Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma

AdMaPlace March 8, 2025

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Introduction

Multiple myeloma (MM) is a bone marrow (BM)-based, multifocal neoplastic proliferation of plasma cells and Extramedullary disease (EMD) is defined by plasma cell neoplasms that arise in tissues distinct from bone [1]. Treatment of MM continues to evolve, resulting in dramatically improved patient outcomes in recent years. Despite these advances, cure remains elusive [2], with EMD playing a major role in the development of relapsed/refractory MM (RRMM) [3, 4] resistant to novel therapies. Typically, EMD is seen in advanced MM, but rarely patients can present with EMD at diagnosis. The prevalence of EMD is approximately 10–15% in all RRMM patients, with only 0.5–6.4 of cases presenting at diagnosis [5,6,7,8,9]. EMD is associated with poor prognosis and is clinically distinct from MM without EMD [3, 10, 11]. Previous reports suggest that EMD can arise in any organ, with the site of origin varying from patient to patient [11, 12]. Although EMD has been defined by plasmacytomas distinct from bone, there are studies and trials which include para-skeletal plasmacytomas as EMD, while others do not [12,13,14,15]. The mechanisms involved in the pathogenesis of EMD remain unknown and unclear diagnostic criteria may hinder the understanding of it. Previous studies have reported risk factors for EMD, with some suggesting the potential role of RAS/BRAF mutations in the intramedullary to extramedullary transition in a limited number of patients [16, 17]. Patients with RAS/BRAF mutations showed a higher likelihood of developing EMD compared to patients without this mutation [16,17,18,19]. Prevalence of RAS/BRAF mutations increases in RRMM patients [20]. Mutations in TP53, deletion 17p (del (17p)), and duplication 1q (dup (1q)) are well-known poor prognostic factors, and previous reports have suggested that these risk factors are enriched in EMD patients [16, 21,22,23]. However, the consequent impact of these abnormalities on EMD remains unknown [20]. Thus, defining the molecular characteristics of EMD is critical to a better understanding of EMD biology and will help with advancing treatment of these patients. In the present retrospective study, we report the landscape of molecular features and clinical outcomes of MM patients with EMD from a cohort of 528 MM patients who had undergone molecular testing at a single center.

Methods

Patient cohort

Five hundred twenty-eight MM patients who presented to Massachusetts General Hospital between 2014 and 2021 were evaluated if they had molecular profiling completed on at least one sample (BM and/or EMD and/or bone plasmacytoma). All patients voluntarily provided informed consent approved by the Institutional Review Board for molecular testing. Clinical data was retrospectively collected from electronic medical records. Histological analysis, fluorescence in situ hybridization (FISH), and mutational analysis were conducted on BM aspirates, BM biopsies, and EMD tumor specimens when available.

Diagnosis of EMD

We defined EMD by the presence of plasmacytomas in organs and soft tissue distinct from bones, based on imaging data. The diagnosis of EMD was determined by imaging (CT, PET CT, or MRI) as part of clinical care (Fig. 1A). In some cases, EMD was confirmed by biopsy. Plasma cell leukemia was not included.

**Fig. 1: *RAS/BRAF* mutations are enriched in extramedullary disease (EMD).**

Mutational analysis

Nucleic acid extraction was performed using Promega Maxwell columns from BM and/or EMD samples obtained from MM patients. Heme panel which is a Multiplexed mutational analysis was conducted with primers designed to cover 91 (until 2018) or 111 (after 2019) genes (Supplementary Table 1), using Anchored Multiplex PCR for single nucleotide variant and insertion/deletion in genomic DNA using ArcherDx platform and Illumina NextSeq. The threshold of tumor cell frequency in BM aspirates and biopsies was determined as 9% based on previous laboratory cutoffs. If samples had a mutation at any time, we defined them as positive for that mutation.

Fluorescent in situ hybridization

Fluorescent in situ hybridization (FISH) was performed at Mayo Clinic laboratories. The probes are listed in Supplementary Table 2. We followed Mayo Clinic laboratories’ interpretation regarding the positivity.

Statistical analysis

Median survival rates for the whole group, and by mutation status, were calculated using the Kaplan-Meier method, while the log-rank test was used to compare survival. In the descriptive analysis, p-values were calculated using Fisher’s exact test. The Kolmogorov-Smirnov test was used to compare the distributions of mutations. All analyses were conducted using Prism software, and a p-value ≤ 0.05 was considered statistically significant.

