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 August 2024 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 August 2024) 

"Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients"

Source

Eleftheria Kampouri, Elizabeth M. Krantz, Hu Xie, Sarah S. Ibrahimi, Erika S. Kiem, Mandeep K. Sekhon, Emily C. Liang, Andrew J. Cowan, Andrew Portuguese, Damian J. Green, Aya Albittar, Jennifer J. Huang, Jordan Gauthier, Ailyn C. Pérez-Osorio, Keith R. Jerome, Danielle M. Zerr, Michael J. Boeckh, Joshua A. Hill; Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients. Blood 2024; 144 (5): 490–495. doi: https://doi.org/10.1182/blood.2024024145  August 1, 2024 

Overview

After CAR T-cell therapy (CARTx), reactivation of Human herpesvirus 6B (HHV-6B) is becoming more recognized, but it's not common. Diagnosing HHV-6B encephalitis is tough because its symptoms can overlap with other conditions. In a study, only 6% of patients showed signs of HHV-6B reactivation, but the virus levels were low and didn't need treatment. Another review found that among hundreds of patients, only a small number had the virus, and symptoms usually got better without treatment. Overall, HHV-6B reactivation after CARTx is rare, so routine monitoring isn't necessary.

 

 

"Human herpesvirus 6 and CAR T-cell toxicity"

Source

Karl S. Peggs; Human herpesvirus 6 and CAR T-cell toxicity. Blood 2024; 144 (5): 465–466. doi: https://doi.org/10.1182/blood.2024024973  August 1, 2024 

Overview

A new study by Kampouri et al. looked at how often Human herpesvirus 6B (HHV-6B) reactivates in patients after CAR T-cell therapy. They monitored 89 patients closely for 12 weeks and reviewed data from 626 other patients. The study found that HHV-6B reactivation and related diseases are rare in this setting, with only 6% showing signs of reactivation, and even fewer developing encephalitis. The virus levels were low and didn’t require treatment. Because of this, the researchers concluded that regular monitoring for HHV-6B after CAR T-cell therapy isn’t necessary.

CAR T-cell therapy can weaken the immune system, making infections a concern, especially viral ones like HHV-6B. However, the study suggests that the risk of HHV-6B reactivation is much lower compared to other treatments like stem cell transplants. This finding is important for doctors managing patients after CAR T-cell therapy, as it helps guide decisions on monitoring and treatment. While the study doesn't answer all questions, it provides valuable insights, especially as more people receive CAR T-cell therapy.

 

 

"Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation"

Source

Elina Alaterre, Sara Ovejero, Caroline Bret, Laure Dutrieux, Dassou Sika, Raul Fernandez Perez, Marion Espéli, Thierry Fest, Michel Cogné, José Ignacio Martin-Subero, Pierre Milpied, Giacomo Cavalli, Jérôme Moreaux; Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation. Blood 2024; 144 (5): 496–509. doi: https://doi.org/10.1182/blood.2023023237  August 1, 2024  

Overview

Plasma cells (PCs) are the final stage of B-cell development, playing a key role in the immune system. Scientists have been able to replicate the process of PC development in the lab, allowing them to study the changes that occur as B-cells transform into plasma cells. However, understanding the early steps of this transformation, especially the genetic and epigenetic changes, has been challenging.

To tackle this, researchers used advanced techniques, including single-cell RNA sequencing (scRNA-seq) and scATAC-seq, to study individual cells during their transition into plasma cells. They discovered that early stages of this process, known as the preplasmablastic and plasmablastic stages, are quite varied among cells. By analyzing both the gene activity and the accessibility of DNA regions, they identified important transcription factors, particularly from the AP-1 family, that seem to play key roles in driving these early changes.

The study also found that some cells had already begun the epigenetic changes needed to become fully mature plasma cells, showing early commitment to this path. These findings provide valuable insights into how plasma cells develop and offer a resource for further research on the molecular mechanisms behind this process.

 

 

"Plasma cells’ fate: it is a complex 'orchestra' "

Source

Paola Neri; Plasma cells’ fate: it is a complex “orchestra”. Blood 2024; 144 (5): 466–467. doi: https://doi.org/10.1182/blood.2024025016 August 1, 2024 

Overview

Alaterre et al. studied how B cells transform into plasma cells (PCs), which are crucial for immune protection. Using advanced single-cell techniques, they uncovered complex genetic and epigenetic changes that occur early in this transformation. These changes determine whether a B cell will become a plasma cell and prepare it for its future role in fighting infections.

When B cells recognize a foreign invader, they multiply and move to specific areas in the body to get activated. Some become short-lived cells that produce low-affinity antibodies, while others return to continue developing and eventually become long-lived plasma cells that settle in the bone marrow.

The transition from B cells to plasma cells is controlled by a network of transcription factors (TFs). These TFs turn on plasma cell-specific genes while turning off B cell-specific ones. Alaterre et al. found that the early stages of this process are more diverse than previously thought, with different cells showing different patterns of gene activation. They identified key TFs, particularly from the AP-1 family, that play crucial roles in guiding these changes.

Interestingly, some cells at an early stage of development were already committed to becoming plasma cells. These cells activated specific pathways, like mTORC1, that help prepare them for their role in producing antibodies. 

This research provides valuable insights into the early steps of plasma cell development, which could help in optimizing immune responses and understanding diseases related to plasma cells.

 

 

"Prognostic value of the “dynamic” R2-ISS in patients with multiple myeloma undergoing anti-CD38 antibody-based triplet therapies"

Source

Kikuchi T, Oda Y, Kondo U, et al. Prognostic value of the “dynamic” R2-ISS in patients with multiple myeloma undergoing anti-CD38 antibody-based triplet therapies. Hematol Oncol. 2024;e3302. https://doi.org/10.1002/hon.3302  August 3, 2024 

Overview

A study looked at how well the second revision of the international staging system (R2-ISS) predicts outcomes in multiple myeloma (MM) patients who start treatment with anti-CD38 antibody-based therapies. Researchers re-evaluated patients' staging at the start of treatment, calling it "dynamic R2-ISS." Data from 150 patients showed that dynamic R2-ISS was effective in predicting both progression-free survival (PFS) and overall survival (OS). Patients with the highest risk level (R2-ISS IV) had very poor outcomes, with a median PFS of just 3.3 months and OS of 11.7 months. This staging method may offer better prognostic insights for MM patients receiving these treatments.

 

 

"Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database"

Source

Binod Dhakal, Hermann Einsele, Jordan M Schecter, William Deraedt, Nikoletta Lendvai, Ana Slaughter, Carolina Lonardi, Sandhya Nair, Jianming He, Akshay Kharat, Patricia Cost, Satish Valluri, Kwee L. Yong; Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database. Blood Adv 2024; bloodadvances.2024012640. doi: https://doi.org/10.1182/bloodadvances.2024012640  August 7, 2024 

Overview

Key Points from the Study:

• "Real-world patients with lenalidomide-refractory multiple myeloma and 13 prior lines of therapy progress rapidly through therapies." 
• "Outcomes remain suboptimal, despite greater use of newer combination therapies, highlighting the need for early use of novel treatments." 

 

 

"Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma"

Source

Mateo Mejia Saldarriaga, Darren Pan, Caitlin Unkenholz, Tarek H. Mouhieddine, Juan Esteban Velez-Hernandez, Katherine Engles, Joshua A. Fein, Jorge Monge, Cara Rosenbaum, Roger Pearse, David Jayabalan, Christian Gordillo, Hei Ton Chan, Samuel Yamshon, Santiago Thibaud, Markus Mapara, Giorgio Inghirami, Suzanne Lentzsch, Ran Reshef, Adriana Rossi, Samir Parekh, Sundar Jagannath, Shambavi Richard, Ruben Niesvizky, Mark Bustoros; Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Blood Adv 2024; 8 (15): 3859–3869. doi: https://doi.org/10.1182/bloodadvances.2023012470  August 13, 2024  

Overview

This study explored how the number of lymphocytes (a type of white blood cell) in the first 15 days after receiving CAR-T therapy affects outcomes for patients with relapsed multiple myeloma (MM). Researchers focused on patients treated with BCMA-targeting CAR-T therapies, which are becoming essential for relapsed/refractory MM.

The study found that patients with higher maximum lymphocyte counts (ALC) after treatment had better outcomes, including longer progression-free survival (PFS) and a stronger response to treatment. Specifically, patients with an ALC above 1.0 × 10³/μL had a much longer PFS (30.5 months) compared to those with lower counts. Those with ALC at or below 0.5 × 10³/μL were at higher risk of early disease progression.

The study suggests that ALC can be a simple and effective marker to predict how well patients will respond to CAR-T therapy. This is the first time ALC has been linked to clinical outcomes in this way for patients with relapsed/refractory MM.

 

 

"Halting multiple myeloma with MALT1 inhibition: suppressing BCMA-induced NF-κB and inducing immunogenic cell death"

Source

Yao Yao, Mei Yuan, Min Shi, Wenyu Li, Yuqian Sha, Yan Zhang, Canli Yuan, Jianping Luo, Zhenyu Li, Chengcheng Liao, Kailin Xu, Mingshan Niu; Halting multiple myeloma with MALT1 inhibition: suppressing BCMA-induced NF-κB and inducing immunogenic cell death. Blood Adv 2024; 8 (15): 4003–4016. doi: https://doi.org/10.1182/bloodadvances.2023012394  August 13, 2024 

Overview

This study explored a new potential target for treating multiple myeloma (MM). Researchers focused on a protein called MALT1, which had not been extensively studied in MM before. They found that MALT1 levels were higher in MM cells and that patients with elevated MALT1 had a poorer prognosis.

