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 July 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 July 2024) 

"A research center’s experience of T-cell–redirecting therapies in triple-class refractory multiple myeloma"

Source

Borja Puertas, Adolfo Fernández-Sánchez, Elena Alejo, Beatriz Rey-Búa, Ana A. Martín-López, Estefanía Pérez-López, Miriam López-Parra, Lucía López-Corral, Norma C. Gutiérrez-Gutiérrez, Ramón García-Sanz, Noemi Puig, Verónica González-Calle, María-Victoria Mateos; A research center’s experience of T-cell–redirecting therapies in triple-class refractory multiple myeloma. Blood Adv 2024; 8 (13): 3478–3487. doi: https://doi.org/10.1182/bloodadvances.2024012773  July 9, 2024 

Overview

Researchers have compared two new treatments for  triple-class refractory (TCR) myeloma. These treatments are:

1. CAR-T cells: Special immune cells that are changed to fight cancer
2. BiAbs: Antibodies that can connect cancer cells to immune cells

The study looked at 73 patients who had tried these treatments. Here's what they found:

• CAR-T cells worked better at first, with 97% of patients responding compared to 57% for BiAbs.
• After about 19 months, both treatments kept the cancer from growing for about the same amount of time.
• Patients who got CAR-T cells lived longer overall - about 49 months compared to 23 months for BiAbs.

Interestingly, when CAR-T didn't work, trying BiAbs next worked well. But when BiAbs didn't work, trying them again didn't help much.

The researchers note that this study has some limits. The patients weren't exactly the same in each group, and different products were used. Still, both treatments seem to help patients with TCR myeloma. The order of treatments may be important for the best results.

This research gives hope for people with hard-to-treat myeloma and shows that more studies are needed to find the best way to use these new treatments.

 

 

"Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification"

Source

Sun, C., Zhang, W., Liu, H. et al. Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification. Sci Rep 14, 15142 (2024). https://doi.org/10.1038/s41598-024-65937-x July 2, 2024. 

Overview

People with multiple myeloma often don't live as long as they could. Scientists are always looking for new ways to understand and treat this disease.

Recently, researchers found that something called "lactylation" might be important in how cancer grows. They wanted to see if genes related to lactylation could help predict how myeloma patients might do over time.

Here's what the study found:

• The team identified 9 special genes related to lactylation that seemed important in MM.
• Using these genes, they created a tool to sort patients into high-risk and low-risk groups. 
• Patients in the high-risk group didn't do as well as those in the low-risk group.
• The researchers made a chart (called a nomogram) that uses these genes and other patient information to predict outcomes even better.
• The high-risk and low-risk groups showed differences in:
  • How their cancer cells behaved
  • How their immune system worked
  • How they might respond to different cancer drugs
• They looked closely at one gene called PFN1. When they reduced this gene in MM cells:
  • The cancer cells stopped growing as much
  • More cancer cells died

This study is exciting because it gives doctors a new way to determine which multiple myeloma patients might need more aggressive treatment early on. It also helps scientists understand MM better, which could lead to new treatments in the future.

 

 

"Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins"

Source

Neri, P., Leblay, N., Lee, H. et al. Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00913-y July 3, 2024. 

Overview

Key points from the study:

• "Novel targeted immunotherapies including antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BTEs) have revolutionized the treatment of multiple myeloma (MM). 
• These agents have been developed to target B cell maturation antigen, G protein-coupled receptor family C group 5 member D and Fc receptor-like protein 5, which are cell-surface transmembrane proteins expressed by the malignant plasma cells, and have shown unprecedented efficacy in patients with heavily pretreated relapsed and/or refractory disease. 
• ADCs, BTEs and CAR T cells targeting these antigens are associated with unique and sometimes severe toxicities. Therefore, careful management and mitigation strategies are required to improve patient outcomes. 
• The effectiveness of these agents is limited by various mechanisms of resistance reflecting the adaptive nature of MM cells and their capacity to exploit the dysregulated immune system associated with this disease. These mechanisms include cancer cell-intrinsic, T cell-related and tumour microenvironment-related factors. 
• Dynamic surveillance for antigen escape and functional evaluation of T cell fitness is required to optimize the sequencing of these immunotherapies and improve patient outcomes."

 

 

"A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy"

Source

Cordas dos Santos, D.M., Tix, T., Shouval, R. et al. A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy. Nat Med (2024). https://doi.org/10.1038/s41591-024-03084-6 July 8, 2024 

Overview

CAR T-cell therapy can be very effective, but it also comes with some risks. Researchers wanted to understand these risks better, especially the chance of dying from something other than cancer coming back.

The study looked at information from 7,604 patients who received CAR T-cell therapy for different types of blood cancer up to March 2024. Here's what they found:

• The risk of dying from treatment-related causes (not cancer coming back) was different for each type of cancer:
  • Mantle-cell lymphoma: 10.6%
  • Multiple myeloma: 8.0%
  • Large B cell lymphoma: 6.1%
  • Indolent lymphoma: 5.7%
• Certain types of CAR T-cell treatments seemed to have higher risks for some cancers.
• Out of 574 deaths not caused by cancer coming back:
  • Over half (50.9%) were due to infections
  • 7.8% were from other cancers
  • 7.3% were from heart or breathing problems
• Surprisingly, the side effects most people associate with CAR T-cell therapy (like brain problems or severe immune reactions) only caused about 11.5% of these deaths.

This study shows that infections are a major concern after CAR T-cell therapy. It suggests that doctors should pay close attention to preventing and treating infections in patients who receive this treatment.

The researchers also say it's important for future studies to report detailed information about deaths not caused by cancer coming back. This will help make the treatment safer for future patients.

While these risks are important to know about, CAR T-cell therapy can still be life-saving for many patients with hard-to-treat blood cancers.

 

 

"Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN"

Source

Chari, A., Kaufman, J.L., Laubach, J. et al. Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 14, 107 (2024). https://doi.org/10.1038/s41408-024-01088-6  July 8, 2024  

Overview

From the study: "The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated Darzalex (daratumumab) plus Revlimid (lenalidomide), Velcade (bortezomib), and dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM)."

The study focused on patients who are transplant-eligible. It paid special attention to older patients and those with high-risk genetic changes in their cancer cells.

Results showed that more patients who got the new combination had no detectable cancer cells left after treatment. This was especially true for patients over 65 and those with high-risk genetic changes.

The new combination also seemed to help patients live longer without their cancer getting worse. However, patients who got the new combination had more side effects, especially those over 65.

Overall, the researchers think adding daratumumab to the usual treatment (VRd) could help patients with high-risk multiple myeloma who are eligible for a transplant.

 

 

"Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis"

Source

Xian, M., Wang, Q., Xiao, L. et al. Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis. Nat Commun 15, 5767 (2024). https://doi.org/10.1038/s41467-024-50073-x  July 9, 2024 

Overview

With multiple myeloma,  the bone marrow plasma cells grow out of control. Patients with fast-growing multiple myeloma tend to have shorter lifespans.

Researchers found that a gene called LILRB1 is linked to worse outcomes in myeloma patients. This gene makes a protein that helps control immune responses. When they removed LILRB1 in lab tests, it slowed down myeloma growth by making cancer cells more likely to die through a process called ferroptosis.

The study showed that LILRB1 works with other proteins to help cells take in cholesterol. Without LILRB1, cells can't absorb cholesterol as well. This causes them to make more cholesterol on their own, which leads to less of a substance that protects against ferroptosis.

