associated with rare but serious cases of drug-induced interstitial pneumonitis. Thus, if a patient receiving lenalidomide develops shortness of breath and/or hypoxia, drug-induced pneumonitis must be on the differential. Permanent drug discontinuation with or without corticosteroids is the mainstay of treatment, and patients are often able to fully recover, underscoring the need for early recognition of this condition.

Predictive model of the efficiency of hematopoietic stem cell collection in patients with multiple myeloma and lymphoma based on multiple peripheral blood markers.

Autologous hematopoietic stem cell transplantation (ASCT) has gained extensive application in the treatment of lymphoma and multiple myeloma (MM). Plenty of studies demonstrate that peripheral blood indicators could be considered potential predictive biomarkers for hematopoietic stem cells (HSCs) collection efficiency, including white blood cell count (WBC), monocyte count (Mono), platelet count (PLT), hematocrit, and hemoglobin levels. Currently, clinically practical predictive models based on these peripheral detection indicators to quickly, conveniently, and accurately predict collection efficiency are lacking. In total, 139 patients with MM and lymphoma undergoing mobilization and collection of ASCT were retrospectively studied. The study endpoint was successful collection of autologous HSCs. We analyzed the effects of clinical characteristics and peripheral blood markers on collection success, and screened variables to establish a prediction model. We determined the optimal cutoff value of peripheral blood markers for predicting successful stem cell collection and the clinical value of a multi-marker prediction approach. We also established a prediction model for collection efficacy. Univariate and multivariate logistic regression analyses showed that the mobilization regimen, Mono, PLT, mononuclear cell count (MNC), and peripheral blood CD34+ cell count (PB CD34+ counts) were significant predictors of successful collection of peripheral blood stem cells (PBSC). Two predictive models were constructed based on the results of multivariate logistic analyses. Model 1 included the mobilization regimen, Mono, PLT, and MNC, whereas Model 2 included the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts. Receiver operating characteristic (ROC) curve analysis showed that the PB CD34+ counts, Model 1, and Model 2 could predict successful HSCs collection, with cutoff values of 26.92 × 106/L, 0.548, and 0.355, respectively. Model 1 could predict successful HSCs collection with a sensitivity of 84.62%, specificity of 75.73%, and area under the curve (AUC) of 0.863. Model 2 could predict successful HSCs collection with a sensitivity of 83.52%, specificity of 94.17%, and AUC of 0.946; thus, it was superior to the PB CD34+ counts alone. Our findings suggest that the combination of the mobilization regimen, Mono, PLT, MNC, and PB CD34+ counts before collection has predictive value for the efficacy of autologous HSCs collection in patients with MM and lymphoma. Using models based on these predictive markers may help to avoid over-collection and improve patient outcomes.

Biomimetic cell membrane decorated ZIF‐8 nanocarriers with IR‐780 and doxorubicin loading for multiple myeloma treatment

AbstractSeveral therapeutic drugs including heptamethine cyanine dye (IR‐780), doxorubicin (DOX), and others have exhibited positive outcomes in the treatment of multiple myeloma (MM). However, curing MM is still hampered by undesired off‐target effects and uncontrolled release of the therapeutics. Herein, we present novel MM‐mimicking nanocarriers by integration of DOX, IR‐780, and MM cell membrane with zeolitic imidazolate framework‐8 (ZIF‐8) nanoparticles (D/INPs@CM) for MM treatment. The nanocarriers were fabricated by co‐loading DOX and IR‐780 into ZIF‐8 and further coated with the cell membrane. After intravenous injection, the D/INPs@CM can enter the bone marrow and target the tumor cells owing to bone marrow homing and homologous targeting properties of the MM cell membrane. Once accumulating in the tumor site, ZIF‐8 decomposed under the acid microenvironment and released the encapsulated DOX and IR‐780. As a result, D/INPs@CM showed the best MM tumor eradication performance compared to D/INPs, without displaying noticeable systemic toxicity. All these features suggest that our biomimetic nanocarriers may have great potential for the precise and targeted therapy of MM and related other hematological malignancies.