Results

Mutational testing reveals RAS/BRAF mutations are likely essential for the development of EMD

Five hundred and twenty-eight patients who underwent mutation analysis at our institution were included in this study. All patients were included in the OS study. Data from 528 patients, with a median follow-up of 3.8 years is presented here (Table 1). Overall, 114 patients (21.6%) were classified as having EMD as plasmacytomas distinct from bones by imaging, while 414 patients (78.4%) did not show any evidence of EMD (Fig.1B). Patients with EMD had poorer prognosis compared to those without EMD; median OS was 5.3 years for 114 EMD patients vs 12.1 years for 414 non-EMD patients (p < 0.001) (Fig. 1B). The median time of developing EMD was 3.2 years, and once patients developed EMD, median survival was only 10.1 months (Data not shown). No significant differences were found between EMD and non-EMD patients regarding MM type, gender, and International Staging System (ISS) stage (Table 1). However, age at diagnosis was significant with younger patients developing EMD (mean age = 59.6) compared to non-EMD patients (mean age = 65.2), (p < 0.001). Age stratification showed that the EMD incidence rate decreases with age at MM diagnosis, especially after the age of 50 years (Supplementary Fig. 1A). To compensate for the influence of the duration of follow-up, we analyzed the data by cumulative incidence curve. The data revealed that MM diagnosis at the age of 50 and under was at a significantly higher risk of EMD development (p = 0.027) (Supplementary Fig. 1B). Treatment details are now included in supplementary information (Supplementary Table 3) as no firm conclusions could be drawn due to patient heterogeneity.

Table 1 Patient Demographics.

Full size table

Among 114 EMD patients, 64 had biopsies of EMD tissue, of whom 24 underwent mutational testing. Twenty-three of 24 samples (95.8%) harbored at least one of the RAS/BRAF mutations (NRAS, KRAS, and BRAF); 12 had NRAS mutations, 6 had KRAS mutations, and 4 had BRAF mutations, and 1 had both KRAS and BRAF mutations (Fig. 1C). For BM, samples with less than 9% tumor cells were excluded from mutation analysis evaluation as mentioned. As a result, there were 7 patients with paired BM samples. Interestingly, two EMD-NRAS-positive patients did not have NRAS mutations in their BM (Fig. 1C). The tumor cell ratios in BM of those two patients were 70% and 75%, and the sequencing coverages were 267x and 183x, respectively, which is sufficient to eliminate false negatives. For both patients, EMD samples were collected prior to BM samples. One patient received chemotherapy between those two-time points, and the other patient had focal radiation therapy at the EMD site. Additionally, one of the patients had two TP53 mutations in the EMD site but only had one in the BM. These mutational discrepancies may suggest the heterogeneity of tumor cells throughout the body and indicate that RAS/BRAF-mutated cells predispose to the development of EMD.

The prognosis of patients with BM-RAS/BRAF is largely defined by EMD development

Since RAS/BRAF mutations were enriched in EMD samples, we compared the incidence of EMD and OS of BM-NRAS, KRAS, BRAF single-positive patients and non-RAS/BRAF patients. There were 374 patients whose BM samples had more than 9% of tumor cells (198 patients had samples taken at diagnosis and 45 patients had samples taken at multiple time points). One hundred and forty-nine of 374 patients (39.8%) harbored BM-RAS/BRAF mutations; 45 single-NRAS, 65 single-KRAS, 18 single-BRAF, and 21 had more than 1 mutation present throughout their clinical course (Fig. 2A). The incidence rates of EMD were significantly higher in patients with BM-NRAS and with more than 1 mutation than non-RAS/BRAF patients (Fig. 2B). Generally, the incidence of EMD increases with recurrences, and the majority (54/114, 47.3%) of patients developed EMD after three or more recurrences in our cohort (Data not shown). Therefore, we examined the percentage of BM-RAS/BRAF mutations in relation to disease progression. Similarly, the percentage of patients with BM-RAS/BRAF mutation gradually increased with each relapse, and the highest rate was observed at the time of 3 or more recurrences in EMD patients (61.1%) (Supplementary Fig. 2). Even considering the percentage of RAS/BRAF mutations is associated with relapses, the percentage of RAS/BRAF mutations in EMD samples (95.1%) was significantly higher than that in BM of EMD patients with three or more recurrences (61.1%) (p = 0.004). This may suggest the existence of clonal heterogeneity and the evolutional processes between BM and EMD. We also analyzed the impact of EMD on OS by BM mutation status. Among 45 BM-NRAS, 65 BM-KRAS patients, and 225 non-BM-RAS/BRAF patients, EMD patients had poorer OS than non-EMD patients (Fig. 2C–E). No statistically significant difference was found in 18 patients with BM-BRAF patients and 21 patients with more than 1 mutation by the development of EMD, but this may be as a consequence of limited patient numbers (Data not shown). Among non-EMD patients, neither BM-KRAS nor NRAS had a negative impact on prognosis. These results indicate that the development of EMD has a greater impact on patient’s prognosis than the BM mutation status itself.

