At the end of every month, the International Myeloma Foundation Newsroom will feature a wrap-up of some of the most fascinating studies about multiple myeloma from medical journals. Here is the December 2023 edition.
The IMF team of medical editors has provided overviews of key studies. Yet, we encourage you to visit the actual articles in the journals for full details and to increase your understanding. Check the IMF Newsroom monthly for updates like this one.
In the Journals (Key Myeloma Research in December 2023)
"Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index."
Source
Óskarsson, J.Þ., Rögnvaldsson, S., Thorsteinsdottir, S. et al. Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index. Blood Cancer J. 13, 177 (2023). https://doi.org/10.1038/s41408-023-00951-2. December 1, 2023.
Overview
In this study, researchers explored a common issue in testing bone marrow samples for plasma cell disorders using multiparameter flow cytometry (MFC). Hemodilution, the dilution of blood in the sample, can affect the accuracy of results. To address this, they used next-generation flow cytometry (NGF) and white blood cell (WBC) count to assess the quality of 351 bone marrow samples from 219 participants in the iStopMM study. They identified specific cell types, like nucleated red blood cells and myeloid precursors, as effective markers for detecting hemodilution. These markers were used to create a novel Bone Marrow Quality Index (BMQI). The BMQI provides a score to evaluate the quality of diagnostic bone marrow samples, offering a useful tool for interpreting results and guiding appropriate actions.
"Cytokine-responsive T- and NK-cells portray SARS-CoV-2 vaccine-responders and infection in multiple myeloma patients."
Source
Enssle, J.C., Campe, J., Moter, A. et al. Cytokine-responsive T- and NK-cells portray SARS-CoV-2 vaccine-responders and infection in multiple myeloma patients. Leukemia (2023). https://doi.org/10.1038/s41375-023-02070-0. December 4, 2023.
Overview
People with multiple myeloma (MM) often get mRNA-based COVID-19 vaccines to lower the risk of severe outcomes. However, the reasons behind varying vaccine responses among MM patients are not clear. We studied immune cells in the blood of 58 MM patients during and after SARS-CoV-2 vaccination and breakthrough infection. Using advanced profiling techniques, we found that those responding well to the vaccine had specific types of immune cells that were highly responsive to key cytokines. Even MM patients with breakthrough infections showed strong immune responses, similar to vaccine responders. Understanding these immune patterns can help design better vaccination strategies for people with weakened immune systems.
"Sample average treatment effect on the treated (SATT) analysis using counterfactual explanation identifies BMT and SARS-CoV-2 vaccination as protective risk factors associated with COVID-19 severity and survival in patients with multiple myeloma."
Source
Mitra, A.K., Mukherjee, U.K., Mazumder, S. et al. Sample average treatment effect on the treated (SATT) analysis using counterfactual explanation identifies BMT and SARS-CoV-2 vaccination as protective risk factors associated with COVID-19 severity and survival in patients with multiple myeloma. Blood Cancer J. 13, 180 (2023). https://doi.org/10.1038/s41408-023-00901-y December 7, 2023
Overview
People with multiple myeloma (MM) often get mRNA-based COVID-19 vaccines to lower the risk of severe outcomes. However, the reasons behind varying vaccine responses among MM patients are not clear. We studied immune cells in the blood of 58 MM patients during and after SARS-CoV-2 vaccination and breakthrough infection. Using advanced profiling techniques, we found that those responding well to the vaccine had specific types of immune cells that were highly responsive to key cytokines. Even MM patients with breakthrough infections showed strong immune responses, similar to vaccine responders. Understanding these immune patterns can help design better vaccination strategies for people with weakened immune systems.
"Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients."
Source
Mai, E.K., Hielscher, T., Bertsch, U. et al. Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients. Leukemia (2023). https://doi.org/10.1038/s41375-023-02105-6. December 7, 2023
Overview
This study focused on understanding the challenges faced by patients with newly diagnosed multiple myeloma (NDMM) during their initial treatment, known as induction therapy (IT). The goal was to identify and predict severe infections and deaths during this critical phase. Analyzing data from 3,700 transplant-eligible NDMM patients treated between 2005 and 2020, the researchers developed a predictive risk score based on four key risk factors: low platelet count, advanced disease stage, higher WHO performance status, and older age. The risk score categorized patients into low, intermediate, and high-risk groups, helping predict the likelihood of severe infection or death. This user-friendly score was validated across multiple trials, making it a valuable tool for identifying NDMM patients at risk during induction therapies..
"Real-world data on outcomes of anti-CD38 antibody-treated, including triple class refractory patients with multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database."
