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Multiple myeloma (MM) frequently causes vertebral fractures (VF). Some are lytic lesions and others have the aspect of benign osteoporotic fractures not requiring anti-myeloma treatment. We explored outcome of these patients with smoldering myeloma (SM) and osteoporotic VF.In this retrospective bi-centric study, patients were identified using a systematic keyword search on electronic medical records. Patients with SM and isolated VF of osteoporotic aspect without indications for myeloma-specific therapy were included.Overall, 13 (7 %) of the 184 identified patients had SM and VF confirmed to be osteoporotic (median number of VF was 3). During follow-up, 12 (92 %) patients evolved to symptomatic MM, 7 (54 %) of them within 18 months (early progressors). Myeloma defining events were new lytic bone lesions in 7 patients (53.8 %). The serum calcium level was significantly higher in the early progressor group (median 2.35 IQR [2.31–2.38] and 2.28 IQR [2.21–2.29] respectively, p = 0.003). Early progressors had a higher number of VF at diagnosis (3.0 [2.0–5.5] vs 1.0 [1.0–2.5], p = 0.18) and more frequently evolved to symptomatic MM because of lytic bone lesions (5 [71 %] vs 2 [33 %], p = 0.13) compared to late progressors.VF of osteoporotic appearance in the context of SM is a rare situation but at high risk of rapid progression to symptomatic MM, suggesting that they may represent bone fragility linked to MM infiltration rather than solely osteoporotic fractures. Further studies are needed to assess if earlier treatment might be beneficial in this population.

Summary: Advances in morphological and functional imaging have led to superior detection of early bone disease, bone marrow infiltration, paramedullary and extramedullary involvement in multiple myeloma. The two functional imaging modalities that are most widely used and standardized are 18F‐fluorodeoxyglucose–Positron emission tomography/computed tomography (FDG PET/CT) and whole‐body magnetic resonance imaging with diffusion‐weighted imaging (WB DW‐MRI). Both prospective and retrospective studies have demonstrated that WB DW‐MRI is more sensitive than PET/CT in the detection of baseline tumour burden and to assess response after therapy. In patients with smouldering multiple myeloma, WB DW‐MRI is now the preferred imaging modality to rule out two or more unequivocal lesions which would be considered a myeloma‐defining event by the updated international myeloma working group (IMWG) criteria. In addition to sensitive detection of baseline tumour burden, both PET/CT and WB DW‐MRI have been successfully used for monitoring response to therapy and provide information that is complementary to IMWG response assessment and bone marrow minimal residual disease. In this article, we present 3 vignettes illustrating how we approach the use of modern imaging in the management of patients with multiple myeloma and precursor states, with a specific focus on recent data that have emerged since the publication of the IMWG consensus guideline on imaging. We have utilized data from prospective and retrospective studies to provide a rationale for our approach to imaging in these clinical scenarios and highlighted knowledge gaps requiring future investigation. [ABSTRACT FROM AUTHOR]

Munawwar Hussain,1 Sarvari Yellapragada,2 Samer Al Hadidi1 1Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Michael E. DeBakey VA Medical Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USACorrespondence: Samer Al Hadidi, Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA, Tel +1 501-526-6990, Fax +1 501-320-7861, Email salhadidi@uams.eduAbstract: Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal failure, anemia, and/or hypercalcemia. Recently, the diagnosis and treatment of MM have evolved due to a better understanding of disease pathophysiology, improved risk stratification, and new treatments. The incorporation of new drugs, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and high-dose chemotherapy followed by hematopoietic stem cell transplantation, has resulted in a significant improvement in patient outcomes and QoL. In this review, we summarize differential diagnoses and therapeutic advances in MM.Keywords: multiple myeloma, myeloma, smoldering myeloma, Waldenstrom macroglobulinemia, light-chain amyloidosis

Summary: Background: Smoldering myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) with a variable risk of progression. The management of high-risk SMM (HR-SMM) remains controversial, particularly with changes in diagnostic criteria that led to reclassifying of some patients with SMM to MM. This study aimed to assess clinician preferences for whether to treat patients with HR-SMM and/or patients with MM diagnosed solely by SLiM criteria (free light chain ratio >100, bone marrow plasma cell percentage >60, greater than two focal marrow lesions on MRI) through an electronic survey. Methods: This was a cross-sectional survey of clinicians, conducted via an anonymous online REDCap survey from May 16th to July 5th, 2023. The survey included questions on demographics, SMM surveillance practices, and management preferences for two clinical scenarios (HR-SMM and MM based solely on the free light chain ratio >100 criterion). Data was analysed descriptively via Microsoft Excel. Findings: A total of 146 clinicians completed the full survey, with 92% recommending against routine treatment for a patient with HR-SMM based on a single time point assessment, instead preferring active surveillance. For patients with MM diagnosed solely on the basis of a free light chain ratio >100, 61% recommended active treatment, while 37% recommended active surveillance. The most common reasons recommending against treatment of HR-SMM were toxicity, lack of demonstrated overall survival benefit, and low MM-defining event rates in clinical trials. Interpretation: The survey indicates that most clinicians recommend against routine treatment for HR-SMM. Active surveillance is the prevailing standard of care and it is therefore an appropriate control arm in future SMM trials. More randomised trials are needed to determine if early treatment of modern-era SMM offers a net benefit to patients. Funding: None.

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

Serum hyperviscosity is a rare laboratory finding. Amongst several causes of serum hyperviscosity, malignant disorders are quite common. Monoclonal gammopathy is a family of disorders in which monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma are the asymptomatic variants whereas multiple myeloma is the malignant variant showing different signs and symptoms related to bone lesions, renal failure and anemia. Initially during sample preparation, pipetting of a serum sample was found to be cumbersome. This sample during routine analysis in the automated analyser flagged repeated alarms for clot detection indicating a possibility of a hyper viscous sample. Serum was subjected to fibrinogen and D- dimer test. The D-Dimer levels were found to be normal and fibrinogen levels were mildly elevated. Routine biochemistry investigations were normal except grossly reversed A/G ratio. Due to gross reversal of A/G ratio, the possibility of Multiple myeloma was entertained. Physician's were alerted on telephone. Serum was sent for electrophoresis which showeda M spike. Bone marrow aspirate showed 13% plasma cells. Considering the above lab results the diagnosis of monoclonal gammopathy of smoldering type was considered. The sample was traced to a 77 years old male, who presented to Medicine OPD with the chief complaints of generalised weakness for two months without any history of fever. On physical examination pallor was evident but there was no icterus, cyanosis, clubbing, lymphadenopathy or edema. On haematological evaluation patient was found to be anemic. Careful tracking of hyperviscous patient's serum followed up by thorough investigation led us to the final conclusion that the case mentioned is a rare case of Smoldering type of multiple myeloma. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a hematologic cancer originating from underlying precursor disorders, called Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). In order to predict the risk of progression from MGUS/SMM to MM, well-known prognostic factors are currently used in the clinical management, but the contribute of myeloma-specific T-cell immunity still remains to be addressed in this context. In this work, we shed light on the relevant dynamics of MM-specific T cells in a long-term cohort of MGUS/SMM patients, in particular describing a new prognostic tool, namely Multi-antigenic Myeloma-specific (MaMs) T-cell assay, which may be useful to assess the presence of a protective MM-specific immunity, possibly representing a novel immunologic marker of effective disease control. Our work can be considered a promising proof-of-concept for future larger studies, aiming to further explore the prognostic impact of MaMs-based tests in the management of patients with monoclonal gammopathies. Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to assess long-term probabilities of progression to MM. In addition, new prognostic immunologic parameters, measuring protective MM-specific T-cell responses, could help to identify patients with shorter time-to-progression. In this report, we described a novel Multi-antigenic Myeloma-specific (MaMs) T-cell assay, based on ELISpot technology, providing simultaneous evaluation of T-cell responses towards ten different MM-associated antigens. When performed during long-term follow-up (mean 28 months) of 33 patients with either MGUS or SMM, such deca-antigenic myeloma-specific immunoassay allowed to significantly distinguish between stable vs. progressive disease (p < 0.001), independently from the Mayo Clinic risk category. Here, we report the first clinical experience showing that a wide (multi-antigen), standardized (irrespective to patients' HLA), MM-specific T-cell assay may routinely be applied, as a promising prognostic tool, during the follow-up of MGUS/SMM patients. Larger studies are needed to improve the antigenic panel and further explore the prognostic value of MaMs test in the risk assessment of patients with monoclonal gammopathies. [ABSTRACT FROM AUTHOR]

Keywords: CD56; flow cytometry; smoldering myeloma EN CD56 flow cytometry smoldering myeloma 587 589 3 08/11/23 20230801 NES 230801 DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. We found that CD56 SP - sp patients had a significantly lower presence of hyperdiploidy compared to the CD56 SP + sp group ( I p i = 0.05 I Fisher's test i ).[9] Twenty six patients progressed to MM (8 patients CD56 SP - sp and 18 patients CD56 SP + sp ) and the median time to progression was 23.5 months. [Extracted from the article]

Abstract Background Myeloma bone disease (MBD) is a common complication that significantly contributes to morbidity and mortality in multiple myeloma (MM). Serum sclerostin level and sympathetic activity can affect MBD. The purpose of this study is evaluation of serum sclerostin level and sympathetic activity (using sympathetic skin response “SSR”) in MM patients, and studying the relationship between both of them as well as their relationship with MBD. 35 smoldering myeloma patients (group I) and 35 newly diagnosed MM (group II) and 35 controls (group III) were included in the study. All the participants were subjected to complete history taking, and clinical examination. Assessment of serum sclerostin level, SSR, MM stages [by the international staging system (ISS)], MBD grading (according to the Durie–Salmon staging system) were done for all patients within 7 days from the diagnosis. Results Undetectable and decreased SSR amplitude are significantly more detected in group I and II (compared with group III). Autonomic manifestations, and loss of SSR is significantly more detected in group II than group I. Autonomic manifestations were absent in group III. SSR amplitude of median and tibial nerves is significantly decreased in group II than group I and III. MBD was detected in all patients of group II. Serum sclerostin and LDH were significantly increased in group II than group I. Group I and II had significantly higher levels of sclerostin when compared with group III. Group II had significantly higher levels of sclerostin and lower levels of ALP in comparison with group I. Serum sclerostin level was correlated positively with LDH and negatively with ALP and SSR amplitude. MBD was significantly affected by ISS stage III, LDH level, SSR affection and serum sclerostin level ≥ 0.40 ng/ml. SSR response affection was the most significant risk factor for advanced MBD followed by increased sclerostin level. Conclusions Serum sclerostin level was significantly increased and sympathetic activity was significantly decreased in MBD. Loss of the SSR response was the most significant risk factor for advanced MBD followed by increased sclerostin level. Recommendations Potentially validating the use of bone-turnover markers in larger studies, in addition to electrophysiological examination of SSR to stratify patients who are at high-risk for progressive MBD, as the use of newer agents with anabolic effects such as anti-sclerostin antibodies have shown potential in repair of MBD. These newer agents could potentially change the treatment landscape in patients with MBD.

