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 April 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 April 2024)
"HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation"
Source
Welters C, Welters M-L, Stadler S, Bullinger L, Strobel J, Hackstein H, Dhamodaran A, Blankenstein T, Hansmann L. HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation. Haematologica 2024;109(4):1121-1127; https://doi.org/10.3324/haematol.2023.283812.
Overview
Scientists discovered a genetic difference in a cell marker called HLA-C*04:09N compared to another marker, HLA-C*04:01. This difference causes an alteration in the structure of the marker, making it harder to detect on the surface of cells. However, a special type of immune cell, called a T-cell, was found to recognize substances presented by HLA-C*04:09N, even though it's not easily visible on the cell surface.
To investigate further, the researchers created cells lacking this marker, then added it back in and found that the marker was indeed present on the cell surface, especially when the cells were treated with a specific protein called IFN-γ. They also found that T-cells were activated when exposed to cells expressing this marker, confirming that the marker was able to interact with the T-cells.
This discovery suggests that even though HLA-C*04:09N may not be easily detected, it can still present substances to T-cells, leading to their activation. This could have implications for medical treatments like stem cell transplants or cellular therapy.
"Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma"
Source
Chen G, Gao X, Jia X, Wang Y, Xu L, Yu D, Chang S, Deng H, Hu K, Wang G, Li B, Xu Z, Lu Y, Wang H, Zhang T, Song D, Yang G, Wu X, Zhu H, Zhu W, Shi J. Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma. Haematologica 2024;109(4):1206-1219; https://doi.org/10.3324/haematol.2023.282789.
Overview
Researchers are still searching for a cure for multiple myeloma (MM). They've found a protein called ribosomal protein S3 (RPS3) that plays a role in MM, but they weren't sure exactly what it did until now.
This study shows that RPS3 is important for MM cells to survive and resist drugs. MM cells have a lot of RPS3, and when scientists removed RPS3 from these cells, they stopped growing and started to die, both in the lab and in animals with MM.
When RPS3 was added to MM cells, they became resistant to a type of drug called proteasome inhibitors, and the animals with MM didn't live as long. The study also found that RPS3 interacts with another protein called thyroid hormone receptor interactor 13 (TRIP13), which is linked to MM and drug resistance.
TRIP13 helps RPS3 work by changing it with a process called phosphorylation. This activates a signal called NF-κB, which helps MM cells survive and resist drugs.
The good news is that a drug called DCZ0415, which blocks TRIP13, can make MM cells more sensitive to drugs like bortezomib. When DCZ0415 was used with bortezomib, it killed more MM cells together than either drug alone.
This research suggests that RPS3 could be a new marker for MM and a target for future treatments.
"Single-cell analysis of the CD8+ T-cell compartment in multiple myeloma reveals disease-specific changes are chiefly restricted to a CD69- subset suggesting potent cytotoxic effectors exist within the tumor bed"
Source
Favaloro J, Bryant CE, Abadir E, Gardiner S, Yang S, King T, Nassif N, Sedger LM, Boyle R, Joshua DE, Ho PJ. Single-cell analysis of the CD8<sup>+</sup> T-cell compartment in multiple myeloma reveals disease specific changes are chiefly restricted to a CD69<sup>-</sup> subset suggesting potent cytotoxic effectors exist within the tumor bed. Haematologica 2024;109(4):1220-1232; https://doi.org/10.3324/haematol.2023.283062.
Overview
In multiple myeloma (MM), researchers know that CD8+ T cells, a type of immune cell, play a role in fighting this disease, but we haven't looked closely at these cells within the cancer's environment.
In this study, scientists examined CD8+ T cells in the bone marrow (BM) and blood of untreated MM patients and compared them to people without the disease. They used special techniques like flow cytometry, mass cytometry, and single-cell RNA sequencing.
They found that BM CD8+ T cells in MM patients were different from those in healthy people, especially in the expression of certain proteins called Granzymes B and K. These proteins were linked to two different types of CD8+ T cells in the BM, marked by a protein called CD69.
One type of CD8+ T cell (CD8+CD69+) in MM patients' BM showed similarities to those in healthy people, while another type (CD8+CD69-) had more mature immune cells. Interestingly, the composition of CD8+ T cells in the blood of MM patients was different from healthy people, showing fewer mature immune cells.
This research suggests that CD8+ T cells in the bone marrow of MM patients behave more like activated immune cells, and understanding these differences could help develop better treatments.
"Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes"
Source
Escure G, Fournier E, Saade C, Issa LHB, Arib I, Tilmont R, Gazeau N, Thiam BM, Chovet M, Delforge M, Gower N, Fléchon L, Cavalieri D, Chauvet P, Nudel M, Goursaud L, Berthon C, Quesnel B, Facon T, Preudhomme C, Duployez N, Manier S. Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes. Haematologica 2024;109(4):1289-1292; https://doi.org/10.3324/haematol.2023.284050. April 2024.
Overview
People with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) have a higher chance of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) compared to others, even without treatment. This risk increases for those with multiple myeloma (MM) who undergo MM-specific therapies.
