(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.

Systemic AL amyloidosis is a challenging disease for which many patients are considered frail in daily clinical practice. However, no study has so far addressed frailty and its impact on the outcome of these patients. We built a simple score to predict mortality based on three frailty-associated variables: age, ECOG performance status (<2 vs. ≥2) and NT-proBNP (<8500 vs. ≥8500 ng/L). Four-hundred and sixteen consecutive newly diagnosed patients diagnosed at ten sites from the Spanish Myeloma Group were eligible for the study. The score was developed in a derivation cohort from a referral center, and it was externally validated in a multicenter cohort. Multivariate analysis showed that the three variables were independent predictors of survival. The score was able to discriminate four groups of patients in terms of overall survival and early mortality in both cohorts. Comorbidity was also analyzed with the Charlson comorbidity index, but it did not reach statistical significance in the model. A nomogram was created to easily estimate the mortality risk of each patient at each time point. This score is a simple, robust, and efficient approach to dynamically assess frailty-dependent mortality both at diagnosis and throughout follow-up. The optimal treatment for frail AL amyloidosis patients remains to be determined but we suggest that the estimation of frailty-associated risk could complement current staging systems, adding value in clinical decision-making in this complex scenario.

Recent studies have advanced the understanding of the pathogenesis of monoclonal gammopathy of uncertain significance (MGUS), describing the influence of a proinflammatory bone marrow environment on the risk of progression. While albumin is a known inflammatory prognostic biomarker in multiple myeloma, its role in MGUS has not been explored. We conducted a retrospective study to investigate the prognostic value of albumin in MGUS. Eight hundred and thirty-eight patients with MGUS were included: 71 (8.5%) presented hypoalbuminemia (≤3.5 g/dL) at diagnosis. Hypoalbuminemia was more common in men (63.4% vs. 49.3%; P = 0.025), older age (≥70 years: 74.6% vs. 57.2%; P = 0.005), and IgA isotype (33.8% vs. 21.4%; P = 0.018). These patients presented lower hemoglobin levels and higher creatinine values (P < 0.001 and P < 0.001). Serum M protein ≥ 1.5 g/dL (HR 18.9 [95% CI, 1.8–200.8]; P = 0.015) and hypoalbuminemia (HR 14.7 [95% CI, 1.7–124.7]; P = 0.014) were identified as independent prognostic factors for progression. In our series, Mayo Clinic and MGUS-like phenotype models were validated, and the incorporation of hypoalbuminemia into these models helped identify a subgroup of intermediate-risk patients with a higher risk of progression. In conclusion, if confirmed by independent studies, hypoalbuminemia could be integrated into existing prognostic models, improving risk stratification and guiding clinical decision-making.

Background: Daratumumab-based regimens represent the gold-standard therapy for newly diagnosed AL amyloidosis patients. However, there are few studies about the efficacy of this treatment in real life. Methods: This study included 99 patients: 27 (27.3%) received daratumumab and proteasome inhibitor-based schemes, 46 (46.4%) were treated with proteasome inhibitors and/or immunomodulator-based regimens, and 26 (26.3%) were treated with chemotherapy. Results: Patients receiving daratumumab and proteasome inhibitor-based regimens achieved higher rates of partial haematological responses or better (100.0% vs. 78.3% vs. 58.3%; p = 0.009 and p < 0.001) and complete responses (74.1% vs. 37.0% vs. 12.5%; p = 0.003 and p < 0.001) than the proteasome inhibitors and/or immunomodulators and chemotherapy groups, respectively. Daratumumab and proteasome inhibitor-based schemes resulted in a shorter time to haematological response (1 month to partial response or better and 4 months to complete response). Moreover, in the group treated with daratumumab and proteasome inhibitor-based regimens, there was a trend of obtaining better and faster organ responses. The benefit of daratumumab and proteasome inhibitor-based regimens was that they resulted in an improvement in progression-free survival (not reached) compared to the proteasome inhibitor and chemotherapy groups (18 months; p = 0.022 and 6 months; p = 0.002). In addition, the clinical benefit was consistent in patients with Mayo Clinic stages III–IV. Conclusions: This study supports the efficacy and superiority of adding daratumumab to the frontline treatment over proteasome inhibitor-based regimens and chemotherapy in AL amyloidosis, including in advanced cardiac disease.

Measurable residual disease (MRD) in bone marrow (bmMRD) is an established surrogate biomarker in multiple myeloma (MM), but the clinical relevance of MRD in the apheresis product (aMRD) remains unclear. We retrospectively analyzed 422 MM patients who underwent autologous stem cell transplantation (ASCT) between 2005 and 2023 at the University Hospital of Salamanca, all evaluated for aMRD by 8-color flow cytometry. Forty-five patients (10%) were aMRD + ve and 377 (90%) were aMRD-ve, and baseline characteristics were similar except for a higher frequency of t(11;14) in aMRD + ve cases. Most patients received ASCT as first-line therapy after induction based on proteasome inhibitors, immunomodulators with/without anti-CD38 monoclonal antibodies combinations. Of note, decting aMRD + ve was up to six times more likely in patients who had a response worse than very good partial response before apheresis (odds ratio (OR) 6.09, P < 0.001). No patients in bmMRD-ve prior to apheresis were aMRD + ve. After ASCT, the aMRD + ve group exhibited lower rates of complete response and bmMRD-ve than patients with aMRD-ve, leading to a shorter progression-free survival (PFS) (hazard ratio 1.70, P = 0.006), and aMRD + ve status was identified as an independent predictor of early relapse (OR 9.75, P = 0.007). In conclusion, aMRD + ve may serve as a peripheral blood early biomarker to identify those with suboptimal responses, reflecting bmMRD persistence and predicting inferior PFS.