When researchers blocked MALT1, either by genetic methods or using a drug called Mi-2, they observed reduced cancer cell growth and tumor development. The drug worked by triggering a specific type of cell death that involves the mitochondria and also disrupted key signaling pathways that help MM cells survive. Notably, inhibiting MALT1 interfered with the NF-κB pathway, which is crucial for MM cell survival.

Moreover, the study found that the MALT1 inhibitor Mi-2 promoted a type of cell death that activates the immune system, making cancer cells more vulnerable to attack by immune cells. This suggests that targeting MALT1 could be an effective strategy for treating MM, offering new hope for patients.

 

"Inference of genomic lesions from single-cell RNA-seq in myeloma improves functional intraclonal and interclonal analysis"

Source

Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Giancarlo Castellano, Alfredo Marchetti, Sonia Fabris, Stefania Pioggia, Ilaria Silvestris, Domenica Ronchetti, Silvia Lonati, Giuseppina Fabbiano, Valentina Traini, Elisa Taiana, Laura Porretti, Federico Colombo, Claudio De Magistris, Margherita Scopetti, Marzia Barbieri, Loredana Pettine, Federica Torricelli, Antonino Neri, Francesco Passamonti, Marta Lionetti, Matteo Claudio Da Vià, Niccolò Bolli; Inference of genomic lesions from single-cell RNA-seq in myeloma improves functional intraclonal and interclonal analysis. Blood Adv 2024; 8 (15): 3972–3984. doi: https://doi.org/10.1182/bloodadvances.2023012409  August 13, 2024 

Overview

This study focused on smoldering multiple myeloma (SMM). Researchers aimed to better understand the genetic changes in these cells by using advanced techniques, including single-cell RNA sequencing (scRNA-seq) and B-cell receptor sequencing.

They analyzed over 20,000 bone marrow PCs from five patients with SMM or MM. By combining different methods, they were able to identify specific genetic changes, such as chromosomal translocations and hyperdiploidy, at the single-cell level. This helped them distinguish between different subtypes of PCs, including clonal (cancerous) and polyclonal (non-cancerous) cells.

The study also showed that integrating transcriptomic data with information about copy number abnormalities (CNA) improved the understanding of how different subclones of PCs function. For example, they identified a subclone in SMM that had unique properties related to light-chain production, and they explored different cell subtypes in a patient with both Wäldenstrom macroglobulinemia and SMM.

Overall, this research provided a new approach to analyzing the genetic and functional landscape of PCs in SMM and MM, which could help in better understanding and treating these conditions.

 

"Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies"

Source

Shuhui Deng, Sanika Derebail, Vera Joy Weiler, Jessica Fong Ng, Elena Maroto-Martin, Madhumouli Chatterjee, Giulia Giorgetti, Chandraditya Chakraborty, Poonam Kalhotra, Ting Du, Yao Yao, Rao Prabhala, Masood Shammas, Annamaria Gulla, Anil Aktas Samur, Mehmet Kemal Samur, Lugui Qiu, Kenneth C. Anderson, Mariateresa Fulciniti, Nikhil C. Munshi; Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies. Blood Adv 2024; 8 (15): 4025–4034. doi: https://doi.org/10.1182/bloodadvances.2023012298  August 13, 2024 

Overview

This study focused on venetoclax, a personalized medicine for multiple myeloma (MM) that has shown significant effectiveness, especially in patients with the t(11;14) translocation. Although venetoclax has been successful in many cases, some patients eventually develop resistance to the drug, leading to relapse.

The researchers aimed to understand how MM cells become resistant to venetoclax. They developed venetoclax-resistant MM cell lines with the t(11;14) translocation and studied the changes that occurred in these cells. They found that resistance was linked to decreased mitochondrial activity and changes in BCL-2 family proteins, which made the cells less responsive to standard MM treatments.

However, the study also discovered that these resistant cells remained sensitive to certain immunotherapies. This finding suggests that patients who develop resistance to venetoclax might still benefit from immunotherapy, emphasizing the importance of carefully planning the sequence of treatments in MM therapy.

 

"Health-related quality of life in patients with hematologic malignancies treated with chimeric antigen receptor T-cell therapy: review and current progress"

Source

Tchernonog E, Moignet A, Anota A, Bernard S, Bouguet G, Colin F, Rioufol C, Ysebaert L, Gyan E. Health-related quality of life in patients with hematologic malignancies treated with chimeric antigen receptor T-cell therapy: review and current progress. Haematologica 2024;109(8):2401-2419; https://doi.org/10.3324/haematol.2022.282363. Vol. 109 No. 8 (2024): August, 2024 

Overview

Chimeric antigen receptor (CAR) T-cell therapy has significantly improved treatment for patients with relapsed or refractory B-cell cancers, with six therapies now approved for use. Although this treatment shows promising results, it can also cause severe side effects, such as cytokine release syndrome and neurotoxicity. Most clinical trials report these side effects but often overlook their impact on patients' overall quality of life (HRQoL).

To address this, researchers conducted a review to investigate how CAR T-cell therapy affects patients' physical and emotional well-being. They found that while trials commonly evaluate the effectiveness of CAR T-cell therapy, they rarely collect data on how the therapy influences patients' daily lives and overall satisfaction. Understanding these effects is crucial, as patients receiving CAR T-cell therapy may encounter significant challenges and have high expectations for a tolerable treatment experience.

The review assessed various HRQoL tools used in clinical trials and real-world studies up to June 2023 to better understand their role. It highlights the need for standardized methods to evaluate quality of life, which could enhance patient care, manage costs, and facilitate better comparisons between different studies.

 

 

"Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible"

Source

Engelhardt M, Kortüm KM, Goldschmidt H, Merz M. Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible. Haematologica 2024;109(8):2420-2435; https://doi.org/10.3324/haematol.2023.283058. Vol. 109 No. 8 (2024): August, 2024 

Overview

Multiple myeloma (MM) is a complex cancer with varying survival rates, ranging from months to many years. While a complete cure is still out of reach for most, achieving durable remission and long-term disease control is possible. This review highlights how new developments in diagnostics and treatment are making significant progress toward this goal.

Recent advances include improved diagnostic tools and criteria, like SLiM-CRAB and measurable residual disease (MRD) assessment, as well as whole-genome and single-cell sequencing. These tools help in earlier detection, better risk assessment, and more personalized treatment by analyzing genetic changes and disease characteristics. Whole-genome sequencing can also reveal key mutations and resistance patterns to therapies.

For newly diagnosed MM patients who are eligible for a stem cell transplant, standard treatment often includes a combination of a CD38 antibody, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone, possibly followed by stem cell transplantation and lenalidomide maintenance. For patients not eligible for transplants, incorporating a CD38 antibody has shown promising results with sustained MRD negativity.

Ongoing clinical trials are exploring the role of advanced therapies like chimeric antigen receptor (CAR) T-cell therapy and bi-specific antibodies in treating MM. These trials aim to determine whether these therapies could replace stem cell transplants or offer a potential cure.

The concept of a "functional cure" is becoming an important goal in MM treatment, meaning effective long-term disease control with minimal ongoing therapy. Achieving this would not only improve patient quality of life but also reduce healthcare costs and resource use. Curing MM would lessen the treatment burden on healthcare systems and patients, allowing resources to be allocated to other needs and improving overall patient outcomes.

 

 

"Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible"

Source

Engelhardt M, Kortüm KM, Goldschmidt H, Merz M. Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible. Haematologica 2024;109(8):2420-2435; https://doi.org/10.3324/haematol.2023.283058. Vol. 109 No. 8 (2024): August, 2024 

Overview

Multiple myeloma (MM) is a complex cancer with varying survival rates, ranging from months to many years. While a complete cure is still out of reach for most, achieving durable remission and long-term disease control is possible. This review highlights how new developments in diagnostics and treatment are making significant progress toward this goal.

Recent advances include improved diagnostic tools and criteria, like SLiM-CRAB and measurable residual disease (MRD) assessment, as well as whole-genome and single-cell sequencing. These tools help in earlier detection, better risk assessment, and more personalized treatment by analyzing genetic changes and disease characteristics. Whole-genome sequencing can also reveal key mutations and resistance patterns to therapies.

For newly diagnosed MM patients who are eligible for a stem cell transplant, standard treatment often includes a combination of a CD38 antibody, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone, possibly followed by stem cell transplantation and lenalidomide maintenance. For patients not eligible for transplants, incorporating a CD38 antibody has shown promising results with sustained MRD negativity.

Ongoing clinical trials are exploring the role of advanced therapies like chimeric antigen receptor (CAR) T-cell therapy and bi-specific antibodies in treating MM. These trials aim to determine whether these therapies could replace stem cell transplants or offer a potential cure.

The concept of a "functional cure" is becoming an important goal in MM treatment, meaning effective long-term disease control with minimal ongoing therapy. Achieving this would not only improve patient quality of life but also reduce healthcare costs and resource use. Curing MM would lessen the treatment burden on healthcare systems and patients, allowing resources to be allocated to other needs and improving overall patient outcomes.

 

 

"Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone"

Source

Ramasamy K, Bahlis NJ, Kumar SK, Kumar A, Cranmer H, Wang B, Dabora J, Labotka R, Richardson PG, Moreau P. Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone. Haematologica 2024;109(8):2585-2593; https://doi.org/10.3324/haematol.2023.283713.Vol. 109 No. 8 (2024): August, 2024 

Overview

The TOURMALINE-MM1 study is one of the few recent randomized trials focusing on patients with relapsed or refractory multiple myeloma (RRMM) who have had at least one previous treatment. This study compared two treatment combinations: ixazomib, lenalidomide, and dexamethasone (IRd) versus lenalidomide and dexamethasone (Rd). 

The final results were based on an average follow-up of 85 months. In studies with RRMM patients who have had multiple relapses, many go on to receive additional therapies. This can make it challenging to interpret overall survival (OS) data.