Multiple Myeloma: Simulation of Therapy Scenarios Using the Monte Carlo Method

AIM. To develop an information and retrieval system for hematologists which would enable effective decision making in multiple myeloma (MM) treatment through simulation and prediction of response to therapy considering a patient’s clinical profile-related characteristics and based on the analysis of data from public science sources. MATERIALS & METHODS. The analysis included 145 therapeutic options and 56,217 MM patients enrolled in 311 clinical studies, the results of which were published in the medical literature from 2003 to 2024. To simulate therapy scenarios, the Monte Carlo method was used for calculating the probability of achieving very good and even better partial response in patients with different characteristics that define not only their clinical profile but also the chemotherapy variants. RESULTS. This study introduces an interactive online application called М-BОТ (available at oncotriage.ru) enabling to predict response to therapy under certain specified conditions and to visualize the result as real-time ranking of therapeutic options via the user interface. Apart from a patient’s clinical profile-related characteristics underlying MM treatment decision making, it is possible to select trials by their types and numbers of patients enrolled. CONCLUSION. The therapy recommendations resulted from simulation of different MM therapy scenarios with the use of the Monte Carlo method considerably extend the potential for rapid retrieval of reliable science information which would confirm the optimal choice of a therapeutic option in the given clinical setting. In future, this approach can be regarded as a basis for building up a support system in individual and consensus decision making. It will allow for predicting the efficacy of multi-stage MM treatment strategies with several therapy lines and their safety as well.

Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma: an open-label, multicenter, phase 1 study (MMY1010).

Despite recent progress in multiple myeloma (MM) treatments, most patients will relapse and require additional treatment. Intravenous daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown good efficacy in the treatment of MM. A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions. We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab, with a shorter administration time and reduced infusion-related reaction rate in global studies. This phase 1, multicenter study (MMY1010; ClinicalTrials.gov Identifier: NCT04121260) evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line (n = 1) or ≥2 prior lines (n = 20) of therapy, including a proteasome inhibitor and an immunomodulatory drug. Primary endpoints were pharmacokinetics and safety. Mean (standard deviation) maximum trough concentration of daratumumab was 826 (335) μg/mL, which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab. Safety was consistent with safety profiles observed in other daratumumab studies, with no new safety concerns identified. Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies. At a median follow-up of 7.5 months, the overall response rate was 57.1%, with a very good partial response or better rate of 38.1% and complete response or better rate of 19.0%. Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM, potentially impacting clinical administration of daratumumab in this population.

Zevorcabtagene Autoleucel: First Approval.

Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.

Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.

Chalazion associated with proteasome inhibitors approved for multiple myeloma: Analysis of FAERS database.

e23325 Background: Proteasome inhibitors (PI) are a class of drugs used in the treatment of Multiple Myeloma. The FDA has approved three PIs for this indication (Bortezomib, Carfilzomib, and Ixazomib). Various studies, and case reports have described the occurrence of chalazion with Bortezomib use and subsequent discontinuation of therapy but it’s association with other PIs from the class remains poorly understood. Methods: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System database to analyze the strength of association of chalazion with Bortezomib, and with other Proteasome Inhibitors in patients above 18 years of age. We employed disproportionality signal analysis and calculated the reporting odds ratio with a 95% confidence interval. Results: Within the FAERS database, a total of 78,596 adverse events were reported with the use of the three FDA approved PIs in adults, out of which chalazion accounted for 56 cases. Most of the cases were reported with Bortezomib use (54 cases), followed by Carfilzomib (2 cases), and Ixazomib (1 case). In cases with mention of sex, and age, 64.7% were in females, and 35.3% in male patients, whereas 47% patients were within the age group of 18-64, and 53% being above 64 years of age. While most of the cases had non-serious outcomes, death was reported in 2 cases, and hospitalization was needed for 5 cases. Only Bortezomib was associated with a significantly positive signal strength (ROR 32.9, 95% CI 25.1-43.1, Chi-squared Yates 1596.27). Conclusions: The study offers the largest retrospective review of association of chalazion with proteasome inhibitors. It is most strongly associated with Bortezomib use, and females are twice as likely to develop it as compared to males. Elderly patients also seem to be at a slightly higher risk. Overall, chalazion seems to account for only a small number of side effects reported with proteasome inhibitors, and a majority of cases have non-serious outcomes.

