The Challenging Management of Acute Thrombotic Microangiopathy in Pregnancy.

Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury. Pregnancy-associated thrombotic microangiopathy is a severe disorder with a high risk of maternal mortality and poor fetal outcomes. Preeclampsia/eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome are the most common causes, and hemolytic uremic syndrome or thrombotic thrombocytopenic purpura are rare causes. Due to overlapping clinical findings, the differential diagnosis is challenging and should be managed by a multidisciplinary team. We present a case of a 38-year-old woman at 40 weeks of second gestation, admitted with thrombotic microangiopathy being the final diagnosis not immediately clear.

Parthenolide Induces ROS-Mediated Apoptosis in Lymphoid Malignancies.

Lymphoid malignancies are a group of highly heterogeneous diseases frequently associated with constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway. Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor. This study evaluated in vitro parthenolide efficacy in lymphoid neoplasms. We assessed parthenolide metabolic activity in NCI-H929 (MM), Farage (GCB-DLBCL), Raji (BL), 697 and KOPN-8 (B-ALL), and CEM and MOLT-4 (T-ALL), by resazurin assay. Cell death, cell cycle, mitochondrial membrane potential (ΔΨmit), reactive oxygen species (ROS) and reduced glutathione (GSH) levels, activated caspase-3, FAS-ligand, and phosphorylated NF-κB p65 were evaluated using flow cytometry. CMYC, TP53, GPX1, and TXRND1 expression levels were assessed using qPCR. Our results showed that parthenolide promoted a metabolic activity decrease in all cell lines in a time-, dose-, and cell-line-dependent manner. The mechanism induced by parthenolide was demonstrated to be cell line dependent. Nonetheless, parthenolide promoted cell death by apoptosis with significant ROS increase (peroxides and superoxide anion) and GSH decrease combined with a ΔΨmit reduction across all studied cell lines. Despite the need to further understand parthenolide mechanisms, parthenolide should be considered as a possible new therapeutic approach for B- and T-lymphoid malignancies.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.

Patients older than 75 years old with multiple myeloma (MM) have shorter survival and are usually treated differently from what features in clinical trials. In this study, the authors characterized the Portuguese population of MM patients above 75 years old, treated between 2009 and 2016. We compared the outcomes obtained with bortezomib-based protocols (BBP), thalidomide-based protocols (TBP), and chemotherapy (CT) using univariate and multivariate controlling for age, performance status, International Staging System score, renal impairment, and number of comorbidities. We retrieved data from 386 patients, treated in 12 hospitals. Three hundred thirty-one cases were analyzed: 119 patients treated with BBP, 65 with TBP, 147 with CT. Median age was 79 years; CT-treated patients were older, had a worse performance status, and have more comorbidities. The median follow-up was 25 months. The 2-year OS was 58% and the median OS was 29.5 months. Patients treated with BBP had more frequently very good partial response (VGPR) or better response, and the subgroup of more fit patients had a significantly longer progression-free survival (PFS) and OS. The most frequently grade 3-4 toxicities were hematologic, infectious, and neurologic and were significantly lower in TBP and CT groups vs BBP. The most common second line was CT, followed by lenalidomide. Patients treated with lenalidomide had a higher probability of VGPR or better and a superior 1-year PFS. Despite the limitations of a retrospective study, our cohort represents the reality of older patients with MM in a western country. The hazard of death or progression was higher for old, fit patients treated, in first line, with CT and with TBP compared with that of BBP.

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

Lenalidomide is effective and safe for the treatment of patients with relapsed multiple myeloma and very severe renal impairment.

Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival than MM patients without renal failure. Although lenalidomide is a highly active drug, this immunomodulatory agent is frequently neglected in this context due to its predominant renal clearance and, consequently, an increased risk of toxicity. This risk might be overcome with the proper lenalidomide dose adjustment to renal function. This study evaluates the outcomes of 23 relapsed MM patients with SRI (baseline creatinine clearance (CrCl) <30 mL/min) treated with lenalidomide-dexamethasone (LenDex), including 56 % (13 patients) under hemodialysis. The median CrCl at start of LenDex was 19 mL/min; an overall response rate (partial response or better) of 56 % was obtained, with a median follow-up from start of LenDex of 52 months (8-79). The median time until maximal response was 4 months, and in 58 % (7/12), the response was longer than 2 years. Nine percent had renal improvement, but all the 13 patients on hemodialysis remained under treatment. LenDex was interrupted in three cases because of adverse events (infections and cutaneous events); 78 % of the patients were on thromboprophylaxis with aspirin. It is important to notice that, after initial dose adjustment of therapy, there should be a continuous process of dose adjustment, taking into account variations in renal function. Furthermore, lenalidomide dose adjustment should be made according to the individual tolerance, even with stable renal function. LenDex dose adjustment, according to these principles, does not negatively impact response and improves treatment tolerance. It has a clear potential to treat this group of patients and to induce long duration of responses [event-free survival (EFS) 20.5 m and overall survival (OS) 42.6 m].

Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

CD20+ T cells in monoclonal B cell lymphocytosis and chronic lymphocytic leukemia: frequency, phenotype and association with disease progression.

Introduction: In monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer. Methods: Here, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussion: CD20+ T cells were more represented within the CD8+ T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vß 5.1 in CD4+ CD20+ T cells in CLL.

Biocides in the Hospital Environment: Application and Tolerance Development.

Hospital-acquired infections are a rising problem with consequences for patients, hospitals, and health care workers. Biocides can be employed to prevent these infections, contributing to eliminate or reduce microorganisms' concentrations at the hospital environment. These antimicrobials belong to several groups, each with distinct characteristics that need to be taken into account in their selection for specific applications. Moreover, their activity is influenced by many factors, such as compound concentration and the presence of organic matter. This article aims to review some of the chemical biocides available for hospital infection control, as well as the main factors that influence their efficacy and promote susceptibility decreases, with the purpose to contribute for reducing misusage and consequently for preventing the development of resistance to these antimicrobials.

Interim FDG18-PET SUVmax Variation Adds Prognostic Value to Deauville 5-Point Scale in the Identification of Patients with Ultra-High-Risk Diffuse Large B Cell Lymphoma.

INTRODUCTION: Interim response evaluation by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (iPET) in diffuse large B cell lymphoma (DLBCL) could be important to rule out disease progression and has been suggested to be predictive of survival. However, treatment guidance by iPET is not yet recommended for DLBCL in clinical practice. We aimed to compare the predictive value of iPET when utilizing the visual Deauville 5-point scale (DS) and the semiquantitative variation of maximum standardized uptake value (ΔSUVmax). MATERIALS AND METHODS: We included 85 patients diagnosed with DLBCL and uniformly treated with standard protocols. iPET with DS of 1-3 and/or ΔSUVmax ≥66% was defined as negative. Univariable and multivariable Cox regression analyses were performed to determine the independent factors affecting progression free survival (PFS) or overall survival (OS) and to estimate PFS and OS. RESULTS: iPET positivity, measured by DS or ΔSUVmax, showed predictive value of disease refractoriness, improved by combining DS and ΔSUVmax. After a median follow-up of 50.1 months, iPET was an independent predictor for both PFS and OS when interpreted by DS, but only for PFS by ΔSUVmax. Combined visual and semiquantitative analysis (D4-5 & ΔSUVmax<66%) was an independent predictor of PFS and OS, and allowed to identify an ultra-high-risk subgroup of patients with very dismal outcome, increasing the discriminating capacity for iPET. CONCLUSION: Our study suggests that combined DS and ΔSUVmax in iPET assessment predicts refractory disease and distinguishes ultra-high-risk DLBCL patients with a very dismal prognosis, who may benefit from PET-guided therapy adjustment.

[Multiple Myeloma Treatment Guidelines by the Portuguese Group of Multiple Myeloma]. / Recomendações do Grupo Português do Mieloma Múltiplo para Tratamento do Mieloma Múltiplo.