Although newer treatments like proteasome inhibitors and immunomodulators have improved MM patients' survival, they also come with risks. Some people may develop therapy-related MDS or AML as a result. These complications are rare but can have a poor outcome.
The risk of developing these complications is influenced by various factors such as age, sex, ethnicity, genetics, and previous treatments received. Certain MM treatments like high-dose melphalan used in stem cell transplantation or lenalidomide maintenance therapy have been linked to an increased risk.
Recent research suggests that some patients may already have small mutated cell populations, called subclones, before being diagnosed with MDS. These subclones can grow during MM treatments, particularly with lenalidomide, and lead to the development of MDS or AML.
Understanding these risks and the presence of these mutated cell populations could help develop safer treatments for MM patients. It's essential to explore alternative therapies to reduce the risk of developing MDS or AML, especially for those with long-term exposure to lenalidomide.
"HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation"
Source
Welters C, Welters M-L, Stadler S, Bullinger L, Strobel J, Hackstein H, Dhamodaran A, Blankenstein T, Hansmann L. HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation. Haematologica 2024;109(4):1121-1127; https://doi.org/10.3324/haematol.2023.283812.
Overview
Scientists discovered a genetic difference in a cell marker called HLA-C*04:09N compared to another marker, HLA-C*04:01. This difference causes an alteration in the structure of the marker, making it harder to detect on the surface of cells. However, a special type of immune cell, called a T-cell, was found to recognize substances presented by HLA-C*04:09N, even though it's not easily visible on the cell surface.
To investigate further, the researchers created cells lacking this marker, then added it back in and found that the marker was indeed present on the cell surface, especially when the cells were treated with a specific protein called IFN-γ. They also found that T-cells were activated when exposed to cells expressing this marker, confirming that the marker was able to interact with the T-cells.
This discovery suggests that even though HLA-C*04:09N may not be easily detected, it can still present substances to T-cells, leading to their activation. This could have implications for medical treatments like stem cell transplants or cellular therapy.
"Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma"
Source
Chen G, Gao X, Jia X, Wang Y, Xu L, Yu D, Chang S, Deng H, Hu K, Wang G, Li B, Xu Z, Lu Y, Wang H, Zhang T, Song D, Yang G, Wu X, Zhu H, Zhu W, Shi J. Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma. Haematologica 2024;109(4):1206-1219; https://doi.org/10.3324/haematol.2023.282789.
Overview
Researchers are still searching for a cure for multiple myeloma (MM). They've found a protein called ribosomal protein S3 (RPS3) that plays a role in MM, but they weren't sure exactly what it did until now.
This study shows that RPS3 is important for MM cells to survive and resist drugs. MM cells have a lot of RPS3, and when scientists removed RPS3 from these cells, they stopped growing and started to die, both in the lab and in animals with MM.
When RPS3 was added to MM cells, they became resistant to a type of drug called proteasome inhibitors, and the animals with MM didn't live as long. The study also found that RPS3 interacts with another protein called thyroid hormone receptor interactor 13 (TRIP13), which is linked to MM and drug resistance.
TRIP13 helps RPS3 work by changing it with a process called phosphorylation. This activates a signal called NF-κB, which helps MM cells survive and resist drugs.
The good news is that a drug called DCZ0415, which blocks TRIP13, can make MM cells more sensitive to drugs like bortezomib. When DCZ0415 was used with bortezomib, it killed more MM cells together than either drug alone.
This research suggests that RPS3 could be a new marker for MM and a target for future treatments.
"Single-cell analysis of the CD8+ T-cell compartment in multiple myeloma reveals disease-specific changes are chiefly restricted to a CD69- subset suggesting potent cytotoxic effectors exist within the tumor bed"
Source
Favaloro J, Bryant CE, Abadir E, Gardiner S, Yang S, King T, Nassif N, Sedger LM, Boyle R, Joshua DE, Ho PJ. Single-cell analysis of the CD8<sup>+</sup> T-cell compartment in multiple myeloma reveals disease specific changes are chiefly restricted to a CD69<sup>-</sup> subset suggesting potent cytotoxic effectors exist within the tumor bed. Haematologica 2024;109(4):1220-1232; https://doi.org/10.3324/haematol.2023.283062.
Overview
In multiple myeloma (MM), researchers know that CD8+ T cells, a type of immune cell, play a role in fighting this disease, but we haven't looked closely at these cells within the cancer's environment.
In this study, scientists examined CD8+ T cells in the bone marrow (BM) and blood of untreated MM patients and compared them to people without the disease. They used special techniques like flow cytometry, mass cytometry, and single-cell RNA sequencing.
They found that BM CD8+ T cells in MM patients were different from those in healthy people, especially in the expression of certain proteins called Granzymes B and K. These proteins were linked to two different types of CD8+ T cells in the BM, marked by a protein called CD69.
One type of CD8+ T cell (CD8+CD69+) in MM patients' BM showed similarities to those in healthy people, while another type (CD8+CD69-) had more mature immune cells. Interestingly, the composition of CD8+ T cells in the blood of MM patients was different from healthy people, showing fewer mature immune cells.