Summary: Background: Biomarker-defined patients with smoldering multiple myeloma (SMM) were included in the diagnostic category of multiple myeloma (MM) by the International Myeloma Working Group (IMWG) in 2014. This includes ≥60% bone marrow plasma cells (BMPCs), free light chain ratio (FLCratio) ≥100, and >1 MRI-defined ≥5 mm focal lesion, also called SLiM CRAB MM. We examined whether the risk of progression of SLiM CRAB MM patients to CRAB positive MM described in recent studies differs from that reported in earlier studies published before the introduction of the new diagnostic criteria. Methods: We conducted a systematic review with meta-analysis, and included studies on Embase and PubMed (01/01/2010–01/11/2022), selecting studies with digitizable progression curves. Inconsistent studies were excluded. We created forest plots using random effects models from digitized and published data and Kaplan–Meier curves. Main outcomes were median time to progression (TTP), 2-year progression risk, and odds ratios (ORs) comparing 2-year progression risks. Findings: Our meta-analysis including 11 studies with 3482 patients found an approximately 3-fold longer TTP and 50% lower 2-year progression risk of SliM CRAB MM patients in recent (published after 2014) compared with earlier studies. Median TTP in patients with ≥60% BMPCs was 30.31 months [18.71–62.93] in recent compared with 9.20 months [6.02–15.56] in earlier studies; the 2-year progression risk was 45.45% [20.12–62.75] compared with 86.21% [65.74–94.45] in the respective time periods. In patients with a FLCratio ≥ 100, the median TTP was 48.06 months [40.51–64.91] vs. 15.33 months [9.38–19.10], and the 2-year progression risk was 31.61% [25.30–37.39] vs. 73.00% [62.39–80.62] in recent and earlier studies, respectively. Tests for heterogeneity showed that the two time periods differed significantly in their ORs when comparing patients who met the high-and low risk criteria. No appropriate recent studies on focal lesions have been published. Interpretation: Recent studies show significantly improved prognosis of biomarker-defined MM with ≥60% BMPCs and FLCratio ≥ 100. This warrants careful evaluation for signs of progression before treatment initiation. Funding: Funding was provided by the Austrian Forum against Cancer.

In the 1960s, through laboratory-based investigations of peripheral blood partnered with detailed clinical annotations, Dr. Waldenström described a condition he called "benign monoclonal gammopathy". These patients were asymptomatic with a detectable monoclonal protein, and did not meet imaging and laboratory criteria for multiple myeloma. In 1978, through observational retrospective review of medical records, Dr. Kyle observed that not all cases of monoclonal gammopathy were benign. He introduced the term monoclonal gammopathy of undetermined significance (MGUS) to describe a condition that may potentially progress to multiple myeloma (MM), highlighting clinical inability in predicting which patients might progress. In 1980, Drs. Kyle and Greipp described 6 cases which did not fit the definitions of MGUS or MM, and they remained asymptomatic after at least 5 years of follow-up; they were proposed to have smoldering multiple myeloma (SMM). Over time, SMM was defined by arbitrary numerical values (≥10 % plasma cells in the bone marrow and serum M-protein concentration ≥ 3 g/dL). Numerous clinical scores have been developed to define high-risk groups for progression to MM. Current statistical models for progression provide only average risk scores, offering limited clinical utility since the risk of progression at an individual level remains unknown. Physician-scientists are focusing on emerging technologies, such as whole genome sequencing, tumor microenvironment analysis, and single-cell RNA sequencing, to understand precursor states at a molecular level. The overarching goal of these technologies is to better characterize monoclonal gammopathy and other myeloma precursor states. This will enable clinicians to provide more precise, individualized risk assessments and ultimately improve patient outcomes. This review outlines the history of MM precursor states, current definitions, challenges in risk stratification models, and the role of emerging technologies in enhancing predictions and outcomes., Competing Interests: Declaration of competing interest Dr. Landgren reports research funding from: NCI/NIH, FDA, LLS, Rising Tide Foundation, MMRF, IMF, Paula and Rodger Riney Foundation, Tow Foundation, Perelman Family Foundation, Myeloma Solutions Fund, Cannon Guzy Family Fund, Amgen, Celgene, Janssen, and Pfizer; has received honoraria for scientific talks/participated in advisory boards for: Abbvie, Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, GSK, Janssen, Juno, and Pfizer; and served on Independent Data Monitoring Committees (IDMC) for international randomized trials by: Takeda, Merck, Janssen, and Novartis – all of the above are outside the submitted work. Dr. Maura reports personal consulting (consultant) for Sanofi and Medidata. All other authors report no relevant conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM., Methods: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life., Results: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively)., Conclusion: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM., (© The Author(s) 2024. Published by Oxford University Press.)

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.

Background: Myeloma bone disease (MBD) is a common complication that significantly contributes to morbidity and mortality in multiple myeloma (MM). Serum sclerostin level and sympathetic activity can affect MBD. The purpose of this study is evaluation of serum sclerostin level and sympathetic activity (using sympathetic skin response "SSR") in MM patients, and studying the relationship between both of them as well as their relationship with MBD. 35 smoldering myeloma patients (group I) and 35 newly diagnosed MM (group II) and 35 controls (group III) were included in the study. All the participants were subjected to complete history taking, and clinical examination. Assessment of serum sclerostin level, SSR, MM stages [by the international staging system (ISS)], MBD grading (according to the Durie–Salmon staging system) were done for all patients within 7 days from the diagnosis. Results: Undetectable and decreased SSR amplitude are significantly more detected in group I and II (compared with group III). Autonomic manifestations, and loss of SSR is significantly more detected in group II than group I. Autonomic manifestations were absent in group III. SSR amplitude of median and tibial nerves is significantly decreased in group II than group I and III. MBD was detected in all patients of group II. Serum sclerostin and LDH were significantly increased in group II than group I. Group I and II had significantly higher levels of sclerostin when compared with group III. Group II had significantly higher levels of sclerostin and lower levels of ALP in comparison with group I. Serum sclerostin level was correlated positively with LDH and negatively with ALP and SSR amplitude. MBD was significantly affected by ISS stage III, LDH level, SSR affection and serum sclerostin level ≥ 0.40 ng/ml. SSR response affection was the most significant risk factor for advanced MBD followed by increased sclerostin level. Conclusions: Serum sclerostin level was significantly increased and sympathetic activity was significantly decreased in MBD. Loss of the SSR response was the most significant risk factor for advanced MBD followed by increased sclerostin level. Recommendations: Potentially validating the use of bone-turnover markers in larger studies, in addition to electrophysiological examination of SSR to stratify patients who are at high-risk for progressive MBD, as the use of newer agents with anabolic effects such as anti-sclerostin antibodies have shown potential in repair of MBD. These newer agents could potentially change the treatment landscape in patients with MBD. [ABSTRACT FROM AUTHOR]