Source
Visram, A., De La Torre, A., White, D. et al. Real-world data on outcomes of anti-CD38 antibody-treated, including triple class refractory patients with multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database. Blood Cancer J. 13, 181 (2023). December 8, 2023. https://doi.org/10.1038/s41408-023-00946-z
Overview
Despite the availability of new treatments, multiple myeloma (MM) is still not curable. In this study, researchers looked at real-world outcomes of patients with MM who were resistant to anti-CD38 monoclonal antibody (mAb) therapy and were then treated with standard-of-care (SoC) regimens. They specifically focused on patients with triple class refractory (TCR) disease, meaning resistance to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb. Among 663 patients who progressed on anti-CD38 mAb therapy, 346 received SoC regimens. The median progression-free survival (PFS) and overall survival (OS) from the start of subsequent therapy were 4.6 months and 13.3 months, respectively. For patients with TCR disease, the outcomes were even more challenging, with a median PFS of 4.4 months and OS of 10.5 months. The study emphasizes the urgent need for more effective treatments for patients with relapsed MM, particularly those with TCR disease.
"BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma."
Source
Dutta, D., Liu, J., Wen, K. et al. BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma. Blood Cancer J. 13, 184 (2023). https://doi.org/10.1038/s41408-023-00955-y December 11, 2023.
Overview
In this study, researchers explored a new approach to improve the effectiveness of bortezomib (BTZ), a common treatment for multiple myeloma (MM). Despite being a standard-of-care, BTZ has limitations due to side effects and the development of resistance over time. To address these issues, the scientists developed nanoparticles (BCMA-BTZ-NPs) that encapsulate BTZ and are coated with BCMA antibodies to enhance target specificity.
The researchers confirmed that the BCMA-BTZ-NPs efficiently entered MM cells expressing BCMA, a specific marker for MM, while not affecting BCMA-knockout cells. The BCMA-BTZ-NPs demonstrated targeted toxicity against MM cells, both in laboratory cell lines and primary tumor cells from MM patients. The nanoparticles entered cells through a receptor-mediated process, avoiding a resistance mechanism associated with upregulating P-glycoprotein.
Moreover, BCMA-BTZ-NPs induced cell death more effectively than non-targeted nanoparticles or free BTZ, triggering mitochondrial depolarization and apoptosis. In cells resistant to BTZ, BCMA-BTZ-NPs inhibited proteasome activity better than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs promoted immunogenic cell death and activated the autophagic pathway more than free BTZ.
In a mouse model, BCMA-BTZ-NPs selectively accumulated at the tumor site, leading to enhanced tumor reduction and prolonged survival in the host. These findings suggest that BCMA-BTZ-NPs could be a promising therapeutic strategy to improve the efficacy of BTZ and warrant further evaluation in clinical settings.
"Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study."
Source
Pérez-Escurza, O., Flores-Montero, J., Óskarsson, J.Þ. et al. Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study. Blood Cancer J. 13, 182 (2023). https://doi.org/10.1038/s41408-023-00944-1. December 11, 2023.
Overview
In this research, scientists explored a method to improve the early detection of monoclonal gammopathy of undetermined significance (MGUS), the earliest stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Detecting MGUS early can be challenging due to low-level infiltration, often undetectable with standard methods. The study used a highly sensitive technique called next-generation flow cytometry (NGF) to analyze bone marrow and blood samples from individuals in the iSTOPMM program.
The researchers examined 164 paired samples from 82 subjects, including 55 with MGUS, 12 with smoldering mulitple myeloma (SMM), and 8 with smoldering Waldenström's macroglobulinemia (SWM). Clonal plasma cells (cPC) were found in 84% of bone marrow samples, and clonal B-lymphocytes (cB-lymphocytes) in 45%, with both coexisting in 39% of cases. The unique features of cPC and/or cB-lymphocytes allowed for a more precise classification of the disease in 29% of patients, including 35% of MGUS cases, 8% of SMM cases, and 25% of SWM cases.
NGF proved to be valuable in providing informative results from blood samples in 49% of cases where bone marrow was positive. This study demonstrates the usefulness of NGF in improving the accuracy of diagnosing early-stage MGUS, offering a potential advancement in the early identification and classification of these conditions.
"Daratumumab, Bortezomib, Lenalidomide and Dexamethasone for Multiple Myeloma."
Source
Sonneveld P, et al. Daratumumab, Bortezomib, Lenalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2023. doi:10.1056/NEJMoa2312054. December 12, 2023.
Overview
In this study, researchers investigated the effectiveness of adding subcutaneous daratumumab, a monoclonal antibody targeting CD38, to the standard treatment regimen (VRd) for newly diagnosed multiple myeloma in patients eligible for transplantation. The trial included 709 patients, randomly assigning them to either the D-VRd group (receiving subcutaneous daratumumab in addition to VRd and lenalidomide maintenance therapy) or the VRd group (receiving only VRd and lenalidomide maintenance therapy).