This research suggests that CD8+ T cells in the bone marrow of MM patients behave more like activated immune cells, and understanding these differences could help develop better treatments.
"Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes"
Source
Escure G, Fournier E, Saade C, Issa LHB, Arib I, Tilmont R, Gazeau N, Thiam BM, Chovet M, Delforge M, Gower N, Fléchon L, Cavalieri D, Chauvet P, Nudel M, Goursaud L, Berthon C, Quesnel B, Facon T, Preudhomme C, Duployez N, Manier S. Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes. Haematologica 2024;109(4):1289-1292; https://doi.org/10.3324/haematol.2023.284050. April 2024.
Overview
People with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) have a higher chance of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) compared to others, even without treatment. This risk increases for those with multiple myeloma (MM) who undergo MM-specific therapies.
Although newer treatments like proteasome inhibitors and immunomodulators have improved MM patients' survival, they also come with risks. Some people may develop therapy-related MDS or AML as a result. These complications are rare but can have a poor outcome.
The risk of developing these complications is influenced by various factors such as age, sex, ethnicity, genetics, and previous treatments received. Certain MM treatments like high-dose melphalan used in stem cell transplantation or lenalidomide maintenance therapy have been linked to an increased risk.
Recent research suggests that some patients may already have small mutated cell populations, called subclones, before being diagnosed with MDS. These subclones can grow during MM treatments, particularly with lenalidomide, and lead to the development of MDS or AML.
Understanding these risks and the presence of these mutated cell populations could help develop safer treatments for MM patients. It's essential to explore alternative therapies to reduce the risk of developing MDS or AML, especially for those with long-term exposure to lenalidomide.
"CD38 expression by plasma cells in extramedullary multiple myeloma"
Source
Notarfranchi L, Accardi F, Mancini C, Martella E, Bonomini S, Segreto R, Vescovini R, Palma ABD, Sammarelli G, Todaro G, Storti P, Burroughs-Garcia J, Iannozzi NT, Raimondi V, Lungu O, Ricci S, Craviotto L, Giuliani N. CD38 expression by plasma cells in extramedullary multiple myeloma. Haematologica 2024;109(4):1297-1300; https://doi.org/10.3324/haematol.2023.284169. .
Overview
Extramedullary disease (EMD) is a rare form of multiple myeloma (MM) where plasma cells grow outside the bone marrow. This condition presents a challenge in MM treatment.
EMD can occur either at the time of diagnosis (primary EMD) or during relapse (secondary EMD). It can be divided into bone-related (EM-B) or soft tissue-related (EM-S), with EM-S being more aggressive and harder to treat.
EM-S can appear in various places, such as the skin, soft tissues, liver, kidneys, lymph nodes, and even the central nervous system. It's linked to high-risk genetic features and resistance to treatments.
Studies have found that a chromosomal abnormality called 1q21 amplification (amp(1q21)) is more common in EMD cases, which may contribute to its development and worsen outcomes.
EM plasma cells also show changes in adhesion molecules, affecting their ability to migrate and survive. For example, they often have reduced CD38 expression, making them less responsive to anti-CD38 antibody treatments like daratumumab.
In a recent study, researchers compared the expression of adhesion molecules in bone marrow and EMD plasma cells from MM patients. They found that EMD samples had lower CD38 expression but higher CD44 expression compared to bone marrow samples.
These findings suggest that EMD plasma cells may have different characteristics that affect their response to treatments. Further research is needed to understand how these differences impact treatment outcomes and to develop more effective therapies for patients with EMD.
"Immune status and selection of patients for immunotherapy in myeloma: a Proposal"
Source
Madhav V Dhodapkar; Immune status and selection of patients for immunotherapy in myeloma: a Proposal. Blood Adv 2024; bloodadvances.2023011242. doi: https://doi.org/10.1182/bloodadvances.2023011242 April 2, 2024.
Overview
New treatments using the body's immune system, like CAR-T cells and bispecific antibodies, are changing how we treat multiple myeloma (MM). Researchers are learning more about how the immune system helps fight this cancer, starting from the early stages of its development.
Myeloma affects the immune system. Changes in immune cells can affect how well treatments work, especially immune therapies. Understanding the immune system's status before treatment is becoming crucial for predicting how well these therapies will work.
MM is a cancer that can occur in different parts of the body, so it's essential to consider where the cancer is located and how the immune system is behaving in those areas. Researchers suggest categorizing MM into five immune types based on its interaction with the immune system, which can help tailor treatments for each patient.
By considering these factors, healthcare professionals can better choose the right immune therapy for each MM patient, leading to better outcomes.
"Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma"
Source
Munawar U, Theuersbacher J, Steinhardt MJ, Zhou X, Han S, Nerreter S, Vogt C, Kurian S, Keller T, Regensburger A-K, Teufel E, Mersi J, Bittrich M, Seifert F, Haider MS, Rasche L, Hillenkamp J, Einsele H, Kampik D, Kortüm KM, Waldschmidt JM. Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma. Haematologica; https://doi.org/10.3324/haematol.2024.285205 [Early view]. April 4, 2024.