Herpes zoster (HZ) is a common illness caused by the reactivation of latent varicella zoster virus (VZV) due to waning immunity, often secondary to old age or an underlying immunocompromised state. Its complications can manifest in variety of ways, including persistent neuralgias, vasculopathies, and stroke. Here, we describe a case of a 45-year-old man with a history of cryptogenic stroke and smoldering myeloma who was admitted with sacral HZ complicated by right lumbosacral radiculopathy and myelitis, otherwise known as Elsberg syndrome (ES). He was found to have an enhancing lesion in the peripheral conus medullaris on magnetic resonance imaging (MRI) with nonspecific inflammation and necrosis on biopsy pathology and cerebrospinal fluid (CSF) polymerase chain reaction (PCR) positive for VZV. The patient was initially treated with intravenous acyclovir and dexamethasone and discharged with a steroid taper and indefinite valacyclovir therapy. Twelve months postdischarge, the patient's right lumbosacral radiculopathy and myelitis had almost completely resolved; however, he continued to require bladder self-catheterization. We believe that the patient's underlying smoldering myeloma lead to an immunocompromised state, allowing for reactivation of latent VZV, resulting in both the patient's cryptogenic stroke years earlier and recent ES. [ABSTRACT FROM AUTHOR]

Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous plasma cell disorder, with a highly variable clinical course. Immunoparesis, defined by total immunoglobulin measurements, has been shown to be an independent risk factor for progression to symptomatic disease. The heavy/light chain (HLC) assay allows precise measurement of the polyclonal immunoglobulin of the same isotype, enabling the evaluation of isotype-matched immunoparesis (IMI). In this study, we prospectively characterized immunoparesis, as determined by HLC measurements, in 53 SMM patients. Severe IMI was present in 51% of patients, while severe IP of uninvolved isotypes (HLC IP) was present in 39%. Most of the patients with severe HLC IP presented with severe IMI, but not the other way around. Isotype specificity of immune suppression was suggested by lower relative values of isotype-matched HLC pairs, both for IgG and IgA SMM. Severe IMI was associated with other risk factors for progression while patients with severe IMI and severe HLC IP showed an even higher risk profile. Both severe IMI and severe IgM HLC IP showed a significantly shorter time to progression. Finally, gene expression analysis demonstrated differences in the bone marrow microenvironment between patients with IMI and IMI plus HLC IP, with an increased expression of genes associated with cytolytic cells. In conclusion, our data supports isotype specificity of early immunoglobulin suppression mechanisms. While suppression of both involved and uninvolved isotypes is associated with risk of progression, the later appears to develop with more advanced disease and could be mediated by different mechanisms. [ABSTRACT FROM AUTHOR]

Background: To compare the NaF uptake in the thoracic aorta and whole heart, as an early indicator of atherosclerosis, in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients with a healthy control (HC) group. Methods: Forty-four untreated myeloma patients (35 MM and nine SMM) and twenty-six age and gender-matched HC subjects were collected. Each individual's NaF uptake in three parts of the aorta (AA: ascending aorta, AR: aortic arch, DA: descending aorta) and the whole heart was segmented. Average global standardized uptake value means were derived by sum of the product of each slice area divided by the sum of those slice areas. Results were reported as target to background ratio (TBR). Results: There was a significant difference between the NaF uptake in the thoracic aorta of myeloma and HC groups [AA (myeloma = 1.82 ± 0.21, HC = 1.24 ± 0.02), AR (myeloma = 1.71 ± 0.19, HC = 1.28 ± 0.03) and DA (myeloma = 1.96 ± 0.28, HC = 1.38 ± 0.03); P-values < 0.001]. The difference in the whole heart NaF uptake between two groups was also significant (P < 0.001). Conclusions: We observed a higher uptake of NaF in the thoracic aorta and whole heart of myeloma patients in comparison to the matched control group. [ABSTRACT FROM AUTHOR]

Abstract: Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course. Ongoing studies to define the ideal timing and patient population are underway, as well as identification of which agents would be of greatest benefit, as the armamentarium for MM continues to grow. [ABSTRACT FROM AUTHOR]

Abstract Background Scleredema is a rare sclerodermoid skin condition characterized by diffuse symmetrical thickening of the upper part of the body. Its association with monoclonal gammopathy and myeloma was recently described; very few cases have been reported to date. Case presentation A 66-year-old Sri Lankan woman who had been followed in a dermatology unit for 34 years with diffuse systemic sclerosis presented with an acute exacerbation of the skin disease. Absence of Raynaud’s phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibodies test results led to reevaluation for the possibility of scleredema. Skin biopsies from four body sites showed normal epidermis and thickened reticular dermis with swollen collagen bundles separated from one another by clear spaces, resulting in fenestration. The skin appendages were not atrophied or bound down. Alcian blue staining showed interstitial mucin deposition. Serum protein electrophoresis demonstrated an abnormal monoclonal band in the β-region with a paraprotein level of 8.9 g/dl. Immunofixation showed an abnormal band in the γ-region consisting of immunoglobulin A and κ. Bone marrow biopsy revealed abnormal monoclonal plasma cells (15%) with multinuclearity. There was no evidence of end organ damage, and whole-body magnetic resonance imaging did not reveal any evidence of bone involvement. The patient’s diagnosis was revised as scleredema type 2 associated with IgA-κ, and she was referred to a hemato-oncologist for chemotherapy, which led to significant improvement in the skin condition. Conclusions Scleredema is a rare disorder that has an enigmatic, rare association with monoclonal gammopathy. Dermatologists should be aware of this rare but important association.

Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin’s Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients’ median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.

Purpose of Review: Smoldering multiple myeloma (SMM) is defined as an asymptomatic clonal proliferation of pre-malignant plasma cells and an increased risk of progression to multiple myeloma (MM) relative to monoclonal gammopathy of undetermined significance. Whether patients with SMM should be treated prior to development of symptomatic disease is fiercely debated and is a highly active area of research. Recent Findings: The ECOG E3A06 study demonstrated that early treatment with lenalidomide significantly reduced the risk of progression to MM compared to observation in patients with high risk SMM. The IMWG recently validated a risk stratification model to include cytogenetics and a personalized risk calculator for individual patients. Beyond this, molecular genomic aberrations and immunological phenomena that promote progression from asymptomatic disease to MM have been recently characterized and may help to more precisely identify patients who are most suitable for early intervention. Summary: As highly effective and tolerable therapies for plasma cell disorders evolve, the field is approaching a paradigm shift that involves the adoption of intervention for patients with SMM who are at high risk for progression to symptomatic myeloma in order to prevent morbidity and mortality. This review highlights our current understanding of the biology of patients with SMM, clarifies the rationale for early intervention, and summarizes early results of various treatment strategies for patients with high-risk smoldering myeloma. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin's Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients' median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment. [ABSTRACT FROM AUTHOR]

Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunoprevention has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunoprevention that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immunomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention. [ABSTRACT FROM AUTHOR]

BackgroundThe PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies.MethodsThe PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients.ResultsFirst, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells.ConclusionsOur data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment.

Background: The PD-1/PD-L1 axis has recently emerged as an immune checkpoint that controls antitumor immune responses also in hematological malignancies. However, the use of anti-PD-L1/PD-1 antibodies in multiple myeloma (MM) patients still remains debated, at least in part because of discordant literature data on PD-L1/PD-1 expression by MM cells and bone marrow (BM) microenvironment cells. The unmet need to identify patients which could benefit from this therapeutic approach prompts us to evaluate the BM expression profile of PD-L1/PD-1 axis across the different stages of the monoclonal gammopathies. Methods: The PD-L1/PD-1 axis was evaluated by flow cytometry in the BM samples of a total cohort of 141 patients with monoclonal gammopathies including 24 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), 38 patients with smoldering MM (SMM), and 79 patients with active MM, including either newly diagnosed or relapsed-refractory patients. Then, data were correlated with the main immunological and clinical features of the patients. Results: First, we did not find any significant difference between MM and SMM patients in terms of PD-L1/PD-1 expression, on both BM myeloid (CD14+) and lymphoid subsets. On the other hand, PD-L1 expression by CD138+ MM cells was higher in both SMM and MM as compared to MGUS patients. Second, the analysis on the total cohort of MM and SMM patients revealed that PD-L1 is expressed at higher level in CD14+CD16+ non-classical monocytes compared with classical CD14+CD16− cells, independently from the stage of disease. Moreover, PD-L1 expression on CD14+ cells was inversely correlated with BM serum levels of the anti-tumoral cytokine, IL-27. Interestingly, relapsed MM patients showed an inverted CD4+/CD8+ ratio along with high levels of pro-tumoral IL-6 and a positive correlation between %CD14+PD-L1+ and %CD8+PD-1+ cells as compared to both SMM and newly diagnosed MM patients suggesting a highly compromised immune-compartment with low amount of CD4+ effector cells. Conclusions: Our data indicate that SMM and active MM patients share a similar PD-L1/PD-1 BM immune profile, suggesting that SMM patients could be an interesting target for PD-L1/PD-1 inhibition therapy, in light of their less compromised and more responsive immune-compartment. [ABSTRACT FROM AUTHOR]

Objective: To determine association of body composition measurements on CT and PET with progression of smoldering myeloma to multiple myeloma. Methods: A retrospective cohort study in 65 patients with smoldering myeloma and PET/CT at diagnosis was performed at a tertiary cancer center. Subjects were between 38 and 87 years of age (mean 64) and included 37 males. Primary outcome was progression-free survival as a function of bone, fat, and muscle metrics on CT and PET (measured at the level of L4 pedicles) and clinical confounders. CT metrics included attenuation of L4 and retroperitoneal fat and various indices derived from the psoas muscle. PET measures included SUVmax and SUVmean of L4, retroperitoneal fat, and psoas. Cox proportional hazards modeling was performed with entry and retention criteria of p < 0.1 and p < 0.05, respectively. Results: SUVmax and SUVmean were associated for each compartment (R2 = 0.78–0.84), and SUVmean (SUV) was used for subsequent analyses. SUV of the L4 vertebral body was associated with attenuation of the L4 vertebral body (p = 0.0032). There was no association between SUV and CT for muscle and fat compartments. In the subset of patients with bone marrow biopsy results (n = 43), there was no association between SUV of L4 and plasma cell concentration on core biopsy or flow cytometry (p = 0.089 and 0.072, respectively). The final Cox model showed association with albumin (HR 0.29, 95%CI 0.088–0.93, p = 0.038), M protein (HR 1.31, 95%CI 1.021–1.68, p = 0.034), and SUV of L4 (HR 1.99, 95%CI 1.037–3.82, p = 0.039). Conclusion: SUV of L4 is a prognostic indicator in patients with smoldering myeloma. [ABSTRACT FROM AUTHOR]

