A research center's experience of T-cell redirecting therapies in triple-class refractory multiple myeloma.

The efficacies of chimeric antigen receptor T (CAR-T) cells and bispecific monoclonal antibodies (BiAbs) for triple-class refractory (TCR) myeloma have not previously been compared, and clinical data on how to rescue patients after relapse from these immunotherapies are limited. A retrospective study of 73 TCR patients included in trials was conducted: 36 received CAR-T and 37 received BiAbs. CAR-T produced a higher overall response rate (ORR) than BiAbs (97.1% vs. 56.8%, P=0.002). After a median of follow-up of 18.7 months, no significant difference in progression-free survival (PFS) was observed between the CAR-T and BiAbs groups (16.6 vs. 10.8 months; P=0.090), whereas overall survival (OS) was significantly longer in the CAR-T than in the BiAbs group (49.2 vs. 22.6 months; P=0.021). BiAbs following CAR-T yielded a higher ORR and longer PFS2 than did non-redirecting T cell therapies after CAR-T (ORR: 87.5% vs. 50.0%, PFS2: 22.9 vs. 12.4 months). By contrast, BiAbs following BiAbs resulted in an ORR of 33% and PFS2 of 8.4 months, which was similar to that produced by the non-redirecting T cell therapies (ORR: 28.6%, PFS2: 8.1 months). Even though this is a pooled analysis of different trials with different products and the patient profile is different for CAR-T and BiAbs, both were effective therapies for TCR myeloma. However, in our experience, while the PFS was similar with the two approaches, CAR-T therapy resulted in better OS, mainly because of the efficacy of BiAbs as rescue therapy. Our results highlight the importance of treatment sequence in real-word experience.

Gammapatía monoclonal de significado incierto / Monoclonal gammopathy of uncertain significance

La gammapatía monoclonal de significado incierto es una neoplasia de células plasmáticas premaligna, con una elevada prevalencia en la población mayor de 50 años, y un riesgo anual de progresión del 1%. Numerosos estudios recientes han permitido un avance en la compresión de la patogenia de estos trastornos y su riesgo de progresión a otras enfermedades. Los pacientes requieren un seguimiento de por vida, siendo fundamental un enfoque multidisciplinar y adaptado al riesgo. En los últimos años, cada vez se reconocen más entidades asociadas a la presencia de una paraproteína, conocidas como gammapatías monoclonales de significado clínico (AU)

Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized (AU)

[Monoclonal gammopathy of uncertain significance]. / Gammapatía monoclonal de significado incierto.

Monoclonal gammopathy of uncertain significance is a premalignant plasma cell neoplasm with a high prevalence in the population over 50 years of age and an annual risk of progression of 1%. Multiple recent studies have led to advances in understanding both the pathogenesis of these disorders and their risk of progression to other diseases. Patients require lifelong follow-up, and a multidisciplinary and risk-adapted approach is essential. In recent years, an increasing number of entities associated with a paraprotein, known as clinically significant monoclonal gammopathies, have been recognized.

Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients.

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, approximetely 70% to immunomodulators, and approximetely 50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 versus 11.3 months (hazard ratio =1.7, 95% confidence interval: 1.1-2.7; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PL, but a significant benefit in PFS was observed with the triplet combination in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Multiple myeloma with t(11;14): impact of novel agents on outcome.

Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.3% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: (1) t(11;14); (2) high-risk chromosomal abnormalities; and (3) standard risk (SR). After 80.1 months (1.2-273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2 vs. 79.5%, P = 0.336; CR: 23.4 vs. 12.8%, P = 0.215). This effect translated into a similar PFS (39.6 vs. 30.0 months; P = 0.450) and OS (107.6 vs. 75.7 months; P = 0.175). In summary, MM t(11;14) patients did not benefit from the introduction of novel agents as much as SR patients did, indicating that other therapies are needed to improve their outcomes.

Novel Agents as Main Drivers for Continued Improvement in Survival in Multiple Myeloma.

(1) Background: New therapeutic strategies have improved the prognosis of multiple myeloma (MM), changing the accepted view of this disease from being incurable to treatable. (2) Methods: We studied 1001 patients with MM between 1980 and 2020, grouping patients into ten-year periods by diagnosis 1980-1990, 1991-2000, 2001-2010 and 2011-2020. (3) Results: After 65.1 months of follow-up, the median OS of the cohort was 60.3 months, and OS increased significantly over time: 22.4 months in 1980-1990, 37.4 months in 1991-2000, 61.8 months in 2001-2010 and 103.6 months in 2011-2020 (p < 0.001). Using novel agents in the front-line setting for myeloma patients yielded a significantly better OS than in those treated with conventional therapies, especially when combinations of at least two novel agents were used. The median OS of patients treated with the combination of at least two novel agents in induction was significantly prolonged compared to those treated with a single novel agent or conventional therapy in induction: 143.3 vs. 61.0 vs. 42.2 months (p < 0.001). The improvement was apparent in all patients regardless of age at diagnosis. In addition, 132 (13.2%) patients were long-term survivors (median OS ≥ 10 years). Some independent clinical predictors of long-term survival were identified: ECOG < 1, age at diagnosis ≤ 65 years, non-IgA subtype, ISS-1 and standard-risk cytogenetic. Achieving CR and undergoing ASCT were positively associated with >10 years of survival. (4) Conclusions: The combination of novel agents appears to be the main factor for the improvement in survival in MM, which is becoming a chronic and even curable disease in a subtype of patients without high-risk features.