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IACH NEWS OF THE WEEK |
October 5, 2025
Prepared by Dr Edwin Uriel Suárez and Dr. Fabio Torres |
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Monoclonal Gammopathy of Undetermined Significance [Review] |
Key points: ● Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell disorder present in approximately 5% of the general population over the age of 50 years.
● MGUS is characterized by the presence of detectable monoclonal (M) proteins, which are identical copies of intact immunoglobulins, immunoglobulin light chains, or both, that are secreted by the clonal plasma cells.
● MGUS is asymptomatic but can progress to cancer — specifically, multiple myeloma, Waldenström’s macroglobulinemia, or solitary plasmacytoma — at a rate of 1% per year. ○ Although the risk of malignant progression is considered to be 1% per year, the actual lifetime probability of progression is lower when adjusted for competing causes of death and is approximately 11% at 25 years. ○ For persons with all three risk factors: a serum M protein level of ≥1.5 g per deciliter, IgA or IgM MGUS, and an abnormal serum free light chain (FLC) ratio, the risk of progression at 20 years is 58% as compared with 5% for persons who have none of these risk factors. ○ Other risk factors include suppression of normal (uninvolved) immunoglobulins (immunoparesis), the presence of high-risk cytogenetic abnormalities, and higher bone marrow plasma-cell involvement (5 to 9% clonal plasma cells vs. <5%). The PANGEA model predicts the risk of progression at baseline and also in a dynamic manner on the basis of the change in M protein levels over time. ■ In low-risk MGUS (See Figure 4 in original paper; including probability of having <10% bone marrow plasma cells, estimated with the iSTOPMM calculator): If laboratory tests are stable, recheck once every 2–3 yr or when symptoms develop If laboratory tests show progression, workup to rule out myeloma or related disorder. ■ All other MGUS in whom there is clinical concern for cancer or nonmalignant progression of MGUS (See Figure 4 in original paper): Bone marrow biopsy; Imaging (whole body low-dose computed tomography [CT] or if IgM MGUS, CT of abdomen; or positron emission tomography-CT; workup as needed if suspected MGCS. If no evidence of cancer or MGCS, recheck laboratory tests in 6 months and then annually thereafter
● A variety of systemic disorders, referred to collectively as monoclonal gammopathy of clinical significance (MGCS), can develop as a result of the secreted monoclonal immunoglobulin in persons with MGUS. ○ More than 100 nonmalignant diseases have been reported to be associated with MGUS, but most such associations are coincidental rather than causal. However, several well-defined nonmalignant diseases are known to be causally related to MGUS, and MGCS is the umbrella term for these disorders (See Table 1 in original paper). ■ A severe prothrombotic state induced by M proteins has recently been described; the state resolves after plasma-cell clone–directed therapy and has been considered the prototype disorder under the rubric of monoclonal gammopathy of thrombotic significance (See the IACH News of the Week - February 16, 2025 and the original paper).
● The diagnosis of progression to cancer or MGCS usually requires histopathological confirmation to ensure that the clinical problem is attributable to the plasma-cell disorder.
