Renal impairment in monoclonal gammopathies and multiple myeloma.

The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.

Anti-LGI1 Autoimmune Encephalitis in a Patient with Rheumatoid Arthritis and MGUS.

Background: Anti-leucine-rich glioma inactivated 1 limbic encephalitis (anti-LGI1 LE) is one of the most frequent autoimmune encephalitis, commonly coexisting with other autoimmune diseases. Rheumatoid arthritis (RA) and monoclonal gammopathy of unknown significance (MGUS) are commonly associated with autoimmune phenomena. However, neither RA nor MGUS have been described in the literature to date as coexisting with anti-LGI1 LE. Case description: We present the case of anti-LGI1 LE in a male patient with rheumatoid arthritis, who was also found to have an MGUS. The patient was initially treated with corticosteroids and IV immunoglobulin. After a mild relapse, his treatment was complemented with rituximab, resulting in complete regression of the disease symptoms. Conclusions: Our report provides evidence for the coexistence of anti-LGI1 LE with RA and/or MGUS, thus extending the differential diagnosis of patients suffering with these disease entities that present with neuropsychiatric symptoms suggestive of encephalitis. Moreover, this case raises challenges on the management of the coexistence of these diseases, given the lack of therapeutic guidelines and their potential interaction on a pathophysiological and a clinical level. LEARNING POINTS: In a patient with known autoimmune or malignant background who presents with neuropsychiatric symptoms, after excluding infectious encephalitis or central nervous system involvement in the primary disease condition, autoimmune limbic encephalitis (LE) should also be considered.In a patient diagnosed with anti-LGI1 LE there should be an extensive check for coexisting occult pre-malignant conditions, even for months after disease presentation.Clinical management and treatment options of anti-LGI1 LE when coexisting with other autoimmune or pre-malignant conditions can be challenging; thus, more research is needed towards that direction.

A clinical case of insulin autoimmune syndrome with monoclonal gammopathy of uncertain significance; complexity in management.

Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycaemia. We discuss a 91-year-old Caucasian lady who presented with syncope and episodic adrenergic and neuroglycopenic symptoms. Despite significantly elevated insulin, C-peptide, and proinsulin levels with the presence of anti-insulin antibodies, a pancreatic mass was not identified. Serum immunoelectrophoresis demonstrated monoclonal gammopathy of undetermined significance (MGUS). Treatment involved high-dose steroids, diazoxide, corn starch and acarbose, however the patient passed away four months later due to worsening co-morbidities. The management of IAS in the setting of MGUS is challenging.

Evaluation of Sarcopenia in Patients with Monoclonal Gammopathy of Undetermined Significance.

Background: We aimed to determine the prevalence of sarcopenia in patients with monoclonal gammopathy of undetermined significance (MGUS) and to evaluate the links between MGUS and sarcopenia. Methods: Eighty-two patients with a diagnosis of MGUS were enrolled in the study. Muscle strength was measured using the handgrip dynamometer. Physical performance was assessed by assessing gait speed over a 6-minute walking test. Muscle mass was determined using a bioelectrical impedance analyzer. Results: Sarcopenia was confirmed in 34.15% of patients. Male predominance was demonstrated in MGUS subjects with sarcopenia, particularly patients with low hand grip strength, low appendicular skeletal muscle mass (ASMM), or low ASMM index (p < 0.001, 0.013, and 0.001, respectively). Higher age and lower serum free light-chain Lambda levels were shown in MGUS patients with low muscle function scores compared to normal scores (p < 0.001, and 0.014, respectively). In addition, having a low ASMM score was related to low body mass index and high-risk group (p = 0.020, 0.033, respectively). Conclusions: We demonstrated that the frequency of sarcopenia is high in patients with MGUS. Whether sarcopenia has a possible role as a factor contributing to the pathogenesis of MGUS should be supported by further studies containing longitudinal data.

Application and pitfalls of immunophenotyping in challenging plasma cell neoplasms: a case series.