The treatment of multiple myeloma has profoundly changed with the introduction of several innovative therapies. The optimization of therapeutic sequencing through the combined use of the various drugs developed in recent years and the attention given to the characteristics of patients have allowed the reduction of toxicities and increased survival and quality of life of patients with multiple myeloma. These treatment recommendations from the Portuguese Multiple Myeloma Group offer guidance for first-line treatment and progression/relapse situations. These recommendations are given highlighting the data that justify each choice and referring to the respective levels of evidence that support these options. Whenever possible, the respective national regulatory framework is presented. These recommendations constitute an advance towards the best treatment of multiple myeloma in Portugal.

O tratamento do mieloma múltiplo tem sido amplamente alterado com introdução de várias terapêuticas inovadoras. A otimização da sequenciação terapêutica através do uso combinado dos vários fármacos desenvolvidos nos últimos anos e a atenção dada às características dos doentes têm permitido diminuir toxicidades e aumentar a sobrevivência dos doentes, bem como aumentar a sua qualidade de vida. As presentes recomendações terapêuticas do Grupo Português do Mieloma Múltiplo oferecem orientações para o tratamento de primeira linha e progressão/recaída. As recomendações são fundamentadas evidenciando os dados que justificam cada escolha e referindo os respetivos níveis de evidência que suportam essas opções. Sempre que possível é apresentado o respetivo enquadramento regulamentar nacional. Estas recomendações constituem um avanço para o melhor tratamento do mieloma múltiplo em Portugal.

Plerixafor for autologous peripheral blood stem cell mobilization in patients previously treated with fludarabine or lenalidomide.

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.

European data on stem cell mobilization with plerixafor in patients with nonhematologic diseases: an analysis of the European consortium of stem cell mobilization.

BACKGROUND: Plerixafor with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma and lymphoma with previous mobilization failure. In this European named patient program we report the experience in insufficiently mobilizing patients diagnosed with nonhematologic diseases. STUDY DESIGN AND METHODS: Thirty-three patients with germ cell tumor (n=11), Ewing sarcoma (n=6), Wiscott-Aldrich disease (n=5), neuroblastoma (n=4), and other nonhematologic diseases (n=7) were included in the study. Plerixafor was limited to patients with previous or current stem cell mobilization failure and given after 4 days of G-CSF (n=21) or after chemotherapy and G-CSF (n=12) in patients who mobilized poorly. RESULTS: Overall, 28 (85%) patients succeeded in collecting at least 2×10(6)/kg body weight (b.w.) CD34+ cells (median, 5.0×10(6)/kg b.w. CD34+ cells; range, 2.0×10(6)-29.5×10(6)/kg b.w. CD34+ cells), and five (15%) patients collected a median of 1.5×10(6)/kg b.w. CD34+ cells (range, 0.9×10(6)-1.8×10(6)/kg b.w. CD34+ cells). Nineteen patients proceeded to transplantation. The median dose of CD34+ cells infused was 3.3×10(6)/kg b.w. (range, 2.3×10(6)-6.7×10(6)/kg b.w. CD34+ cells). The median numbers of days to neutrophil and platelet engraftment were 11 (range, 9-12) and 15 (range, 10-25) days, respectively. CONCLUSION: These data emphasize the role of plerixafor in combination with G-CSF or chemotherapy and G-CSF as an effective mobilization regimen with the potential of successful stem cell collection. Accordingly, plerixafor seems to be safe and effective in patients with nonhematologic diseases. Larger prospective studies are warranted to further assess its use in these patients.

Enterococcus Virulence and Resistant Traits Associated with Its Permanence in the Hospital Environment.

Enterococcus are opportunistic pathogens that have been gaining importance in the clinical setting, especially in terms of hospital-acquired infections. This problem has mainly been associated with the fact that these bacteria are able to present intrinsic and extrinsic resistance to different classes of antibiotics, with a great deal of importance being attributed to vancomycin-resistant enterococci. However, other aspects, such as the expression of different virulence factors including biofilm-forming ability, and its capacity of trading genetic information, makes this bacterial genus more capable of surviving harsh environmental conditions. All these characteristics, associated with some reports of decreased susceptibility to some biocides, all described in this literary review, allow enterococci to present a longer survival ability in the hospital environment, consequently giving them more opportunities to disseminate in these settings and be responsible for difficult-to-treat infections.

Hematological changes in SARS-COV-2 positive patients.

