EANM guidelines on the use of [18F]FDG PET/CT in diagnosis, staging, prognostication, therapy assessment, and restaging of plasma cell disorders.

We provide updated guidance and standards for the indication, acquisition, and interpretation of [18F]FDG PET/CT for plasma cell disorders. Procedures and characteristics are reported and different scenarios for the clinical use of [18F]FDG PET/CT are discussed. This document provides clinicians and technicians with the best available evidence to support the implementation of [18F]FDG PET/CT imaging in routine practice and future research.

The role of therapeutic plasma exchange in plasma cell disorders.

Therapeutic plasma exchange (TPE) is an extracorporeal technique where patient's plasma containing pathogenic substances is separated and removed from the whole blood, while the cellular component is returned to the patient mixed with replacement solution via an apheresis machine. Due to its ability to remove pathogenic substances from plasma including immunoglobulins, TPE has proven efficacious in the management of various disorders across different medical disciplines, including plasma cell dyscrasias, which are characterized by the abundant secretion of non-functional immunoglobulins produced by an abnormally proliferating plasma cell clone. This review summarizes the current indications of TPE in plasma cell-related disorders and discusses its application, safety, and therapeutic effects.

Expert-Level Immunofixation Electrophoresis Image Recognition based on Explainable and Generalizable Deep Learning.

BACKGROUND: Immunofixation electrophoresis (IFE) is important for diagnosis of plasma cell disorders (PCDs). Manual analysis of IFE images is time-consuming and potentially subjective. An artificial intelligence (AI) system for automatic and accurate IFE image recognition is desirable. METHODS: In total, 12 703 expert-annotated IFE images (9182 from a new IFE imaging system and 3521 from an old one) were used to develop and test an AI system that was an ensemble of 3 deep neural networks. The model takes an IFE image as input and predicts the presence of 8 basic patterns (IgA-, IgA-, IgG-, IgG-, IgM-, IgM-, light chain and ) and their combinations. Score-based class activation maps (Score-CAMs) were used for visual explanation of the models prediction. RESULTS: The AI model achieved an average accuracy, sensitivity, and specificity of 99.82, 93.17, and 99.93, respectively, for detection of the 8 basic patterns, which outperformed 4 junior experts with 1 years experience and was comparable to a senior expert with 5 years experience. The Score-CAMs gave a reasonable visual explanation of the prediction by highlighting the target aligned regions in the bands and indicating potentially unreliable predictions. When trained with only the new system images, the models performance was still higher than junior experts on both the new and old IFE systems, with average accuracy of 99.91 and 99.81, respectively. CONCLUSIONS: Our AI system achieved human-level performance in automatic recognition of IFE images, with high explainability and generalizability. It has the potential to improve the efficiency and reliability of diagnosis of PCDs.

Melphalan on day -1 versus day -2 in patients with plasma cell disorders undergoing autologous stem cell transplant.

High-dose melphalan-based autologous stem cell transplant (ASCT) remains a standard of care for plasma cell disorders (PCDs). Currently, there is variability in the literature surrounding the timing of melphalan administration to avoid potential cytotoxic effects, although the administration has been safely proposed when given at least 8 hours prior to stem cell infusion. The objectives of this study were to assess differences in safety and efficacy outcomes between day -1 and day -2 single-dose melphalan administration in patients undergoing ASCT for PCDs. A retrospective chart review was performed at our institution comparing patients receiving melphalan on day -1 to an equal number of patients receiving melphalan on day -2. The primary endpoint was time to neutrophil engraftment from stem cell infusion. Univariate analyses were performed. Mean time to neutrophil engraftment from stem cell infusion was identical at 10.7 days for both cohorts (p = 0.88). Mean time to platelet engraftment from stem cell infusion was shorter with day -1 administration (17.4 vs. 18.6 days, p = 0.06). Mean time to neutrophil and platelet engraftment from melphalan infusion were significantly shorter with day -1 administration. Similar outcomes were observed for length of hospitalization, infection- and mucositis-related toxicities, hematologic response, transplant-related mortality, and overall survival. Our findings show no difference in time to neutrophil engraftment from stem cell infusion and a trend toward shorter time to platelet engraftment with day -1 administration. Based on our study, day -1 melphalan administration is an acceptable and safe practice.