Multiple myeloma (MM) is an incurable malignant plasma cell neoplasm, representing the second most common hematopoietic cancer. As plasma cell neoplasms are clonal and often secrete a monoclonal protein (M-spike), laboratory diagnosis is usually straightforward, especially when ancillary studies such as immunohistochemistry, flow cytometry, and protein electrophoresis are available in addition to microscopic examination. Despite the repertoire of diagnostic tools, rare cases pose diagnostic dilemmas, especially when reagent antibodies do not react as expected, extent of disease is patchy, or when disease occurs in unique age groups. In this retrospective study, we report a series of challenging diagnostic cases, discussing aberrant findings and comparing them to more classic counterparts. Twelve cases collected during routine clinical sign-out were reanalyzed and include examples of MGUS, classic multiple myeloma, t(11;14) rearranged myeloma, minimal residual disease, AA and AL amyloidosis, truncated light chain, non-secretory and non-producer myeloma, biphenotypic myeloma, oligoclonal expansion after bone marrow transplant, and plasma cell leukemia in a young adult. This cohort showcases the diversity of atypical presentations of plasma cell neoplasms, and we highlight standardized approaches to workup to avoid diagnostic pitfalls.

Is It Possible to Predict Tumor Progression Through Genomic Characterization of Monoclonal Gammopathy and Smoldering Multiple Myeloma?

The study of monoclonal serum proteins has led to the generation of two major theories: one proposing that individuals who had monoclonal proteins without any symptoms or evidence of end-organ damage have a benign condition, the other one suggesting that some individuals with asymptomatic monoclonal proteins may progress to multiple myeloma and thus are affected by a monoclonal gammopathy of undetermined significance (MGUS). Longitudinal studies of subjects with MGUS have supported the second theory. Subsequent studies have characterized and defined the existence of another precursor of multiple myeloma, smoldering multiple myeloma (SMM), intermediate between MGUS and multiple myeloma. Primary molecular events, chromosome translocations, and chromosome number alterations resulting in hyperploidy, required for multiple myeloma development, are already observed in myeloma precursors. MGUS and SMM are heterogeneous conditions with the presence of tumors with distinct pathogenic phenotypes and clinical outcomes. The identification of MGUS and SMM patients with a molecularly defined high risk of progression to MM offers the unique opportunity of early intervention with a therapeutic approach on a low tumor burden.

Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens.

BACKGROUND: Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance. METHODS: To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM. RESULTS: Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated. CONCLUSION: Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.

A Case Report: Monoclonal Gammopathy of Undetermined Significance Presenting With Renal Amyloidosis and Reactive Thrombocytosis.

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-neoplastic condition involving plasma cells or lymphoplasmacytic proliferation-clinical presentations ranging from asymptomatic to symptoms of systematic organ involvement. It is commonly associated with light chain amyloidosis and usually strengthens during diagnosis. It is usually associated with thrombocytopenia in addition to anemia. This case report focuses on a 63-year-old Hispanic female who initially presented without any symptoms but with severe thrombocytosis. The finding of renal amyloidosis boosts the final diagnosis of MGUS. Rarely a patient is initially presented with severe thrombocytosis despite thrombocytopenia, which is commonly associated with plasma cell disorders. The case emphasizes the need for considering plasma cell disorders in patients with abnormal hematologic manifestations. It highlights the importance of timely identification and intervention to prevent irreversible organ damage by providing a detailed analysis of the clinical presentation and diagnostic evaluation.

Uncommon Presentation of IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Anti-Myelin-Associated Glycoprotein (MAG)-Associated Demyelinating Peripheral Neuropathy as Respiratory Failure: A Case Report.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal free immunoglobulin light chain ratio. MGUS can be associated with immune-mediated neuropathies, including chronic inflammatory demyelinating neuropathy and its variants. Here, we report the case of a 76-year-old male who presented with progressive weakness, initially in the lower extremities and later including the upper extremities. Serum protein electrophoresis and immunofixation identified an IgM kappa monoclonal protein and further testing confirmed high titers of anti-myelin-associated glycoprotein (MAG) antibodies, leading to a diagnosis of anti-MAG-associated demyelinating peripheral neuropathy. The coexistence of MGUS and anti-MAG antibodies requires meticulous diagnosis and management, especially in patients who present with atypical symptoms of the disease.

Autoimmune Diseases and Plasma Cells Dyscrasias: Pathogenetic, Molecular and Prognostic Correlations.