Introduction: The novel SARS-CoV-2 infection has been spreading around the world since January 2020 causing the Corona Virus Disease 2019. Leukopenia, lymphopenia and hypercoagulability with elevated D- Dimers have been described in COVID-19 patients to date. This study aimed to clarify if some blood parameters can be used as biomarkers to facilitate diagnosis and establish prognosis. Methods: We selected patients who had tested positive for SARS-CoV-2 and had had a hemogram performed between the March 15 and April 15, 2020. Socio-demographic and analytical data were obtained from 274 patients at admission in two Portuguese public hospitals. We then analyzed the hemogram parameters at admission in the intensive care and collected data on patient survival during the SARS-CoV-2 disease follow-up. The data were analyzed using appropriate statistical tests. Results: Patients requiring the intensive care unit (ICU) present an increase in leukocytes and neutrophils (+3.1 × 109/L and +6.4 × 109/L, respectively), a lymphocyte decrease and a platelet rise (-1.6 × 109/L and +60.8 × 109/L, respectively). The erythrocytes, hemoglobin and median globular volume tend to decrease (-0.5 × 1012, - 1.2 g/dL; -3 fL, respectively). The lactic acid dehydrogenase (LDH) at admission was significantly higher (+58.1 U/L). The age, sex, platelets, lymphocyte count neutrophil counts, neutrophil/lymphocyte ratio, erythrocytes and cell hemoglobin concentration mean (CHCM) are independently associated with mortality (odds ratio (OR) = 0.046, p < 0.001; OR = 0.2364, p = 0.045; OR = 9.106, p = 0.001; OR = 0.194, p = 0.033; OR = 0.062, p = 0.003; OR = 0.098, p = 0.002; OR = 9.021, p < 0.001; OR = 7.016, p = 0.007, respectively). Conclusion: The hematological data at admission in the health care system can predict the mortality of the SARS-CoV-2 infection and we recommend its use in the clinical decisions and patient prognosis evaluation.

Methotrexate-Associated Lymphoproliferative Disorder in a Patient with Psoriasis: A Case Report and Review of the Literature.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs) are heterogeneous clinicopathological entities developing in patients receiving immunosuppression. Outside the posttransplant setting, methotrexate (MTX), a drug commonly used for the treatment of autoimmune diseases, is an immunosuppressive agent frequently reported to be associated with LPD. MTX-associated LPD (MTX-LPD) includes a spectrum of lymphocytic proliferations, ranging from polyclonal hyperplasia to malignant lymphoma. MTX-LPD diagnosis can be challenging, as signs and symptoms are often nonspecific and may overlap with those of several other conditions, including exacerbation of the underlying autoimmune disease. Spontaneous regression of LPD after MTX discontinuation is characteristic of MTX-LPD, therefore avoiding chemotherapeutic intervention in a significant proportion of patients. Other cases, however, should receive chemotherapy.

Hodgkin's variant of Richter transformation during ibrutinib therapy: A case report and review of the literature.

Hodgkin's variant of Richter transformation is a rare complication of chronic lymphocytic leukemia and is associated with inferior outcomes compared to de novo Hodgkin lymphoma. Further data concerning prognosis and treatment of Hodgkin's variant of Richter transformation occurring in the setting of novel targeted therapies are needed.

Genomic characterisation of multiple myeloma: study of a Portuguese cohort.

Multiple myeloma (MM) genomic complexity reflects in the variable patients' clinical presentation. Genome-wide studies seem to be a reasonable alternative to identify critical genomic lesions. In the current study, we have performed the genomic characterisation of a Portuguese cohort of patients with MM by array comparative genomic hybridisation. Overall, the most frequently detected alterations were 13q deletions, gains of 1q, 19p, 15q, 5p and 7p and trisomy 9. Even though some identified genomic alterations were previously associated with a prognostic value, other abnormalities remain with unknown, but putative significance for patients' clinical practice. These genomic alterations should be further assessed as possible biomarkers.

Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma.

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.

Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma.

PURPOSE: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. EXPERIMENTAL DESIGN: We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. RESULTS: Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P < 0.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN- nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient' stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years. CONCLUSIONS: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.