Using protein turnover assay to explore the drug mechanism of Carfilzomib.

Carfilzomib (CFZ) is the second-generation proteasome inhibitor that is approved by Food and Drug Administration (FDA) of USA for the treatment of relapsed and refractory multiple myeloma. Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated. Since CFZ primarily functions as a proteasome inhibitor, profiling CFZ-induced changes in protein turnover at the systematic level is sufficient and necessary. In this study, we characterize the effects of CFZ on the stability of 15,000 human proteins using Protein Turnover Assay (ProTA). CFZ affects fundamental cellular glycolysis, nitric oxide production and proteasome subunit homeostasis in multiple myeloma cells. In addition, LY294002 or KU-0063794 has synergistic effects with CFZ in multiple myeloma treatment. A profound understanding of how cells respond to chemotherapeutic agents provides insights into the basic mechanism of drug function and the rationale for CFZ combination therapy.

Hospitalization risk in multiple myeloma episodes of care.

e23101 Background: The Enhancing Oncology Model (EOM) is a total cost of care (TCOC) program that was initiated in July 2023. Participating groups are expected to reduce expenditures while delivering high-quality care. Hospitalization (IP) is an important quality metric and cost driver in TCOC programs such as EOM. Understanding how cancer treatment may impact IP is essential for success. Multiple Myeloma (MM) treatment has transformed with multi-agent treatment as the standard of care (SOC), routinely incorporating 3 or more drugs used concurrently to maximize response. We examined the impact multi-drug treatment had on IP rates in MM patients. Methods: Using Parts A, B and D Medicare claims data from EOM baseline period (January 2019 - June 2022) for 12 participating practices, we extracted a unique count of chemotherapy drugs and IP admissions attributed to 6-month episodes of care. Dexamethasone (dex) was included even if claims were not found. Planned and cancer-surgery related IP were excluded using the Clinical Classifications Software Planned Admission Procedure Categories and per EOM specifications. IPs were dichotomized as Yes/No. A logistic regression model was developed to evaluate the association between the number of unique drugs and the unplanned IP, adjusting for variables: prior chemo, age at episode start, race, and HCC count. A 3-drug regimen was established as the reference (including dex) based on SOC. Results: 11,613 episodes had a primary diagnosis of MM, with at least one IP occurring in 2,382 episodes. The number of episodes (% IP) per drug count group are 1-2: 6636(16.3%); 3: 3772 (23.6%); 4: 863 (30.8%); 5+: 342 (40.9%). Detailed statistics are provided in Table 1. Compared to a 3-drug regimen, 4+ drugs increased the risk of IP, while episodes with 1-2 drugs had a lower risk of IP after adjusting for age, race, HCC count and prior treatment. Conclusions: Our findings can guide the design of care transforming interventions aimed at avoiding unnecessary IP while using guideline concordant SOC treatments for MM, driving TCOC reduction. Identifying patients with a higher likelihood of IP helps practices target patient monitoring programs. To understand why patients with prior treatment had lower IP identifying maintenance following initial treatment and patients receiving 3 or more drugs after failure of prior therapy, are worth exploring further. CMMI Disclaimer: The statements contained in this document are solely those of the authors and do not necessarily reflect the views or policies of CMS. The authors assume responsibility for the accuracy and completeness of the information contained in this document. [Table: see text]

Incidence and prevention of skeletal‐related events in multiple myeloma patients: A population‐based real‐world experience

AbstractNovel treatments in multiple myeloma (MM) could influence the incidence of skeletal‐related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real‐world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow‐up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow‐up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26–33) per 100 person years. 48% experienced > 1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

Unlocking hope: talquetamab in multiple myeloma treatment: a bispecific breakthrough targeting CD3 and GPRC5D