To address this, the study used advanced statistical methods to adjust for the effects of these additional therapies. When not adjusting for subsequent treatments, the hazard ratio (HR) for IRd compared to Rd was 0.94, meaning there was no significant difference in survival between the two treatments. However, after adjusting for the impact of additional therapies, the HR improved to 0.89, suggesting that IRd might be more effective.

For patients who had already received two or more lines of therapy, IRd showed a more substantial benefit. The HR was 0.52 to 0.68, indicating a stronger survival advantage for IRd compared to Rd.

These findings underline the complexity of measuring treatment benefits in multiple myeloma and the need to account for the impact of additional therapies when evaluating overall survival.

 

 

"Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: part 1 results of a phase I/II study"

Source

Terpos E, Gavriatopoulou M, Ntanasis-Stathopoulos I, Malandrakis P, Fotiou D, Migkou M, Theodorakakou F, Spiliopoulou V, Kostopoulos IV, Syrigou R-E, Eleutherakis-Papaiakovou E, Gkolfinopoulos S, Tsitsilonis OE, Kastritis E, Dimopoulos MA. Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: part 1 results of a phase I/II study. Haematologica 2024;109(8):2594-2605; https://doi.org/10.3324/haematol.2023.284347. Vol. 109 No. 8 (2024): August, 2024  

Overview

A recent study looked at combining belantamab mafodotin (belamaf) with lenalidomide and dexamethasone (belamaf-Rd) for treating newly diagnosed multiple myeloma in older patients who are not eligible for a stem cell transplant. Thirty-six patients, with an average age of 72.5 years, received belamaf at three different doses (2.5, 1.9, or 1.4 mg/kg) every 8 weeks. Due to side effects, the treatment schedule was extended to every 12 weeks.

The most common severe side effects included fatigue, rash, diarrhea, and COVID-19. Ocular issues were also noted, with varying rates of serious eye problems depending on the dose. Despite these issues, the overall effectiveness was high, with 83.3% of patients achieving a very good partial response and 52.8% achieving a complete response or better. There were no reports of disease progression over an average follow-up of 20.3 months, although six patients stopped treatment due to infections, including COVID-19 and pneumonia.

Based on the balance between effectiveness and side effects, the recommended dose for further study is 1.9 mg/kg every 8 weeks, extended to every 12 weeks to reduce eye-related side effects. Overall, belamaf-Rd showed significant clinical activity and a reduction in vision-related problems in this older patient group.

 

 

"A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma"

Source

Sabol HM, Ashby C, Adhikari M, Anloague A, Kaur J, Khan S, Choudhury SR, Schinke C, Palmieri M, Barnes CL, Ambrogini E, Nookaew I, Delgado-Calle J. A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma. Haematologica 2024;109(8):2606-2618; https://doi.org/10.3324/haematol.2023.284443. Vol. 109 No. 8 (2024): August, 2024 

Overview

Multiple myeloma (MM) remains difficult to cure because the disease often relapses and becomes resistant to treatment. Researchers have found that a protein called NOTCH3 is more active in MM cells from newly diagnosed and relapsed patients compared to healthy individuals. High levels of NOTCH3 in these cells are linked to poorer responses to a common drug used in MM treatment, bortezomib (BOR). 

Cells in the tumor environment, like osteocytes (bone cells), can increase NOTCH3 levels in MM cells, making them more resistant to BOR. This NOTCH3 activation also leads to increased levels of a molecule called CXCL12, which further protects MM cells from the effects of BOR by activating a specific signaling pathway.

When scientists blocked CXCL12 in MM cells with high NOTCH3 levels, these cells became more sensitive to BOR treatment in laboratory tests and in bone models. This research highlights a new pathway involving NOTCH3 and CXCL12 that helps MM cells survive treatment and suggests that targeting this pathway could improve treatment outcomes for patients with MM.

 

 

"Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation"

Source

Garderet L, Gras L, Koster L, de Wreede L, Montserrat R, Vincent L, Fenk R, Karunanithi K, Deeren D, Kaufmann M, Kuball J, Ozdogu H, Cascon MJP, Passweg J, Rye A, Salmenniemi U, Snowden J, Hansen CT, Leleu X, Gastaud L, Sokolowska JD, Raj K, Beksac M, Schönland S, Hayden P, McLornan D. Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2024;109(8):2619-2627; https://doi.org/10.3324/haematol.2023.284520. Vol. 109 No. 8 (2024): August, 2024 

Overview

Autologous stem cell transplantation (ASCT) is a treatment option for patients with light chain deposition disease (LCDD), but there isn't much data on its long-term effectiveness. A study of 51 LCDD patients from a European registry who received ASCT between 1995 and 2021 provides new insights. 

Before the transplant, patients had severe kidney issues, with 45% needing dialysis. The study found that ASCT improved patients' responses to treatment significantly, with a rise from 41% to 66% in those achieving a very good partial response or better within 100 days after the transplant. Kidney function showed some improvement in the first three months, but no further changes were seen in the following months. Importantly, none of the patients who were not dependent on dialysis before the transplant required it afterward.

With a median follow-up of 84 months, the overall survival rate was 88% after six years. Progression-free survival was 44%. The risk of disease relapse was 17% within two years, and the risk of death from causes other than the disease was low at 2%. About 27% of patients needed a kidney transplant within four years of ASCT, typically done between 6 and 53 months after the stem cell transplant.

Overall, ASCT is a viable and effective treatment for LCDD patients, even those who were on dialysis at the time of the transplant, with favorable long-term survival and low non-relapse mortality rates.

.

 

 

"Non-myeloma light chain cast nephropathy: a multicenter retrospective study on clinicopathological characteristics"

Source

Martins AC, Gibier J-B, Ronsin C, Kandel-Aznar C, Moreau A, Chapal M, Francisco D, Sakhi H, Oniszczuk J, Gueguen L, Grunenwald A, Devaux M, Karras A, Royal V, Rabant M, Gnemmi V, Olagne J, Van Huyen J-PD, Isnard P. Non-myeloma light chain cast nephropathy: a multicenter retrospective study on clinicopathological characteristics. Haematologica 2024;109(8):2721-2725; https://doi.org/10.3324/haematol.2024.285031. Vol. 109 No. 8 (2024): August, 2024 

Overview

Kidney damage is a serious issue for patients with multiple myeloma (MM), and light chain cast nephropathy (LCCN) is a major complication linked to poor outcomes. LCCN happens when monoclonal light chains from the blood form casts in the kidneys, leading to kidney problems. While kidney involvement in other B-cell cancers is less common, it can still occur.

A recent study looked at 23 patients with non-MM B-cell cancers who developed LCCN to understand how it compares to MM-related LCCN. The study involved patients from five hospitals, and their kidney biopsies were analyzed by two pathologists.

The study found that in non-MM LCCN, patients had similar kidney issues to those with MM. Most patients experienced severe kidney injury, with many needing dialysis. However, the levels of light chains in the blood were lower in non-MM cases compared to MM cases. LCCN in non-MM patients can occur either at the same time as the cancer diagnosis or several years later, which means ongoing kidney monitoring is important for these patients.

Overall, the study highlights the need for regular kidney function checks in patients with B-cell cancers, even if they are not initially diagnosed with LCCN. It also stresses the importance for pathologists to look for kidney casts in these patients, as they might be missed if not specifically looked for.

 

 

"Deciphering the genetics and mechanisms of predisposition to multiple myeloma"

Source

Went, M., Duran-Lozano, L., Halldorsson, G.H. et al. Deciphering the genetics and mechanisms of predisposition to multiple myeloma. Nat Commun 15, 6644 (2024). https://doi.org/10.1038/s41467-024-50932-7  August 5, 2024 

Overview

Multiple myeloma (MM) affects plasma cells, and while it is not curable, researchers are studying its genetic links. A large study involving nearly 11,000 MM patients and over 360,000 healthy controls found 35 genetic locations related to MM risk, including 12 that were previously unknown.

The study revealed two key genetic mechanisms for inherited MM risk:

1. Longer Telomeres: Telomeres are protective caps on the ends of chromosomes, and longer telomeres were linked to a higher risk of MM.
2. Higher Levels of BCMA and IL5RA: These are proteins associated with immune system function. The genetic variant rs34562254-A increases the levels of BCMA and IL5RA, which is linked to a higher risk of developing MM.

The study also found that a specific genetic change in the TNFRSF13B gene affects MM risk by boosting B-cell responses. This is different from loss-of-function variants in the same gene, which can lead to B-cell immunodeficiency.

Overall, this research improves our understanding of the genetic factors that contribute to MM and highlights important biological pathways involved in the disease.

 

 

"Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence"

Source

Martinez-Lopez, J., Lopez-Muñoz, N., Chari, A. et al. Measurable residual disease (MRD) dynamics in multiple myeloma and the influence of clonal diversity analyzed by artificial intelligence. Blood Cancer J. 14, 131 (2024). https://doi.org/10.1038/s41408-024-01102-x  August 7, 2024 

Overview

Assessing minimal residual disease (MRD) in multiple myeloma (MM) patients can help predict survival. At the University of California, San Francisco, researchers looked at MRD using next-generation sequencing (NGS) of immunoglobulin genes for 482 MM patients diagnosed between 2008 and 2020.

The study found:

• In Newly Diagnosed Patients: 119 out of 304 achieved MRD negativity at a very low level (10−6) at least once. These patients had a longer progression-free survival (PFS) compared to those who remained MRD positive.
• In Relapsed Patient: 64 out of 178 reached MRD negativity at 10−6. They also experienced a longer PFS compared to those who were MRD positive.

The researchers categorized MRD dynamics into three groups using artificial intelligence:

1. Group A:  Patients with consistently MRD negative samples.
2. Group B: Patients with declining but still detectable MRD.
3. Group C: Patients with either increasing or stable MRD.