Smoldering multiple myeloma (SMM) is an intermediate clinical stage in the spectrum of monoclonal plasma cell disorders. It represents a heterogeneous clinically defined condition in which some patients (approximately 50%) have monoclonal gammopathy of undetermined significance (premalignancy), and some (approximately 50%) have multiple myeloma (biologic malignancy). Using specific prognostic factors, patients with SMM, in whom malignant transformation has already likely occurred, can be identified. These patients are considered to have high-risk SMM. Patients with newly diagnosed high-risk SMM are candidates for early intervention with lenalidomide or lenalidomide plus dexamethasone for 2 years, or enrollment in clinical trials., Competing Interests: Disclosure No significant conflicts of interests to disclose. Dr S.V. Rajkumar reports grants from NIH, United States outside the submitted work. Dr S. Kumar reports consultancy from BMS/Celgene, Takeda, United States, and Janssen, United States, and research funding from BMS, United States/Celgene, Takeda, Novartis, Switzerland, AbbVie, Janssen, and Amgen, United States. Dr L. Bergsagel reports grants from the NCI, United States, research funding from Pfizer, United States, consultancy for Pfizer, and AbbVie., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) frequently causes vertebral fractures (VF). Some are lytic lesions and others have the aspect of benign osteoporotic fractures not requiring anti-myeloma treatment. We explored outcome of these patients with smoldering myeloma (SM) and osteoporotic VF. In this retrospective bi-centric study, patients were identified using a systematic keyword search on electronic medical records. Patients with SM and isolated VF of osteoporotic aspect without indications for myeloma-specific therapy were included. Overall, 13 (7 %) of the 184 identified patients had SM and VF confirmed to be osteoporotic (median number of VF was 3). During follow-up, 12 (92 %) patients evolved to symptomatic MM, 7 (54 %) of them within 18 months (early progressors). Myeloma defining events were new lytic bone lesions in 7 patients (53.8 %). The serum calcium level was significantly higher in the early progressor group (median 2.35 IQR [2.31-2.38] and 2.28 IQR [2.21-2.29] respectively, p  = 0.003). Early progressors had a higher number of VF at diagnosis (3.0 [2.0-5.5] vs 1.0 [1.0-2.5], p  = 0.18) and more frequently evolved to symptomatic MM because of lytic bone lesions (5 [71 %] vs 2 [33 %], p  = 0.13) compared to late progressors. VF of osteoporotic appearance in the context of SM is a rare situation but at high risk of rapid progression to symptomatic MM, suggesting that they may represent bone fragility linked to MM infiltration rather than solely osteoporotic fractures. Further studies are needed to assess if earlier treatment might be beneficial in this population., Competing Interests: KC has no conflict of interest. SH has no conflict of interest. SB has received grant from SERVIER, unrelated to his work. JH has no conflict of interest. KB has Honoria and research grant from Amgen, Theramex, and Kyowa Kirin, unrelated to his work. RB has received Honoria from Astra Zaneca, unrelated to his work. RC has received Honoria and research grant from ALEXION and research grant from REGENRON, unrelated to his work. XM has received Honoria from BMS, Galapagos, GSK, Novartis, Pfizer, unrelated to his work. RS received consulting fees or honoraria from GSK, Bristol Myer Squib, Boehringer, Janssen, Amgen, Pfizer and Roche, travel fees from Amgen and GSK, unrelated to his work., (© 2024 The Authors.)

Background: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy., Objective: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM)., Methods: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m 2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast., Results: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025., Conclusions: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention., Trial Registration: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638., International Registered Report Identifier (irrid): DERR1-10.2196/51368., (©David J Lee, Elizabeth K O'Donnell, Noopur Raje, Cristina Panaroni, Robert Redd, Jennifer Ligibel, Dorothy D Sears, Omar Nadeem, Irene M Ghobrial, Catherine R Marinac. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.03.2024.)

We explore the predictive role of 2014-updated International Myeloma Working Group (IMWG) diagnostic criteria and of some of currently available risk models for progression to symptomatic myeloma when applied in our unselected population of 75 smoldering multiple myeloma (SMM) patients observed between 2000 and 2015. Risk scores including routinely used clinical parameters such as bone marrow plasmacell infiltration rate, immunoparesis, serum monoclonal component (sMC) value, and altered free light chain ratio (FLCr), were clinically useful to identify SMM patients at higher risk of progression. Time to myeloma progression in our ultra-high risk SMM according to IMWG diagnostic update criteria was very short (12.4 months). Our analysis identified as independent reliable predictors of progression altered FLCr as well as increasing plasma cell infiltration which are part of most commonly applied risk models. Waiting for new scoring systems, bone marrow evaluation and complete laboratory screening are still milestones for SMM management. [ABSTRACT FROM AUTHOR]

We report on a 52-year-old patient with an initial diagnosis of smoldering myeloma (SMM), who was monitored by means of dynamic and static positron emission tomography/computed tomography (PET/CT) with the radiotracer 1⁸F-fluorodeoxyglucose (18F-FDG). Baseline PET/CT revealed no pathological signs. Six months later, a transition to symptomatic, multiple myeloma (MM) was diagnosed. The transition was not accompanied by focal, hypermetabolic lesions on PET/CT. However, a diffusely increased 18F-FDG uptake in the bone marrow, accompanied by a marked increase of semi-quantitative (standardized uptake value, SUV) and quantitative, pharmacokinetic 18F-FDG parameters, was demonstrated. After successful treatment, including tandem autologous transplantation, the diffuse uptake in the bone marrow as well as the semi-quantitative and quantitative parameters showed a marked remission. This response was also confirmed by the clinical follow-up of the patient. These findings suggest that in MM a diffuse 18F-FDG uptake in the bone marrow may indeed reflect an actual bone marrow infiltration by plasma cells. Moreover, SUV values and kinetic parameters, not only from myeloma lesions but also from random bone marrow samples, may be used for MM monitoring. This could be particularly helpful in the follow-up of myeloma patients negative for 18F-FDG-avid focal lesions.

