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.

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/m2 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.
BACKGROUND: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638.
UNASSIGNED: DERR1-10.2196/51368.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: None.

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.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: Funding was provided by the Austrian Forum against Cancer.

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.

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.

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.