Interleukin-6 is a highly prognostic biomarker for POEMS syndrome [Retrospective study]

Highlights: 

●      POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin changes) is a rare paraneoplastic clonal plasma cell disorder that remains a diagnostic challenge due to its diverse clinical manifestations. POEMS can lead to interleukin-6 (IL-6) significant morbidity and multiorgan dysfunction.

●      This study demonstrated the clinical importance of baseline IL-6 levels among patients with POEMS syndrome.

●      Elevation of IL-6 is uniquely associated with specific presenting features, which are distinctly not associated with elevated vascular endothelial growth factor (VEGF), lymphadenopathy, or coexisting Castleman disease.

●       IL-6 offers prognostic insight beyond hypoalbuminemia and the Wang score.

A retrospective analysis was performed of patients with a new diagnosis of POEMS syndrome seen at the Mayo Clinic, Rochester (2011 to 2019), who had IL-6 testing within 90 days of diagnosis. Of the 117 patients seen during that period, 52 met inclusion criteria. Among these, 21 (40.4%) had elevated baseline IL-6 levels (median value 3 times the upper-limit of normal; interquartile range 1.3, 4.4). The median (range) VEGF plasma levels across the cohort were 342.5 pg/ml (<31–2780) [normal range 31–86 pg/ml]. Elevated IL-6 was associated with male sex, hepatomegaly, ascites, cherry angiomata, low albumin, endocrinopathy, reduced Diffusing Capacity of the Lung for Carbon Monoxide, mixed sclerotic/ lytic bone lesions, and higher light chain values. IL-6 elevation was not associated with VEGF level. Elevated IL-6 at diagnosis is associated with distinct clinical features, a shortened event-free survival, especially for those who do not achieve hematologic response, and perhaps most importantly, a strikingly inferior overall survival.

IVIG prophylaxis should be initiated following bispecific antibody therapy in multiple myeloma regardless of IgG levels [Review]

Key points:

See Table 1 and Figure 1 in original article. 

●      Bispecific antibodies (bsAbs), such as teclistamab, elranatamab, linvoseltamab, and talquetamab, have shown impressive efficacy in multiple myeloma (MM) but carry substantial infectious risks that do not dissipate over time. With every continued month on B-cell maturation antigen (BCMA) bsAb therapy, 3% of patients develop de novo high-grade infections.

●      Immunoglobulin replacement therapy (IgRT), which includes both intravenous immunoglobulin and subcutaneous immunoglobulin, may lower these risks. Primary prophylaxis has been associated with a 90% reduction in Grade 3 or higher infection rates.

●      An IgG threshold of 400 mg/dL does not adequately risk-stratify infections. Withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM receiving bsAb therapy.

Visualizing amyloidosis: The role of radionuclide imaging in systemic amyloidosis [Review]

Key points: 

See Figure 1 in original article.

●      Cardiac involvement, seen in up to 80% of patients, is the most common manifestation of systemic amyloidosis, particularly in the two most common subtypes: immunoglobulin light chain (AL) and transthyretin (ATTR), and is associated with significant morbidity and mortality.

●      The kidneys are affected in up to 70% of cases, with other organs including the liver, gastrointestinal tract, lungs, soft tissue, and nervous system, also often involved; most patients present with multi-organ involvement.

●      The traditional gold standard for diagnosis is the histological demonstration of amyloid deposition via Congo Red staining, followed by confirmatory subtyping. Radionuclide imaging has replaced this traditional approach for most patients with ATTR amyloidosis.

●      Once the diagnosis has been made, assessment of the presence and extent of organ involvement is required. This relies on surrogate assessments of organ function, such as proteinuria for renal involvement and cardiac biomarkers for cardiac involvement. This comes with the inherent limitations of using non-specific markers for disease assessment, particularly in the presence of concomitant diseases.

●      In isolated cardiac presentations, particularly in older males with carpal tunnel syndrome, cardiac scintigraphy can help ensure that a diagnosis of ATTR cardiomyopathy with a co-existing but unrelated monoclonal gammopathy is not overlooked. However, it should not negate nor delay the need for biopsy and subtyping. Cardiac scintigraphy may have a limited role in supporting the diagnosis of AL amyloidosis (a negative cardiac scintigraphy scan makes ATTR unlikely) in the rare circumstance when amyloid deposits are present, but histological typing fails and further biopsy is contraindicated.

●      The elimination of invasive biopsies for diagnosing ATTR cardiac amyloidosis has led to a significant increase in diagnosed cases over the past decade. Previously underdiagnosed, recent data using cardiac scintigraphy scans indicate that the prevalence of this condition in males increases with age, reaching approximately 6% at 85 years.

●      The ability to accurately assess the extent of disease involvement via imaging, akin to Positron Emission Tomography (PET)/Computed Tomography staging in lymphoma, would be practice-changing and is an unmet need in the management of amyloidosis.

●      To date, several amyloid-binding PET tracers have been assessed in systemic amyloidosis. These include ¹¹C-Pittsburgh Compound-B, several ¹⁸F-radiolabelled tracers: ¹⁸F-florbetapir, ¹⁸Fflorbetaben, ¹⁸F-flutemetamol, and ¹⁸F-sodium fluoride; and most recently ¹²⁴I-evuzamitide. See Table 1 in original article.

●      The future of radionuclide imaging for amyloidosis looks bright, offering more precise and personalized patient care.

International consensus statement on diagnosis, evaluation, and research of Richter transformation: the ERIC recommendations [Consensus]

Key points:

See Tables 1, 2, and 3 in original article.

●       Richter transformation (RT) occurs in 2% to 10% of patients with chronic lymphocytic leukemia (CLL).

●       RT can occur in patients who have not received any treatment or who have received only targeted therapies for their CLL

●       There are no therapeutic strategies proven to reduce the risk of RT in CLL.

●       RT should be suspected in patients with clinical decline, B-symptoms, elevated lactate dehydrogenase, rapidly enlarging lymphadenopathy, and/or discordant response to CLL treatment.

●       There should be strong consideration for RT in patients with discordant, enlarging lymphadenopathy (e.g., one nodal group growing rapidly compared with others).

●       In patients with a clinical suspicion of RT, a Positron Emission Tomography/Computed Tomography (PET/CT) scan should be obtained.

●       The most accessible lesion with the highest avidity should be targeted for biopsy (excisional biopsy is strongly recommended).

●       Standardized Uptake Value (SUV) avidity of <5 suggests a low likelihood of RT.

●       In cases in which the most accessible lesion has avidity, that is, much lower than a less-accessible lesion (eg., an axillary node with an SUV of 6 vs. a retroperitoneal node with an SUV of 22), we recommend attempting to biopsy the lesion with higher avidity.

●       If an excisional biopsy cannot be performed, we recommend multiple core biopsies as an alternative. Fine needle aspirates are insufficient and cannot be used in the diagnosis of RT.

●       Clonal relationship of the RT tissue and antecedent CLL cells should be tested (by comparing immunoglobulin gene rearrangement from the RT tissue with the immunoglobulin gene rearrangement in the CLL cells), because it is one of the strongest prognostic factors for RT survival: patients with clonally unrelated RT have a markedly better prognosis.

●       At present, next-generation sequencing of the RT tissue offers limited clinical value in determining prognosis.

●       Unlike standard diffuse large B-cell lymphoma, we recommend bone marrow biopsy at the time of treatment to determine the presence of bone marrow disease, and to assess the status of CLL.

●       Current standard-of-care treatment with R-CHOP–like regimens has poor efficacy. If possible, patients with RT should be treated on clinical trials.

●       In clinical practice, R-CHOP followed by consolidative allogeneic stem cell transplantation in eligible patients is the most commonly applied regimen.

●       A biopsy is recommended to distinguish residual CLL from refractory disease when the end-of-treatment PET-CT scan shows persistent Deauville 4 or 5 lesions.

●       Patients with detectable CLL by peripheral blood flow cytometry at restaging do not need an additional bone marrow biopsy to assess CLL disease response.

●       The response of RT and CLL should be objectively assessed and reported based on both the Lugano criteria and the International Workshop on CLL guidelines.

