Application of diffusion-weighted whole-body MRI for response monitoring in multiple myeloma after chemotherapy: a systematic review and meta-analysis.

OBJECTIVE: Myeloma Response Assessment and Diagnosis System recently published provides a framework for the standardised interpretation of DW-WBMRI in response assessment of multiple myeloma (MM) based on expert opinion. However, there is a lack of meta-analysis providing higher-level evidence to support the recommendations. In addition, some disagreement exists in the literature regarding the effect of timing and lesion subtypes on apparent diffusion coefficient (ADC) value changes post-treatment. METHOD: Medline, Cochrane and Embase were searched from inception to 20th July 2021, using terms reflecting multiple myeloma and DW-WBMRI. Using PRISMA reporting guidelines, data were extracted by two investigators. Quality was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 method. RESULTS: Of the 74 papers screened, 10 studies were included comprising 259 patients (127 males and 102 females) and 1744 reported lesions. Responders showed a significant absolute ADC change of 0.21×10-3 mm/s2 (95% CI, 0.01-0.41) with little evidence of heterogeneity (Cochran Q, p = 0.12, I2 = 45%) or publication bias (p = 0.737). Non-responders did not show a significant absolute difference in ADC (0.06 ×10-3 mm/s2, 95% CI, -0.07 to 0.19). A percentage ADC increase of 34.78% (95% CI, 10.75-58.81) was observed in responders. Meta-regression showed an inverse trend between ADC increases and time since chemotherapy initiation which did not reach statistical significance (R2 = 20.46, p = 0.282). CONCLUSIONS: This meta-analysis supports the use of the DW-WBMRI as an imaging biomarker for response assessment. More evidence is needed to further characterise ADC changes by lesion subtypes over time. KEY POINTS: • In multiple myeloma patients who received chemotherapy, responders have a significant absolute increase in ADC values that is not seen in non-responders. • A 35% increase in ADC from baseline values is found to classify response post-induction chemotherapy which corroborates with expert opinion from the Myeloma Response Assessment and Diagnosis System. • More evidence is needed to further characterise ADC changes by lesion subtypes over time after induction of therapy.

Optimising cardiovascular care of patients with multiple myeloma.

Multiple myeloma (MM) is the third most common haematological malignancy, with increasing prevalence over recent years. Advances in therapy have improved survival, changing the clinical course of MM into a chronic condition and meaning that management of comorbidities is fundamental to improve clinical outcomes. Cardiovascular (CV) events affect up to 7.5% of individuals with MM, due to a combination of patient, disease and treatment-related factors and adversely impact survival. MM typically affects older people, many with pre-existing CV risk factors or established CV disease, and the disease itself can cause renal impairment, anaemia and hyperviscosity, which exacerabate these further. Up to 15% of patients with MM develop systemic amyloidosis, with prognosis determined by the extent of cardiac involvement. Management of MM generally involves administration of multiple treatment lines over several years as disease progresses, with many drug classes associated with adverse CV effects including high rates of venous and arterial thrombosis alongside heart failure. Recommendations for holistic management of patients with MM now include routine baseline risk stratification including ECG and echocardiography and administration of thromboprophylaxis drugs for patients treated with immunomodulatory drugs. Close surveillance of high-risk patients with collaboration between haematology and cardiology is required, with prompt investigation in the event of CV symptoms, in order to identify and treat complications early. Decisions regarding discontinuation of cardiotoxic therapies should be made in a multidisciplinary setting, taking into account the severity of the complication, prognosis, expected benefits and the availability of effective alternatives.

Bing-Neel Syndrome Case Report: A Previously Undocumented IgG Variant with MRI, PET/CT, and PET/MRI Imaging.

Waldenstrom's macroglobulinaemia is the most commonly reported subtype of lymphoplasmacytic lymphoma (LPL); it is characterised by IgM secretion. Neurological complications are common usually as a result of hyperviscosity. In rare cases, cells can infiltrate the central nervous system; this is known as Bing-Neel syndrome. We report the case of a 57-year-old male with lymphoplasmacytic lymphoma of the IgG-subtype with neurological symptoms and the consequent finding of lymphoplasmacytoid cells in his cerebrospinal fluid as well as deposits on MRI and PET-CT imaging. This is the first report of Bing-Neel syndrome in IgG-subtype LPL. We discuss the biological and radiological markers of his disease, including PET imaging, which has been minimal in this area to date.