Overview
Belantamab mafodotin (belantamab) is a new treatment for multiple myeloma, approved for patients who haven't responded to other therapies. It's a different option for those who can't have CAR-T or bispecific antibody treatments.
But it can cause eye problems like corneal microcysts and keratopathy, making its wider use challenging. Researchers found that a substance called soluble BCMA (sBCMA) in the tears of myeloma patients might be linked to how much cancer they have.
Interestingly, the cells on the surface of the eye don't have the same receptors as the cancer cells, but they can still absorb belantamab-sBCMA complexes through a process called pinocytosis.
By understanding this process better, researchers can work on ways to prevent or reduce these eye problems, like using other treatments before belantamab or combining it with other drugs. This could improve the safety of belantamab for more patients with multiple myeloma.
"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 S Kwek, Alexander Cheung, Sophia Anna Bylsma, Erik Hansen, Jeffrey Lee Wolf, Sandy W Wong, Nina Shah, Kole T Roybal, Thomas G Martin, Chun Jimmie Ye, Lawrence Fong; CD4+ CAR-T cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR-T cell therapy. Blood Adv 2024; bloodadvances.2023012416. doi: https://doi.org/10.1182/bloodadvances.2023012416 April 4, 2024. .
Overview
From the article:
- "Despite the high initial rates of response to anti-BCMA CAR-T cell therapy in myeloma, those responses are frequently short-lived.
- Exhausted CD4+ CAR-T cells, identified by single cell assays in the patients' blood and marrow, are linked to early relapse."
.
"VRD versus VCD as induction therapy before autologous stem cell transplantation in multiple myeloma: a nationwide population-based study"
Source
Nørgaard, J.N., Moore, K.L.F., Slørdahl, T.S. et al. VRD versus VCD as induction therapy before autologous stem cell transplantation in multiple myeloma: a nationwide population-based study. Blood Cancer J. 14, 60 (2024). https://doi.org/10.1038/s41408-024-01047-1 April 9, 2024
Overview
For young and healthy patients with newly diagnosed multiple myeloma (MM), a common treatment is induction therapy followed by autologous stem cell transplantation (ASCT). Over time, the choice of induction therapy has evolved from doublet to triplet to quadruplet regimens. The most popular regimens are Velcade (bortezomib), Cytoxan (cyclophosphamide), and dexamethasone (VCD) as well as Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone (VRD). However, there hasn't been a large study comparing these two regimens.
In Norway, there has been a shift from VCD to VRD induction therapy in recent years. To understand the outcomes, researchers studied patients who underwent ASCT for MM from 2008 to 2020. They found that patients who received VRD had better progression-free survival (PFS) and overall survival (OS) compared to those who received VCD. This was particularly noticeable in patients who received maintenance therapy after ASCT.
However, the study has limitations since it was retrospective and not randomized. But it provides valuable insights for doctors deciding on the best induction therapy for MM patients eligible for ASCT. Overall, the study suggests that VRD may be preferred over VCD for induction therapy in newly diagnosed MM patients eligible for ASCT.
"Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma"
Source
Jiang, H., Wang, L., Zhang, Q. et al. Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma. Oncogene (2024). https://doi.org/10.1038/s41388-024-03020-5 April 9, 2024
Overview
Researchers have identified a promising method called ferroptosis to overcome chemoresistance in multiple myeloma (MM). However, the role and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis in MM cells are not well understood. Through laboratory and animal models, they found that MM cells became more vulnerable to ferroptosis when interacting with BMSCs.
The study revealed that BMSCs increased the iron levels in MM cells, activating the steroid biosynthesis pathway, particularly the production of lanosterol, which generates reactive oxygen species (ROS) in MM cells. The interaction between CD40 ligand and CD40 receptor was identified as the critical signaling pathway controlling lanosterol biosynthesis. Disrupting this interaction using an anti-CD40 neutralizing antibody or depleting Cd40l in BMSCs reduced the iron level and lanosterol production in MM cells in mouse models.
This research sheds light on how BMSCs influence ferroptosis in MM cells and underscores the potential of non-apoptosis strategies for treating refractory or relapsed MM patients.
"A novel small molecule inhibitor of CD73 triggers immune-mediated multiple myeloma cell death"
Source
Ray, A., Du, T., Wan, X. et al. A novel small molecule inhibitor of CD73 triggers immune-mediated multiple myeloma cell death. Blood Cancer J. 14, 58 (2024). https://doi.org/10.1038/s41408-024-01019-5 April 9, 2024.
Overview
From the article:
- "CD73 is the key ectoenzyme involved in the generation of AMP-derived adenosine, which contributes to immunosuppression in the multiple myeloma (MM) bone marrow milieu.
- Blocking CD73 activity with a potent, selective, orally bioavailable CD73 inhibitor ORIC-533 decreases adenosine generation, overcomes immune suppression, and restores immune cell-mediated MM cell lysis.
- Based on these preclinical studies, a multi-center clinical trial of ORIC-533 has been initiated in patients with relapsed refractory MM (NCT05227144)."