After a median follow-up of 47.5 months, the D-VRd group showed a lower risk of disease progression or death compared to the VRd group. Specifically, 84.3% of patients in the D-VRd group had progression-free survival at 48 months, compared to 67.7% in the VRd group. The percentage of patients achieving a complete response or better was significantly higher in the D-VRd group (87.9% vs. 70.1%), as was the percentage of patients with minimal residual disease (MRD)-negative status (75.2% vs. 47.5%).
While both groups experienced grade 3 or 4 adverse events, the most common were neutropenia and thrombocytopenia. Serious adverse events occurred in 57.0% of the D-VRd group and 49.3% of the VRd group. In conclusion, the addition of subcutaneous daratumumab to the treatment regimen demonstrated a significant benefit in terms of progression-free survival for transplantation-eligible patients with newly diagnosed multiple myeloma. This study was funded by the European Myeloma Network in collaboration with Janssen Research and Development. (ClinicalTrials.gov number: NCT03710603, EudraCT number: 2018-002992-16).
"Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers."
Source
Olli Dufva, Sara Gandolfi, Jani Huuhtanen, Olga Dashevsky, Hanna Duàn, et al. Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers. Immunity, 2023. DOI:https://doi.org/10.1016/j.immuni.2023.11.008. December 12, 2023.
Overview
Highlights:
- "Tumor-Natural Killer (NK) cell interaction triggers transcriptional states dictated by tumor features
- CRISPR and PRISM screens reveal cancer subtype-specific NK cell evasion mechanisms
- NK resistance genes include SELPLG, SPN, MUC1, FUT8, and GMDS
- Single-cell CRISPR screens identify MHC-I, IFN-γ, and NF-κB regulation as mechanisms"
"Addressing the disparities: the approach to the African American patient with multiple myeloma."
Source
Bhutani, M., Blue, B.J., Cole, C. Mikhael, J., et al. "Addressing the disparities: the approach to the African American patient with multiple myeloma." Blood Cancer J. 13, 189 (2023)https://doi.org/10.1038/s41408-023-00961-0
Overview
African American patients with multiple myeloma face significant challenges, including differences in how often the disease occurs, delays in diagnosis, limited access to treatment, lower participation in clinical trials, and unequal use of healthcare services, all of which lead to poorer outcomes. This review, conducted by a team of experts dedicated to addressing health disparities in multiple myeloma, sheds light on these inequalities.
The disparities arise from various factors, including historical, sociocultural, individual, and disease-related characteristics. Healthcare providers play a crucial role in improving these issues by being aware of these factors and tailoring their care accordingly. The review provides an overview of disparities at both biological and non-biological levels, identifies barriers to clinical care, and suggests best practices. The goal is to ensure that African American patients with multiple myeloma receive the best possible care, addressing the unique challenges they may face.
"Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma."
Source
Munawar, U., Zhou, X., Prommersberger, S. et al. Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma. Commun Biol 6, 1299 (2023). https://doi.org/10.1038/s42003-023-05683-4
Overview
The way we treat multiple myeloma is changing, moving from traditional drugs to newer immunotherapies. These include monoclonal antibodies, immunoconjugates, T-cell engaging antibodies, and CART cells, leading to better response rates. However, some patients still experience relapses, and we don't fully understand why.
This study focuses on a potential reason for resistance to T-cell mediated immunotherapies in multiple myeloma. The researchers found that a mechanism called "impaired death receptor signaling" might be responsible. This means that the signals telling cancer cells to die when targeted by the immune system may not work properly in some cases.
The study suggests that this resistance seems specific to newer immunotherapies, while traditional treatments still work in the laboratory setting. To support this idea, the researchers present a clinical case confirming that a particular pathway, the FADD/BID axis, is crucial for effective responses to these newer immunotherapies.
In summary, this research identifies impaired death receptor signaling as a potential reason why T-cell mediated immunotherapies might not work well in some cases of multiple myeloma, highlighting the need to understand these resistance mechanisms for better treatment outcomes.
"What happens to regulatory T cells in multiple myeloma."
Source
Chen, H., Wang, X., Wang, Y. et al. What happens to regulatory T cells in multiple myeloma. Cell Death Discov. 9, 468 (2023). https://doi.org/10.1038/s41420-023-01765-8. December 21, 2023.
Overview
In multiple myeloma, an abnormal environment around the tumor and the ability of cancer cells to evade the immune system are linked to regulatory T cells (Tregs). Tregs are crucial for maintaining self-tolerance and controlling the overall immune response against infections or tumors. In patients with multiple myeloma, there are irregularities in the number, function, and distribution of Tregs. These irregularities may be linked to the stage of the disease, the level of risk, and the prognosis of patients.
During treatment, Tregs respond differently to various treatment plans, impacting how well multiple myeloma responds to therapy. Monitoring changes in Tregs could also help predict the effectiveness of treatment. The review also explores the potential use of Tregs in treating multiple myeloma.
In conclusion, understanding the role of Tregs in multiple myeloma is essential for improving treatments. There is still much to learn about how Tregs function and their application in managing this disease