Groups A and B had significantly longer PFS than Group C. Additionally, patients who were MRD positive but had not yet relapsed had more clonal diversity compared to those who had relapsed.

This study showed that MRD assessment combined with clonal diversity analysis can help predict disease progression and guide treatment decisions in MM patients.

 

 

"Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in the MajesTEC-1 study"

Source

Diana Cortes-Selva, Tatiana Perova, Sheri Skerget, Deeksha Vishwamitra, Sarah Stein, Rengasamy Boominathan, Onsay Lau, Karl Calara-Nielsen, Cuc Davis, Jaymala Patel, Arnob Banerjee, Tara Stephenson, Clarissa Uhlar, Rachel Kobos, Jenna Goldberg, Lixia Pei, Danielle Trancucci, Suzette Girgis, Shun Xin Wang Lin, Liviawati S. Wu, Philippe Moreau, Saad Z. Usmani, Nizar J. Bahlis, Niels W. C. J. van de Donk, Raluca I. Verona; Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in the MajesTEC-1 study. Blood 2024; 144 (6): 615–628. doi: https://doi.org/10.1182/blood.2023022823  August 8, 2024 

Overview

Teclistamab is a type of therapy for multiple myeloma that helps activate T-cells to attack cancer cells. A study looked at how well this treatment works based on patients' immune systems and tumor characteristics. They analyzed 165 patients from the MajesTEC-1 study who were treated with 1.5 mg/kg of teclistamab.

The study found that patients with higher levels of T-cells in their blood before treatment had better outcomes. Responders had fewer regulatory T cells (which can suppress immune activity) and lower levels of certain molecules that inhibit T-cell function. These patients also had a T-cell profile that indicated a stronger ability to attack cancer cells. Interestingly, the level of BCMA on cancer cells did not affect how well teclistamab worked.

Patients who responded well to teclistamab had healthier immune systems, while nonresponders showed signs of immune suppression and T-cell dysfunction. This highlights the role of a patient's immune profile in predicting how well they will respond to this treatment.

 

 

"Immunotherapy: the teclistamab fitness test"

Source

Liliana E. Lucca; Immunotherapy: the teclistamab fitness test. Blood 2024; 144 (6): 591–592. doi: https://doi.org/10.1182/blood.2024025046  August 8, 2024 

Overview

In an article in the journal Blood, researchers examine how the immune system impacts the effectiveness of teclistamab, a new treatment for multiple myeloma (MM). Teclistamab is a bispecific antibody that helps T-cells target and kill MM cells. 

The study analyzed 165 MM patients from the MajesTEC-1 trial. They found that patients who responded well to teclistamab had higher levels of T-cells, especially CD8 T-cells, and fewer regulatory T-cells (which suppress the immune response). Responders also had more naïve T-cells and fewer exhausted T-cells.

Interestingly, the level of BCMA on cancer cells did not affect how well teclistamab worked. Instead, higher levels of soluble BCMA (sBCMA) were linked to poorer responses. 

The study suggests that assessing immune system characteristics, such as the number and type of T-cells, could help predict which patients will benefit from teclistamab. However, finding reliable biomarkers is challenging, and more research is needed to confirm these findings and improve patient selection.

 

 

"Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma"

Source

Xiong, S., Zhou, J., Tan, T.K. et al. Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma. Nat Commun 15, 6810 (2024). https://doi.org/10.1038/s41467-024-50910-z  August 9, 2024 

Overview

Multiple myeloma starts in plasma cells, which are a kind of immune cell that makes antibodies. Researchers have been exploring how changes in the DNA's structure might help myeloma cells grow and resist treatment.

In this study, scientists created a detailed map of "super-enhancers" in myeloma cells. Super-enhancers are regions of DNA that control the activity of genes involved in cancer. They found that myeloma cells often gain new super-enhancers that turn on a gene called PPP1R15B. This gene helps control a protein complex that affects cell growth and survival.

When PPP1R15B is turned off, it triggers a pathway that causes myeloma cells to die, slows down protein production, and reduces the production of antibodies. Using a drug called Raphin1 to inhibit PPP1R15B makes another myeloma drug, bortezomib, work even better.

This research shows that targeting PPP1R15B could be a promising new approach to treat multiple myeloma by disrupting the balance of proteins in these cancer cells.

 

 

"Progression-free survival as a surrogate endpoint in myeloma clinical trials: an evolving paradigm"

Source

Pawlyn, C., Schjesvold, F.H., Cairns, D.A. et al. Progression-free survival as a surrogate endpoint in myeloma clinical trials: an evolving paradigm. Blood Cancer J. 14, 134 (2024). https://doi.org/10.1038/s41408-024-01109-4  August 12, 2024 

Overview

In the treatment of multiple myeloma, overall survival (OS) has traditionally been used to measure the effectiveness of new therapies. However, as treatments improve and patients live longer, using OS alone to evaluate new drugs can delay approvals. Instead, the Food and Drug Administration (FDA) and European Medicines Agency have started using other measures, like progression-free survival (PFS) and minimal residual disease (MRD), to make quicker decisions about new treatments.

This review highlights the need to carefully interpret PFS as a measure of treatment benefit, especially for different patient groups. It also discusses the importance of designing studies to understand any differences between PFS and OS. The review emphasizes the value of analyzing subgroups of patients to better identify who might benefit most from new treatments.

 

 

"A roadmap towards improving outcomes in multiple myeloma"

Source

Mohty, M., Facon, T., Malard, F. et al. A roadmap towards improving outcomes in multiple myeloma. Blood Cancer J. 14, 135 (2024). https://doi.org/10.1038/s41408-024-01115-6  August 12, 2024 

Overview

Most multiple myeloma (MM) patients eventually relapse or stop responding to current treatments. While new therapies like bispecific monoclonal antibodies and CAR-T cell therapy offer hope for better outcomes, there are important non-treatment factors that need to be addressed to improve patient results in the future.

This review highlights several key issues:

• Gathering real-world evidence about treatment effectiveness.
• Better defining frailty and assessing disease risk dynamically.
• Identifying high-risk disease more accurately.
• Ensuring wider access to new drugs.
• Increasing diversity and representation in clinical research.

Addressing these issues is crucial for improving outcomes for multiple myeloma patients.

 

 

"Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma"

Source

Chakraborty, R., Cheruvalath, H., Patwari, A. et al. Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma. Blood Cancer J. 14, 137 (2024). https://doi.org/10.1038/s41408-024-01114-7  August 12, 2024 

Overview

Bispecific antibodies (bsAbs) that target BCMA and GPRC5D have shown strong responses in treating relapsed or refractory multiple myeloma (MM), with response rates ranging from 57% to 71%. These therapies, including teclistamab, elranatamab, and talquetamab, have received FDA approval for patients who have already undergone at least four prior treatments. Traditionally, these drugs are given continuously until the disease progresses or the patient experiences intolerable side effects.

Recent research suggests that fixed-duration dosing with planned breaks might be a better approach. Continuous dosing can lead to T-cell exhaustion and reduced effectiveness over time, while treatment-free breaks could help rejuvenate T-cells and reduce the risk of infections. Additionally, continuous exposure might drive some forms of relapse. A study of 201 patients who stopped bsAb treatment for reasons other than disease progression found that 82.6% remained in remission after a median follow-up of 15.5 months.

The findings suggest that fixed-duration therapy could be as effective as continuous therapy, with added benefits including reduced risk of infections and lower treatment burden. Ongoing and future studies will explore fixed-duration and response-adapted strategies to optimize treatment for MM patients.

 

 

"Liquid biopsy of peripheral blood using mass spectrometry detects primary extramedullary disease in multiple myeloma patients"

Source

Vlachová, M., Pečinka, L., Gregorová, J. et al. Liquid biopsy of peripheral blood using mass spectrometry detects primary extramedullary disease in multiple myeloma patients. Sci Rep 14, 18777 (2024). https://doi.org/10.1038/s41598-024-69408-1 August 13, 2024.  

Overview

In multiple myeloma (MM)  plasma cells invade the bone marrow. A more severe form, called extramedullary disease (EMD), occurs when these cancer cells spread to areas outside the bone marrow. Liquid biopsies, which are less invasive than traditional biopsies, could help diagnose MM and EMD more effectively.

In this study, researchers used MALDI-TOF mass spectrometry to analyze blood samples and distinguish between MM and primary EMD. They developed a predictive model using a method called partial least squares-discriminant analysis (PLS-DA). This model showed high sensitivity (86.4%), accuracy (78.4%), and specificity (72.4%) in identifying primary EMD. This approach is promising for quickly and accurately diagnosing primary EMD in a less invasive manner.

 

 

"Dihydrolipoamide dehydrogenase (DLD) is a novel molecular target of bortezomib"

Source

Feng, Y., Luo, H., Huang, J. et al. Dihydrolipoamide dehydrogenase (DLD) is a novel molecular target of bortezomib. Cell Death Dis 15, 588 (2024). https://doi.org/10.1038/s41419-024-06982-2 August 13, 2024/

Overview

Proteasome inhibitors (PIs), like bortezomib and calfizomib, are key treatments for multiple myeloma (MM). This study explored how bortezomib works in MM cells and found that it targets a protein called dihydrolipoamide dehydrogenase (DLD). DLD helps process a molecule involved in cell energy and proteasome function.

The study showed that bortezomib binds to DLD and stops it from working. When DLD was removed from MM cells, these cells had lower levels of a molecule called NADH, which is important for assembling the proteasome. This led to less proteasome activity and made the cells more sensitive to bortezomib.

The research also found that high levels of DLD are linked to worse outcomes in MM. When they used a DLD inhibitor called CPI-613, it worked well with bortezomib to fight MM in lab tests and animal studies. These findings suggest that targeting DLD could help make MM treatments more effective.