High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution.

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.

Immune thrombocytopenia -- what are the new treatment options?

INTRODUCTION: Primary immune thrombocytopenia (ITP) is a minor disease for many patients; however, the natural history is variable and unpredictable. Many patients who are in otherwise good health can be left untreated, especially if their platelet counts are close to 20 × 10(9)/l. The overall mortality rate for ITP is < 1%, and the morbidity and mortality associated with treatment can be worse than the disease. AREAS COVERED: ITP is not purely due to platelet destruction and in a significant proportion platelet production is sub-optimal; the review will cover the newer developments with the thrombopoietin receptor agonists (TPOrAs) of which two agents, romiplostim and eltrombopag, are now licensed and these will be placed in context to conventional treatment. EXPERT OPINION: There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses.

Stem cell transplantation in chronic lymphocytic leukaemia - steering a safe course over shifting sands.

There is no clear consensus regarding the optimal management of chronic lymphocytic leukaemia. Many patients are diagnosed at an advanced age and will die with chronic lymphocytic leukaemia, but of other unrelated causes. A significant minority are diagnosed at an earlier age, or with more aggressive disease, and despite chemotherapy, are likely to die of chronic lymphocytic leukaemia. The infusion of autologous or allogeneic haemopoietic stem cells, following a variety of conditioning regimes, offers the possibility of longer remissions or even cure. We explore the key questions facing clinicians in this field: Who is it best to transplant? When is it best to transplant? How is it best to transplant?

Follicular lymphoma: managing an indolent malignancy.

Follicular lymphoma is by far the most common indolent non-Hodgkin lymphoma worldwide. Management is complicated by difficulty in accurately predicting individual outcomes and judging whether, when and how best to intervene. This article illustrates key issues in the management of this fascinating and enigmatic disease.

Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment.

Follicular lymphoma has considerable clinical heterogeneity, and there is a need for easily quantifiable prognostic biomarkers. Microvessel density has been shown to be a useful prognostic factor based on numerical assessment of vessel numbers within histologic sections in some studies, but assessment of tumor neovascularization through angiogenic sprouting may be more relevant. We therefore examined the smallest vessels, single-staining structures measuring less than 30 microm(2) in area, seen within histologic sections, and confirmed that they were neovascular angiogenic sprouts using extended focal imaging. Tissue microarrays composing diagnostic biopsies from patients at the extremes of survival of follicular lymphoma were analyzed with respect to numbers of these sprouts. This analysis revealed higher angiogenic activity in the poor prognostic group and demonstrated an association between increased sprouting and elevated numbers of infiltrating CD163(+) macrophages within the immediate microenvironment surrounding the neovascular sprout.

Transplantation in chronic lymphocytic leukemia: timing and expectations.

Stem cell transplantation in chronic lymphocytic leukemia (CLL) is an evolving field. Younger patients with high-risk disease might derive the greatest benefit from this approach and the availability of reduced-intensity conditioning regimens has made allogeneic stem cell transplantation more relevant to patients with CLL. Patient selection, timing of transplantation, and method of conditioning, stem cell delivery and immunosuppression appear to influence outcomes. We collect and review the available data to assist clinical decision-making in this field.

Activated macrophages in the tumour microenvironment-dancing to the tune of TLR and NF-kappaB.

A large number of variables have been identified which appear to influence macrophage phenotype within the tumour microenvironment. These include reciprocal chemical and physical interactions with tumour cells and with non-malignant cells of the tumour microenvironment, tissue oxygen tension, and the origin and prior experience of the particular macrophage population. In this review we outline the key evidence for these influences and consider how macrophage phenotype is acquired and the relevance of the TLR-NF-kappaB pathway.

Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma.

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.