Co-occurrence of Cytogenetic Abnormalities and High-Risk Disease in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma [Systematic review].

Highlights: 

Consistent diagnostic identification of high-risk multiple myeloma (MM) patients is important for standard-of-care treatment allocation and clinical research. The association of ≥two high-risk cytogenetic abnormalities (HRCAs) with the poorest outcome in newly diagnosed MM and relapsed/refractory MM, and across treatment modalities, allows for more focused development of novel approaches to these patients with high unmet need.  The authors did not consider the type of HRCA, but rather any two or more HRCA.

A systematic review of randomized controlled trials of MM that reported testing for HRCAs between January 1, 2000, and December 9, 2021, was performed. Twenty-four trials, including 13,926 patients, were identified. Groups were contacted and asked to perform a novel, federated analysis of their data for single hit (one HRCA) and double hit (≥two HRCAs), using a centrally provided algorithm. Analysis results were centrally collated and meta-analyzed to assess the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) for one/≥two HRCAs across patient subgroups using random-effects models. The HR for PFS was 2.28 (95% CI, 2.05 to 2.54) for patients with ≥two HRCAs and 1.51 (95% CI, 1.38 to 1.65) for patients with one HRCA. The HR for OS was 2.94 (95% CI, 2.49 to 3.47) and 1.69 (95% CI, 1.52 to 1.88) for the two subgroups, respectively.  Strikingly, the prognostic impact of ≥two HRCAs was maintained in trials initiated in the past decade with modern combination

therapies, highlighting the ongoing unmet need of high-risk MM. It is possible that additional HRCAs, such as del(1p), should be considered as well, and that some combinations of specific HRCAs are worse than others.

Outcomes of patients with relapsed or refractory primary mediastinal B‐cell lymphoma treated with anti‐CD19 CAR‐T cells: CARTHYM, a study from the French national DESCAR‐T registry [Retrospective study].  

Highlights:

●       Primary mediastinal B‐cell lymphoma (PMBL) is often cured with dose‐dense anthracycline‐based regimens, but the prognosis at relapse or progression remains poor.

●       While anti‐CD19 chimeric antigen receptor (CAR) T-cell therapy has dramatically improved outcomes in relapsed or refractory (R/R) large B‐cell lymphoma, far less is known about their efficacy in PMBL.

●       In this study, based on the systematic documentation of all patients treated with CAR-T cells prospectively enrolled in the DESCAR-T registry in France, the authors describe the outcomes and the main determinants of treatment success in 82 patients with PMBL who were treated over a 6-year period.

●       This study demonstrates the excellent outcomes of R/R PMBL patients treated with anti‐CD19 CAR‐T cells, particularly axi‐cel.

●       Neither the response to bridging therapy nor the type of bridging therapy (chemotherapy versus immune checkpoint inhibitors) were associated with long‐term outcomes.

From July 2018 to January 2024, 87 PMBL patients underwent leukapheresis and were recorded in the DESCAR-T registry, and 82 were included in the study. Axi‐cel CAR‐T cells were used in 62 patients, tisa-cel in 14 patients, and liso‐cel in 6 patients. The authors observed a best complete response rate, 2‐year progression‐free survival, and 2‐year overall survival of 68.1%, 57.4%, and 73.8%, respectively.  

Genomic landscape of testicular follicular lymphoma is characterized by frequent 1p36/TNFRSF14 alterations [Case series].

Highlights: 

●       Testicular follicular lymphoma (T-FL) is a very rare and clinically indolent lymphoma occurring in children and young adults. Less than 30 cases have been previously reported with a median age of occurrence at 5 years (range, 3-69 years), with most patients (93%) presenting in clinical stage IE (ie. localized to testis). It is included with classic FL in the current fifth edition of the World Health Organization classification, whereas it is considered a separate, distinct entity in the 2022 International Consensus Classification.

●       Although T-FL shows some clinicopathologic similarities to pediatric-type FL, it notably lacks MAP2K1 mutations and may be best classified as a separate entity.

