Meletios Α. Dimopoulos

Outcomes of Patients With AL Amyloidosis and End‐Stage Renal Disease After Initiation of Therapy

In AL amyloidosis, advanced renal disease can impact treatment options and cause significant morbidity. Patients with ESRD requiring dialysis are a group with currently unmet needs. In this collaborative study, we identified 362 patients from three European centers who initiated dialysis during the course of the disease. Median survival after the initiation of dialysis was 40 months. Heart involvement, higher BMPC infiltration at diagnosis, and lambda light chain type were associated with inferior survival. At the time of dialysis initiation, cardiac biomarkers were prognostic for postdialysis outcome, but they did not perform the same as in patients not on dialysis. Higher FLCs levels at dialysis initiation were also prognostic, independently of cardiac biomarkers and other adverse factors. After starting dialysis, 151 patients received further treatment; median postdialysis survival for those that achieved CR/VGPR was significantly improved with 63.8 vs. 42 months for patients who achieved PR or less. In conclusion, patients with AL amyloidosis that require dialysis still represent a group of patients with poor outcomes, although, they can have prolonged postdialysis survival if they achieve deep hematologic response and have limited cardiac and clonal disease; such patients could also be considered for renal transplantation.

DimopoulosBlood Cancer Journal

Final analysis results from DREAMM-3, a phase 3 study of belantamab mafodotin versus pomalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma

Targeting B-cell maturation antigen (BCMA) has transformed the relapsed/refractory multiple myeloma (RRMM) landscape with unprecedented overall survival (OS) outcomes versus standard-of-care triplet regimens. Belantamab mafodotin, an anti-BCMA antibody-drug conjugate, has a multimodal mechanism of action involving minimal immunosuppression and no evidence of induction of T-cell exhaustion [ 1 , 2 ]. DREAMM-3 (NCT04162210) was a confirmatory phase 3 study to support the initial United States Food and Drug Administration and European Medicines Agency authorization of belantamab mafodotin monotherapy for patients with RRMM who had ≥4 prior lines of therapy (LOTs) [ 3 , 4 ]; approval was withdrawn following DREAMM-3 findings, as the primary endpoint of progression-free survival (PFS) superiority against the doublet comparator, pomalidomide-dexamethasone, was not met [ 5 , 6 , 7 ]. Subsequently, belantamab mafodotin combination regimens with bortezomib-dexamethasone (BVd) and pomalidomide-dexamethasone (BPd) have received approval for patients with RRMM who have received ≥1 prior LOT in multiple countries [ 8 ]. In the US, BVd was approved for patients with RRMM who have received ≥2 prior LOT [ 9 ].

Advanced cardiac AL amyloidosis carries ~40% 12-month mortality despite anti-PCD therapy, regardless of isotype.

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients

Myeloma Elderly Prognostic Score ( MEPS ): A Proposed Prognostic Score Integrating Age, Renal Function, Performance Status, and Ultra‐High‐Risk Cytogenetics

Progression of Disease Within 24 Months (POD24) is an Independent Prognostic Factor for Survival in Waldenström Macroglobulinemia

Introduction: The prognostic significance of progression of disease within 24 months (POD24) is well-established in many lymphomas, but data in Waldenström Macroglobulinemia (WM) remain limited and constrained by the frontline regimen utilized. Methods: This retrospective, single-center study enrolled consecutive, unselected newly-diagnosed WM (NDWM) patients who received frontline treatment with DRC between January 1, 2002 and September 15, 2021. Individuals without a progression event and a follow-up of less than 24 months were excluded. A landmark approach was utilized in order to evaluate the prognostic impact of POD24 in subsequent OS. Results: A total of 206 NDWM patients were enrolled; median age 70 years, 123 (59.7%) males. POD24, occurring in 47 (22.8%) patients, was associated with inferior OS post the 24-month landmark (5-year OS 62.8% vs 82.1% in non-POD24, p=0.001), maintained when adjusting for R-IPSSWM scores (aHR=1.65; 95% CI, 1.01-2.70; p = 0.044). When accounting for non-WM related death as a competing event, the cumulative incidence of WM-related mortality at 5 years was 21.6% and 7.1% between POD24 and non-POD24, respectively. POD24 maintained its prognostic significance when further adjusting for R-IPSSWM (aSHR= 1.88, 95%CI: 1.01-3.49, p=0.048). Conclusion: POD24 seems to be a predictor of inferior survival in patients with NDWM treated frontline with DRC. Even when accounting for immortal time bias through landmark analysis and adjusting for baseline risk via the R-IPSSWM and competing risks, patients with POD24 demonstrated a significantly higher risk of mortality. These findings suggest that POD24 could represent a high-risk phenotype that may require tailored management. Micro-Abstract: This retrospective study evaluated the prognostic significance of disease progression within 24 months (POD24) among 206 newly-diagnosed Waldenström Macroglobulinemia (WM) patients receiving frontline treatment with dexamethasone, rituximab, and cyclophosphamide (DRC). POD24 occurred in 22.8% of this cohort. Landmark analysis demonstrated that POD24 is associated with inferior subsequent overall survival, showing a 5-year OS of 62.8% versus 82.1%. Furthermore, the cumulative incidence of WM-related death at five years was significantly higher for the POD24 group (21.6% versus 7.1%) after accounting for competing risks. Ultimately, POD24 represents a high-risk phenotype requiring tailored management.

International Myeloma Working Group Recommendations for the Diagnosis and Management of Solitary Plasmacytomas

DimopoulosThe Lancet

Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial

Signals in Peripheral Blood: Tracking Redox Status and DNA Damage Response During the Progression of Multiple Myeloma

Clinical outcomes in newly diagnosed patients with Waldenström's macroglobulinaemia treated in a tertiary academic centre

The Hippo Pathway in Metaplastic Breast Carcinoma: Prognostic Significance and Therapeutic Implications

Background/objectives: Metaplastic breast carcinoma (MpBC) is a rare, poorly differentiated breast cancer defined by the presence of ductal carcinoma along with areas of matrix-producing, spindle-cell, sarcomatous, or squamous differentiation. It does not express hormone receptors and has a poor overall prognosis. The Hippo molecular pathway was recently related to cancer progression and adjuvant therapy resistance. The objective of this study was to evaluate the expression of Hippo pathway transducers, YAP/TAZ, CCND1, and CTGF, in MpBC and their relation to the clinicopathological characteristics of the disease. Methods: Specimens from patients with MpBC treated at our department from 2003 to 2021 were analyzed utilizing immunohistochemistry and real-time PCR. Results: Forty-four female patients (62.6 ± 14.7 years old) met inclusion criteria and were included in this study. Strong nuclear YAP/TAZ expression was found in 61.4% of patients, while the expressions of CCND1 and CTGF were 3.9% and 12.5%, respectively. Patients presenting at an advanced stage had a statistically worse prognosis compared to the ones diagnosed with stage IA disease. Adjuvant chemotherapy was associated with better overall survival, while disease recurrence was significantly associated with a worse prognosis. Conclusions: Advanced stage at diagnosis and disease recurrence were significantly associated with worse prognosis in MpBC. However, adjuvant chemotherapy significantly led to better overall survival. The Hippo pathway is frequently deregulated (nuclear YAP/TAZ in 61.4% of patients), suggesting it is a compelling novel therapeutic target for this aggressive disease.

Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs

Infections remain a challenge during treatment of patients with multiple myeloma (MM) with anti-B-cell maturation antigen (BCMA) and anti-G protein-coupled receptor class C group 5 member D (GPRC5D) bispecific antibodies (bsAbs). However, the mechanism underlying different rates and severity of infections induced by the 2 bsAbs remains poorly understood. Single-cell RNA sequencing of bone marrow (BM) aspirates of 11 patients with MM and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. GPRC5D expression was restricted to malignant and less to normal plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted BM mature B cells, from 4.9% to 0% (P< .001), and normal PCs, from 0.17% to <0.0002% (P< .001), during treatment of 62 patients with relapsed MM. This was observed throughout therapy. Additional flow cytometry (n = 31) and single-cell RNA sequencing studies (n = 8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, confirming no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that although GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onward. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and supports individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B-cell malignancies or autoimmune diseases.

Venetoclax-Dexamethasone Versus Pomalidomide-Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma: Primary Results of the Randomized, Phase III CANOVA Study

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma

DimopoulosBlood

Safety and efficacy of linvoseltamab (LINVO) combined with anti-CD38 monoclonal antibodies (mAbs) daratumumab (DARA) or isatuximab (ISA) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial results from the multicohort, Phase 1b LINKER-MM2 trial

Incidence and risk factors for infections in the real-world setting in newly diagnosed myeloma patients treated with modern induction regimens

Patterns of minimal residual disease trajectories in 323 newly diagnosed patients with multiple myeloma and correlation with progression-free survival

Results of the promise study from ~30,000 individuals screened for monoclonal gammopathies

Isatuximab with bortezomib, cyclophosphamide, and dexamethasone followed by isatuximab and lenalidomide maintenance in newly diagnosed multiple myeloma patients with severe renal impairment: Final analysis of a phase 2 study by the greek myeloma study group

Validation of the new ims/IMWG consensus genomic staging (CGS) of high-risk multiple myeloma (HRMM) in a contemporary cohort of 1209 patients