Symptomatic multiple myeloma (MM) is a plasma cell neoplasm that represents the final stage of a continuum of clinical conditions that start from monoclonal gammopathy of unknown significance (MGUS), then transits in the more advance, but still asymptomatic, smoldering MM (SMM), with a final evolution in symptomatic MM. To investigate SMM microenvironment modifications, we studied 16 patients diagnosed at our hospital. Eight of them (group A) developed MM within 2 years from diagnosis while the others (group B) had stable SMM. Samples were bone marrow biopsies at diagnosis and after 2 years (± 4 months) and were analyzed by immunohistochemical analysis. Firstly, we found a significant increase in both CD4+ cells (11 vs 17%, p < 0.01) and CD8+ cells (15 vs 18%, p < 0.01) between diagnosis and at follow-up samples (whole cohort). This was associated to an increase in the CD4+/CD8+ ratio (0.74 vs 0.93, p < 0.01). Secondly, we discovered an increased expression of T cell inhibitory molecules during SMM evolution. In fact, plasma cell PD-L1 and microenvironment cell LAG3 expression increased from 1 to 12% (p = 0.03) and 4 to 10% (p = 0.04), respectively, from diagnosis to follow-up. Also, plasma cells and microenvironment cells HLA-DR expression augmented during SMM evolution from 7 to 10% (p = 0.04) and 29 to 39% (p = 0.01), respectively. When comparing group A vs group B, we found an increased CD68-KP1+ cell infiltration in favor of group B at diagnosis (23 vs 28%, p = 0.01) and a greater plasma cell infiltration at follow-up (50 vs 26%, p < 0.01). Our findings suggest how immune escape mechanisms appear earlier during multiple myeloma evolution, and that LAG3 could be a possible immunologic target in this setting. [ABSTRACT FROM AUTHOR]

Objective: To determine the value of low-dose whole-body CT (WBCT) in the management of patients with multiple myeloma (MM) and precursor states.Materials and Methods: The study group comprised 116 patients (mean age: 68 ± 11 years, 48% women) who underwent WBCT for the work-up or surveillance of MM or MM precursor disease. WBCTs were reviewed for the presence of MM-related bone disease and incidental findings requiring therapy. The medical records, results from bone marrow aspirations and biopsies and follow-up imaging studies were reviewed to assess the influence of WBCT on patient management.Results: Whole-body CT led to a change in management in 32 patients (28%). Of those, 17 patients with MM precursor disease were found to have MM-related bone disease, 13 patients had progression of MM, requiring a change in treatment, in one patient hepatocellular carcinoma was diagnosed, requiring a change in therapy, and one patient had a rib lesion requiring intervention. In 65 patients (56%), WBCT was performed for surveillance of MM precursor disease or stable treated MM, and did not detect new lesions, thereby providing reassurance to the hematologist on disease status and management. In 15 patients (13%) WBCT was performed as a new baseline before a change or new therapy. In 4 patients (3%), WBCT was performed for a change in symptoms, but did not detect lesions that would lead to a change in management.Conclusion: Whole-body CT provides important information for disease monitoring and detection of incidental findings, thereby improving the management of patients with MM. [ABSTRACT FROM AUTHOR]

Background: Smoldering myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) with a variable risk of progression. The management of high-risk SMM (HR-SMM) remains controversial, particularly with changes in diagnostic criteria that led to reclassifying of some patients with SMM to MM. This study aimed to assess clinician preferences for whether to treat patients with HR-SMM and/or patients with MM diagnosed solely by SLiM criteria (free light chain ratio >100, bone marrow plasma cell percentage >60, greater than two focal marrow lesions on MRI) through an electronic survey., Methods: This was a cross-sectional survey of clinicians, conducted via an anonymous online REDCap survey from May 16th to July 5th, 2023. The survey included questions on demographics, SMM surveillance practices, and management preferences for two clinical scenarios (HR-SMM and MM based solely on the free light chain ratio >100 criterion). Data was analysed descriptively via Microsoft Excel., Findings: A total of 146 clinicians completed the full survey, with 92% recommending against routine treatment for a patient with HR-SMM based on a single time point assessment, instead preferring active surveillance. For patients with MM diagnosed solely on the basis of a free light chain ratio >100, 61% recommended active treatment, while 37% recommended active surveillance. The most common reasons recommending against treatment of HR-SMM were toxicity, lack of demonstrated overall survival benefit, and low MM-defining event rates in clinical trials., Interpretation: The survey indicates that most clinicians recommend against routine treatment for HR-SMM. Active surveillance is the prevailing standard of care and it is therefore an appropriate control arm in future SMM trials. More randomised trials are needed to determine if early treatment of modern-era SMM offers a net benefit to patients., Funding: None., Competing Interests: GRM has received royalties from MashupMD for writing. He declares no conflicts of interest with pharmaceutical companies or any that are relevant to this work. EC receives research funding from Arnold Ventures. RC has consulted for Sanofi, Janssen and Adaptive, and received research funding from Abbvie. BD reports consulting for Janssen, Sanofi, COTA, Inc, Multiple Myeloma Research Foundating and Plexus communication, as well as serving on a data safety monitoring committee for BMS., (© 2023 The Author(s).)