These findings suggest that targeting LILRB1 could be a promising new way to treat MM. By blocking this gene, doctors might be able to make cancer cells more vulnerable to ferroptosis and slow down the disease.

 

 

"Understanding CAR-T therapy in myeloma: 1 cell at a time"

Source

Madhav V. Dhodapkar; Understanding CAR-T therapy in myeloma: 1 cell at a time. Blood Adv 2024; 8 (13): 3560–3561. doi: https://doi.org/10.1182/bloodadvances.2024013292  July 9, 2024 

Overview

Scientists are studying how special immune cells called CAR T-cells work to fight multiple myeloma. Here's what they found:

• CAR T-cells are modified immune cells designed to attack cancer.
• Researchers looked at 15 patients with multiple myeloma who received CAR T-cell therapy.
• Patients who did better had more CAR T-cells that stuck around longer in their bodies.
• Patients who didn't do as well had more "tired" CAR T-cells that couldn't fight cancer effectively.
• The study shows that looking at individual cells can help us understand why some patients respond better to treatment than others.
• Other factors that might affect how well CAR T-cells work include:
  • The patient's own immune system
  • The cancer cells themselves
  • Other cells in the area around the tumor
• Scientists are using this information to make better CAR T-cell treatments. They're trying to:
  • Use CAR T-cells earlier in treatment
  • Make CAR T-cells that last longer in the body
  • Target multiple parts of the cancer cell at once

More research is needed to fully understand how CAR T-cells work and how to make them even better at fighting cancer.

 

 

"CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy"

Source

Guy Ledergor, Zenghua Fan, Kai Wu, Elizabeth McCarthy, Axel Hyrenius-Wittsten, Alec Starzinski, Hewitt Chang, Mark Bridge, Serena Kwek, Alexander Cheung, Sophia Bylsma, Erik Hansen, Jeffrey Wolf, Sandy Wong, Nina Shah, Kole T. Roybal, Thomas Martin, Chun J. Ye, Lawrence Fong; CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy. Blood Adv 2024; 8 (13): 3562–3575. doi: https://doi.org/10.1182/bloodadvances.2023012416  July 9, 2024 

Overview

Multiple myeloma often relapses fter treatment. CAR T-cell therapy has shown promise for patients whose cancer has returned or isn't responding to other treatments. This therapy targets a specific protein called BCMA on cancer cells.

While many patients initially respond well to CAR T-cell therapy, most eventually see their cancer return. Scientists wanted to understand why this happens. They found that patients who had longer-lasting responses to the treatment had more CAR T cells that stayed in their body. These patients also had more of a certain type of immune cell called CD8+ T-effector memory cells.

On the other hand, patients whose cancer came back quickly had more of a different type of cell called cytotoxic CD4+ CAR T cells. These cells grew quickly at first but showed signs of being "tired" or not working well.

The researchers also discovered that certain cells in the bone marrow, where multiple myeloma grows, might be making the CAR T cells less effective.

This research helps explain why CAR T-cell therapy doesn't always work long-term for multiple myeloma patients. It could lead to ways to make the treatment more effective in the future.

 

 

"Immune dysfunction prior to and during vaccination in multiple myeloma: a case study based on COVID-19"

Source

Martín-Sánchez, E., Tamariz-Amador, LE., Guerrero, C. et al. Immune dysfunction prior to and during vaccination in multiple myeloma: a case study based on COVID-19. Blood Cancer J. 14, 111 (2024). https://doi.org/10.1038/s41408-024-01089-5 July 10, 2024 

Overview

Multiple myeloma often relapses fter treatment. CAR T-cell therapy has shown promise for patients whose cancer has returned or isn't responding to other treatments. This therapy targets a specific protein called BCMA on cancer cells.

While many patients initially respond well to CAR T-cell therapy, most eventually see their cancer return. Scientists wanted to understand why this happens. They found that patients who had longer-lasting responses to the treatment had more CAR T cells that stayed in their body. These patients also had more of a certain type of immune cell called CD8+ T-effector memory cells.

On the other hand, patients whose cancer came back quickly had more of a different type of cell called cytotoxic CD4+ CAR T cells. These cells grew quickly at first but showed signs of being "tired" or not working well.

The researchers also discovered that certain cells in the bone marrow, where multiple myeloma grows, might be making the CAR T cells less effective.

This research helps explain why CAR T-cell therapy doesn't always work long-term for multiple myeloma patients. It could lead to ways to make the treatment more effective in the future.

 

 

"RASping myeloma genomics"

Source

Bruno Paiva, María-José Calasanz; RASping myeloma genomics. Blood 2024; 144 (2): 129–131. doi: https://doi.org/10.1182/blood.2024024869  July 11, 2024 

Overview

In a recent study published in Blood, Schavgoulidze et al analyzed somatic mutations in over 10,000 patients with plasma cell neoplasms using targeted sequencing. Their findings revealed that mutations in the KRAS, NRAS, and BRAFV600E genes are the most common secondary events in multiple myeloma (MM). However, these mutations may have limited use as therapeutic targets and biomarkers for monitoring treatment.

Previous studies on the genomic landscape of MM were disappointing compared to other blood cancers like Waldenström macroglobulinemia or hairy cell leukemia, which have unifying mutations used in diagnosis and treatment. Unlike these cancers, MM lacks a unifying somatic mutation in most patients, making it crucial to explore the frequency and impact of mutations in the MAPK pathway.

Schavgoulidze et al made three key observations:

1. KRAS/NRAS/BRAFV600E mutations are present in 60.7% of MM patients, a higher rate than other genetic alterations in MM. This suggests these mutations play a significant role in MM development.
2. These mutations are more frequent in advanced stages of MM but are not linked to treatment resistance or relapse. They might indicate early progression in smoldering MM but don't necessarily predict prognosis.
3. The specific mutated codons and the subclonal nature of these mutations limit their effectiveness as treatment targets. While some studies showed success with combined BRAF/MEK inhibition in certain patients, these findings were not consistent across all studies.

The study's major contribution is demonstrating the feasibility of targeted sequencing in routine diagnostics, analyzing over 10,000 patients, including those with low tumor burdens. This effort paves the way for incorporating next-generation sequencing in regular clinical practice, guiding future treatment and monitoring strategies.

 

 

"RAS/RAF landscape in monoclonal plasma cell conditions"

Source

Anais Schavgoulidze, Jill Corre, Mehmet Kemal Samur, Celine Mazzotti, Luka Pavageau, Aurore Perrot, Titouan Cazaubiel, Xavier Leleu, Margaret Macro, Karim Belhadj, Murielle Roussel, Sabine Brechignac, Lydia Montes, Denis Caillot, Laurent Frenzel, Philippe Rey, Jean-Marc Schiano de Colella, Thomas Chalopin, Caroline Jacquet, Valentine Richez, Frederique Orsini-Piocelle, Jean Fontan, Salomon Manier, Ludovic Martinet, Adam Sciambi, Mohamad Mohty, Herve Avet-Loiseau; RAS/RAF landscape in monoclonal plasma cell conditions. Blood 2024; 144 (2): 201–205. doi: https://doi.org/10.1182/blood.2023022295 July 11, 2024  

Overview

Multiple myeloma shows a lot of diversity at the molecular level, with the RAS/RAF pathway being the most frequently mutated in about 50% of patients. These mutations often appear as secondary events, not primary ones. Researchers analyzed over 10,000 patients with various plasma cell disorders to understand the RAS/RAF mutations better.