"Treatment patterns for AL amyloidosis after frontline daratumumab, bortezomib, cyclophosphamide, and dexamethasone treatment failures"
Source
Zanwar, S., Gertz, M.A., Muchtar, E. et al. Treatment patterns for AL amyloidosis after frontline daratumumab, bortezomib, cyclophosphamide, and dexamethasone treatment failures. Leukemia (2024). https://doi.org/10.1038/s41375-024-02243-5 April 9, 2024
Overview
In systemic immunoglobulin light chain amyloidosis (AL), swiftly achieving a hematologic very good partial response (VGPR) is crucial for improved organ responses and survival. The phase III ANDROMEDA trial showed that adding daratumumab to bortezomib, cyclophosphamide, and dexamethasone (D-VCd) significantly increased hematologic complete response (CR) and VGPR rates compared to VCd alone in previously untreated patients. However, about one-fourth of patients may not achieve a deep response with D-VCd induction, requiring subsequent treatment.
A study evaluated patients who needed subsequent treatment due to suboptimal response, progression, or toxicity after frontline D-VCd therapy. Patients receiving subsequent treatment for rising involved serum-free light chains (sFLC) after achieving a deep response without progression were also included. Options for subsequent therapy varied, but consolidating with ASCT or BCL2 inhibitor-based therapy showed better outcomes compared to continuing daratumumab-based combinations.
Despite limitations in the study's retrospective nature and variable practice patterns, ASCT and BCL2 inhibitor-based treatments demonstrated superior CR rates and event-free survival (EFS) compared to daratumumab-based combinations. However, the suitability of each option depends on factors like patient fitness and genetic characteristics. Nonetheless, when feasible, non-daratumumab-based regimens are likely preferred for patients who fail frontline D-VCd therapy, especially if a deep response is not achieved within two months.
"Distinguishing ASH Clinical Practice Guidelines from Other Forms of ASH Clinical Advice"
Source
Adam Cuker, Robert Kunkle, Rachel Sara Bercovitz, Michael T. Byrne, Benjamin Djulbegovic, Sandra L Haberichter, Jennifer Holter-Chakrabarty, Richard Lottenberg, Menaka Pai, Suely Meireles Rezende, Matthew D Seftel, Roy L. Silverstein, Deirdra R Terrell, Matthew C Cheung; Distinguishing ASH Clinical Practice Guidelines from Other Forms of ASH Clinical Advice. Blood Adv 2024; bloodadvances.2023011102. doi: https://doi.org/10.1182/bloodadvances.2023011102 April 9, 2024
Overview
From the article: "The objective of this article is to highlight similarities and differences between ASH Clinical Practice Guidelines (CPGs) and other forms of ASH clinical advice and to discuss the implications of these differences for end users.
"Like a bridge over troubled water: keeping the myeloma down en route to CAR-T."
Source
Richter, J. Like a bridge over troubled water: keeping the myeloma down en route to CAR-T. Blood Cancer J. 14, 64 (2024). https://doi.org/10.1038/s41408-024-01049-z April 12, 2024
Overview
Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a vital treatment for relapsed and refractory multiple myeloma (RRMM). However, logistical challenges often necessitate bridging therapy (BT) between T-cell collection and CAR-T infusion. This interim treatment serves several purposes: maintaining disease control, reducing CAR-T-related toxicities, and potentially enhancing remission durability.
Recent FDA approvals of idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) have expanded treatment options for RRMM. Yet, logistical hurdles such as limited apheresis availability and manufacturing timelines pose challenges. Patients may face a 2-month gap between disease confirmation and CAR-T infusion, highlighting the need for effective BT.
A study by Afrough et al., based on real-world data, underscores the importance of BT in RRMM management. Their findings suggest that patients who do not require BT have significantly longer progression-free survival (PFS) and overall survival (OS) with shorter hospital stays and potentially lower rates of toxicities.
While some patients may not need BT, those requiring it can benefit from tailored approaches. Alkylator-based BT, especially intensively dosed, showed inferior outcomes compared to other strategies. Disease burden and growth kinetics play crucial roles in BT selection.
Efforts to optimize BT aim to minimize morbidity and improve outcomes. Future directions include earlier CAR-T utilization and exploring the role of bispecific antibodies as BT modalities. Ultimately, reducing the need for aggressive BT may enhance CAR-T efficacy.
In conclusion, proactive management, including early referral to CAR-T centers and initiation of logistical processes, is essential to optimize outcomes and minimize the need for extensive BT in RRMM patients undergoing CAR-T therapy.
"Real-world impact of bridging therapy on outcomes of ide-cel for myeloma in the U.S. Myeloma Immunotherapy Consortium"
Source
Afrough, A., Hashmi, H., Hansen, D.K. et al. Real-world impact of bridging therapy on outcomes of ide-cel for myeloma in the U.S. Myeloma Immunotherapy Consortium. Blood Cancer J. 14, 63 (2024). https://doi.org/10.1038/s41408-024-00993-0 April 12, 2024
Overview
Idecabtagene vicleucel (ide-cel) stands as the first FDA-approved gene therapy for relapsed refractory multiple myeloma (RRMM), offering new hope for patients. Yet, its implementation poses logistical and treatment challenges, particularly in selecting bridging therapy (BT) and customizing T-cell manufacturing.