 

 

"The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma"

Source

Anthony M. Cirrincione, Alexandra M. Poos, Bachisio Ziccheddu, Marcella Kaddoura, Marc-Andrea Bärtsch, Kylee Maclachlan, Monika Chojnacka, Benjamin Diamond, Lukas John, Philipp Reichert, Stefanie Huhn, Patrick Blaney, Dylan Gagler, Karsten Rippe, Yanming Zhang, Ahmet Dogan, Alexander M. Lesokhin, Faith Davies, Hartmut Goldschmidt, Roland Fenk, Katja C. Weisel, Elias K. Mai, Neha Korde, Gareth J. Morgan, Saad Usmani, Ola Landgren, Marc S. Raab, Niels Weinhold, Francesco Maura; The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma. Blood 2024; 144 (7): 771–783. doi: https://doi.org/10.1182/blood.2024024299 August 15, 2024

Overview

In multiple myeloma (MM), having a hyperdiploid (HY) karyotype or specific IgH gene changes are known early events in the disease. This study looked at whole-genome sequencing from 1,173 MM samples to see if other genetic changes happen before these key events.

The researchers found that in 9.4% of patients with an HY karyotype but without IgH changes, there were earlier deletions of genetic material. These deletions often affected genes that help control tumor growth, suggesting they play a role in the development of MM. Additionally, they identified "postgain" deletions that appear to drive the disease, which were linked to poor outcomes in newly diagnosed patients.

This study offers new insights into the timing and impact of different genetic changes in MM, revealing that some deletions may occur earlier than previously thought and affect the disease's progression.

 

 

"Role and timing of chromosome deletions in multiple myeloma"

Source

Stéphane Minvielle, Eric Letouzé; Role and timing of chromosome deletions in multiple myeloma. Blood 2024; 144 (7): 688–689. doi: https://doi.org/10.1182/blood.2024025269 August 15, 2024 

Overview

In an issue of Blood, Cirrincione and colleagues explored the timing and role of chromosome deletions in multiple myeloma (MM), revealing their significant impact as both early and secondary drivers of the disease.

MM develops through multiple stages, starting with precursor conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Traditionally, hyperdiploidy (extra chromosomes) and IgH translocations were thought to be the first genetic events in MM. However, new research using whole genome sequencing and advanced computational methods shows that chromosome deletions can actually occur before these gains in some cases. 

The study found that in 9.4% of hyperdiploid tumors, deletions of key tumor suppressor genes (TSGs) such as CDKN1B, MAX, and TRAF3 happen before chromosome gains. This challenges the previous belief that hyperdiploidy is always the earliest event. Additionally, about one-third of patients had "postgain" deletions, which occur after chromosome gains and affect TSGs and oncogenes, leading to more complex disease and poorer outcomes.

Overall, these findings suggest that deletions play a crucial role in the development of MM, potentially occurring before or alongside other key genetic changes. This insight may help in understanding how MM develops and how to better predict and treat the disease.

 

 

"Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity"

Source

Lind, J., Aksoy, O., Prchal-Murphy, M. et al. Dual therapeutic targeting of MYC and JUNB transcriptional programs for enhanced anti-myeloma activity. Blood Cancer J. 14, 138 (2024). https://doi.org/10.1038/s41408-024-01117-4  August 19, 2024 

Overview

In multiple myeloma (MM), two important transcription factors, MYC and JUNB, drive cancer growth but work differently. This study found that MYC and JUNB each control separate sets of genes and do not affect each other's activity. MYC levels remain unchanged even when JUNB is reduced, and JUNB activity isn’t affected by MYC reduction. Using a new treatment, MZ-1, that targets MYC and combining it with strategies to target JUNB led to better results in killing MM cells, both in lab tests and mouse models. This research suggests that targeting both MYC and JUNB could be a promising new approach to treating MM and improving patient outcomes.

 

 

"Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma"

Source

Mara John, Moutaz Helal, Johannes Duell, Greta Mattavelli, Emilia Stanojkovska, Nazia Afrin, Alexander Michael Leipold, Maximilian Johannes Steinhardt, Xiang Zhou, David Žihala, Anjana Anilkumar Sithara, Julia Mersi, Johannes M Waldschmidt, Christine Riedhammer, Sofie-Katrin Kadel, Marietta Truger, Rudolf A. Werner, Claudia Haferlach, Hermann Einsele, Kai Kretzschmar, Tomáš Jelínek, Andreas Rosenwald, K. Martin Kortüm, Angela Riedel, Leo Rasche; Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma. Blood 2024; blood.2024024590. doi:https://doi.org/10.1182/blood.2024024590 August 20, 2024

Overview

Extramedullary disease (EMD) is a high-risk feature in multiple myeloma (MM) that remains difficult to treat, even with new immunotherapies. This study used advanced techniques to analyze 14 EMD tissue samples. The researchers found that the immune and supportive cells around the tumors varied widely, both within individual patients and between different patients. They also discovered that tumor cells had significant genetic differences, with new subclones appearing in certain areas, indicating instability in the tumor's DNA.

Two important antigens, GPRC5D and TNFRSF17, which are targets for specific antibody treatments, showed different patterns of expression within the tumors. The researchers observed that T-cells were often found mixed with MM cells. However, there was a difference in how these T-cells were distributed: exhausted T-cells (which are less effective) were spread throughout the tumor, while more active T-cells and certain macrophages were found in tumor-free areas.

The study also found that the cells in EMD were part of a complex network that influenced immune response, blood vessel formation, and energy production in the tumor. Overall, these findings suggest that targeting both the exhausted and active T-cells, as well as using checkpoint inhibitors, could be new ways to treat EMD in multiple myeloma.

 

 

"Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance"

Source

Thomsen, H., Chattopadhyay, S., Weinhold, N. et al. Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance. Blood Cancer J. 14, 140 (2024). https://doi.org/10.1038/s41408-024-01121-8 August 20, 2024

Overview

Genome-wide association studies (GWASs) have found certain genetic markers, called single nucleotide polymorphisms (SNPs), linked to the risk of developing monoclonal gammopathy of unknown significance (MGUS). Researchers thought that looking at groups of these markers, called haplotypes, might be more effective in identifying the genetic risks for MGUS.

Using data from a previous GWAS involving 992 MGUS cases and 2,910 controls from three European populations, they identified 23 haplotypes that were strongly linked to MGUS risk. These findings were consistent across all three populations. In 10 specific regions of the genome, the data showed that these haplotypes were involved in important biological functions, like controlling genes and regulating immune responses.

Some of the haplotypes were linked to pathways that are crucial for MM cell survival, such as the ubiquitin-proteasome system, PI3K/AKT/mTOR, innate immunity, cell death regulation, and NOTCH signaling. These pathways are also important targets for current MM treatments, suggesting that focusing on haplotypes could help identify key genetic factors that contribute to MGUS and MM.

 

 

"Beyond BCMA: newer immune targets in myeloma"

Source

Melinda S. Y. Tan, Yunxin Chen, Eric L. Smith; Beyond BCMA: newer immune targets in myeloma. Blood Adv 2024; 8 (16): 4433–4446. doi: https://doi.org/10.1182/bloodadvances.2023010856  August 27, 2024 

Overview

New immunotherapy approaches targeting B-cell maturation antigen (BCMA) have greatly improved treatment for multiple myeloma (MM), especially for patients whose cancer has returned or resisted other treatments. These include antibody-drug conjugates, CAR T-cell therapy, and T-cell engagers. While these treatments are effective, most patients eventually relapse, so researchers are exploring new targets like GPRC5D, FcRH5, and SLAMF7 to treat these relapses.

As more immunotherapy options are developed, they will play a crucial role in treating patients who relapse after BCMA-targeting therapies, particularly when the cancer no longer shows BCMA. Using different T-cell therapies in sequence and combining them with other treatments could lead to chemotherapy-free options. However, it's important to carefully plan treatment timing, protect T-cell health, address the loss of target antigens, and understand the complex environment around the tumor to get the best results and avoid side effects. This summary highlights new targets being developed for MM and key safety and effectiveness data from clinical trials.

 

 

"Outpatient administration of CAR T-cell therapies using a strategy of no remote monitoring and early CRS intervention"

Source

Fateeha Furqan, Vineel Bhatlapenumarthi, Binod Dhakal, Timothy S. Fenske, Faiqa Farrukh, Walter Longo, Othman Akhtar, Anita D’Souza, Marcelo Pasquini, Guru Subramanian Guru Murthy, Lyndsey Runaas, Sameem Abedin, Meera Mohan, Nirav N. Shah, Mehdi Hamadani; Outpatient administration of CAR T-cell therapies using a strategy of no remote monitoring and early CRS intervention. Blood Adv 2024; 8 (16): 4320–4329. doi: https://doi.org/10.1182/bloodadvances.2024013239  August 27, 2024 

Overview

Recent research has shown that it's possible to safely give CAR T-cell therapy to cancer patients in an outpatient setting, even without intensive at-home monitoring. This study looked at patients with blood cancers who received CAR T-cell therapy for CD19 and BCMA targets between 2022 and 2023. The patients were closely monitored at the cancer center every day for the first 7 to 10 days, then twice a week through day 30.

The main goal was to see how many patients needed to be hospitalized within 3, 7, and 30 days after their CAR T-cell infusion. Doctors used an early intervention strategy to manage cytokine release syndrome (CRS), a common side effect, by giving the drug tocilizumab to patients showing even mild signs of CRS.

Out of 58 patients (33 with myeloma, 24 with lymphoma, and 1 with acute lymphoblastic leukemia), 41% were hospitalized within the first 3 days, 38% between days 4 and 7, and 21% between days 8 and 30. Most hospitalizations were due to CAR T-cell–related side effects. However, using tocilizumab in 35 patients prevented hospitalization in 15 of them. The nonrelapse death rates were low, at 1.7% after 1 month and 3.4% after 6 months.