They found that almost 61% of patients had RAS/RAF mutations at diagnosis or relapse, but these mutations were much less common in early, presymptomatic cases. Interestingly, the types of mutations in these patients were different from those typically seen in solid tumors, with a higher number of Q61 mutations.

In 29 patients who had two different mutations, single-cell sequencing showed that these mutations often occurred in different subclones, indicating an ongoing process of mutation. These findings suggest that targeting the RAS/RAF pathway might not be effective for treatment or monitoring residual disease in multiple myeloma.

 

 

"IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse"

Source

Brandon D. Ng, Adhithi Rajagopalan, Anastasia I. Kousa, Jacob S. Fischman, Sophia Chen, Alyssa Massa, Harold K. Elias, Dylan Manuele, Michael Galiano, Andri L. Lemarquis, Alexander P. Boardman, Susan DeWolf, Jonah Pierce, Bjarne Bogen, Scott E. James, Marcel R. M. van den Brink; IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model. Blood 2024; 144 (2): 171–186. doi: https://doi.org/10.1182/blood.2023022293 July 11, 2024 

Overview

Multiple myeloma affects plasma cells and is incurable with standard treatments. CAR T cells, which are modified to attack cancer cells, have shown success in leukemia and lymphoma by targeting the CD19 antigen. Recently, CAR T cells targeting BCMA (B-cell maturation antigen) have shown promise in treating myeloma, but they sometimes fail when BCMA levels are low on cancer cells.

To improve outcomes for patients with low BCMA expression, researchers explored a new approach by combining CAR T cells that secrete interleukin-18 (IL-18), a proinflammatory cytokine, and target multiple antigens. In a mouse model of myeloma, CAR T cells targeting both BCMA and BAFF-R (B-cell activating factor receptor) did not effectively eliminate myeloma when these antigens were weakly expressed. However, CAR T cells that secreted IL-18 and targeted these antigens were able to clear the myeloma.

IL-18-secreting CAR T cells developed into more effective T cells, increased interferon-gamma production, changed the myeloma bone marrow environment, and activated macrophages to fight the cancer. Targeting both BCMA and BAFF-R simultaneously enhanced the strength of the CAR T cells' signals and improved their ability to fight myeloma.

This dual-antigen approach, combined with IL-18 secretion, showed the ability to eliminate larger amounts of myeloma in mice, demonstrating a new potential treatment strategy for myeloma with low antigen expression.

 

 

"Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma"

Source

Puccio N, Manzotti G, Mereu E, Torricelli F, Ronchetti D, Cumerlato M, Craparotta I, Di Rito L, Bolis M, Traini V, Manicardi V, Fragliasso V, Torrente Y, Amodio N, Bolli N, Taiana E, Ciarrochi A, Piva R, Neri A. Combinatorial strategies targeting NEAT1 and AURKA as new potential therapeutic options for multiple myeloma. Haematologica; https://doi.org/10.3324/haematol.2024.285470 [Early view].  July 11, 2024. 

Overview

With multiple myeloma (MM), abnormal plasma cells grow uncontrollably in the bone marrow. The disease has a complex clinical and molecular profile due to severe genomic changes. A key factor in myeloma is the deregulation of long non-coding RNAs (lncRNAs), which affects disease progression and resistance to therapy. One such lncRNA, NEAT1, plays a crucial role in myeloma cell growth, making it a promising target for treatment.

Researchers combined transcriptomic and computational methods with high-throughput drug screening to find drugs that work well with NEAT1 inhibition to slow myeloma cell growth. They discovered that AURKA inhibitors are particularly effective. When NEAT1 is silenced and AURKA inhibitors are used together, the combination disrupts microtubule organization and mitotic spindle assembly, leading to cell death.

Data from a large multiple myeloma patient dataset (CoMMpass) showed that high levels of AURKA are linked to shorter progression-free and overall survival. Patients with high levels of both NEAT1 and AURKA have even worse outcomes. Further analysis of MM cells with reduced NEAT1 revealed that the AURKA regulator TPX2 is a new NEAT1 target, explaining the synergy between NEAT1 inhibition and AURKA inhibitors.

Targeting NEAT1 and AURKA together could be a powerful strategy for treating multiple myeloma.

 

 

"Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high risk smoldering multiple myeloma included in the GEM-CESAR trial"

Source

Puig N, Agulló C, Contreras T, Pérez J-J, Aires I, Calasanz M-J, García-Sanz R, Castro S, Martínez-López J, Rodríguez-Otero P, González-Calle V, González MS, Oriol A, Gutiérrez NC, Ríos-Tamayo R, Rosiñol L, Álvarez M- Ángel, Bargay J, González-Rodríguez A-P, Alegre A, Escalante F, Iñigo M-B, de la Rubia J, Teruel A-I, de Arriba F, Palomera L, Hernández MT, López-Jiménez J, Reinoso M, García-Mateo A, Ocio EM, Bladé J, Lahuerta J-J, Cedena M-T, Paiva B, Miguel JFS, Mateos M-V. Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high risk smoldering multiple myeloma included in the GEM-CESAR trial. Haematologica; https://doi.org/10.3324/haematol.2024.285742 [Early view].  July 11, 2024. 

Overview

Researchers are exploring a method called quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein in patients with monoclonal gammopathies. This study focused on high-risk smoldering myeloma (HRsMM) and included 62 patients from the GEM-CESAR trial. 

After 24 cycles of maintenance therapy, the study found that detecting the M-protein with mass spectrometry (MS) or clonal plasma cells with next-generation flow cytometry (NGF) could identify patients with shorter median progression-free survival (PFS). Specifically, patients with detectable M-protein or clonal plasma cells had significantly shorter PFS compared to those without. However, achieving complete response (CR) or stringent complete response (sCR) did not predict different outcomes.

When using NGF as a reference, combining results from NGF and MS showed a high negative predictive value (NPV) for MS: 81% overall and 73% at the end of treatment. Patients who remained negative in both MS and NGF tests over time had very favorable outcomes, with their median PFS not yet reached, compared to 1.66 years and 2.18 years for those who never achieved peripheral residual disease (PRD) or minimal residual disease (MRD) negativity.

Key takeaways from this study are:

1. Standard response categories may not be useful for monitoring treatment in HRsMM patients.
2. MS could be a valuable, non-invasive tool for guiding bone marrow evaluations due to its high NPV when referenced with NGF.
3. Sequential results from MS can identify HRsMM patients who are likely to have long-term disease control.

This trial was registered at ClinicalTrials.gov (identifier: NCT02415413).

 

 

"A multidisciplinary group-based survivorship intervention for those living with multiple myeloma: a feasibility study"

Source

Eilert, N., Murphy, NJ., Cummins, H. et al. A multidisciplinary group-based survivorship intervention for those living with multiple myeloma: a feasibility study. Pilot Feasibility Stud 10, 100 (2024). https://doi.org/10.1186/s40814-024-01524-1  July 15, 2024.  

Overview

Multiple myeloma is still an incurable cancer, but better understanding and management have significantly improved survival rates. However, there are few support programs for survivors, even though many have unmet needs. This study evaluated a new group-based support program for multiple myeloma survivors to see if it was practical and helpful.

The study was conducted within a routine cancer support service using a mixed-method, repeated measures approach. Seven participants, all over 18 with multiple myeloma and deemed suitable by their doctor, attended six weekly online group sessions. These sessions included physical exercise and self-management advice. The participants completed various assessments before, immediately after, and sometime after the intervention.