(Smoldering) multiple myeloma: mismatch between tumor load estimated from bone marrow biopsy at iliac crest and tumor load shown by MRI.

In multiple myeloma and its precursor stages, precise quantification of tumor load is of high importance for diagnosis, risk assessment, and therapy response evaluation. Both whole-body MRI, which allows to investigate the complete bone marrow of a patient, and bone marrow biopsy, which is commonly used to assess the histologic and genetic status, are relevant methods for tumor load assessment in multiple myeloma. We report on a series of striking mismatches between the plasma cell infiltration estimating the tumor load from unguided biopsies of the bone marrow at the posterior iliac crest and the tumor load assessment from whole-body MRI.

Physical Function, Psychosocial Status, and Symptom Burden Among Adults with Plasma Cell Disorders and Associations with Quality of Life.

BACKGROUND: The plasma cell disorders (PCDs), multiple myeloma (MM), and light-chain amyloidosis (AL) are disproportionately diseases of older adults, whose care may be complicated by frailty associated with advancing age. We sought to evaluate the prevalence of functional deficits and symptoms in a cohort of persons with PCDs and associations of demographic, disease-related, functional, and psychosocial measures with quality of life (QoL). PATIENTS AND METHODS: Adults with PCDs were recruited into an observational registry in 2018-2020. Patients completed a functional assessment and European Organization for Research and Treatment of Cancer QoL questionnaire (QLQ-C30). Associations of covariates of interest with QoL were evaluated via univariate linear regression. RESULTS: Among 121 adults, the mean age was 68.6. Diagnoses were 74% MM, 14% AL, 7% both MM and AL, and 5% other PCDs. The median time from diagnosis was 34.9 months. Median lines of therapy were 2, with 11% having received ≥4th-line therapy.Patients with functional deficits had lower mean QoL scores: dependence in IADLs (66.3 vs. 79.9, P = .001) and recent falls (56.7 vs. 76.8, P = .001). Patients ≤6 months from diagnosis had lower QoL (66.7) than those ≥2 years from diagnosis (77.3, P = .03). However, patients on later lines of therapy (≥4th-line) had lower QoL (62.2) than those on 1st-line treatment (76.0, P = .04). CONCLUSIONS: Patients with physical impairments and more advanced PCDs had lower QoL than those without deficits or earlier in their disease course. Early identification of physical impairments may facilitate interventions that mitigate these deficits and thereby improve QoL for patients with PCDs.

Safety and efficacy of daratumumab in Chinese patients with relapsed or refractory multiple myeloma: a phase 1, dose-escalation study (MMY1003).

Daratumumab monotherapy demonstrated favorable safety and efficacy in relapsed/refractory multiple myeloma (RRMM) patients in the global phase 1/2 GEN501 and phase 2 SIRIUS studies. MMY1003 evaluated daratumumab monotherapy specifically in Chinese patients with RRMM. This 3-part, open-label, phase 1, dose-escalation study included patients with ≥ 2 prior lines of therapy. Part 3 included patients who had received a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and experienced disease progression on their last regimen. Patients received intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 and 16 mg/kg in parts 2 + 3. Primary endpoints were dose-limiting toxicity (DLT; part 1), pharmacokinetics (parts 1 + 2), and adverse events (AEs). Fifty patients enrolled. The first 3 patients in part 1 received daratumumab 8 mg/kg; remaining patients in parts 1-3 received daratumumab 16 mg/kg. In the daratumumab 16 mg/kg group (n = 47), patients received a median of 4 prior lines of therapy; 32% were refractory to a PI and IMiD, and 79% were refractory to their last prior therapy. No DLTs occurred. Thirty-six (77%) patients reported grade 3/4 treatment-emergent AEs. Thirteen (28%) patients experienced infusion-related reactions. At an 18.5-month median follow-up, overall response rate was 43%. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and not reached, respectively; 12-month PFS and OS rates were 35% and 70%. Pharmacokinetic results (n = 22) were consistent with other studies. Safety, pharmacokinetics, and efficacy of daratumumab monotherapy were confirmed in Chinese patients with RRMM. This trial is registered on ClinicalTrials.gov (NCT02852837).

Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review.

BACKGROUND: Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL-PCD) and lymphocytic proliferative disease (CNL-LPD). METHODS: The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL-MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL-PCD and CNL-LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. RESULTS: A 73-year-old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG-λ monoclonal M protein. A CT scan showed splenomegaly. Next-generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL-MGUS. We summarized 10 cases of CNL-PCD and 1 case of CNL-LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL-PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL-PCD. CONCLUSIONS: Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL-PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL-PCD.

Whole-body magnetic resonance imaging (WBMRI) versus whole-body computed tomography (WBCT) for myeloma imaging and staging.

Myeloma-associated bone disease (MBD) develops in about 80-90% of patients and severely affects their quality of life, as it accounts for the majority of mortality and morbidity. Imaging in multiple myeloma (MM) and MBD is of utmost importance in order to detect bone and bone marrow lesions as well as extraosseous soft-tissue masses and complications before the initiation of treatment. It is required for determination of the stage of disease and aids in the assessment of treatment response. Whole-body low-dose computed tomography (WBLDCT) is the key modality to establish the initial diagnosis of MM and is now recommended as reference standard procedure for the detection of lytic destruction in MBD. In contrast, whole-body magnetic resonance imaging (WBMRI) has higher sensitivity for the detection of focal and diffuse plasma cell infiltration patterns of the bone marrow and identifies them prior to osteolytic destruction. It is recommended for the evaluation of spinal and vertebral lesions, while functional, diffusion-weighted MRI (DWI-MRI) is a promising tool for the assessment of treatment response. This review addresses the current improvements and limitations of WBCT and WBMRI for diagnosis and staging in MM, underlining the fact that both modalities offer complementary information. It further summarizes the corresponding radiological findings and novel technological aspects of both modalities.

Automation and validation of a MALDI-TOF MS (Mass-Fix) replacement of immunofixation electrophoresis in the clinical lab.

Objectives: A matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) method (Mass-Fix) as a replacement for gel-based immunofixation (IFE) has been recently described. To utilize Mass-Fix clinically, a validated automated method was required. Our aim was to automate the pre-analytical processing, improve positive specimen identification and ergonomics, reduce paper data storage and increase resource utilization without increasing turnaround time. Methods: Serum samples were batched and loaded onto a liquid handler along with reagents and a barcoded sample plate. The pre-analytical steps included: (1) Plating immunopurification beads. (2) Adding 10 µl of serum. (3) Bead washing. (4) Eluting the immunoglobulins (Igs), and reducing to separate the heavy and light Ig chains. The resulting plate was transferred to a second low-volume liquid handler for MALDI plate spotting. MALDI-TOF mass spectra were collected. Integrated in-house developed software was utilized for sample tracking, driving data acquisition, data analysis, history tracking, and result reporting. A total of 1,029 residual serum samples were run using the automated system and results were compared to prior electrophoretic results. Results: The automated Mass-Fix method was capable of meeting the validation requirements of concordance with IFE, limit of detection (LOD), sample stability and reproducibility with a low repeat rate. Automation and integrated software allowed a single user to process 320 samples in an 8 h shift. Software display facilitated identification of monoclonal proteins. Additionally, the process maintains positive specimen identification, reduces manual pipetting, allows for paper free tracking, and does not significantly impact turnaround time (TAT). Conclusions: Mass-Fix is ready for implementation in a high-throughput clinical laboratory.

Clinicopathological spectrum of solitary Plasmacytoma: a single center experience from coastal India.