A retrospective multicenter study examined RRMM patients undergoing ide-cel treatment, aiming to understand the impact of different BT approaches on outcomes. The study included patients from multiple U.S. medical centers, observing their response to various BT regimens, such as selinexor, alkylator-based therapies, proteasome inhibitor (PI) combinations, and immunomodulatory therapy (IMiD) with or without monoclonal antibodies (mAb).
Patients who received no BT before ide-cel exhibited prolonged progression-free survival (PFS) and overall survival (OS), suggesting potentially less aggressive disease. Conversely, alkylator-based BT correlated with inferior outcomes, highlighting the importance of early intervention with CAR T-cell therapy before standard treatment resistance develops.
Tailoring BT based on individual patient characteristics, treatment history, and disease aggressiveness is crucial. While stable disease might prompt reconsideration of BT necessity, the risk of toxicity due to inadequate cytoreduction should be carefully weighed. Caution is advised with intensified alkylator therapy, emphasizing the need for personalized assessments in BT selection.
In conclusion, navigating BT strategies for ide-cel treatment requires a nuanced approach, considering both disease dynamics and patient-specific factors to optimize outcomes and minimize risks.
"CD56 expression predicts response to Daratumumab-based regimens"
Source
Robinette, A.J., Huric, L., Dona, K. et al. CD56 expression predicts response to Daratumumab-based regimens. Blood Cancer J. 14, 62 (2024). https://doi.org/10.1038/s41408-024-01051-5 April 12, 2024
Overview
Daratumumab (Dara) and Isatuximab (Isa) are monoclonal antibodies targeting CD38, a protein abundant in plasma and multiple myeloma (MM) cells. While CD38 levels predict responses to anti-CD38 antibodies, other factors influence drug efficacy. CD56, another protein found in most MM cases, activates specific pathways and impacts drug response, especially when combined with immunomodulatory drugs (IMiDs).
This investigation revealed that CD56 expression enhances response to Dara-IMiD therapy but not Isa-based treatments. Interestingly, Dara reduces CD56 levels and signaling. CD56 and CD38 often coexist, with CD56 influencing CD38 expression independently. Moreover, patients with "High CD56" MM display a distinct immune profile, which Dara can reverse, enhancing immune cell-mediated killing of MM cells.
1q+ status correlates with shorter progression-free survival (PFS) to Dara but not Isa, with CD56 expression partly offsetting the negative impact of 1q+. This suggests that while CD56-mediated changes in gene expression might drive Dara responses in 1q- patients, 1q+ patients respond to Isa through different mechanisms, possibly involving alternative genes or immune factors.
Though limited by sample size and timing of CD38-CD56 clone assessment, our study underscores the potential for precision medicine in MM. Understanding CD56's role helps tailor anti-CD38 therapy, utilizing routine MM markers like 1q status and CD56 expression to guide treatment selection. These findings pave the way for personalized MM therapy, improving patient outcomes through targeted interventions.
"Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma"
Source
Cui, J., Liu, Y., Lv, R. et al. Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02237-3 April 12, 2024
Overview
This study investigates the impact of minor clones of gain/amplification of chromosome 1q+ [(gain/amp(1q)] on the survival of multiple myeloma (MM) patients and their correlation with chromosomal instability (CIN). Analyzing data from 998 newly diagnosed MM patients, researchers found that among the 513 patients with 1q+, 55 had minor clones (≤20%). Surprisingly, patients with minor clones showed similar survival outcomes to those without gain/amp(1q). Further analysis revealed that these patients had a clonal architecture resembling those without gain/amp(1q). Interestingly, there was a significant increase in the size of the minor clone of 1q+ indicating a potential early stage in the progression of this genetic abnormality in MM. These findings suggest a "two-step" process in the evolution of 1q+ in MM.
"In multiple myeloma, monthly treatment with zoledronic acid beyond two years offers sustained protection against progressive bone disease"
Source
Lund, T., Gundesen, M.T., Juul Vangsted, A. et al. In multiple myeloma, monthly treatment with zoledronic acid beyond two years offers sustained protection against progressive bone disease. Blood Cancer J. 14, 65 (2024). https://doi.org/10.1038/s41408-024-01046-2 April 15, 2024
Overview
This study investigates the effectiveness of zoledronic acid (ZOL) treatment in reducing bone destruction in multiple myeloma (MM) patients over a four-year period. MM often leads to bone pain and fractures due to lytic bone destruction. ZOL has been a standard treatment to reduce bone disease progression and improve survival. However, it also carries risks, such as kidney failure and medication-related jaw problems.
The study followed newly diagnosed MM patients for four years, comparing those who received ZOL treatment for two years to those who continued treatment for four years. The primary goal was to assess the risk of progressive bone disease (PBD). The results showed that continuing ZOL treatment for four years significantly reduced the risk of PBD compared to stopping treatment after two years.