The program was found to be feasible, with high participation rates. Participants generally found it acceptable and appropriate, suggesting some improvements for future sessions. The intervention's effectiveness showed mixed results. While participants reported benefits like peer support, feeling connected, and improved well-being, and there were large improvements in most physical outcomes, there were no reported improvements in quality of life or fatigue.

This study is the first to investigate a new support program for multiple myeloma survivors, emphasizing the importance of peer support. Future clinical trials will build on these findings to establish the program's effectiveness for routine care.

 

 

"UnSETtling energy dependence of t(4;14) MM"

Source

P. Leif Bergsagel, Marta Chesi; UnSETtling energy dependence of t(4;14) MM. Blood 2024; 144 (3): 244–245. doi: https://doi.org/10.1182/blood.2024024871  July 18, 2024   

Overview

In this issue of Blood, Sobh et al reveal that NSD2 overexpression in t(4;14) multiple myeloma (MM) redirects S-adenosylmethionine (SAM) to the epigenome. This impairs SAM-dependent creatine production, making the cells rely on adenylate kinase 2 (AK2) for mitochondrial ATP distribution.

The t(4;14) chromosome translocation, discovered nearly 30 years ago, uniquely dysregulates two oncogenes, one on each derivative chromosome. On der14, the enhancer increases FGFR3 expression in most patients, with somatic mutations further activating it in 40% of cases. On der4, patients express a fusion transcript involving NSD2, leading to an amino-truncated NSD2 that mislocalizes from nuclei to nucleoli. NSD2 acts as a histone H3 lysine 36 dimethylase (H3K36me2), increasing H3K36me2 and decreasing H3K27me3 globally in t(4;14) MM.

Using a genome-wide CRISPR screen, Sobh and colleagues found that cells with NSD2 overexpression depend heavily on metabolic pathways, particularly AK2. This protein is crucial for maintaining energy balance in cells. They showed that NSD2 overexpression diverts one-carbon metabolism towards methylation, depleting creatine and increasing reliance on AK2.

This study is important because it highlights how extensive epigenome methylation can deplete cellular resources. It also identifies a potential therapeutic target in AK2 for t(4;14) MM, a subtype with limited treatment progress. While an inhibitor targeting NSD2's methyltransferase activity is in clinical trials, therapies targeting AK2 could offer new treatment avenues. Furthermore, AK2 may be a target in other lymphoid tumors, broadening the impact of this research.

 

 

"NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome"

Source

Amin Sobh, Elena Encinas, Alisha Patel, Greeshma Surapaneni, Emilie Bonilla, Charlotte Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphné Dupéré-Richer, Alberto Riva, Benjamin G. Barwick, Daohong Zhou, Lawrence H. Boise, Constantine S. Mitsiades, Baek Kim, Richard L. Bennett, Navdeep S. Chandel, Jonathan D. Licht; NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome. Blood 2024; 144 (3): 283–295. doi: https://doi.org/10.1182/blood.2023022859  July 18, 2024   

Overview

Chromosomal translocation (4;14) is an adverse prognostic factor in multiple myeloma (MM) because it causes overexpression of the histone methyltransferase NSD2. A genome-wide CRISPR screen in MM cells revealed that NSD2 overexpression makes the cells vulnerable to the loss of adenylate kinase 2 (AK2). AK2 is crucial for transferring high-energy phosphate from the mitochondria. Suppressing AK2 in t(4;14) MM cells reduced NADP(H) levels, which are essential for converting ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage, and cell death.

NSD2 overexpression increases chromatin methylation, depleting S-adenosylmethionine and hindering creatine synthesis from its precursor, guanidinoacetate. Supplementing with creatine restored NADP(H) levels, reduced DNA damage, and rescued AK2-deficient t(4;14) MM cells. This shows that NSD2-driven creatine depletion makes t(4;14) MM cells particularly sensitive to AK2 loss. 

Additionally, AK2 depletion in t(4;14) cells disrupted protein folding in the endoplasmic reticulum due to impaired mitochondrial ATP use. This increased the cells' sensitivity to proteasome inhibition. These findings highlight a new mechanism where abnormal carbon transfer to the epigenome creates a metabolic weakness, offering potential therapeutic targets for treating t(4;14) MM.

 

 

"Optimization of older adults by a geriatric assessment–guided multidisciplinary clinic before CAR T-cell therapy"

Source

Samuel J. Yates, John F. Cursio, Andrew Artz, Keriann Kordas, Michael R. Bishop, Benjamin A. Derman, Satyajit Kosuri, Peter A. Riedell, Justin Kline, Andrzej Jakubowiak, Mylove Mortel, Shalitha Johnson, Mariam T. Nawas; Optimization of older adults by a geriatric assessment–guided multidisciplinary clinic before CAR T-cell therapy. Blood Adv 2024; 8 (14): 3785–3797. doi: https://doi.org/10.1182/bloodadvances.2024012727 July 23, 2024 

Overview

Assessing whether older adults (65 and up) are suitable for chimeric antigen receptor T-cell (CAR-T) therapy can be challenging. Researchers examined the effectiveness of using a geriatric assessment-guided multidisciplinary clinic (GA-MDC) for selecting and preparing these patients. Sixty-one patients were evaluated, with ages ranging from 58 to 83 years (average age 73). Each patient received a recommendation to either "proceed" or "decline" CAR-T therapy based on their geriatric assessment.

Out of these, 53 patients eventually received CAR-T therapy: 47 were advised to proceed, while 6 were advised to decline. The median survival time was 14.2 months for those receiving BCMA-directed CAR-T therapy and 16.6 months for those receiving CD19-directed CAR-T therapy. Patients advised to proceed generally had fewer geriatric impairments, spent less time in the hospital (17 days compared to 31 days), and had lower intensive care unit admission rates (6% compared to 50%).

Overall, patients who followed the "proceed" recommendation had better survival outcomes: 16.6 months vs. 11.4 months for CD19-directed therapy and 16.4 months vs. 4.2 months for BCMA-directed therapy. Even when accounting for other health factors, the GA-MDC recommendation was a strong predictor of survival. Patients without serious vulnerabilities did well, while those with high vulnerability faced more toxicity and poorer outcomes after CAR-T therapy.

 

 

"Incidence and outcomes of cytomegalovirus reactivation after chimeric antigen receptor T-cell therapy"

Source

Rick Y. Lin, Anthony D. Anderson, Yoichiro Natori, Mohammed Raja, Michele I. Morris, Antonio Jimenez Jimenez, Amer Beitinjaneh, Trent Wang, Mark Goodman, Lazaros Lekakis, Jay Spiegel, Noa G. Holtzman, Denise Pereira, Cara Benjamin, Akina Natori, Krishna V. Komanduri, Jose F. Camargo; Incidence and outcomes of cytomegalovirus reactivation after chimeric antigen receptor T-cell therapy. Blood Adv 2024; 8 (14): 3813–3822. doi: https://doi.org/10.1182/bloodadvances.2024012922  July 23, 2024 

Overview

Cytomegalovirus (CMV) reactivation is a serious issue for patients who have undergone allogeneic hematopoietic cell transplantation, but there is less information on its effects after chimeric antigen receptor (CAR) T-cell therapy. This study examines CMV reactivation in 95 adult patients who received CAR T-cell therapy between February 2018 and February 2023.

Key findings include:

• 33% of patients experienced CMV reactivation, while 11% had clinically significant CMV infection (cs-CMV).
• CMV reactivation typically occurred around 19 days after CAR T-cell infusion.
• Patients with severe cytokine release syndrome, and those treated with corticosteroids, anakinra, or multiple immunosuppressants, had higher rates of CMV reactivation.
• Using corticosteroids, tocilizumab, anakinra, and multiple immunosuppressants was linked to higher rates of cs-CMV.
• Patients on two or more immunosuppressants were twice as likely to experience CMV reactivation.
• The one-year mortality rate was significantly higher (57%) for those with CMV reactivation compared to those without (23%).

Immunosuppressive treatments, especially corticosteroids used to manage CAR T-cell therapy side effects, are major risk factors for CMV reactivation.

 

 

"Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16"

Source

Peter Mollee, John Reynolds, Wojt Janowski, Hang Quach, Philip Campbell, Simon Gibbs, Sophie Lee, Edwin Lee, Kerry Taylor, Tara Cochrane, Craig Wallington-Gates, Fiona Kwok, Nicholas Weber, Ian Kerridge, Helen Weston, P. Joy Ho, Michael Francis Leahy, Noemi Horvath, Andrew Spencer; Daratumumab, cyclophosphamide, bortezomib, and dexamethasone for transplant-ineligible myeloma: AMaRC 03-16. Blood Adv 2024; 8 (14): 3721–3730. doi: https://doi.org/10.1182/bloodadvances.2023012539  July 23, 2024 

Overview

In a study testing new treatments for patients with myeloma who cannot have a stem cell transplant, researchers found that adding the drug daratumumab to the standard treatment, which is Velcade (bortezomib), Cytoxan (cyclophosphamide), and dexamethasone, or VCD, led to better results. The study included 121 patients who were randomly assigned to receive either just VCD or VCD plus daratumumab (VCDD). Results showed that patients in the VCDD group had a longer period without their disease worsening compared to those in the VCD group. Specifically, 68% of VCDD patients were still disease-free after 18 months, compared to 48% of VCD patients. The VCDD group also had better overall responses to treatment. Additionally, 72% of VCDD patients completed the full course of therapy without severe side effects. This suggests that VCDD could be a better option for treating myeloma in patients who are not eligible for a stem cell transplant.

 

 

"Role of minimal residual disease assessment in multiple myeloma"

Source

Szalat R, Anderson K, Munshi N. Role of minimal residual disease assessment in multiple myeloma. Haematologica 2024;109(7):2049-2059; https://doi.org/10.3324/haematol.2023.284662

Overview

Recent treatments for multiple myeloma like monoclonal antibodies and CAR T-cell therapy have greatly improved survival for many patients. However, multiple myeloma is still not curable, and some patients experience early relapse and shorter survival.

To better manage MM, doctors are using new methods to detect minimal residual disease (MRD)—traces of cancer that remain after treatment. Finding MRD negativity (no detectable cancer) is a strong sign of better prognosis and is increasingly used in clinical trials. 

Several ongoing trials are exploring how MRD assessment can guide treatment decisions. For example:

• The PERSEUS trial is testing whether stopping Darzalex (daratumumab) in patients with sustained MRD negativity is beneficial and if it should be restarted if MRD returns.
• The AURIGA trial is comparing adding daratumumab to Revlimid (lenalidomide) versus just using lenalidomide in patients who have achieved a partial response but still have MRD.
• The DRAMMATIC trial is investigating whether to continue or stop treatment based on MRD status after high-dose chemotherapy and stem cell transplant.
• The OPTIMUM trial is looking at adding Ninlaro (ixazomib) to lenalidomide in MRD-positive patients.

Overall, MRD assessment has become a key tool for evaluating treatment success and guiding therapy, and its use is expanding in both clinical trials and everyday practice.

 

 

"Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma"

Source

Shin D, Kim M-J, Chun S, Kim D, Lee C, Ahn K-S, Jung E, Kim D, Lee B-C, Hwang D, Kim Y, Yoon S-S. Elucidation of molecular basis of osteolytic bone lesions in advanced multiple myeloma. Haematologica 2024;109(7):2207-2218; https://doi.org/10.3324/haematol.2023.283784. Vol. 109 No. 7 (2024): July, 2024 

Overview

Osteolytic bone lesions are a serious problem for people with multiple myeloma (MM), leading to lower quality of life and poor prognosis. Researchers are studying why these bone lesions occur and found that a protein called Fms-like tyrosine kinase 3 ligand (FLT3L) might be involved. 

In a study of 86 MM patients, 306 patients with acute myeloid leukemia (AML), and 52 with acute lymphoblastic leukemia (ALL), FLT3L levels were highest in MM patients, especially those with bone lesions. The study showed that FLT3L increases the levels of another protein called DKK1, which blocks bone formation by interfering with WNT signaling—a key process in bone growth. 

The findings suggest that FLT3L could be a useful marker to predict bone lesions in MM and might also be a target for new treatments to prevent these harmful bone changes. FLT3L and DKK1 were especially high in a specific subtype of MM called hyperdiploidy, highlighting their potential role in managing and treating MM-related bone issues.

 

 

"Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study"

Source

Miguel JF, Mateos M-V. Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study. Haematologica 2024;109(7):2219-2228; https://doi.org/10.3324/haematol.2023.284089.

Overview

In the past decade, treatments for multiple myeloma have greatly improved, but many patients still experience relapses, and new treatment options are needed. A recent phase II study tested a new combination of drugs for relapsed and hard-to-treat multiple myeloma. The study looked at adding Xpovio (selinexor) to the standard treatment of  Darzalex (daratumumab), Veclde (bortezomib), and dexamethasone (DVd). 

The study involved 57 patients split into two groups: one with heavily treated patients and another with those who had recently relapsed. In the heavily treated group (24 patients), the combination had an overall response rate of 50%, with two patients achieving a complete response. The median time before the disease worsened was 7 months. In the recently relapsed group (33 patients), the overall response rate was 82%, with 33% of patients achieving a complete response. The median time before the disease worsened was 24 months, and in patients resistant to lenalidomide, it was 22.1 months.

The main side effects included low blood platelet levels (thrombocytopenia) and nausea, with 62% of patients needing dose adjustments. While the study didn’t meet its main goal, the combination of selinexor with DVd showed promising results and could be a new option for treating relapsed multiple myeloma.

 

 

"Carfilzomib, thalidomide, and dexamethasone are safe and effective in relapsed and/or refractory multiple myeloma: final report of the single-arm, multicenter, phase II ALLG MM018/AMN002 study"

Source

Ninkovic S, Harrison SJ, Lee J-J, Murphy N, Lee JH, Estell J, Chen VM, Horvath N, Kim K, Eek R, Augustson B, Bang S-M, Huang S-Y, Rajagopal R, Szabo F, Engeler D, Butcher BE, Mollee P, Durie B, Chng WJ, Quach H. Carfilzomib, thalidomide, and dexamethasone are safe and effective in relapsed and/or refractory multiple myeloma: final report of the single-arm, multicenter, phase II ALLG MM018/AMN002 study. Haematologica 2024;109(7):2229-2238; https://doi.org/10.3324/haematol.2023.284238

Overview

A recent study tested a treatment combination of Kyprolis (carfilzomib), Thalomid (thalidomide), and dexamethasone (KTd) for patients with relapsed or hard-to-treat multiple myeloma. This study looked at how well this combination works and how safe it is.

The study included 93 patients who had previously received one to three lines of therapy. They were treated with KTd for up to 18 months. Carfilzomib was given in increasing doses, thalidomide was taken daily, and dexamethasone was given weekly. After the initial phase, thalidomide was stopped, but carfilzomib and dexamethasone continued.