This study shows that outpatient CAR T-cell therapy can be done safely without needing intensive at-home monitoring if early CRS management is in place.

 

 

"Gamma gap as a prognostic marker of treatment response in patients with multiple myeloma"

Source

Hassan, E.A., Hameed, R.Y. Gamma gap as a prognostic marker of treatment response in patients with multiple myeloma. Ir J Med Sci (2024). https://doi.org/10.1007/s11845-024-03784-5  August 20, 2024 

Overview

This study focuses on how the gamma gap (GG)—the difference between total serum protein and albumin—can help in assessing how well multiple myeloma (MM) treatments are working.

The study included 60 newly diagnosed myeloma patients from medical centers in Baghdad, Iraq, and 30 healthy individuals for comparison. Researchers used various tests, including serum electrophoresis and immunofixation, to detect and measure abnormal proteins (M-spike) produced by the cancer cells. They also calculated the gamma gap by subtracting albumin from total serum protein.

Results showed that most MM patients had detectable M-spikes, with the most common being IgG type, particularly κ and λ types. The study found a strong link between the gamma gap and M-spike levels before and after treatment, showing that the gamma gap is a reliable indicator of treatment response.

The gamma gap could be a useful tool for monitoring how well MM patients respond to treatment, providing important information for managing the disease.

 

 

"Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics"

Source

Elbahoty, M.H., Papineni, B. & Samant, R.S. Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics. Clin Exp Metastasis (2024). https://doi.org/10.1007/s10585-024-10305-2  August 20, 2024 

Overview

Globally, the prevalence of multiple myeloma (MM) has been steadily increasing. In the United States, more than 30,000 cases will be diagnosed in 2024 and it accounts for about 2% of cancer diagnoses and more than 2% of cancer deaths, more than double the worldwide figure.

Both symptomatic and active MM are distinguished by uncontrolled plasma cell growth, which results in severe renal impairment, anemia, hypercalcemia, and bone loss. Many drugs have been approved by the FDA and are now widely used in clinical practice for MM.

Although triplet and quadruplet induction regimens, autologous stem cell transplantation (ASCT), and maintenance treatment are used, MM continues to be an incurable illness characterized by relapses that may occur at various phases of its progression.

MM patients with frailty, extramedullary disease, plasma cell leukemia, central nervous system recurrence, functional high risk, and the elderly are among those with the greatest current unmet needs.

The high cost of care is an additional challenge. MM cells are highly protein secretory cells, and thus, are dependent on the activation of certain translation pathways. MM also has a high chance of altering ribosomal protein-encoding genes like MYC mutation. In this article, researchers discuss the importance of ribosome biogenesis in promoting MM and RNA polymerase I inhibition as an upcoming treatment with potential promise for MM patients. 

 

 

"Gamma gap as a prognostic marker of treatment response in patients with multiple myeloma"

Source

Hassan, E.A., Hameed, R.Y. Gamma gap as a prognostic marker of treatment response in patients with multiple myeloma. Ir J Med Sci (2024). https://doi.org/10.1007/s11845-024-03784-5  August 20, 2024 

Overview

This study focuses on how the gamma gap (GG)—the difference between total serum protein and albumin—can help in assessing how well multiple myeloma (MM) treatments are working.

The study included 60 newly diagnosed myeloma patients from medical centers in Baghdad, Iraq, and 30 healthy individuals for comparison. Researchers used various tests, including serum electrophoresis and immunofixation, to detect and measure abnormal proteins (M-spike) produced by the cancer cells. They also calculated the gamma gap by subtracting albumin from total serum protein.

Results showed that most MM patients had detectable M-spikes, with the most common being IgG type, particularly κ and λ types. The study found a strong link between the gamma gap and M-spike levels before and after treatment, showing that the gamma gap is a reliable indicator of treatment response.

The gamma gap could be a useful tool for monitoring how well MM patients respond to treatment, providing important information for managing the disease.

 

 

"Targeted protein degradation in hematologic malignancies: clinical progression towards novel therapeutics"

Source

Feng, Y., Hu, X. & Wang, X. Targeted protein degradation in hematologic malignancies: clinical progression towards novel therapeutics. Biomark Res 12, 85 (2024). https://doi.org/10.1186/s40364-024-00638-1 August 21, 2024

Overview

Targeted therapies like small molecule kinase inhibitors have advanced the treatment of blood cancers by altering protein activity. However, their effectiveness can be limited by issues such as drug toxicity, resistance due to mutations, and the lack of key active sites. Targeted protein degradation (TPD) is a new and rapidly growing approach that offers a solution by selectively breaking down specific proteins in the body. Unlike traditional drugs, TPD works with smaller amounts and reduces the risk of drug-related side effects. 

TPD is also effective in cases where mutations might cause drug resistance, as it completely degrades the targeted protein. The two main techniques in TPD are Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs). This review looks at both preclinical studies and clinical trials over the last 20 years, summarizing the safety and effectiveness of PROTACs and MGDs in treating blood cancers. It also discusses the challenges and opportunities for these innovative techniques, highlighting their potential for future use in treating blood cancer patients.

 

 

"Infections and their prognostic significance before diagnosis of chronic lymphocytic leukemia, non-Hodgkin lymphoma, or multiple myeloma"

Source

Packness, E., Davidsson, O.B., Rostgaard, K. et al. Infections and their prognostic significance before diagnosis of chronic lymphocytic leukemia, non-Hodgkin lymphoma, or multiple myeloma. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02816-2 August 22, 2024

Overview

Immunodeficiency is a common problem in B cell cancers, making patients more prone to infections. While the risk of infections after diagnosis is well known, less is understood about infections before a diagnosis.

In this study, researchers used data from Danish health registers to examine infection rates before the diagnosis of various B cell cancers, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), and others. They looked at antimicrobial prescriptions as a way to track infections.

The study included over 30,000 patients who had more than 200,000 antimicrobial prescriptions. It found that the risk of infections was higher up to 15 years before the cancer diagnosis, with a sharp increase in the year before diagnosis. Patients who had more than two antimicrobial prescriptions in the year before their diagnosis had a significantly shorter overall survival, regardless of other known risk factors.

The study found that people with B cell cancers show signs of weakened immune systems years before being diagnosed, and frequent infections in the year before diagnosis are linked to a shorter overall survival.

 

 

"Disparities in time to treatment with oral antimyeloma medications"

Source

Gasoyan, H., Anwer, F., Kovach, J.D. et al. Disparities in time to treatment with oral antimyeloma medications. Blood Cancer J. 14, 142 (2024). https://doi.org/10.1038/s41408-024-01128-1  August 23, 2024 

Overview

This study looked at the time it took for adults with multiple myeloma to start taking oral medications after being diagnosed. Researchers used data from the Taussig Cancer Center’s Myeloma Patient Registry, focusing on patients diagnosed between January 2017 and December 2021.

The study included 720 patients with an average age of 67 years. Of these, 55% were male, 77% were White patients, 22% were Black patients, and 1% were from other races. Patients had different types of insurance, with 36% on private insurance, 29% on traditional Medicare, 25% on Medicare Advantage, and 8.3% on Medicaid. Over a third of the patients lived in highly disadvantaged areas.

The study found that 75% of patients filled a prescription for oral myeloma medication (excluding corticosteroids) within a median time of 28 days. However, certain factors were linked to delays in getting the medication. Black patients, older patients, those diagnosed while in the hospital, and those with poor kidney function were less likely to start their oral medication within 30 days. Insurance type and living in a disadvantaged area did not significantly affect the timing of starting the medication.

This study highlights that race, age, hospital diagnosis, and kidney function can impact how quickly multiple myeloma patients start their oral treatment.

 

 

"Disparities in relapsed or refractory multiple myeloma: recommendations from an interprofessional consensus panel"

Source

Gasoyan, H., Anwer, F., Kovach, J.D. et al. Disparities in time to treatment with oral antimyeloma medications. Blood Cancer J. 14, 142 (2024). https://doi.org/10.1038/s41408-024-01128-1  August 23, 2024 

Overview

Many studies have shown that patients in the U.S. with multiple myeloma face racial, socioeconomic, and geographic disparities, especially in diagnosis and initial treatment. However, less is known about these disparities in treating relapsed/refractory multiple myeloma (RRMM), even though there are many new treatment options available.

This review highlights how these disparities affect RRMM treatment and suggests ways to reduce their impact. For example, immunomodulatory drugs can create problems such as incorrect dosing and increased financial burden for patients with fewer resources. Access to experts at high-volume medical centers is crucial, as drugs like carfilzomib and dexamethasone are often prescribed differently in trials than in real-life situations, leading to higher toxicity levels.

Disparities also exist in advanced treatments like CAR T-cell therapy and bispecific antibody therapy, which are less available outside of large centers. Additionally, supportive care in RRMM, like pain management and primary care access, varies greatly, with Black patients and those in rural areas often receiving less adequate care.

To address these issues, the review suggests several solutions: working closely with community oncologists, screening patients for social risk factors, building trust in clinical trials, and ensuring ongoing access to primary care. As treatment options for RRMM continue to grow, these efforts are essential to make sure all patients in the U.S. have equal access to care.

 

 

"Longitudinal assessment of established risk stratification models in patients with monoclonal gammopathy of undetermined significance"

Source

Zuern, K., Hielscher, T., Werly, A. et al. Longitudinal assessment of established risk stratification models in patients with monoclonal gammopathy of undetermined significance. Blood Cancer J. 14, 148 (2024). https://doi.org/10.1038/s41408-024-01126-3  August 27, 2024 

Overview

Monoclonal gammopathy of undetermined significance (MGUS) can sometimes progress to multiple myeloma or other plasma cell disorders. To predict this risk, there are three main risk models: Mayo2005, Sweden2014, and NCI2019. This study looked at 427 patients with MGUS, diagnosed using 2014 guidelines, to see how well these models work over time.