Introduction: Multiple myeloma (MM) is generally an incurable hematological malignancy with heterogeneous overall survival rates ranging from a few months to more than 10 years. Survival is especially poor for patients who developed disease that is refractory to immunomodulatory drugs and proteasome inhibitors.Areas covered: This review will discuss the importance of CD38-targeting antibodies for the treatment of MM patients to improve their outcome.Expert commentary: Intense immuno-oncological laboratory research has resulted in the development of functionally active monoclonal antibodies against cell surface markers present on MM cells. In this respect, CD38-targeting antibodies such as daratumumab, MOR202, and isatuximab, have high single agent activity in heavily pretreated MM patients by virtue of their pleiotropic mechanisms of action including Fc-dependent effector mechanisms and immunomodulatory activities. Importantly, CD38-targeting antibodies are well tolerated, with infusion reactions as most frequent adverse event. Altogether, this makes them attractive combination partners with other anti-MM agents. Daratumumab is already approved as monotherapy and in combination with lenalidomide-dexamethasone as well as bortezomib-dexamethasone in pretreated MM patients. Furthermore, results from studies evaluating CD38-targeting antibodies in newly diagnosed MM patients are also promising, indicating that CD38-targeting antibodies will be broadly used in MM, resulting in further improvements in survival. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Concomitant diagnosis of metastatic prostate cancer and a multiple myeloma in older male patients is challenging as both malignancies are usually associated with bone lesions. Exact knowledge, experience, and an interdisciplinary approach are required in order to differentiate between both malignancies and determine the exact treatment strategy. [ABSTRACT FROM AUTHOR]

IL-6 activity in normal plasma cells (nPCs) and abnormal plasma cells (aPCs) is CD126 (subunit of IL-6 receptor) dependent. We quantified CD126 expression on nPCs and aPCs in monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and multiple myeloma (MM). CD126 was detected on all nPCs and aPCs indicating that CD126 does not have diagnostic utility. CD126 expression was higher in aPCs than in nPCs in 85% SMM but only 41% MGUS and there was evidence that CD126 was higher in aPCs than nPCs in the SMM (p = .048) but not MGUS (p = .96) patients. There is also a greater association between nPC and aPC CD126 expression in low risk MGUS than observed in high risk MGUS and SMM, suggesting normal regulation of CD126 decreases with disease progression. Future studies need to elucidate the role of bone marrow milieu versus escape from normal CD126 regulation in malignant transformation of clonal plasma cells. [ABSTRACT FROM AUTHOR]

Abstract Background Pseudohyperphosphatemia is a rare laboratory finding in MM, especially in patients with smoldering myeloma (SMM) progressing to symptomatic multiple myeloma (MM). Laboratorians and clinicians should be aware of this phenomenon and take necessary actions to avoid misdiagnosis. Methods Specimens from a monoclonal IgG kappa SMM patient with extremely high serum phosphorus concentrations measured by the Roche phosphomolybdate assay were re-evaluated using serial dilutions and the ORTHO VITROS assay free from monoclonal gammaglobulin interference. Serum free kappa/lambda chain ratio was also assessed. Results Both serial dilutions and the ORTHO VITROS assay normalized serum phosphorus concentrations, suggesting the extremely high serum phosphorus concentrations measured by the Roche assay is due to interference from monoclonal gammaglobulin. Additionally, the patient's serum free kappa/lambda ratio was >100. Based on serum free kappa/lambda ratio, disease progression from SMM to MM was diagnosed. Conclusions Prompt and appropriate laboratory investigations ensure correct diagnosis of pseudohyperphosphatemia and help clinicians properly manage patients. To our knowledge, this patient is the first reported case of pseudohyperphosphatemia in patients with progression from SMM to MM. [ABSTRACT FROM AUTHOR]

Background: Biomarker-defined patients with smoldering multiple myeloma (SMM) were included in the diagnostic category of multiple myeloma (MM) by the International Myeloma Working Group (IMWG) in 2014. This includes ≥60% bone marrow plasma cells (BMPCs), free light chain ratio (FLCratio) ≥100, and >1 MRI-defined ≥5 mm focal lesion, also called SLiM CRAB MM. We examined whether the risk of progression of SLiM CRAB MM patients to CRAB positive MM described in recent studies differs from that reported in earlier studies published before the introduction of the new diagnostic criteria., Methods: We conducted a systematic review with meta-analysis, and included studies on Embase and PubMed (01/01/2010-01/11/2022), selecting studies with digitizable progression curves. Inconsistent studies were excluded. We created forest plots using random effects models from digitized and published data and Kaplan-Meier curves. Main outcomes were median time to progression (TTP), 2-year progression risk, and odds ratios (ORs) comparing 2-year progression risks., Findings: Our meta-analysis including 11 studies with 3482 patients found an approximately 3-fold longer TTP and 50% lower 2-year progression risk of SliM CRAB MM patients in recent (published after 2014) compared with earlier studies. Median TTP in patients with ≥60% BMPCs was 30.31 months [18.71-62.93] in recent compared with 9.20 months [6.02-15.56] in earlier studies; the 2-year progression risk was 45.45% [20.12-62.75] compared with 86.21% [65.74-94.45] in the respective time periods. In patients with a FLCratio ≥ 100, the median TTP was 48.06 months [40.51-64.91] vs. 15.33 months [9.38-19.10], and the 2-year progression risk was 31.61% [25.30-37.39] vs. 73.00% [62.39-80.62] in recent and earlier studies, respectively. Tests for heterogeneity showed that the two time periods differed significantly in their ORs when comparing patients who met the high-and low risk criteria. No appropriate recent studies on focal lesions have been published., Interpretation: Recent studies show significantly improved prognosis of biomarker-defined MM with ≥60% BMPCs and FLCratio ≥ 100. This warrants careful evaluation for signs of progression before treatment initiation., Funding: Funding was provided by the Austrian Forum against Cancer., Competing Interests: The authors declare no relevant conflicts of interest., (© 2023 The Author(s).)