The main goal was to see how long patients stayed without their disease worsening. Secondary goals included the overall response rate and overall survival. The study found that:

• Progression-Free Survival (PFS):  The median PFS was 22.3 months, with 46.3% of patients being disease-free after 2 years.
• Overall Survival: The median overall survival was not reached, but 73.8% of patients were alive after 2 years.
• Overall Response Rate:  88% of patients responded to the treatment, with 73% achieving a very good partial response or better.

The treatment was generally well-tolerated, though some side effects like low blood platelet levels and nausea were common. The safety profile was similar to that of each individual drug used in the combination. 

Interestingly, the treatment worked well for both Asian and non-Asian patients, and there was no significant difference in outcomes based on ethnicity. KTd also proved to be effective regardless of how many previous treatments patients had or their genetic risk factors.

Overall, the KTd combination is a promising option for treating relapsed multiple myeloma, especially in cases where other treatments might be limited by cost, access, or kidney issues. It provides an alternative to other commonly used treatments and has shown positive results in extending survival and managing the disease effectively.

 

 

"Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis"

Source

Richardson PG, Perrot A, Miguel JS, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang S-Y, Minarik J, Cavo M, Prince HM, Macé S, Zhang R, Dubin F, Morisse MC, Anderson KC. Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis. Haematologica 2024;109(7):2239-2249; https://doi.org/10.3324/haematol.2023.284325

Overview

The ICARIA-MM study investigated whether adding isatuximab, an anti-CD38 antibody, to the standard treatment of Pomalyst (pomalidomide) and dexamethasone (Pd) improves outcomes for patients with relapsed or hard-to-treat multiple myeloma. The study included 307 patients who had previously failed at least two other treatments.

The final analysis, after about 52 months of follow-up, found that:

• Overall Survival (OS): Patients receiving Sarclisa (isatuximab), Pomalyst (pomalidomide), and dexamethasone (Isa-Pd) had a median survival of 24.6 months, compared to 17.7 months for those on Pd alone. This represents a significant 6.9-month improvement in survival with Isa-Pd.
• Progression-Free Survival (PFS): The time patients remained without their disease worsening was also longer with Isa-Pd (17.5 months) compared to Pd (12.9 months).

Overall, Isa-Pd was well-tolerated and provided a meaningful benefit in overall survival for patients with relapsed or refractory multiple myeloma, showing that it could be a valuable addition to the treatment regimen.

 

 

"Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden"

Source

Rögnvaldsson S, Thorsteinsdóttir S, Syriopoulou E, Sverrisdottir I, Turesson I, Eythorsson E, Oskarsson JT, Long TE, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Olafsson I, Thorsteinsdottir I, Aspelund T, Gislason GK, Olafsson A, Sigurdsson JK, Hultcrantz M, Durie BGM, Harding S, Bjorkholm M, Landgren O, Love TJ, Kristinsson SY. Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden. Haematologica 2024;109(7):2250-2255; https://doi.org/10.3324/haematol.2023.284365

Overview

A study explored whether having a history of cancer increases the risk of developing monoclonal gammopathy of undetermined significance (MGUS), a condition that can lead to multiple myeloma (MM). 

The study had two parts:

1. Screening Study: It checked if prior cancers were linked to higher rates of MGUS in a group of 75,422 people. 
2. Progression Study: It looked at whether prior cancer affected the progression of MGUS to MM in 13,790 individuals with MGUS.

The results showed that:

• Risks of MGUS: Having a history of cancer slightly increased the risk of MGUS, but only for cancers diagnosed within a year before MGUS screening.
• Progression of MGUS: A prior cancer was generally linked to a higher risk of MGUS progressing to MM, except for patients with myeloid malignancies, who had a lower risk.

The study found that having a prior cancer is not a major cause of plasma cell disorders. Therefore, people with a history of cancer do not need special MGUS screening or different management.

 

 

"Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study"

Source

Schjesvold FH, Ludwig H, Delimpasi S, Robak P, Coriu D, Tomczak W, Pour L, Spicka I, Dimopoulos M-A, Masszi T, Chernova NG, Sandberg A, Thuresson M, Norin S, Bakker NA, Mateos M-V, Richardson PG, Sonneveld P. Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study. Haematologica 2024;109(7):2331-2336; https://doi.org/10.3324/haematol.2023.284635

Overview

This study compared the impact on health-related quality of life (HRQoL) for two treatments in patients with relapsed or refractory multiple myeloma (RRMM): Elrexfio (melflufen) plus dexamethasone and Pomalyst (pomalidomide) plus dexamethasone.

These were the studies key findings:

• Treatment Groups: The study looked at 158 patients from the OCEAN trial who received either melflufen plus dexamethasone or pomalidomide plus dexamethasone.
• HRQoL Measurement: HRQoL was assessed using three questionnaires, measuring aspects like general health, physical and emotional well-being, and disease symptoms.
• Results:  Both treatments showed similar HRQoL scores at the start and throughout the study. Most patients experienced stable or improved HRQoL scores over time.
• Conclusion: Melflufen plus dexamethasone was found to be comparable to pomalidomide plus dexamethasone in terms of HRQoL, despite the higher frequency of blood-related side effects in the melflufen group.

This study demonstrated that melflufen plus dexamethasone maintains HRQoL similarly to pomalidomide plus dexamethasone, making it a viable option for patients with advanced RRMM.

 

 

"Belantamab mafodotin: an important treatment option for vulnerable patients with triple class exposed relapsed and/or refractory multiple myeloma"

Source

Mateos MV, Weisel K, Terpos E, Delimpasi S, Kastritis E, Zamagni E, Delforge M, Ocio E, Katodritou E, Gay F, Larocca A, Leleu X, Otero PR, Schjesvold F, Cavo M, Dimopoulos MA. Belantamab mafodotin: an important treatment option for vulnerable patients with triple class exposed relapsed and/or refractory multiple myeloma. Haematologica 2024;109(7):2337-2340; https://doi.org/10.3324/haematol.2023.284694

Overview

A group of leading European myeloma experts is responding to the European Medicines Agency’s decision not to renew the marketing authorization for belantamab mafodotin. They argue that this drug is crucial for treating patients with multiple myeloma (MM) who have not responded to other therapies.

Here are key points of this letter to the editor:

• Multiple Myeloma Treatment: Multiple myeloma is a serious blood cancer with limited treatment options for patients who have tried and failed several standard drugs.
• Blenrep (belantamab mafodotin): This drug, a BCMA-targeted therapy, was the first approved for patients who have exhausted other treatments. It has shown significant benefits in clinical trials, including a good overall response rate and manageable safety profile.
• Clinical Trials: Despite some trials not meeting all their goals, belantamab mafodotin has demonstrated effectiveness in improving patient outcomes compared to other treatments. It has a favorable safety profile and is especially useful for patients who are elderly or frail.
• Accessibility and Convenience: The drug is easier to administer compared to other advanced therapies like CAR T-cell treatments, making it a better option for patients in remote areas or those with limited support.

The experts believe that belantamab mafodotin remains an essential treatment option for patients with advanced multiple myeloma, and its benefits should be considered in future treatment strategies.