The study found that most patients stayed in their initial risk group according to these models. However, a few patients moved to different risk groups as time went on. The models consistently predicted risk of progression, whether checked at diagnosis or during yearly follow-ups. When patients moved to a higher risk group, their chance of disease progression increased significantly in all three models.

Overall, these risk models are useful for ongoing assessment of MGUS patients. If a patient’s risk level increases, it’s important to monitor them more closely in clinical practice.

 

 

"The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial"

Source

Malek, E., Rana, P.S., Swamydas, M. et al. The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial. Nat Commun 15, 7388 (2024). https://doi.org/10.1038/s41467-024-51442-2  August 27, 2024 

Overview

A recent phase 1b study tested the safety and effectiveness of vactosertib, a new drug that blocks the TGFβ signaling pathway, combined with pomalidomide for treating relapsed or refractory multiple myeloma (RRMM). The study included patients who had already tried at least two other treatments.

The results showed that vactosertib, taken orally, was safe and well-tolerated at a dose of 200 mg twice daily. The combination of vactosertib and pomalidomide led to good clinical responses, with 82% of patients remaining free from disease progression after six months. The treatment also had positive effects on the immune system, reducing levels of TGFβ and the number of CD8+ T-cells with an immunosuppressive marker.

Lab experiments showed that the drug combo killed multiple myeloma cells and boosted the activity of CD8+ T-cells, which are important for fighting cancer. Overall, vactosertib appears to be a promising treatment that could enhance the effectiveness of immunotherapy for patients who have not responded well to other treatments.

 

 

"Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features"

Source

Sierro-Martínez, B., Escamilla-Gómez, V., Pérez-Ortega, L. et al. Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00984-0  August 27, 2024. 

Overview

CAR therapy targeting BCMA is being explored for treating multiple myeloma, but there's a need for better options. This study introduces a new, improved CAR therapy called CARTemis-1 and looks at how the manufacturing process affects its quality.

The researchers tested CARTemis-1 in the lab and in animal models. They found that a version with a longer spacer was more effective at killing cancer cells. They also added a safety gene to the therapy to help monitor its effects. CARTemis-1 was able to overcome issues with soluble BCMA, showing strong anti-cancer effects both in the lab and in animals.

The study also compared two methods for expanding CAR-T cells. Using IL-7/IL-15 for expansion led to better cell growth and less cell exhaustion compared to IL-2. CARTemis-1 produced under good manufacturing practices (GMP) met all quality standards and showed improved cell characteristics and effectiveness against myeloma cells.

The researchers plan to test CARTemis-1 in a Phase I/II clinical trial for multiple myeloma patients.

 

 

"Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses"

Source

Sikander Ailawadhi, Bertrand Arnulf, Krina K. Patel, Michele Cavo, Ajay K. Nooka, Salomon Manier, Natalie S Callander, Luciano J. Costa, Ravi Vij, Nizar J. Bahlis, Philippe Moreau, Scott R. Solomon, Ingerid Weum Abrahamsen, Rachid C Baz, Annemiek Broijl, Christine Chen, Sundar Jagannath, Noopur Raje, Christof Scheid, Michel Delforge, Reuben Benjamin, Thomas Pabst, Shinsuke Iida, Jesus G. Berdeja, Sergio A Giralt, Anna Truppel-Hartmann, Yanping Chen, Xiaobo Zhong, Fan Wu, Julia Piasecki, Laurie Eliason, Devender S. Dhanda, Jasper Felten, Andrea Caia, Mark Cook, Mihaela Popa-Mckiver, Paula Rodriguez-Otero; Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood 2024; blood.2024024582. doi: https://doi.org/10.1182/blood.2024024582  August 28, 2024

Overview

In a recent Phase 3 clinical trial called KarMMa-3, patients with hard-to-treat (triple-class-exposed) multiple myeloma who had already tried three or more lines of treatment were given either idecabtagene vicleucel (ide-cel) or standard treatments. The trial found that ide-cel significantly improved progression-free survival (PFS), which is how long patients lived without their disease getting worse. The median PFS for patients on ide-cel was 13.8 months, compared to just 4.4 months for those on standard treatments. Ide-cel also had a higher overall response rate (ORR), with 71% of patients seeing some level of response compared to 42% with standard treatments. 

Patients on ide-cel were more likely to have a complete response (44% vs. 5%). Even though overall survival data was complicated by many patients switching from standard treatments to ide-cel upon disease progression, ide-cel still showed benefits. Both groups had longer survival times than expected based on past data, but ide-cel's benefit was clear. Additionally, ide-cel was associated with better patient-reported outcomes and no new safety concerns. This study confirms ide-cel's effectiveness and favorable safety profile for treating multiple myeloma.

 

 

"Prognostic impact of cytogenetic abnormalities by FISH in AL amyloidosis with daratumumab-based frontline therapy"

Source

SikaRajshekhar Chakraborty, Saurabh Zanwar, Ute Hegenbart, Divaya Bhutani, Morie A Gertz, Angela Dispenzieri, Shaji K Kumar, Anita D'Souza, Anannya Patwari, Andrew J Cowan, GuiZhen Chen, Paolo Milani, Giovanni Palladini, Vaishali Sanchorawala, Geethika Bodanapu, Stefan Schönland, Suzanne Lentzsch, Eli Muchtar; Prognostic impact of cytogenetic abnormalities by FISH in AL amyloidosis with daratumumab-based frontline therapy. Blood 2024; blood.2024025899. doi: https://doi.org/10.1182/blood.2024025899  August 28, 2024

Overview

An international study looked at how different genetic abnormalities affect outcomes in patients with AL amyloidosis who were treated with a combination of daratumumab, bortezomib, cyclophosphamide, and dexamethasone (Dara-VCD) or daratumumab with bortezomib and dexamethasone (Dara-VD). Researchers focused on various genetic abnormalities, including t(11;14), +1q (gain or amplification of chromosome 1q), hyperdiploidy, deletion of chromosome 13q, deletion of chromosome 17p, and high-risk myeloma translocations (such as t[4;14], t[14;16], or t[14;20]).

The study found that the most common abnormalities were t(11;14) (53.4%), deletion of chromosome 13q (28.9%), +1q (22.3%), hyperdiploidy (19.4%), high-risk translocations (6.6%), and deletion of chromosome 17p (4.5%). Among these, only +1q was linked to a worse treatment response, with lower rates of very good partial response or better, and a higher risk of poorer outcomes. 

Patients with +1q had a significantly lower rate of achieving a very good partial response compared to those without +1q. The median time without disease progression was 49.6 months, and the 2-year overall survival rate was about 81%. The presence of +1q was associated with worse outcomes, making it important to consider this factor in future clinical trials to help improve results for patients with this genetic abnormality.

 

 

"Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses"

Source

Sikander Ailawadhi, Bertrand Arnulf, Krina K. Patel, Michele Cavo, Ajay K. Nooka, Salomon Manier, Natalie S Callander, Luciano J. Costa, Ravi Vij, Nizar J. Bahlis, Philippe Moreau, Scott R. Solomon, Ingerid Weum Abrahamsen, Rachid C Baz, Annemiek Broijl, Christine Chen, Sundar Jagannath, Noopur Raje, Christof Scheid, Michel Delforge, Reuben Benjamin, Thomas Pabst, Shinsuke Iida, Jesus G. Berdeja, Sergio A Giralt, Anna Truppel-Hartmann, Yanping Chen, Xiaobo Zhong, Fan Wu, Julia Piasecki, Laurie Eliason, Devender S. Dhanda, Jasper Felten, Andrea Caia, Mark Cook, Mihaela Popa-Mckiver, Paula Rodriguez-Otero; Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood 2024; blood.2024024582. doi: https://doi.org/10.1182/blood.2024024582  August 28, 2024

Overview

In a recent Phase 3 clinical trial called KarMMa-3, patients with hard-to-treat (triple-class-exposed) multiple myeloma who had already tried three or more lines of treatment were given either idecabtagene vicleucel (ide-cel) or standard treatments. The trial found that ide-cel significantly improved progression-free survival (PFS), which is how long patients lived without their disease getting worse. The median PFS for patients on ide-cel was 13.8 months, compared to just 4.4 months for those on standard treatments. Ide-cel also had a higher overall response rate (ORR), with 71% of patients seeing some level of response compared to 42% with standard treatments. 

Patients on ide-cel were more likely to have a complete response (44% vs. 5%). Even though overall survival data was complicated by many patients switching from standard treatments to ide-cel upon disease progression, ide-cel still showed benefits. Both groups had longer survival times than expected based on past data, but ide-cel's benefit was clear. Additionally, ide-cel was associated with better patient-reported outcomes and no new safety concerns. This study confirms ide-cel's effectiveness and favorable safety profile for treating multiple myeloma.

 

 

"B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation"

Source

Pfeuffer, L., Siegert, V., Frede, J. et al. B-cell intrinsic RANK signaling cooperates with TCL1 to induce lineage-dependent B-cell transformation. Blood Cancer J. 14, 151 (2024). https://doi.org/10.1038/s41408-024-01123-6  August 28, 2024. 

Overview

In a new study, researchers developed a mouse model that shows features of both chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). This model uses active RANK signaling and the TCL1 oncogene. In younger mice, TCL1 and RANK increase the number of CLL-like B1-lymphocytes. As the mice age, the disease shifts to MM, which starts from B2-cells and progresses severely, mimicking human MM with symptoms like clonal plasma cell expansion, paraproteinemia, anemia, kidney and bone failure, and a supportive tumor environment. The study highlights how RANK activation affects different B-cell types and shows that blocking RANK signaling can slow MM progression in human cell models. This suggests that further research on RANK signaling could improve understanding and treatment of B-cell malignancies.