BACKGROUND: Plasma cell disorders are a rare group of hematological malignancies that accounts for 10% of all hematological neoplasms. Solitary plasmacytomas are rarer entities accounting for less than 5% of all the plasma cell dyscrasias. They encompass three subtypes - Solitary Plasmacytoma of Bone (SPB) and Solitary Extramedullary Plasmacytoma (SEP) and multiple solitary plasmacytomas (MSP). In this study, we discuss the clinical, histopathological and immunohistochemical characteristics of solitary plasmacytomas. METHODS: A 13 year retrospective analysis of solitary plasmacytomas was performed from a single tertiary care center. Bone marrow evaluation was done concurrently at the time of diagnosis to rule out the presence of multiple myeloma. RESULTS: A total of 29 cases fulfilled the diagnostic criteria for SP during the study period. SPB accounted for 55.2%, SEP for 44.4% and MSP for 3.4% of the cases. The most common sites involved were the paranasal sinuses and vertebrae. Other infrequent sites included lymph node, tonsil and lungs. The mean age of presentation of SPB was a decade later than SEP. A male preponderance was observed in both subtypes. CONCLUSION: Solitary plasmacytoma is a rare entity, the diagnosis of which requires a systematic approach. There is limited data available in the literature on the clinico-pathological characteristics of SP from India.

MCL1 gene co-expression module stratifies multiple myeloma and predicts response to proteasome inhibitor-based therapy.

Multiple myeloma (MM) is the second most common hematologic cancer, characterized by abnormal accumulation of plasma cells in the bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems of prognostic impact have been proposed, but they do not predict the response to treatment nor do they correlate to plasma cell development pathways. Here we describe the classification of MM into two distinct subtypes based on the expression levels of a gene module coexpressed with MCL1 (MCL1-M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib-based therapy. Moreover, the two MM subtypes were associated with two different plasma cell differentiation pathways (enrichment of a preplasmablast signature versus aberrant expression of B cell genes). 1q gain, harboring 63 of the 87 MCL1-M members including MCL1, was found in about 80% of the MM with upregulated MCL1-M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1-M captured both MM cell-intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1-M members were co-expressed in mouse germinal center B cells. Together, these findings indicate that MCL1-M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1-M signature-based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care. Article Summary: A pathogenic mechanism-guided molecular classification would facilitate treatment decision and etiology research of multiple myeloma. On the basis of the expression levels of a gene module coexpressed with MCL1, we have established a classification scheme assigning multiple myeloma into two subtypes with distinct prognosis, treatment responses and pathogenic backgrounds.

Polyclonal Immunoglobulin G N-Glycosylation in the Pathogenesis of Plasma Cell Disorders.

The pathological progression from benign monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) and finally to active myeloma (MM) is poorly understood. Abnormal immunoglobulin G (IgG) glycosylation in myeloma has been reported. Using a glycomic platform composed of hydrophilic interaction UPLC, exoglycosidase digestions, weak anion-exchange chromatography, and mass spectrometry, polyclonal IgG N-glycosylation profiles from 35 patients [MGUS (n = 8), SMM (n = 5), MM (n = 8), complete-response (CR) post-treatment (n = 5), relapse (n = 4), healthy age-matched control (n = 5)] were characterized to map glycan structures in distinct disease phases of multiple myeloma. N-Glycan profiles from MGUS resembled normal control. The abundance of neutral glycans containing terminal galactose was highest in SMM, while agalactosylated glycans and fucosylated glycans were lowest in MM. Three afucosyl-biantennary-digalactosylated-sialylated species (A2G2S1, A2BG2S1, and A2BG2S2) decreased 2.38-, 2.4-, and 4.25-fold, respectively, from benign to active myeloma. Increased light chain sialylation was observed in a longitudinal case of transformation from MGUS to MM. Bisecting N-acetylglucosamine was lowest in the CR group, while highest in relapsed disease. Gene expression levels of FUT 8, ST6GAL1, B4GALT1, RECK, and BACH2 identified from publicly available GEP data supported the glycomic changes seen in MM compared to control. The observed differential glycosylation underlined the heterogeneity of the myeloma spectrum. This study demonstrates the feasibility of mapping glycan modifications on the IgG molecule and provides proof of principle that differential IgG glycosylation patterns can be successfully identified in plasma cell disorders.

Current Multidisciplinary Lymphoma and Myeloma Management for Surgeons.