 

 

"A population-based study on 8672 multiple myeloma patients diagnosed 2008-2021 from the Swedish Myeloma Registry"

Source

Blimark CH, Carlson K, Day C, Einarsdottir S, Juliusson G, Karma M, Knut-Bojanowska D, Larfors G, Turesson I, Villegas-Scivetti M, Sverrisdóttir I. Risk of infections in multiple myeloma. A population-based study on 8672 multiple myeloma patients diagnosed 2008-2021 from the Swedish Myeloma Registry. Haematologica; https://doi.org/10.3324/haematol.2024.285645 [Early view].  July 18, 2024. 

Overview

Recent advancements in multiple myeloma (MM) treatments have improved survival rates, but they also highlight new infection risks for these patients. A Swedish study of 8,672 MM patients and 34,561 matched controls found that MM patients are five times more likely to get significant infections compared to people without MM.

Here are the study's key findings: 

• Infection Risks: MM patients have a 5-fold increased risk of bacterial infections and a 7-fold increased risk of viral and fungal infections.
• Timing of Risks: The risk of infections is highest during the first year after an MM diagnosis and remains elevated for up to 5 years.
• Pre-Diagnosis Risks: Infection risks are also higher in the years leading up to an MM diagnosis.
• Mortality: Infection is a major cause of death among MM patients, contributing to 32% of deaths within 2 months of diagnosis and 27% of deaths after one year.

This study shows that despite improved treatments, infections are still a significant threat for MM patients, underscoring the need for effective prevention strategies.

 

"LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway"

Source

Xie, L., Chen, C., Zhang, T. et al. LILRB4 regulates multiple myeloma development through STAT3-PFKFB1 pathway. Cell Death Dis 15, 515 (2024). https://doi.org/10.1038/s41419-024-06883-4 July 18, 2024

Overview

Multiple myeloma (MM) may be difficult to treat with immunotherapy alone. Researchers have found that a molecule called leukocyte immunoglobulin-like receptor B4 (LILRB4) is often highly present in multiple myeloma cells and is linked to worse outcomes for patients.

Here are the key findings of this study:

• LILRB4 and MM: High levels of LILRB4 are associated with shorter overall survival in MM patients.
• Effects of Targeting: LILRB4: Reducing LILRB4 levels slows MM cell growth in both lab tests and animal models.
• Mechanism: LILRB4 is activated by another molecule, IKZF1, which helps MM cells grow by triggering certain pathways in the cells.
• Therapeutic Potential: Blocking LILRB4 with specific antibodies can effectively slow down MM progression.

This research suggests that targeting LILRB4 might be a promising new strategy for treating MM with immunotherapy.

 

"A.R.R.O.W.2: Once- vs twice-weekly carfilzomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma"

Source

Meletios-Athanasios A. Dimopoulos, Daniel Coriu, Sosana Delimpasi, Ivan Spicka, Terry E Upchurch, Belle Fang, Rakhshandra Talpur, Edward Anthony Faber, Meral Beksac, Xavier Leleu; A.R.R.O.W.2: Once- vs twice-weekly carfilzomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Blood Adv 2024; bloodadvances.2024013101. doi: https://doi.org/10.1182/bloodadvances.2024013101  July 18, 2024 

Overview

In treating relapsed or refractory multiple myeloma (RRMM), a common regimen is Kyrpolis (carfilzomib) given twice a week along with Revlimid (lenalidomide) and dexamethasone. However, a new study explored a once-weekly carfilzomib schedule to see if it was just as effective but more convenient for patients.

Here are the details of this study:

• Objective: Compare the effectiveness of once-weekly carfilzomib (56 mg/m²) with the standard twice-weekly dose (27 mg/m²) in RRMM patients.
• Study Design: 454 patients were divided into two groups: one received the once-weekly regimen (228 patients), and the other received the twice-weekly regimen (226 patients).
• Results:
  • Overall Response Rate (ORR): The once-weekly group had an ORR of 82.5%, while the twice-weekly group had 86.3%. The once-weekly regimen did not meet the criteria for being statistically non-inferior.
  • Complete Response: 46.9% of the once-weekly group achieved a complete response, compared to 36.3% in the twice-weekly group.
  • Progression-Free Survival: Similar in both groups.
  • Safety: The safety profiles were comparable.
• Conclusion: Although the once-weekly regimen did not statistically meet the noninferiority benchmark for overall response rate, it showed similar efficacy and safety. This suggests that once-weekly carfilzomib could be a convenient and effective treatment option for RRMM patients.

 

"Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma"

Source

Ziccheddu, B., Giannotta, C., D’Agostino, M. et al. Genomic and immune determinants of resistance to daratumumab-based therapy in relapsed refractory multiple myeloma. Blood Cancer J. 14, 117 (2024). https://doi.org/10.1038/s41408-024-01096-6  July 19, 2024 

Overview

In the treatment of relapsed or refractory multiple myeloma (RRMM), the combination of Darzalex (daratumumab), Revlimid (lenalidomide), and dexamethasone (Dara-Rd) has improved patient outcomes and extended progression-free survival. However, many patients still experience relapse. To understand why, researchers studied 32 patients undergoing this treatment and used advanced techniques to analyze their responses.

Here are the details of this study:

• Genomic Analysis: Whole-genome sequencing before and after treatment identified specific genetic changes linked to early relapse. These included loss of the RPL5 gene, mutations from APOBEC, and changes in MYC genes and chromothripsis.
• Immune System Changes: Flow cytometry on blood samples revealed that patients who relapsed had notable changes in their immune system. These included a decrease in CD38-positive NK cells, ongoing T-cell exhaustion, and less reduction of regulatory T cells over time.
• Conclusion: The study highlights how both genetic and immune system changes contribute to resistance against Dara-Rd treatment. Understanding these factors can help in developing better strategies to overcome resistance and improve treatment outcomes for RRMM patients.

 

"Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma"

Source

Rees, M.J., Mammadzadeh, A., Bolarinwa, A. et al. Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma. Blood Cancer J. 14, 122 (2024). https://doi.org/10.1038/s41408-024-01081-z  July 23, 2024 

Overview

Researchers looked at three types of BCMA-directed therapies (BDTs) for treating multiple myeloma: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs). They reviewed data from 339 patients treated with these therapies between 2018 and 2023. 

They found that:

• ADCs were used in older patients with more advanced disease.
• CAR-T and TCEs had better results in terms of progression-free survival (how long patients stayed without their disease getting worse) and overall survival compared to ADCs.
• Patients who had received a prior BDT had worse results, especially with CAR-T.

CAR-T was the most effective overall and is recommended as the first choice when possible. However, for patients who have already had a BDT or have rapidly worsening disease, other options might be better.

 

"Class Ⅱ ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma"

Source

Jiasi Zhang, Yuxi Liu, Liping Zuo, Fengjuan Fan, Han Yan, Fei Zhao, Junying Li, Chi Ma, Qun Li, Aoshuang Xu, Jian Xu, Bo Zhang, Yu Hu, Chunyan Sun; Class Ⅱ ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma. Blood Adv 2024; bloodadvances.2023010335. doi: https://doi.org/10.1182/bloodadvances.2023010335  July 23, 2024 

Overview

Patients with multiple myeloma (MM) have many genetic changes. Some patients have one specific change, t(4;14), which usually means a worse outcome for these patients. Ferroptosis is a new type of cancer treatment that’s not fully understood in relation to these genetic changes. This study found that MM cells with the t(4;14) change are more affected by a certain class of ferroptosis drugs than those without it. The study showed that a protein called MMSET helps these cells become more sensitive to ferroptosis by increasing levels of certain fatty acids. Adding these fatty acids can make MM cells without the t(4;14) change more sensitive to ferroptosis too.