●       This study also adds valuable data for the clinical management of T-FL: a watch-and-wait approach after orchiectomy might be the preferred management in these patients.

●       Larger studies with longer clinical follow-up are needed to establish the optimal management of this rare lymphoma.

This study reports the clinicopathologic characteristics and the genomic landscape in the largest cohort (n=7) of T-FL to date. This very rare t(14;18)-negative lymphoma in children and young adults presents with a limited clinical stage and shows a remarkably indolent clinical course.  See comment "Testicular follicular lymphoma: let me count the ways" by E. Jaffe and L. Quintanilla-Martinez.

Serum free light chains in a racially diverse population including African Americans and populations from South Africa [Retrospective study].

Highlights: 

●       Detection of light chain (LC) monoclonal gammopathies (MGs) traditionally relies on serum-free LC (FLC) κ, λ, and their ratio (κ/λ) reference ranges based on a mostly White population.

●       These findings highlight the importance of basing disease definitions, such as monoclonal gammopathy of undetermined significance (MGUS), on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among black individuals, avoiding unnecessary financial, psychological, and medical consequences.

The authors investigated FLC values in a racially diverse population by screening 10,035 individuals for heavy chain MG, identifying 9028 negative cases whose FLC were measured.  Participants included 4149 from the PROMISE study (United States, n = 2383; South Africa, n = 1766) and 4879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1074 of 10 035 individuals (10.7%) were diagnosed with LC monoclonal gammopathy of undetermined significance (MGUS), with 99% being κ-restricted.  To avoid overdiagnosis, the authors propose a new κ/λ ratio reference range (0.686 to 2.10) for populations of African descent with normal renal function, with standard values for κ and λ being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs. 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being κ-restricted, consistent with LC myeloma rates.

Adopting their proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences.

How I treat iron-refractory iron deficiency anemia—An expert opinion-based treatment guidance for children and adults [Review]

Key points: 

●       Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive hereditary microcytic anemia characterized by partial or complete resistance to oral iron supplementation, caused by elevated plasma hepcidin levels resulting from pathogenic variants in the TMPRSS6 gene (encoding matriptase-2, a transmembrane protease that inhibits hepatic hepcidin synthesis).

●       Biallelic TMPRSS6 variants are classified as (possibly) pathogenic (class 3 or higher), along with the characteristic clinical and biochemical profile. Although IRIDA is typically considered an autosomal recessive disorder, heterozygous TMPRSS6 variants can result in a milder phenotype with less need for intravenous therapy.

●       In absolute iron deficiency anemia, a weekly hemoglobin (Hb) increase of approximately 0.8 g/dL is expected; however, in IRIDA, this Hb increase in time is likely lower due to reduced iron availability. 

●       IRIDA non-responders: those with < 1 g/dL Hb increase after 4 weeks of oral therapy.

●       Transferrin saturation (TSAT) is usually <5%–10% (<15% post-­ iron therapy).

●       In IRIDA patients. See Table 1 in the original article for characteristics of IRIDA.

●       Other causes of IRIDA, including gastrointestinal conditions (e.g., Helicobacter pylori infection, celiac disease, or atrophic gastritis), must be excluded.

●       Initiate intravenous therapy only after oral therapy proves ineffective or severe anemia is present. Initiate IV iron therapy (up to 500 mg per dose each 2 weeks). Assessing the total iron deficit is not applicable for IRIDA patients, as it is an iron distribution disorder.

●       Regularly monitor phosphate levels (at least after two administrations) during ferric carboxymaltose therapy due to the risk of hypophosphatemia.

●       Monitoring before each administration (≥1 week since the last dose): Hb, ferritin, and TSAT.

●       Aim for Hb levels that support quality of life: Maintain appropriate Hb levels while minimizing ferritin to prevent prolonged iron loading in the reticuloendothelial system.

●       Identify individual ferritin set point for iron dosing: Determine the ferritin level at which TSAT increases and Hb levels improve, tailored to each patient.