 

 

"EANM guidelines on the use of [18F]FDG PET/CT in diagnosis, staging, prognostication, therapy assessment, and restaging of plasma cell disorders"

Source

Nanni, C., Deroose, C.M., Balogova, S. et al. EANM guidelines on the use of [18F]FDG PET/CT in diagnosis, staging, prognostication, therapy assessment, and restaging of plasma cell disorders. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06858-9  August 29, 2024. 

Overview

Multiple myeloma (MM) is a type of cancer where abnormal plasma cells grow and produce excess proteins in the bone marrow. These abnormal cells can also spread to other areas outside the bone marrow. A key factor in MM's growth is interleukin-6, a substance that promotes cell survival and bone damage. This damage leads to complications like bone loss and kidney failure. Advanced MM shows increased blood vessel growth and severe disease progression.

MM is more common in older adults, especially between ages 60 and 70, and is more frequent in men and Black individuals compared to women and people of Asian descent. Risk factors include exposure to pesticides, radiation, and having a precursor condition called monoclonal gammopathy of undetermined significance (MGUS).

MM varies greatly among patients, which is seen in their genetic makeup. Two main genetic types are identified: hyper-diploid, with extra chromosomes, and non-hyper-diploid, with fewer chromosomes and specific gene translocations. These genetic changes can affect prognosis, though their impact can vary depending on the treatment used.

New technologies, like high-throughput sequencing, reveal more about the genetic diversity within MM patients. This includes different subclones of cells, which can make the disease harder to treat and contribute to resistance over time.

In MM, patients produce abnormal proteins (M-proteins) that can indicate disease activity and response to treatment. Measuring these proteins helps in monitoring and managing the disease. Bone marrow tests are used to assess the disease and genetic abnormalities, which help in determining the prognosis.

Treatment for MM has greatly advanced over the past two decades, evolving from mostly using alkylating agents and steroids to including newer drug classes like proteasome inhibitors and monoclonal antibodies. These new treatments offer more options but also add complexity to management, especially in relapsed cases.

International guidelines help guide treatment, but choices depend on individual factors like age, health, and previous treatments. Monitoring during and after treatment includes checking M-protein levels and using other tests to measure disease progression. New therapies, such as CAR T-cells and bispecific antibodies, offer hope for improved outcomes in patients with hard-to-treat MM. Supportive care is also crucial to manage complications like bone disease and infections.

 

 

"Mass spectrometry–based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma"

Source

Tadeusz Kubicki, Dominik Dytfeld, David Barnidge, Dhananjay Sakrikar, Anna Przybyłowicz-Chalecka, Krzysztof Jamroziak, Paweł Robak, Jarosław Czyż, Agata Tyczyńska, Agnieszka Druzd-Sitek, Krzysztof Giannopoulos, Tomasz Wróbel, Adam Nowicki, Tomasz Szczepaniak, Anna Łojko-Dankowska, Magdalena Matuszak, Lidia Gil, Bartosz Puła, Łukasz Szukalski, Agnieszka Końska, Jan Maciej Zaucha, Jan Walewski, Damian Mikulski, Olga Czabak, Tadeusz Robak, Ken Jiang, Jennifer H. Cooperrider, Andrzej J. Jakubowiak, Benjamin A. Derman; Mass spectrometry–based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma. Blood 2024; 144 (9): 955–963. doi: https://doi.org/10.1182/blood.2024024041  August 29, 2024 

Overview

Mass spectrometry is a sensitive tool for detecting monoclonal proteins in the blood of multiple myeloma patients. This study explored how mass spectrometry can be used to measure measurable residual disease (MRD) after a stem cell transplant. Researchers analyzed blood samples from 138 patients in a Phase 3 trial comparing two post-transplant therapies. They found that mass spectrometry in the blood closely matched MRD results from bone marrow tests, especially as time passed after the transplant.

Patients who tested negative for MRD using mass spectrometry had better progression-free survival (PFS), with significant results after 18 treatment cycles. Combining mass spectrometry blood results with bone marrow MRD tests gave the best predictions for patient outcomes. The study shows that mass spectrometry is a useful addition to current MRD testing methods and may help improve disease monitoring after transplant in multiple myeloma patients. More research is needed to confirm the best timing for mass spectrometry in this context.

 

 

"An ATLAS to map MRD with peripheral blood"

Source

Andrew J. Yee; An ATLAS to map MRD with peripheral blood. Blood 2024; 144 (9): 919–920. doi: https://doi.org/10.1182/blood.2024025189  August 29, 2024 

Overview

In an issue of *Blood*, Kubicki and colleagues present findings from the EXENT platform, a new assay that uses mass spectrometry to measure monoclonal proteins in the blood. The study analyzed samples from the ATLAS trial, which compared two post-transplant therapies in multiple myeloma patients: carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone. The authors evaluated how well the blood-based mass spectrometry assay performs in detecting minimal residual disease (MRD) compared to bone marrow tests using next-generation sequencing (NGS) or multiparameter flow cytometry.

One of the major advantages of using a blood-based mass spectrometry assay is that it eliminates the need for invasive bone marrow biopsies, allowing for easier and more frequent monitoring of disease. Blood tests can also provide a more comprehensive view of the disease, avoiding the limitations of bone marrow sampling, such as missing areas of the disease or not accounting for disease outside the bone marrow. The importance of MRD as an endpoint in treatment is expected to grow, especially following favorable voting by the FDA’s Oncology Drug Advisory Committee to use MRD as a criterion for accelerated drug approval.

The EXENT platform uses a technique called matrix-assisted laser desorption ionization (MALDI) combined with time-of-flight mass spectrometry. This method is much more sensitive than traditional serum protein electrophoresis and immunofixation, detecting monoclonal proteins at levels as low as 0.0015 g/dL. While mass spectrometry was not as sensitive as NGS in detecting MRD, it still provided valuable information. Patients who tested negative for MRD in both blood and bone marrow had the best outcomes, showing that mass spectrometry can complement bone marrow MRD tests.

An interesting finding from the study is how the predictive value of blood-based MRD changes over time during treatment. The agreement between blood and bone marrow MRD results improved after 18 cycles of treatment. This suggests that blood-based MRD may become more reliable as a patient progresses through treatment. Additionally, mass spectrometry can detect new, non-cancerous proteins that appear after recovery from high-dose therapy, which might otherwise be mistaken for residual disease.

Another promising approach is a clonotypic mass spectrometry assay, which identifies the unique sequence of the patient’s monoclonal protein. This method can achieve sensitivities comparable to NGS and may even surpass it in some cases. However, it requires a baseline sample to determine the sequence, which might not be available for patients who have already started treatment.

As more data emerges from ongoing trials, such as DRAMMATIC and REMNANT, the role of MRD testing in guiding treatment decisions will become clearer. The hope is that blood-based MRD testing using mass spectrometry will eventually replace the need for bone marrow biopsies, offering a less invasive and more convenient option for monitoring multiple myeloma patients. Kubicki and colleagues provide valuable insights into how the EXENT platform can complement existing MRD tests and help move toward a future where "liquid biopsies" become the standard in disease monitoring.

 

 

"IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma"

Source

Sun, J., Corradini, S., Azab, F. et al. IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02391-8  August 30, 2024.  

Overview

Tumor-associated macrophages (TAMs) in the tumor environment often promote tumor growth, survival, and resistance to treatment. A key factor in this process is IL-10, an immunosuppressive cytokine that helps recruit and develop TAMs.

This study explored how IL-10 contributes to TAM development in multiple myeloma (MM) and evaluated the potential of blocking IL-10/IL-10R/STAT3 signaling as a therapy. Researchers found that IL-10 is overexpressed in the bone marrow of MM patients and drives the polarization of TAMs into a pro-tumor, M2-like state. These TAMs, in turn, promote MM cell growth and drug resistance.

Importantly, the study showed that inhibiting the IL-10/IL-10R/STAT3 pathway with specific treatments prevented the harmful effects of TAMs and re-sensitized MM cells to therapy. This suggests that targeting this pathway could be a new and effective strategy for treating MM, potentially improving outcomes when combined with existing therapies. Further research is needed to assess the effectiveness of this approach in patients.

 

 

"Writers, readers, and erasers RNA modifications and drug resistance in cancer"

Source

Chen, D., Gu, X., Nurzat, Y. et al. Writers, readers, and erasers RNA modifications and drug resistance in cancer. Mol Cancer 23, 178 (2024). https://doi.org/10.1186/s12943-024-02089-6  August 30, 2024 

Overview

Cancer drug resistance often leads to treatment failure, recurrence, and metastasis. One key factor in this resistance is the modification of RNA, which alters how genes are expressed in cancer cells. These modifications include m6A, m1A, m5C, m7G, Ψ, and A-to-I editing, and they play a crucial role in processes like RNA splicing, stability, and translation. These changes can help cancer cells survive, grow, and resist treatment.

In blood cancers like leukemia and multiple myeloma (MM), these RNA modifications are linked to resistance to chemotherapy. For example, in leukemia, certain RNA modifications help cancer cells resist drugs like doxorubicin and cytarabine by supporting their survival and preventing cell death. In MM, modifications like m6A help cancer cells avoid being killed by chemotherapy drugs such as bortezomib and melphalan.

Targeting these RNA modifications offers a promising new approach to overcoming drug resistance. However, research is still in its early stages, and more studies are needed to develop effective treatments. Scientists are particularly focused on inhibitors that target m6A modifications, but drugs for other types of RNA modifications are still scarce. Developing these inhibitors and combining them with existing cancer therapies could improve treatment outcomes and help prevent cancer from returning.

Understanding how RNA modifications contribute to drug resistance could lead to new, more effective cancer treatments. These insights might also help in designing personalized therapies based on the specific epigenetic profiles of individual cancers.