Although there are more than 100 clinically distinct lymphoid neoplasms with varied prognoses and treatment approaches, they generally share high sensitivity to glucocorticoids, cytotoxic chemotherapy, and radiation. The disease control rates for lymphoid malignancies are higher than many solid tumors, and many are curable even when presenting with extensive involvement. Novel targeted therapies have improved disease control and cure rates for nearly all subtypes of lymphoid neoplasms. Surgical oncologists will primarily be involved in obtaining biopsies of sufficient quality to allow accurate diagnosis. However, there are scenarios in which surgical intervention may be necessary to address an oncologic emergency.

Hospital Associated Disability among Older Adults with Plasma Cell Disorders Receiving Autologous Stem Cell Transplant.

Increasing number of older adults with Plasma Cell Disorders (PCDs) are receiving autologous stem cell transplant (ASCT) in the US. Hospital associated disability (HAD) is a common complication associated with acute care hospitalization among older adults. To estimate the prevalence and prognostic significance of HAD among older adults with MM undergoing ASCT. This retrospective cohort study used consecutive adults ≥ 18 y with PCD receiving ASCT at a single institution between 1/2013 and 5/2023. Trained nursing staff assessed Katz Activities of Daily Living (ADL) at admission and every 3 days thereafter under our Virtual Acute Care for Elders program. The primary outcome was development of HAD defined as ≥1 point decline on the Katz Activities of Daily Living (ADL) scale from hospital admission to discharge. We examined the association between putative risk factors such as age, Karnofsky performance status (KPS), baseline ADL score, Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and HAD using modified Poisson regression models with robust variance estimators. Subsequently, we studied the impact of HAD on downstream adverse events including 30-day readmission rates and long term survival. We included 778 adults with a median age of 62 y (QR 56-68 y), with 56% males and 55% non-Hispanic Whites. In the overall population, 112 (14.4%) developed HAD, with much higher incidence among older adults ≥ 65 y compared to those <65 y at ASCT (22% vs. 9%, P value < .01). In multivariable analysis, increasing age (RR 1.56; 95% CI 1.25-1.94, per 10 y increase), female sex (RR 1.79; 95% CI 1.27-2.53) and KPS ≤ 70 (RR 2.55; 95% CI 1.32-4.94) were associated with an increased risk of developing HAD. As compared to those without, patients with HAD had a two-fold higher risk of 30-day readmission (95% CI 1.16-3.39) and a 3.7-fold increased risk of all-cause mortality (95% CI 2.15-6.22). Nearly one in 4 older adults ≥ 65 y developed HAD while undergoing ASCT which was associated with a two-fold increased risk of 30-day readmission. Interventions to prevent HAD and its downstream consequences are critically needed.

Integrative medicine in multiple myeloma and plasma cell disorders.

INTRODUCTION: Integrative Medicine (IM) use and efficacy is poorly defined in those with plasma cell disorders (PCD). A 69-question survey on the subject was hosted on HealthTree.org for 3 months. METHOD: The survey included questions about complementary practice use, PHQ-2 score, quality of life, and more. Mean outcome values were compared between IM users and non-users. Proportions of supplement users and IM patients were compared between patients currently on myeloma specific treatment and patients not currently on treatment. RESULTS: The top 10 IM modalities reported among 178 participants were aerobic exercise (83 %), nutrition (67 %), natural products (60 %), strength exercise (52 %), support groups (48 %), breathing exercises (44 %), meditation (42 %), yoga (40 %), mindfulness-based stress reduction (38 %), and massage (38 %). The survey showed most patients participated in IM modalities, though they felt uncomfortable discussing them with their oncologist. Participant characteristics were compared between groups (users and non-users) using two-sample t-tests and chi-square tests. Use of vitamin C (3.6 vs. 2.7; p = 0.01), medical marijuana (4.0 vs. 2.9; p = 0.03), support groups (3.4 vs. 2.7; p = 0.04), and massage (3.5 vs. 2.7; p = 0.03) were associated with a higher quality of life scores on MDA-SI MM. There were no other significant associations between supplement use or IM practices and the MDA-SI MM, brief fatigue inventory, or PHQ-2. CONCLUSION: This study provides a foundation in the understanding of IM use in PCD, but more research is needed to evaluate individual IM interventions and their efficacy.