**Fig. 2: Impact of BM-*RAS/BRAF* mutations on the development of EMD and overall survival (OS).**

Poor prognosis of patients with dup (1q) and del (17p) is conferred by the development of EMD

Since the presence of EMD impacts patients’ prognosis, we analyzed molecular abnormalities other than RAS/BRAF mutations in EMD and non-EMD patients. We had three EMD samples analyzed for FISH with the only common abnormality being dup (1q), suggesting a possible underlying contribution of this molecular abnormality to EMD development. In addition to dup (1q), we analyzed del (17p), and TP53 mutation status in bone marrow samples. Among the 362 patients whose BM was analyzed for dup (1q), 160 patients (44.2%) were positive (Fig. 3A). As previously reported, patients with dup (1q) had a poorer prognosis than those without it (Median OS 7.4 years vs 9.6 years, p = 0.023) (Fig. 3B). Patients with dup (1q) also had a higher incidence of EMD compared to those without it (27.5% vs 12.9%, p < 0.001, Odds ratio 2.57) (Fig. 3C). Next, we classified patients into four groups: EMD with and without dup (1q), and non-EMD with and without dup 1q, in order to examine the association between high-risk features, EMD development, and OS. Surprisingly, the presence of dup (1q) did not differentially affect OS in either EMD or non-EMD groups (Fig. 3D). TP53 is on chromosome 17 and both del (17p) and TP53 mutation are reported as risk factors on MM. Regarding del (17p), 83 patients (20.4%) were positive among the 407 patients whose BM was analyzed (Fig. 3E). Similarly, patients with del (17p) also had poorer prognosis compared with those without it (Median OS 7.7 years vs 8.9 years, p = 0.024) (Fig. 3F) and had a higher incidence of EMD (31.3% vs 16.4%, p = 0.003, Odds ratio 2.33) (Fig. 3G). Interestingly, the presence of del (17p) did not differentially affect OS in EMD versus non-EMD patients (Fig. 3H). This suggests that poor prognosis of del (17p) is largely conferred by the development of EMD. With respect to TP53 mutation, it was present in 52 out of 374 patients (13.9%) (Fig.3I). Similar to the dup (1q) and del (17p) data, patients had a poorer prognosis compared to patients with TP53 wild-type (wt) (Median OS 5.1 years vs 9.0 years, p < 0.0001) (Fig. 3J) and these patients had a higher incidence of EMD as well (32.7% vs 16.1%, p = 0.003, Odds ratio 2.33) (Fig. 3K). However, unlike the other poor prognostic factors, there was a statistical difference between TP53 mut and wt even after stratification by EMD development (Fig. 3L). Additionally, there was no statistically significant difference in OS between EMD (Median OS 3.4 years) and non-EMD (Median OS 5.5 years) if the patients had TP53 mutation (p = 0.07). Although the number is limited, these data may indicate that the reason why dup (1q) and del (17p) present a poor prognosis may be largely due to their propensity to develop EMD. On the other hand, TP53 mutations have a negative impact on OS regardless of EMD development.

**Fig. 3: Poor outcomes are noted in EMD patients with or without duplication 1q (dup (1q)) and deletion 17p (del (17p)).**

The site of TP53 mutation, but not RAS/BRAF, likely affects EMD development

We next sought to understand the influence of RAS/BRAF and TP53 mutation sites on EMD occurrence. All mutations from BM and EMD samples were plotted (Fig. 4A–D). Our results showed that most of the mutations were seen in recurrent mutation sites and no difference was found between EMD and non-EMD patients among RAS/BRAF mutation sites (Fig. 4A–C). In contrast, there were differences in TP53 mutation sites between EMD and non-EMD patients. Non-EMD patients showed mutations distributed throughout the gene, while EMD patients had more mutations in the C-terminus of the TP53 gene (Fig. 4D) (p = 0.009). One patient showed two TP53 mutations in both C- and N-terminus in the EMD sample but only an N-terminal TP53 mutation in a subsequent BM sample. Notably, six of 17 EMD patients had TP53 mutations accumulated in the sites of aa175, 248, and 273 which are reported as gain-of-function mutation sites in other cancers, while only 2 were found in 35 non-EMD patients. (35.3%: 5.7%, p = 0.011). This suggests that TP53 mutations have different molecular effects depending on their sites and gain-of-function may contribute to the development of EMD.

**Fig. 4: Mutation sites differ with respect to *TP53*, but not *RAS/BRAF*, in EMD versus non-EMD patients.**

Discussion

Several studies have conducted mutational analyses in MM patient samples and demonstrated significant heterogeneity [24,25,26,27]. The clinical course of MM patients also varies widely across patients, which underscores the use of an individualized treatment approach. In recent years, there has been an unmet need to elucidate the molecular mechanisms underlying the development of EMD, one of the most refractory and intractable conditions of MM even with the availability of novel T cell redirected therapies. Myeloma typically occurs in older people and its incidence in patients below the age of 50 is low. In the past, there has been a multi-center retrospective study which showed that patients younger than 50 showed favorable factors with regard to ISS stage, as well as a fair prognosis [28]. However, according to our data, there was no clear correlation between ISS staging and EMD development. Our cumulative incidence data revealed that patients who were diagnosed with MM under the age of 50 were at a higher risk for EMD development even in the era of new drugs. Going forward, larger prospective studies will be needed to confirm our preliminary findings.

Numerous past studies have reported clinical data on EMD; however, sample sizes were often limited and the definition of EMD has not been clear or consistent [5,6,7,8]. With the definition of EMD as organ plasmacytoma distinct from bones, our data shows a strong relationship between EMD and RAS/BRAF mutations observed in MM patients. It is known that RAS/BRAF mutations are usually observed in advanced-stage MM rather than MGUS, SMM, or newly diagnosed MM, and previous data indicate that RAS/BRAF mutations are acquired throughout the clinical course with disease progression as a consequence of clonal evolution [29]. In solid cancers, commonly occurring missense mutations in three members of RAS family genes result in their constitutive activation, and importantly, these mutations serve as predictors of poor patient survival [30, 31]. This is largely due to the association of RAS/BRAF mutations with the presence of metastases at diagnosis and with inherent or acquired resistance to treatments [32,33,34]. Our data indicates that EMD incidence is higher in BM-RAS/BRAF patients than non-BM-RAS/BRAF patients and the development of EMD is a poor prognostic factor regardless of the BM mutational status. Having a RAS/BRAF mutation alone does not result in a uniform clinical phenotype, nor does it directly determine prognosis. In our cohort, EMD patients with BM-KRAS had the worst outcome, with an OS of 3.0 years. Several studies have reported that the prognosis of patients who had KRAS mutations is worse than that of non-RAS/BRAF patients [35,36,37]. The poorer OS among EMD patients may be a contributing factor to the unfavorable prognosis of BM-KRAS patients in previous studies.

Whole genome sequencing studies have revealed that the genetic landscape of metastasis in solid cancers is distinct from the original site and is thought to be an evolutionary process [38, 39]. It has been reported that multiple myeloma patients have a mixture of clones in their BM and the dominance of these clones changes throughout the clinical course, leading to refractory disease [40]. Interestingly, in our cohort, two EMD-NRAS-positive patients did not have NRAS mutations in their BM. Also, one of those EMD samples had two TP53 mutations, one of which was not detectable in BM. Of note, both BM samples were acquired after EMD samples, and one patient only had radiotherapy without systemic therapy between the two biopsies. Previous studies have shown similar results, but the authors concluded that detection limitations may have occurred owing to the low tumor burden in the BM [16]. However, BM samples collected in our study met the 9% tumor cell frequency threshold, which is sufficient to detect mutational burden. Although RAS/BRAF mutations are likely essential to the development of EMD and incidence of EMD is enriched in BM-RAS/BRAF patients, there was no difference in the site of RAS/BRAF mutation between EMD and non-EMD patients. It is also possible that patients who were negative for RAS/BRAF mutations in BM may have had mutated cells at an undetectable level which was not a dominant clone. These data may suggest a temporal and spatial heterogeneity of MM cells in patients.

Although RAS/BRAF mutations are likely essential for the development of EMD, not all BM-RAS/BRAF patients develop EMD suggesting that the mutation alone is not sufficient to develop EMD. It is well known that dup (1q), del (17p), and TP53 mutations are poor prognostic factors, and these are enriched in EMD patients which we confirmed in our cohort. Surprisingly, our detailed analyses revealed that EMD is a poor prognostic factor even in patients with dup (1q) and del (17p). In addition, there was no statistical difference in OS with or without the presence of these risk factors in both EMD and non-EMD patient groups. This indicates that the manner in which these are poor prognostic factors is largely due to the propensity to the development of EMD. TP53 is one of the most significant tumor suppressor genes, and its mutation is often observed in a variety of cancers [41]. It consists of four domains, with most mutations contained in the DNA binding domain [42]. Some studies have shown the distinct functions of TP53 N-terminus and C-terminus, with the C-terminus controlling site-specific DNA binding and structural changes within the central DNA binding domain. It is reported that the TP53 gene has not only loss-of-function but also gain-of-function mutations [43]. Those gain-of-function mutations are known to promote cancer progression and metastasis in xenograft models and are associated with poor clinical outcomes in patients [44,45,46,47]. In the context of myeloma, it has been previously reported that mutations of TP53 are associated with poor clinical outcomes, as they are linked with more aggressive and advanced forms of the disease, but the exact molecular role of TP53 mutations in MM patients is unclear, including the mechanism of loss-of-function and gain-of-function mutations [47]. Interestingly, we found significant differences in the site of TP53 mutations between EMD and non-EMD patients; non-EMD patients had mutations distributed throughout the gene, while EMD patients showed more mutations near the C-terminus, and accumulated in the sites of aa175, 248, and 273. These specific mutations are known as gain-of-function mutations. Currently, the function of TP53 mutations in MM is poorly understood and no risk classification based on the site of TP53 mutation exists. Our data indicates that the site of TP53 mutations has a molecularly important impact on the development of EMD and that specific mutations may help to elucidate the underlying mechanisms of EMD. It also suggests that not all TP53 mutations should be considered equal and that depending on mutation site the prognostic significance may vary. To our knowledge, this is the first report suggesting the relevance between EMD and TP53 gain-of-function mutations. This analysis encompasses both newly diagnosed and RRMM; therefore, a more extensive and homogeneous prospective study in the future would be desirable. This was also why no specific conclusions could be drawn on impact of treatment on our current cohort.

In summary, EMD sites may have different mutational landscapes from the BM in MM which suggests that RAS/BRAF mutations may play a critical role in the development of EMD, coupled with other associated molecular abnormalities, especially dup (1q) and del (17p), and site-specific TP53 mutations. By integrating clinical outcomes and molecular features, we have revealed the clinical impact of EMD on MM patients and its association with the influences of known risk factors. These results will enable us to provide more accurate EMD risk stratification and provide insights for novel approaches in the treatment of MM.

Categories: Cancer genomics, Genetics research, Myeloma

Tags: Cancer genomics, Genetics research, Myeloma

Engineering bone/cartilage organoids: strategy, progress, and application

The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.

AdMaPlace March 9, 2025

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Type 2 immunity in allergic diseases

Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.

AdMaPlace March 9, 2025

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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

AdMaPlace March 9, 2025

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Targeting of TAMs: can we be more clever than cancer cells?

With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.

AdMaPlace March 9, 2025

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The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development

Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.

AdMaPlace March 8, 2025

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Introduction

Methods

Patient cohort

Diagnosis of EMD

Mutational analysis

Fluorescent in situ hybridization

Statistical analysis

Results

Mutational testing reveals RAS/BRAF mutations are likely essential for the development of EMD

The prognosis of patients with BM-RAS/BRAF is largely defined by EMD development

Poor prognosis of patients with dup (1q) and del (17p) is conferred by the development of EMD

The site of TP53 mutation, but not RAS/BRAF, likely affects EMD development

Discussion

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