Multiple myeloma (MM) presents a significant global health burden, with disparities in incidence and outcomes reflecting challenges in recognition and treatment. Talquetamab, a bispecific CD3 T-cell engager targeting G-protein coupled receptor family C group 5 member D (GPRC5D), has emerged as a promising immunotherapy for relapsed/refractory MM (RRMM). In August 2023, talquetamab received accelerated approval from the US FDA for RRMM treatment, followed by conditional marketing authorization from the EMA. Clinical trials demonstrated talquetamab's efficacy, with overall response rates (ORR) of 69% and 76% in heavily pretreated RRMM patients. The phase I monumenTAL-1 trial showcased talquetamab's effectiveness, particularly in high-risk MM and extramedullary disease, with ORRs around 71-74%. Subsequent phase 2 results reaffirmed its efficacy, even in patients with prior T-cell redirection therapies. Combination therapy with daratumumab further enhanced talquetamab's efficacy, addressing concerns of T cell exhaustion. Pharmacokinetic studies revealed sustained responses and manageable adverse events with subcutaneous administration, facilitating convenient dosing regimens. However, talquetamab carries risks of cytokine release syndrome (CRS) and neurologic toxicity, necessitating close monitoring and prompt management. Common adverse events included fever, CRS, musculoskeletal pain, and infections, although severe events were infrequent. Vigilant management strategies, including prophylactic measures and supportive care, mitigate these risks. In conclusion, talquetamab represents a significant advancement in RRMM treatment, offering a promising avenue for T-cell redirection therapy. Ongoing research aims to optimize treatment sequencing and combination strategies, fostering improved outcomes for MM patients. Continued investigation will refine the strategic integration of talquetamab and other immunotherapies, paving the way for enhanced treatment efficacy and patient care in RRMM.

ACUTE MYOCARDIAL INFARCTION DURING VRD CHEMOTHERAPY IN A PATIENT WITH MULTIPLE MYELOMA: A CLINICAL CASE

Acute myocardial infarction is a critical condition associated with significant morbidity and mortality rates. Myocardial infarction-related acute myocardial injury is characterized by a rapid elevation and subsequent decline in cardiac troponin concentration. According to the relevant data patients with multiple myeloma are in a high-risk category for venous and arterial thrombosis. Therefore, the incidence of cardiovascular complications, which include myocardial infarction, in these patients is higher than in the general population. The development of metaplastic anemia further compounds this risk by diminishing myocardial oxygen supply. Moreover, chemotherapy for oncohematological diseases carries the potential for cardiotoxic cardiovascular complications. Immunomodulator drugs like Thalidomide and Lenalidomide, frequently utilized in multiple myeloma treatment, have been associated with Lenalidomide-induced myocardial infarction—a prevalent adverse effect. The use of proteasome inhibitors such as Bortezomib and Carfilzomib poses an increased risk for myocardial infarction development. This clinical case presents an instance of acute myocardial infarction in a multiple myeloma patient during low cumulative chemotherapy dosage, comprising Lenalidomide and Bortezomib. It underscores the necessity for enhanced clinical, instrumental, and laboratory monitoring before each specific chemotherapy course in high-risk multiple myeloma patients. Such monitoring facilitates the early detection of chemotherapy-induced cardiotoxic effects, allowing for timely intervention and management.

Personalized Treatment of Multiple Myeloma in Frail Patients.

As the treatment landscape for multiple myeloma (MM) continues to expand at a rapid pace, management of older adults and frail patients becomes increasingly challenging. As these patients have traditionally been underrepresented on clinical trials, there is limited guidance on the optimal approach to frail patients with newly diagnosed multiple myeloma (NDMM) or relapsed and refractory multiple myeloma (RRMM). Frailty is an independent predictor of tolerability and response to antineoplastic treatment. Stringent eligibility criteria have often excluded these patients, but recently some large trials have included frailty sub-analyses to help guide management. In general, triplet regimens are preferred to doublet regimens in this population and enrollment on a clinical trial should be prioritized when possible. In this review, we summarize the MM frailty scoring tools that have been developed to identify and assess this vulnerable population. We present the clinical trials over the past decade that have enrolled frail patients and/or have included subgroup analyses to help elucidate the response and tolerability of different regimens in this underrepresented group. We provide practical advice regarding assessment and management of frail patients NDMM and RRMM.

Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.

Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter. We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

Chinese expert consensus on diagnosis and treatment of high risk multiple myeloma (2024)

High-risk multiple myeloma (HRMM) refers to patients with multiple myeloma whose overall survival time is less than 2-3 years under current standardized diagnosis and treatment. By combining various static and dynamic prognostic factors, risk stratification is performed to identify HRMM patients early and treat patients with personalized strategies, with the aim of significantly improving adverse survival outcomes in HRMM patients. Although the clinical value of HRMM has reached a consensus domestically in recent years, there still exist confusions and ambiguities in the definition, high-risk factors, risk stratification, and treatment of HRMM, necessitating standardization. In order to enhance the diagnostic and treatment capabilities of Chinese physicians in HRMM, the Professional Committee of Hematologic Malignancies of the Chinese Anti-Cancer Association (CACA) and the Multiple Myeloma Expert Committee of the Chinese Society of Clinical Oncology (CSCO) have organized relevant experts to develop this consensus. This consensus aims to clarify the definition of HRMM, high-risk factors, and risk stratification system, and provide treatment recommendations for HRMM, thereby improving the quality of life and prognosis of Chinese HRMM patients.

Cardio-Oncology: A New Discipline in Medicine and Its Relevance to Hematology.

Cardio-oncology, a burgeoning subspecialty, addresses the complex interplay between cardiology and oncology, particularly in light of increased cardiovascular (CV) disease mortality in cancer patients. This review provides a comprehensive overview of cardio-oncology with a focus on the therapies used in hematological malignancies. We explore the bidirectional relationship between heart failure and cancer, emphasizing the need for collaborative care. The review discusses risk stratification, highlighting the importance of baseline CV risk assessment and personalized surveillance regimens. Primary and secondary prevention strategies, including pharmacological interventions, are outlined. The review also delves into the cardiotoxicity associated with hematological cancer therapies, focusing on anthracyclines, Bruton kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, CAR-T cell therapy, immune checkpoint inhibitors, multiple myeloma treatments, and hematopoietic stem cell transplantation. We then highlight the high risk of venous and arterial thromboembolisms in cancer patients and the challenges of anticoagulation management in cardio-oncology. Finally, the review touches on the importance of long-term follow-up and appropriate screening in cancer survivors at high risk of CV morbidity and mortality, based on their CV risk profile and the type and dose of cardiotoxic therapies they received such as anthracyclines or high radiation doses.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

Influence of lithium ion doping and mitoxantrone hydrochloride loading on the structure and in vitro biological properties of mesoporous bioactive glass microspheres in the treatment of multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell hematologic tumor in which bone pain is a typical symptom. The current main treatment methods not only easily cause multidrug resistance but also cause bacterial infections. Therefore, improving multidrug resistance and bacterial infection during MM therapy and repairing bone defects caused by bone pain are necessary. In this work, we propose a drug delivery platform of lithium-doped bioactive glass microspheres (7Li-MBGs) with a mesoporous structure (2–5 nm) and a high specific surface area (636 m2/g) to achieve these functions. Interestingly, lithium ions are network modifier doped into the silicon-oxygen network. This in turn affects the dissolution and release behavior of silicon ions in the MBGs network. Thus, the bioactive response as well as drug release of the MBGs were enhanced. During this process, hydroxyapatite easily forms on the surface, which has a therapeutic effect on bone defects caused by MM. The drug (mitoxantrone hydrochloride, MTO) release mechanism is diffusion-driven, suggesting that drug/platform interactions are key determinants of release kinetics and depend on the release medium environment and platform structure. In vitro antibacterial and cytotoxicity experiments proved that the synergistic effect of Li ions and the MTO improved the antibacterial ability of the MBGs (> 98%) and the ability to treat MM. Therefore, the proposed 7Li-MBGs drug delivery platform can effectively release drugs in the long-term, repair bone defects, inhibit bacterial growth and tumor cell activity, and provide new ideas for the treatment of MM.