The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.

• MeSH
• dexamethason terapeutické užití   aplikace a dávkování   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom * patologie   farmakoterapie   mortalita   diagnóza   MeSH
• oligopeptidy terapeutické užití   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• staging nádorů * MeSH
• thalidomid analogy a deriváty   terapeutické užití   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• validační studie MeSH
• Názvy látek
• carfilzomib MeSH Prohlížeč
• dexamethason MeSH
• humanizované monoklonální protilátky * MeSH
• isatuximab MeSH Prohlížeč
• oligopeptidy MeSH
• pomalidomide MeSH Prohlížeč
• thalidomid MeSH

We performed real world evidence (RWE) analysis of daratumumab, lenalidomide and dexamethasone (Dara-Rd) versus lenalidomide and dexamethasone (Rd) treatment in relapsed/refractory multiple myeloma patients (RRMM). In total, 240 RRMM patients were treated with Dara-Rd from 2016 to 2022 outside of clinical trials in all major Czech hematology centers. As a reference, 531 RRMM patients treated with Rd were evaluated. Patients' data were recorded in the Czech Registry of Monoclonal Gammopathies (RMG). Partial response (PR) or better response (ORR) was achieved in significantly more patients in Dara-Rd than in Rd group (91.2% vs. 69.9%; p < 0.001). The median progression free survival (PFS) was 26.9 months in the Dara-Rd and 12.8 months in the Rd group (p < 0.001). Median overall survival (OS) was not reached in the Dara-Rd compared to 27.2 months in the Rd group (p = 0.023). In patients with 1-3 previous treatment lines, there was significant PFS benefit of Dara-Rd compared to Rd (median PFS not reached vs. 13.2 months; p < 0.001). In patients with > 3 previous treatment lines, there was no significant PFS benefit of Dara-Rd treatment (7.8 months vs. 9.9 months; p = 0.874), similarly in patients refractory to PI + IMIDs (11.5 months vs. 9.2 months; p = 0.376). In RWE conditions, the median PFS in RRMM patients treated with Dara-Rd is shorter when compared to clinical trials. In heavily pretreated RRMM patients, efficacy of Dara-Rd treatment is limited; best possible outcomes of Dara-Rd are achieved in minimally pretreated patients.

• Klíčová slova
• Multiple myeloma, Relapse, Response rate, Treatment,
• MeSH
• dexamethason škodlivé účinky   MeSH
• lenalidomid terapeutické užití   MeSH
• lidé MeSH
• mnohočetný myelom * diagnóza   farmakoterapie   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• daratumumab MeSH Prohlížeč
• dexamethason MeSH
• lenalidomid MeSH

PURPOSE: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. METHODS: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. RESULTS: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. CONCLUSION: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

• MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• nádorové biomarkery MeSH
• nádorové cirkulující buňky * patologie   MeSH
• plazmatické buňky patologie   MeSH
• plazmocelulární leukemie * MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery MeSH

INTRODUCTION: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. METHODS: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. RESULTS: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. CONCLUSIONS: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics.

• Klíčová slova
• high-risk cytogenetics, isatuximab, multiple myeloma,
• MeSH
• dexamethason škodlivé účinky   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• mnohočetný myelom * diagnóza   farmakoterapie   genetika   MeSH
• oligopeptidy MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• carfilzomib MeSH Prohlížeč
• dexamethason MeSH
• humanizované monoklonální protilátky MeSH
• isatuximab MeSH Prohlížeč
• oligopeptidy MeSH

The IKEMA study (Randomized, Open Label, Multicenter Study Assessing the Clinical Benefit of Isatuximab Combined With Carfilzomib [Kyprolis®] and Dexamethasone Versus Carfilzomib With Dexamethasone in Patients With Relapse and/or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines; #NCT03275285) was a randomized, open-label, multicenter phase 3 study investigating isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs Kd in patients with relapsed multiple myeloma. This subanalysis analyzed the depth of response of Isa-Kd vs Kd. The primary end point was progression-free survival (PFS); secondary end points included overall response rate, very good partial response or better (≥VGPR) rate, complete response (CR) rate, and minimal residual disease (MRD) negativity rate (assessed in patients with ≥VGPR by next-generation sequencing at a 10-5 sensitivity level). At a median follow-up of 20.7 months, deeper responses were observed in the Isa-Kd arm vs the Kd arm, with ≥VGPR 72.6% vs 56.1% and CR of 39.7% vs 27.6%, respectively. MRD negativity occurred in 53 (29.6%) of 179 patients in the Isa-Kd arm vs 16 (13.0%) of 123 patients in the Kd arm, with 20.1% (Isa-Kd, 36 of 179 patients) vs 10.6% (Kd, 13 of 123 patients) reaching MRD-negative CR status. Achieving MRD negativity resulted in better PFS in both arms. A positive PFS treatment effect was seen with Isa-Kd in both MRD-negative patients (hazard ratio, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (hazard ratio, 0.670; 95% CI, 0.452-0.993). Exploratory analysis indicates that both current CR and MRD-negative CR rates are underestimated due to M-protein interference (potential adjusted CR rate, 45.8%; potential adjusted MRD-negative CR rate, 24.0%). In conclusion, there was a clinically meaningful improvement in depth of response with Isa-Kd. The CR rate in Isa-Kd was 39.7%. Mass spectrometry suggests that the potential adjusted CR rate could reach an unprecedented 45.8% of patients treated with Isa-Kd.