Current risk stratification and staging of multiple myeloma and related clonal plasma cell disorders [Review]

Key points: 

●      Clonal plasma cell disorders encompass a spectrum of conditions, including multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), Waldenström macroglobulinemia (WM), and immunoglobulin light chain (AL) amyloidosis.

○      In MGUS, SMM, and MM, progression risk varies widely and is influenced by a complex interplay of tumor burden, cytogenetic abnormalities, bone marrow microenvironment, and host factors.

■      MGUS is defined by the presence of a circulating monoclonal (M) protein <3 g/dL, clonal bone marrow plasma cells (BMPCs) < 10%, and no evidence of end-organ damage attributable to the plasma cell disorder. MGUS affects only 3–6% of adults over the age of 50. The annual risk of progression from MGUS to MM or related malignancies requiring treatment is approximately 1% per year. The International Myeloma Working Group (IMWG) risk stratification model, the iStopMM study, presence of immunoparesis, and a high fraction of clonal plasma cells in the bone marrow are important risk factors associated with an early progression of MGUS to MM. See Table 2 in original article.

■      SMM is defined by the presence of ≥3 g/dL of serum M protein and/or at least 10% clonal BMPCs with the absence of myeloma-defining events. The risk of progression of SMM to active MM is around 10% per year for the first 5 years after diagnosis. 0.53% of cases of SMM were identified in the eligible screened population in the iStopMM study. The authors (Zanwar and Rajkumar) recommend the 20/2/20 risk stratification schema as a reliable framework for assessing progression risk in SMM, given its simplicity and reproducibility. See Table 3 in original article.

■      MM accounts for approximately 10% of all newly diagnosed hematologic malignancies, with over 36,000 new cases and more than 12,000 MM-related deaths annually in the United States.  A subset of patients with high-risk disease continues to experience suboptimal outcomes, with overall survival ranging from only 3–5 years, even with access to novel and immune-based therapies. The International Myeloma Society (IMS) and IMWG introduced a new risk stratification framework in 2024 (See Table 1 in original article). Using this new schema, approximately 20% of patients were identified as high-risk.

○      WM, while usually indolent, presents its distinct spectrum of molecular abnormalities and disparate clinical outcomes.

■      WM is an IgM-secreting lymphoplasmacytic lymphoma (LPL) that arises from activated B-cells. Age-adjusted incidence rate is 0.42 per 100,000 person-years. About 20% of patients have a preceding diagnosis of smoldering WM (SWM) before progressing to active or symptomatic disease. SMW  is defined by ≥10% bone marrow infiltration by LPL and/or an M-protein level ≥3 g/dL in the absence of WM-related symptoms/signs requiring treatment. Given its simplicity, external validation, and relevance in the modern treatment landscape, the authors recommend using the Modified Staging System for WM for risk stratification in active WM (stratifying patients into four risk groups based on age, serum lactate dehydrogenase, and serum albumin). See Table 4 in original article.

○      In AL amyloidosis, clinical trajectories are heavily dictated by the nature and extent of organ involvement. See Table 5 in original article.

■      AL amyloidosis is characterized by the excess production of immunoglobulin light chains (or rarely heavy chains) secondary to a clonal plasma cell disorder, which are deposited as misfolded proteins in various organs, resulting in the consequent damage. Globally, the incidence is estimated at 3 to 12 cases per million person-years. The authors recommended using both the Mayo 2012 model and the modified Mayo 2004 model for baseline risk assessment (see Table 5 in original article). With the advent of high-sensitivity troponin-T, revised cutoffs have been proposed and validated. Conversions for these are described elsewhere.

European Commission approves DARZALEX® (daratumumab) as the first licensed treatment for patients with high-risk smouldering multiple myeloma

“Landmark approval is based on results from the Phase 3 AQUILA study, showing fixed-duration treatment with daratumumab significantly reduced the risk of progression to active multiple myeloma or death by 51 percent compared to active monitoring. This milestone marks a critical advance in early intervention for multiple myeloma as the first authorised treatment, offering a new treatment paradigm for patients with high-risk smouldering disease”.