Multiple myeloma and monoclonal gammopathy of undetermined significance are plasma cell dyscrasias characterized by monoclonal proliferation of pathological plasma cells with uncontrolled production of immunoglobulins. Autoimmune pathologies are conditions in which T and B lymphocytes develop a tendency to activate towards self-antigens in the absence of exogenous triggers. The aim of our review is to show the possible correlations between the two pathological aspects. Molecular studies have shown how different cytokines that either cause inflammation or control the immune system play a part in the growth of immunotolerance conditions that make it easier for the development of neoplastic malignancies. Uncontrolled immune activation resulting in chronic inflammation is also known to be at the basis of the evolution toward neoplastic pathologies, as well as multiple myeloma. Another point is the impact that myeloma-specific therapies have on the course of concomitant autoimmune diseases. Indeed, cases have been observed of patients suffering from multiple myeloma treated with daratumumab and bortezomib who also benefited from their autoimmune condition or patients under treatment with immunomodulators in which there has been an arising or worsening of autoimmunity conditions. The role of bone marrow transplantation in the course of concomitant autoimmune diseases remains under analysis.

Differences in the proteome within extracellular vesicles between premalignant and malignant plasma cell disorders.

BACKGROUND: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM. METHODS: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography-based method and evaluated their proteome using a label-free proteomics workflow. RESULTS: In total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients. CONCLUSIONS: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

Early Detection of Precursor Diseases of Multiple Myeloma.

Precursor diseases of multiple myeloma (MM) are monoclonal gammopathy of uncertain significance and smoldering MM. While it is well known that a percentage of those affected by these conditions will progress to MM, it is difficult to predict who will progress and when, and guidelines for screening for these conditions are lacking. Moreover, there are various models for risk stratification, though there are ongoing efforts to improve these models in order to predict who may benefit from treatment. Finally, there are various clinical trials, both past and ongoing, expanding the scope of possible treatment options for precursor diseases.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes.

BACKGROUND: Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. METHODS: This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. RESULTS: We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. CONCLUSIONS: Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

SOHO State of the Art Updates and Next Questions: Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma.

Monoclonal proteins are common, with a prevalence in the United States around 5% and the incidence increases with age. Although most patients are asymptomatic, the vast majority of cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma (MM). In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. In this review, we summarize the current diagnosis treatment guidelines for MGUS and SMM and highlight recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Gammopathic dermopathy: characterization of cutaneous MGUS.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a clonal plasma cell disorder that is considered preneoplastic, asymptomatic, and only requiring observation. However, MGUS may result in cutaneous complications, which are poorly understood, causing treatment delays and patient suffering. We present 30 patients with cutaneous findings associated with MGUS, characterizing clinical presentations, isoforms, treatments, and outcomes. These included: MGUS-associated 'rashes' (pruritic eczematous rashes), reactive and mucin-depositional conditions (pyoderma gangrenosum, scleromyxedema), M-protein-related deposition disorders (POEMS syndrome, Waldenstrom macroglobulinemia), and cutaneous lymphomas. Twelve of 30 (40%) patients received multiple myeloma drugs (MMDs). Eleven (92%) patients improved, and those not receiving MMDs rarely improved, suggesting that MMDs have efficacy for cutaneous manifestations of MGUS. Therefore, trialing MMDs may be warranted for patients with MGUS not responding to other therapies. Moreover, evaluation for monoclonal gammopathy in elderly patients with intractable pruritus or other chronic skin conditions that are non-responsive to skin-directed therapies should be considered.

A Unique Case of Cellulitis Secondary to Mycobacterium chelonae in a Patient With Monoclonal Gammopathy of Undetermined Significance.

We report a case of an 84-year-old patient with Monoclonal Gammopathy of Undetermined Significance (MGUS) treated with multiple courses of antibiotics and steroids before being diagnosed with Mycobacterium chelonae infection. It is known that MGUS affects both humoral and cellular immunity with impairment of antibody production, function of T-cells, natural killer (NK) cells, and dendritic cells. This case report demonstrates the need to consider patients with MGUS as immunocompromised and draws attention to the correlation between MGUS and Mycobacterium infections. The delay in diagnosis exemplifies the importance of considering atypical pathogens and involving sub-specialists early in the treatment of infections in patients with a history of MGUS.

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

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. TRIAL REGISTRATION: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51368.

Smouldering multiple myeloma: To seek or not to seek? To treat or not to treat. That is the question.

In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence-based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193-1206.

Decreased neutrophil function in newly diagnosed multiple myeloma patients is restored with lenalidomide therapy.

OBJECTIVES: Bacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. METHODS: Phagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay. RESULTS: PMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment. CONCLUSION: Our results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.