Although there was a slight increase in side effects with prolonged treatment, such as jaw problems and kidney issues, the benefits of reduced bone destruction outweighed these risks. The study suggests that longer-term ZOL treatment may be beneficial for MM patients, especially in preventing bone-related complications. However, further research is needed to optimize treatment intervals and minimize side effects.
"Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma"
Source
Sahin I, Kawano Y, Sklavenitis-Pistofidis R, et al. Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma. Blood Adv. 2019;3(7):995-1002.. Blood Adv 2024; 8 (8): 1958. doi: https://doi.org/10.1182/bloodadvances.2024013092 April 23, 2024
Overview
This study explores the role of Citron Rho-interacting serine/threonine kinase (CIT) in multiple myeloma (MM). CIT, a protein involved in cell division, was found to be highly expressed in MM plasma cells compared to healthy individuals. MM patients with high CIT expression had worse overall survival rates. Silencing CIT in MM cell lines led to decreased cell proliferation, suggesting its importance in MM growth. Interestingly, low levels of the TP53 gene correlated with increased CIT dependency. These findings propose CIT as a potential target for future MM therapies.
"Pomalidomide, bortezomib, and dexamethasone for newly diagnosed multiple myeloma patients with renal impairment"
Source
Jian Y, Chang L, Shi M-X, et al. Pomalidomide, bortezomib, and dexamethasone for newly diagnosed multiple myeloma patients with renal impairment. Blood Adv. 2023;7(24):7581-7584.. Blood Adv 2024; 8 (8): 1991. doi: https://doi.org/10.1182/bloodadvances.2024013036 April 23, 2024
Overview
This study explores the effectiveness of the Pomalyst (pomalidomide), Velcade (bortezomib) and dexamethasone (PVD) combination therapy in newly diagnosed multiple myeloma (NDMM) patients with renal impairment (RI). Renal impairment is a common issue in NDMM patients, affecting up to 40% of cases and leading to adverse survival outcomes. The PVD regimen was administered to NDMM patients with RI, and favorable results were observed. A significant number of patients achieved renal response, with improvements in renal function observed within three months of treatment initiation. Additionally, high rates of hematological response were noted, indicating the efficacy of PVD in this patient population. Safety profiles were comparable to previous studies, although grade ≥3 adverse events were still common. Overall, the findings suggest that the PVD regimen could be a promising treatment option for NDMM patients with RI, warranting further investigation in randomized trials.
"TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors"
Source
McAvera, R.M., Morgan, J.J., Herrero, A.B. et al. TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors. Sci Rep 14, 8797 (2024). https://doi.org/10.1038/s41598-024-58828-8 April 16, 2024
Overview
Researchers have found that some patients with multiple myeloma have a specific genetic change called deletion of chromosome 1p- [del(1p)], which is linked to a poorer outcome. Within this deleted region, there's a gene called TRIM33, which helps control cell division and repair damaged DNA. In this study, researchers discovered that myeloma patients who are missing TRIM33 tend to have more problems with their DNA and a worse prognosis. When they reduced the levels of TRIM33 in lab experiments, researchers noticed that cells had more DNA damage and repaired it more slowly. This gene also affects how other important proteins are tagged for repair. Interestingly, when the researchers tested a drug called Olaparib, which targets a specific DNA repair process, on cells lacking TRIM33, it worked better. Combining Olaparib with bortezomib seemed to be even more effective. These findings suggest that targeting TRIM33 could be a promising approach to treating high-risk multiple myeloma patients, especially when combined with drugs like Olaparib.
"Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation"
Source
Shuichiro Takahashi, Simone A. Minnie, Kathleen S. Ensbey, Christine R. Schmidt, Tomoko Sekiguchi, Samuel R. W. Legg, Ping Zhang, Motoko Koyama, Stuart D. Olver, Alika D. Collinge, Sara Keshmiri, Melissa L. Comstock, Antiopi Varelias, Damian J. Green, Geoffrey R. Hill; Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation. Blood 2024; 143 (16): 1656–1669. doi: https://doi.org/10.1182/blood.2023022000 April 18, 2024
Overview
From the article:
- "T cells from bone marrow egress to blood during stem cell mobilization (SCM) and preferentially home back to marrow after adoptive transfer.
- Treg depletion during SCM expands polyfunctional effector T cells in mobilized grafts and enhances antimyeloma immunity after autologous stem cell transplant (ASCT)."
"Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications"
Source
Schoeller K, Ihorst G, Reinhardt H, Holler M, Scheubeck S, Herget G, Wäsch R, Engelhardt M. Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications. Haematologica 2024;109(4):1279-1284; https://doi.org/10.3324/haematol.2023.283884. Vol. 109 No. 4 (2024): April, 2024
Overview
Over the years, there have been improvements in treating multiple myeloma (MM), but it's still challenging because older patients often have other health problems alongside MM, which can affect their ability to tolerate treatment.