Combining ferroptosis drugs with another drug called bortezomib works well in fighting MM with the t(4;14) change. This combination reduces key cell survival factors and boosts the effectiveness of the treatment. Overall, targeting ferroptosis with these drugs could be a new way to treat MM patients with the t(4;14) change more effectively.

 

 

"Clinical Outcomes After Idecabtagene Vicleucel in Older Multiple Myeloma Patients: A Multicenter Real-world Experience"

Source

Nilesh Kalariya, Michelle A.T. Hildebrandt, Doris K Hansen, Surbhi Sidana, Jack Khouri, Christopher James Ferreri, William N Doyle, Omar A. Castaneda Puglianini, Ciara L Freeman, Vanna Hovanky, Hitomi Hosoya, Leyla Shune, Krina K. Patel; Clinical Outcomes After Idecabtagene Vicleucel in Older Multiple Myeloma Patients: A Multicenter Real-world Experience. Blood Adv 2024; bloodadvances.2024013540. doi: https://doi.org/10.1182/bloodadvances.2024013540 July 23, 2024  

Overview

CAR T-cell therapy, like Carvykti (idecabtagene vicleucel, or ide-cel), is often used for treating multiple myeloma, but there's less information about how it works for older patients who may have more health issues. In a study of 156 patients, including 75 aged 65 and older, researchers looked at the safety and effectiveness of ide-cel, focusing on how age and health conditions affect outcomes.

Older patients in this study had a median age of 69 and faced higher levels of frailty and health problems compared to younger patients. Despite these challenges, their overall response rate to ide-cel was 86.7%, similar to the 73% response seen in younger patients from earlier studies. The median time without disease progression was 9.1 months, and overall survival was 26.5 months for older patients.

Serious side effects like severe cytokine-release syndrome (CRS) and neurotoxicity were rare, occurring in only 1% and 4% of older patients, respectively. Although older patients had more health issues like taking many medications, having multiple comorbidities, and organ dysfunction, these factors did not lead to worse outcomes with ide-cel treatment compared to younger patients.

Overall, this study suggests that ide-cel therapy is effective and safe for both younger and older patients, even those with significant health challenges.

 

 

"KDM6A Regulates Immune Response Genes in Multiple Myeloma"

Source

Daphne Dupere-Richer, Alberto Riva, Benjamin G Barwick, Sayantan Maji, Heidi Casellas Roman, Jianping Li, Umasankar De, Amin Sobh, Gabrielle Quickstad, Crissandra Piper, Marta Kulis, Teresa Ezponda, José-Ignacio Ignacio Martín-Subero, Giovanni Tonon, Weizhou Zhang, Constantine S. Mitsiades, Lawrence H Boise, Richard L Bennett, Jonathan D Licht; KDM6A Regulates Immune Response Genes in Multiple Myeloma. Blood 2024; blood.2024024518. doi: https://doi.org/10.1182/blood.2024024518  July 24, 2024 

Overview

KDM6A is a protein that helps control gene activity and is important in fighting cancer, including multiple myeloma (MM). Researchers studied MM cells with and without KDM6A to understand its role. They found that KDM6A helps activate genes that are crucial for the immune system to recognize and fight tumors. In MM patients with low KDM6A levels, these immune-related genes are not working properly. 

The study showed that KDM6A binds to parts of the genome that regulate gene activity, and without it, certain genes are turned off, which reduces the tumor's ability to be recognized by the immune system. Adding a drug that restores normal gene activity improved the expression of important immune genes. In experiments with mice, removing KDM6A from cells led to faster tumor growth and fewer immune cells attacking the tumor. This suggests that KDM6A is key to keeping tumors visible to the immune system and could be a target for new treatments.

 

 

"Coefficient of variation and texture analysis of 18F-FDG PET/CT images for the prediction of outcome in patients with multiple myeloma"

Source

Pellegrino, S., Origlia, D., Di Donna, E. et al. Coefficient of variation and texture analysis of 18F-FDG PET/CT images for the prediction of outcome in patients with multiple myeloma. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05905-7  July 24, 2024 

Overview

In multiple myeloma (MM), the way cancer spreads in the bone marrow can vary, making it hard to determine how serious the disease is and predict patient outcomes. This study explored whether analyzing images from a PET/CT scan could help predict survival in MM patients.

The researchers looked at scans from 46 patients before they started treatment. They measured how much the cancer cells took up a special marker (SUVmax and SUVmean) and used texture analysis to understand how varied the cancer was in both focal areas (hot spots) and diffuse bone marrow involvement. 

After following the patients for about 4 years, they found that certain scan features could predict how long patients would live. Specifically, the texture of the hot spots (FL CoV) and the amount of marker in the diffuse areas (DI SUVmax) were linked to survival. Patients with lower values for these measurements had a better chance of living longer.

Combining these measurements provided even clearer predictions. Patients with both favorable readings (low FL CoV and low DI SUVmax) had the best survival rates. This study suggests that analyzing PET/CT scans in detail can help doctors predict patient outcomes by assessing how aggressive the disease is in different parts of the bone marrow.

 

 

"IgG replacement in multiple myeloma"

Source

Wonnaparhown, A., Hilal, T., Squire, J. et al. IgG replacement in multiple myeloma. Blood Cancer J. 14, 124 (2024). https://doi.org/10.1038/s41408-024-01107-6  July 25, 2024

Overview

T cell engagers (TCEs) like CAR T cell therapy and bispecific antibodies have greatly helped in treating multiple myeloma (MM). However, they can lead to secondary immunodeficiency and low levels of certain antibodies (hypogammaglobulinemia or HG). This makes patients more prone to infections, which can be a major problem as they live longer with the disease.

To address this, doctors use immunoglobulin G replacement therapy (IgG-RT), which has been effective in treating similar issues in other conditions. Yet, there is no standard approach for using IgG-RT in MM patients after TCE treatment. 

This study looks at the risk of infections and HG in MM patients, and how IgG-RT can help. It also highlights the need for better methods to start, dose, and manage IgG-RT, as well as the importance of recognizing and screening for secondary immunodeficiency. Improving these strategies can help reduce infection risks and improve patient outcomes.

 

 

"Unlocking the therapeutic potential of selective CDK7 and BRD4 Inhibition against multiple myeloma cell growth"

Source

Yao Y, Deng S, Ng JF, Yuan M, Chakraborty C, Joy Weiler V, Munshi N, Fulciniti M. Unlocking the therapeutic potential of selective CDK7 and BRD4 Inhibition against multiple myeloma cell growth. Haematologica; https://doi.org/10.3324/haematol.2024.285491 [Early view].  July 25, 2024

Overview

Even with recent treatment advances, multiple myeloma is still incurable. Researchers are looking for new ways to target the disease more effectively. One promising approach involves blocking two proteins, CDK7 and BRD4, which are crucial for the growth and survival of MM cells.

Previous studies showed that stopping CDK7 disrupts the cell cycle and metabolism, making it a good target for treatment. Since CDK7 and BRD4 control different parts of the disease, targeting both at the same time seems to be more effective. When tested together, these therapies worked better at killing MM cells and reducing tumor growth compared to using either treatment alone.

This combined approach not only showed strong results in MM cells but also in cells from another cancer, Waldenström’s macroglobulinemia (WM). It was effective in stopping tumor growth in lab models, suggesting that this dual therapy could be a powerful new strategy for treating both multiple myeloma and Waldenström’s macroglobulinemia.