• MeSH
• dexamethason terapeutické užití   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mnohočetný myelom * terapie   MeSH
• oligopeptidy MeSH
• reziduální nádor farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• carfilzomib MeSH Prohlížeč
• dexamethason MeSH
• humanizované monoklonální protilátky MeSH
• isatuximab MeSH Prohlížeč
• oligopeptidy MeSH

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

• MeSH
• hematologické nádory * MeSH
• lidé MeSH
• lymfom * patologie   MeSH
• Světová zdravotnická organizace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.

• Klíčová slova
• clinical presentation, plasma cell disease, risks factors, survival, treatment,
• MeSH
• cyklin D1 genetika   MeSH
• exozom genetika   MeSH
• genetická predispozice k nemoci MeSH
• histondemethylasy genetika   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• míra přežití MeSH
• mnohočetný myelom diagnóza   epidemiologie   genetika   terapie   MeSH
• mutace MeSH
• nádorové biomarkery genetika   MeSH
• plazmatické buňky imunologie   patologie   MeSH
• represorové proteiny genetika   MeSH
• rizikové faktory MeSH
• transkripční elongační faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• CCND1 protein, human MeSH Prohlížeč
• CDCA7L protein, human MeSH Prohlížeč
• cyklin D1 MeSH
• DIS3 protein, human MeSH Prohlížeč
• ELL2 protein, human MeSH Prohlížeč
• exozom MeSH
• histondemethylasy MeSH
• KDM1A protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• represorové proteiny MeSH
• transkripční elongační faktory MeSH

Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma.

• Klíčová slova
• antibody drug conjugates, monoclonal antibodies, multiple myeloma,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVES AND DESIGN: A novel risk stratification algorithm estimating risk of death in patients with relapsed multiple myeloma starting second-line treatment was recently developed using multivariable Cox regression of data from a Czech registry. It uses 16 parameters routinely collected in medical practice to stratify patients into four distinct risk groups in terms of survival expectation. To provide insight into generalisability of the risk stratification algorithm, the study aimed to validate the risk stratification algorithm using real-world data from specifically designed retrospective chart audits from three European countries. PARTICIPANTS AND SETTING: Physicians collected data from 998 patients (France, 386; Germany, 344; UK, 268) and applied the risk stratification algorithm. METHODS: The performance of the Cox regression model for predicting risk of death was assessed by Nagelkerke's R2, goodness of fit and the C-index. The risk stratification algorithm's ability to discriminate overall survival across four risk groups was evaluated using Kaplan-Meier curves and HRs. RESULTS: Consistent with the Czech registry, the stratification performance of the risk stratification algorithm demonstrated clear differentiation in risk of death between the four groups. As risk groups increased, risk of death doubled. The C-index was 0.715 (95% CI 0.690 to 0.734). CONCLUSIONS: Validation of the novel risk stratification algorithm in an independent 'real-world' dataset demonstrated that it stratifies patients in four subgroups according to survival expectation.

• Klíčová slova
• algorithm, relapsed multiple myeloma, risk stratification, survival, validation,
• MeSH
• algoritmy MeSH
• hodnocení rizik MeSH
• lidé MeSH
• mnohočetný myelom * MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Francie MeSH
• Německo MeSH

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10-16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.

• MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• exprese genu genetika   MeSH
• genetická transkripce genetika   MeSH
• hypoxie genetika   patologie   MeSH
• kostní dřeň patologie   MeSH
• lidé MeSH
• mnohočetný myelom genetika   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové cirkulující buňky patologie   MeSH
• nádorové kmenové buňky patologie   MeSH
• nádorové mikroprostředí genetika   MeSH
• pohyb buněk genetika   MeSH
• prognóza MeSH
• proliferace buněk genetika   MeSH
• zánět genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH