← Blood Podcast
Blood Podcast
Busulfan-melphalan conditioning in newly diagnosed, transplant-eligible multiple myeloma; and use of spatial transcriptomics to probe the three-dimensional properties of multiple myeloma bone marrow microenvironments
00:13:13
Loading summary
Transcript1 lines
- [00:02]
A
Welcome to the October 9, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. Today we'll learn more about a study comparing busulfan melphalan with melphalan alone as the conditioning protocol for for newly diagnosed transplant eligible multiple myeloma. Then we will discuss data on how three dimensional transcriptomics can reveal complex interactions between plasma cells and bone marrow microenvironments. We first examine data in the Blood article entitled High dose Busulfan Melphalan versus Melphalan and reinforced VRD in newly diagnosed multiple myeloma A phase three GEM trial by Juan Jose La Huerta of the Hospital Universitario Doce de Octobra in Madrid, Spain and colleagues. Patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant typically receive melphalan as a transplant conditioning agent. This agent has been in use for over 30 years and is currently dosed as 200 milligrams per meter squared, nicknamed Mel 200. Retrospective studies have suggested that adding intravenous busulfan to melphalan, the regimen nicknamed Bumel, might be more effective than Mel200. However, prospective data on the comparative merits of these approaches for first line therapy in newly diagnosed patients has been lacking. The authors of the first study known as GEM12, designed a phase three trial to compare Bumel with MEL200 following an intensified induction and consolidation regimen composed of bortezomib, lenalidomide and dexamethasone or vrd. This intensified regimen, which they refer to as reinforced vrd, included higher doses of lenalidomide and dexamethasone and additional cycles. Recent years have seen the addition of a CD38 inhibitor such as daratumumab or isatuximab to VRD to create a four drug induction and consolidation regimen that is now the preferred treatment. However, VRD by itself remains a potential option, particularly in low resource settings where CD38 inhibitors may not be available. The current publication describes the results of GEM12 at a median follow up of 101 months or about 8.4 years. 458 patients with newly diagnosed multiple myeloma were enrolled at 69 sites in Spain 23% had stage 3 disease while the rest had stages 1 or 2. 20% of these patients also had high risk cytogenetics after 6 cycles of induction therapy. With the dose intensified VRD regimen, patients were randomized between MEL200 or Bumel transplant conditioning. Three months after transplant they received two additional cycles of dose intensified VRD as consolidation therapy. 332 patients who were still in the study after consolidation were re randomized to participate in the GEM14 study. This study compared maintenance therapy using lenalidomide plus dexamethasone with or without the addition of the proteasome inhibitor ixizomib. All 458 patients in the intention to treat population of GEM12 were included in the current analysis. The global progression free survival or PFS and overall survival or OS results for the reinforced VRD regimen used in this trial were among the highest that have been reported for a three drug induction and consolidation regimen in multiple myeloma. Median PFS for the global trial population was 78 months with a 9 year PFS rate of 41.4%. The 9 year OS rate for the global population was 66%. Safety results were also mostly similar between the two arms with the exception of a slightly higher rate of grades two to four infections in the BUMEL arm. The authors found few differences in patient outcomes between the two treatment arms. Patients who received BUMEL had a median PFS of 89.0 months compared with 73.1 months for for Mil 200, a numerical difference that was not statistically significant. 9 year OS rates and complete response rates were also not statistically different between the two arms. One parameter that did reach statistical significance was the overall minimal residual disease negativity rate which was slightly higher in the bumel arm at 68% compared with 58% for MEL200. Post hoc subanalysis was revealed that patients with stages 2 or 3 disease had a higher median PFS with Bumel while Those with stage 1 disease had a higher median PFS with MEL200. Patients with high risk cytogenetics in the form of translocation 1416 or Del1p also had improved PFS with Bumel in comparison to MEL200. The authors concluded that the reinforced VRD regimen was associated with favorable results for patients with newly diagnosed multiple myeloma. Their results also suggested that patients with higher stage disease or higher risk cytogenetics might benefit from transplant conditioning with bumel rather than mel200. In an accompanying commentary, Donna Reese of the Princess Margaret Cancer Centre in Toronto, Canada, said that these results suggest a potential role for BUMEL in selected high risk patients who also receive reinforced VRD in settings where CD38 inhibitors are unavailable. She noted, however, that a broader, more clear cut indication for BUMEL may never emerge as induction and consolidation regimens continue to be refined and improved with the addition of immunotherapeutic agents. Next up, we'll discuss findings from the blood article entitled Profiling the spatial architecture of multiple myeloma in human bone marrow trephine biopsy specimens with spatial Transcriptomics by Raymond K.H. yip of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia and colleagues. Multiple myeloma develops in the bone marrow where more than one malignant plasma cell subclone is often present at diagnosis. Considerable research has shown that expansion, selection and evolution of these subclones is influenced by the bone marrow microenvironment, with impacts on characteristics such as treatment resistance and disease progression. Components of the bone marrow microenvironment are thought to influence the growth and differentiation of non transformed hematopoietic cells as well. Single cell gene expression studies have shed considerable light on the genes and cell types that influence the development of multiple myeloma from its precursor, monoclonal gammopathy of undetermined significance or MGUs and smoldering myeloma. While informative, single cell studies are typically performed on digested tissue, thus losing three dimensional information carried in the bone marrow architecture, these studies identify cell types by gene expression patterns but do not generally reveal these cells so spatial patterns or the existence of local gene expression programs. The authors of the second paper that we're discussing today investigated the role of the bone marrow microenvironment in multiple myeloma using high resolution subcellular gene expression studies of bone marrow samples that retained their original three dimensional structures. They used a commercially available spatial transcriptomics system to look at three dimensional patterns of gene expression in bone marrow trephine biopsy samples from patients with suspected plasma cell disorders. Because these samples are typically preserved using methods that destroy much of the RNA present, the authors developed new bone marrow preservation methods that were compatible with their spatial transcriptomics platform. Using cluster analysis of single cell gene expression patterns, they were able to map cell types onto three dimensional bone marrow images, confirming cell identities using established gene expression and protein markers. They identified the majority of cell types expected to be present in bone marrow, including plasma cells, supporting the validity of their methods. After validating their preservation methods, the authors performed high resolution three dimensional in situ imaging of RNA transcripts in bone marrow samples. Using a panel that could detect the expression of thousands of different genes, they analyzed bone marrow samples from 21 patients. Seven patients had premalignant disease, including two with MGUS and five with smoldering myeloma another 10 patients had newly diagnosed multiple myeloma. As controls, the authors used samples from four patients with lymphoma who underwent biopsy but did not have bone marrow involvement. When the authors looked at control and premalignant samples, they found fairly similar proportions of different cell types, with evidence of a slight expansion of plasma cells in the precursor conditions. Most of the multiple myeloma samples, on the other hand, showed greatly expanded plasma cell populations with correspondingly smaller proportions of cells in non transformed hematopoietic lineages such as megakaryocytes and red blood cells. Looking only at plasma cells, the authors again used cluster analysis to differentiate among subtypes with with distinct gene expression patterns. In the control and premalignant samples, they found evidence for two common plasma cell subtypes. The multiple myeloma samples, on the other hand, were much more diverse, showing evidence of an additional 14 plasma cell subtypes whose identities and proportions were unique to each patient. Some of these subtypes had identifiable functional patterns, such as an inflammatory gene signature or or high expression of proliferative markers. The multiple myeloma samples showed two distinct spatial patterns for these plasma cell subtypes. Some samples were dominated by a single type of plasma cell located throughout the bone marrow architecture. Other samples instead showed evidence of multiple spatially restricted plasma cell subtypes, each with a distinct gene signature. Some of these spatially distinct plasma cell subpopulations had gene expression patterns that correlated with the patient's cytogenetic findings. For example, some plasma cell clusters from a patient with translocation 414 showed overexpression of FGFR3. The authors analyzed stromal cell populations as well to gain information on the spatial organization of the bone marrow microenvironment. Here, they found clusters of cells expressing genes that identified them as endothelial cells, mesenchymal cells, osteoblasts, and other cell types expected to be present in the bone marrow stroma. Unlike the diversity of plasma cell subpopulations, however, they found only subtle variations in the numbers and spatial distribution of stromal cells between the control premalignant and multiple myeloma samples. When they examined the types of plasma and stromal cells present within small, spatially restricted neighborhoods, however, they found many diverse microenvironments, each of which was associated with a distinct plasma cell subtype. The authors concluded that these findings argue against the commonly held view that there is a universal bone marrow microenvironment that supports the expansion of malignant plasma cell clones in all patients with multiple myeloma. Instead, they found that there were multiple unique plasma cell niches that varied from patient to patient, as well as across the bone marrow's three dimensional structure within a single patient. In an accompanying commentary, Leo Raske of the University Hospital Wurzburg in Wurzburg, Germany, and Niels Weinhold of Heidelberg University in Heidelberg, Germany said that this paper demonstrates the feasibility of using spatial transcriptomics to probe the three dimensional architecture of tumor microenvironments in multiple myeloma. They noted, however, that that this architecture is only one feature of the intra and inter patient variability that will need to be understood to advance our understanding of this complex and heterogeneous condition. For a list of additional authors, as well as more detailed articles and commentaries on which this podcast is based, Please go to bloodjournal.org thank you for listening.