● No therapy is needed for MGUS, and the schedule for clinical follow-up is dictated by the underlying risk stratification. |
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Assessment of Systematic JAK2V617F Screening in 996 Patients With Venous Thromboembolism [Retrospective and prospective monocentric study] |
Highlights: ● In cases of splanchnic thrombosis (ST) with no obvious cause, myeloproliferative neoplasm (MPN) driver mutations should be screened. In such patients, an MPN is diagnosed in 30%–40% of cases. ● JAK2V617F mutation can also be identified in individuals without overt MPN. ● The notable prevalence of the JAK2V617F mutation in patients with venous-thrombosis embolism (VTE) raises the possibility that screening for this mutation might be a valuable addition to thrombophilia assessment, regardless of blood count or thrombotic site. In this study the authors evaluated the role of the JAK2V617F mutation in the management of patients with a history of VTE. They conducted a retrospective study of patients tested for the JAK2V617F mutation over a 10-year period to describe their clinical profiles; and a prospective monocentric study in which they systematically tested patients with VTE for the JAK2V617F mutation using quantitative polymerase chain reaction. In total, 5357 patients have been tested for the JAK2V617F mutation, and 733 (13.7%) were positive. Among them, 674 (92.0%) were diagnosed with MPN, and 59 patients (8.0%) had normal blood count (NBC) . In JAK2V617F positive patients, as compared to MPN patients, NBC patients were younger (56.1 vs. 66.3 years, p < 0.001) and had lower variant allele frequency (VAF) (5.3 vs. 22.6%; p < 0.001). Two thirds of thrombosis events were venous. ST was the most frequent venous location (n = 11; 45.8%). Interestingly, deep vein thrombosis (DVT) of the lower limb and/or pulmonary embolism (PE) was the second most frequent location (n = 10; 41.7%). In patients with arterial thrombosis (n = 10), stroke was, by far, the first location (n = 7; 70.0%). During the prospective phase, they included 996 patients with VTE. JAK2V617F mutation was detected in 3.8% of patients (n = 38). Among these, 10 were diagnosed with MPN, and 28 remained classified as having an NBC. The VAF was lower in NBC patients: 0.13% vs. 3.87% (p = 0.02). The most common sites of thrombosis in NBC patients were PE (46.4%, n = 13) and DVT (35.7%, n = 10), while in MPN patients, DVT (50%, n = 5) and ST (30%, n = 3) predominated. Notably, the proportion of ST was higher in MPN patients compared to JAK2- Wild type and NBC patients (30.0% vs. 3.5% and 10.7%, respectively). |
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Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN [Clinical trial] |
Highlights: In patients with chronic lymphocytic leukemia (CLL) including patients with high-risk features, acalabrutinib and acalabrutinib-obinutuzumab resulted in more prolonged progression-free survival (PFS) compared to chlorambucil-obinutuzumab. ELEVATE-TN is an ongoing (18 countries) phase 3 randomized (1:1:1) open-label clinical trial evaluating the efficacy and safety of acalabrutinib (a second-generation, covalent Bruton tyrosine kinase inhibitor) alone or in combination with obinutuzumab (anti-CD20 antibody) vs. chemoimmunotherapy for treatment-naive (TN) CLL. The study consisted of three arms: acalabrutinib-obinutuzumab (Arm A), acalabrutinib (Arm B), and chlorambucil-obinutuzumab (Arm C), (stratified by presence or absence of del(17p), Eastern Cooperative Oncology Group score: 0-1 vs. 2, and geographic region of origin) with crossover to acalabrutinib monotherapy if progression/unacceptable toxicity occurred. After 6 years of follow-up, the PFS (primary endpoint) was significantly longer for patients in the acalabrutinib-containing arms, with a PFS rate of 78.0% (95% confidence interval [CI], 70.6-83.7) for acalabrutinib-obinutuzumab, 61.5% (95% CI, 53.4-68.7) for acalabrutinib monotherapy, and 17.2% (95% CI, 11.2-24.3) for chlorambucil-obinutuzumab. These findings were similar in patients with high-risk genomic features (del(17p)), mutated TP53, unmutated immunoglobulin heavy chain variable region gene, and complex karyotype). Overall survival (OS) was significantly longer for patients in the acalabrutinib-obinutuzumab arm than the chlorambucil-obinutuzumab arm (hazard ratio [HR], 0.62; 95% CI, 0.39-0.97; p = 0.0349). However, OS was not significantly different between acalabrutinib-obinutuzumab and acalabrutinib monotherapy (HR, 0.69; 95% CI, 0.44-1.09; p = 0.1220). No new data on safety were present. |
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Pembrolizumab in Relapsed or Refractory Mycosis Fungoides or Sézary Syndrome [Letter] |
Highlights: Pembrolizumab in monotherapy has shown efficacy in patients with mycosis fungoides/Sézary syndrome (MF/SS); however, the use of 5 or more systemic therapies appears to reduce its efficacy, accompanied by a significant frequency of immune-related adverse events (IRAEs). Cutaneous T-cell lymphomas are characterized by the clonal expansion of T cells, primarily involving the skin. The most typical forms (70%) are MF and SS. A recent case series of 30 patients with MF/SS showed data for pembrolizumab, an immune checkpoint inhibitor as monotherapy. Ninety percent of patients received pembrolizumab on a schedule of 200mg every 3 weeks. After a follow-up of 20.4 (95% confidence interval [CI], 6.4-78.4) months, the overall response rate, evaluated in 29 patients, was 48% (9 partial, 5 complete). Patients with early-stage disease (stages I-IIA) had a higher response rate (7 of 9 patients) compared to those with late-stage disease (stages IIB-IV, 7 of 20 patients). Regarding the site of involvement, the most significant response was observed in the skin (16/29 [55%]) and lymph nodes (7/13 [54%]). The median overall survival was 20.6 months (95% CI, 10.0-34.2). Concerning toxicity, thirteen patients (43%) experienced an IRAE, the majority (85%) of which were grade I-II. However, pembrolizumab was discontinued after an IRAE in five patients. In conclusion, pembrolizumab is a treatment option for relapsed or refractory MF/SS, potentially more effective in early stages and before other treatment options, although the development of an IRAE is a limitation to consider. However, allogeneic hematopoietic stem cell transplantation remains the only potential curative option for this form of lymphoma. |
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Prevention and treatment of venous thromboembolism in patients with multiple myeloma: Clinical practice guidelines on behalf of the European Myeloma Network [Guidelines] |
Highlights: This expert consensus introduces key updates, including the simplification of risk stratification by grouping intermediate- and high-risk patients with multiple myeloma (MM) using the IMPEDE-VTE score, and advocates for the use of factor Xa inhibitors alongside low-molecular-weight heparins (LMWH) for primary thromboprophylaxis. A recent Expert Panel Consensus on Practice Guidelines for the Prevention and Treatment of Venous Thromboembolism in Patients with Multiple Myeloma, on behalf of the European Myeloma Network, has launched evidence-based recommendations for preventing and treating venous thromboembolism (VTE) in MM patients. The main recommendations were: · Recommendations 1 and 2: The panel recommends providing educational materials to patients with MM on VTE (Grade 1A), and implementing systematic VTE risk assessment for all MM patients at the initial diagnosis, treatment initiation, relapse/progression, and whenever treatment regimens are modified (Grade 1A). · Recommendations 3 and 4: The panel recommends the implementation of the IMPEDE‐VTE score for VTE risk assessment in all patients with MM (Grade 1B), and the stratification of patients into two risk groups as either high/intermediate or low risk for VTE (Grade 2A). · Recommendations 5 and 6: The panel suggests patients who receive immunomodulatory drug (IMiD)‐based regimens or carfilzomib combinations should be stratified as high/intermediate risk for VTE (Grade 2Β), and suggests risk assessment for VTE upon primary diagnosis and antimyeloma treatment initiation, following induction completion or disease remission, at diagnosis of disease progression or recurrence, when modifications of therapeutic lines are scheduled (Grade 2B) · Recommendation 7: The panel recommends pharmacological thromboprophylaxis with direct anti‐Xa agents or LMWH to patients classified as high/intermediate risk for VTE (Grade 1B). · Recommendation 8 and 9: The panel recommends the regular assessment of bleeding risk for patients at high/intermediate risk for VTE scheduled for pharmacological prophylaxis (Grade 1A), and recommends low‐dose aspirin for patients classified as low risk (Grade 2B). · Recommendation 10: The panel recommends applying pharmacological thromboprophylaxis for at least 6 months from the last risk evaluation (no grade of recommendation) The recommendations of thromboprophylaxis and treatment of VTE in patients with MM do not differ from other clinical scenarios, recommending a minimum duration of 6 months for antithrombotic treatment in patients with VTE and MM and the extension of the antithrombotic treatment beyond 6 months in patients with active MM (Grade 1A) or in patients receiving ongoing IMiD or carfilzomib therapy. A reduced dose of apixaban (2.5 mg twice daily) can be used in these patients. Finally, regarding the prophylaxis and treatment of catheter-related VTE, routine pharmacological prophylaxis is not recommended for preventing catheter-related VTE. A minimum duration of anticoagulation of 3 months is recommended for symptomatic catheter‐related VTE in patients with MM (Grade 2C). |
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