To make treatments more personalized, doctors suggest assessing how fit patients are overall. This involves using scores called comorbidity indices (CI), which help determine if patients are "fit" or "frail" based on their health conditions. These scores are helpful in adjusting treatments and reducing side effects caused by therapy.
There are different confidence intervals (CIs) used in clinics, like the International Myeloma Working Group (IMWG) frailty index or Revised Myeloma Comorbidity Index (R-MCI). These scores divide patients into groups based on their risk level, which can affect how long they survive without the disease getting worse (progression-free survival) and how well they tolerate treatment.
The R-MCI is especially useful because it works well with both past and current patient data and is easy to use. It even has a website where doctors can access it easily. While all CIs help identify patients at different risk levels, the R-MCI stands out for its reliability.
Although using CIs to tailor treatment is common in other blood diseases, it's not yet standard practice for MM. However, studies show that adjusting treatments based on a patient's fitness level can improve outcomes. But there's still a need for more research and standardized tools to assess fitness accurately.
Currently, only a quarter of MM doctors use frailty scores to help make treatment decisions, while most rely on their clinical judgment alone. But ongoing research suggests that using CIs to guide treatment decisions could become more common in the future.
Further studies, especially clinical trials, are needed to determine the best-personalized treatment options for MM patients. Recent research has shown a positive trend toward incorporating frailty assessments into treatment decisions, with the R-MCI being a promising tool in this regard.
"Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial"
Source
Shi, M., Wang, J., Huang, H. et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial. Nat Commun 15, 3371 (2024). https://doi.org/10.1038/s41467-024-47801-8 April 20, 2024.
Overview
A new treatment called bispecific BC19 CAR T cells shows promise in treating relapsed and refractory multiple myeloma (RRMM). This treatment targets two proteins, BCMA and CD19, and has been tested both in the lab and in mice. Results show that BC19 CAR T cells effectively kill cancer cells that have these proteins.
In a study involving 50 patients with R/R MM, the treatment was found to be safe, with only a small percentage experiencing severe side effects like cytokine release syndrome or neurotoxic events. The treatment also led to promising outcomes, with a high overall response rate (92%) and significant progression-free survival and overall survival rates.
These findings suggest that bispecific BC19 CAR T cells could be a safe and effective option for treating RRMM.
"Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk"
Source
Callander, N.S., Silbermann, R., Kaufman, J.L. et al. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer J. 14, 69 (2024). https://doi.org/10.1038/s41408-024-01030-w April 22, 2024
Overview
In two studies called MASTER and GRIFFIN, researchers tested different combinations of drugs to treat newly diagnosed multiple myeloma (NDMM) in patients who are eligible for a transplant. They found that adding a drug called daratumumab to standard treatments improved outcomes.
In the MASTER study, a combination of Darzalex (daratumumab), Kyprolis (carfilzomib), Revlimid (lenalidomide), and dexamethasone (D-KRd) showed good results. In the GRIFFIN study, another combination called daratumumab, lenalidomide, Velcade (bortezomib), and dexamethasone (D-RVd) also performed well.
Researchers then looked at a subgroup of patients with high-risk genetic abnormalities in their cancer cells. They found that both D-KRd and D-RVd treatments were effective in these patients, with high rates of complete response or better.
Additionally, tests showed that many patients became negative for minimal residual disease (MRD), meaning there were very few cancer cells left after treatment. Progression-free survival (PFS) rates were also good, especially for patients with fewer high-risk genetic abnormalities.
Overall, these findings suggest that adding daratumumab to standard treatments is a promising approach for treating NDMM, especially in patients with high-risk genetic abnormalities. However, more research is needed to find effective treatments for patients with the highest risk disease.
"Trends in Volumes and Survival After Hematopoietic Cell Transplantation in Racial/Ethnic Minorities"
Source
Rangarajan, Wael Saber, Theresa Hahn; Trends in Volumes and Survival After Hematopoietic Cell Transplantation in Racial/Ethnic Minorities. Blood Adv 2024; bloodadvances.2023012469. doi: https://doi.org/10.1182/bloodadvances.2023012469 April 25, 2024
Overview
From the article:
- "The number of autologous hematopoietic cell transplants (autoHCT) and allogeneic hematopoietic cell transplants (alloHCT) grew faster in Non-Hispanic African Americans and Hispanics compared to Non-Hispanic Whites.
- Survival after autoHCT and alloHCT improved over time for all racial/ ethnic groups, though African Americans have worse outcomes."
"The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression"
Source
Medina-Herrera, A., Vazquez, I., Cuenca, I. et al. The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression. Blood Cancer J. 14, 74 (2024). https://doi.org/10.1038/s41408-024-01053-3 April 29, 2024
Overview
In this study, researchers looked at the genetic makeup of 57 smoldering multiple myeloma patients at high risk of progression who were part of a clinical trial. They found that certain genetic mutations and alterations were more common in these high-risk patients. Some mutations were associated with worse outcomes, while others were linked to better outcomes.
Importantly, the study identified new genetic markers that could predict resistance to treatment. This information could help doctors tailor treatments for SMM patients, especially those at high risk of progression, to improve outcomes.