Patients with multiple myeloma have experienced a great improvement in survival over the past century because of the introduction of novel therapeutic strategies. However, a subgroup of patients with ...poorer outcomes than expected is considered high risk and identified by the presence of patient- and disease-based factors such as frailty, extramedullary disease, cytogenetic abnormalities, or even relapses occurring earlier than expected according to the baseline factors. Although the management of patients with high-risk features is not well established because of the lack of specific trials in this subgroup of patients and because of their underrepresentation in the clinical trials, treatment should be planned on 2 pillars: (1) poor prognosis with the presence of high-risk features can be at least improved or even abrogated by achieving a deep and sustained response over time, and (2) this can most likely be obtained through using the best therapeutic options and in a response-adapted way. Some clinical trials that have been planned or are ongoing include only patients with high-risk features, using the most effective therapies (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies) as well as chimeric antigen receptor T cells and T-cell engagers that will unravel what the best therapeutic approach will be to overcome the poor prognosis of the presence of high-risk features.
Immunoparesis or suppression of polyclonal immunoglobulins is a very common condition in newly diagnosed myeloma patients. However, the recovery of polyclonal immunoglobulins in the setting of immune ...reconstitution after autologous stem cell transplantation and its effect on outcome has not yet been explored. We conducted this study in a cohort of 295 patients who had undergone autologous transplantation. In order to explore the potential role of immunoglubulin recovery as a dynamic predictor of progression or survival after transplantation, conditional probabilities of progression-free survival and overall survival were estimated according to immunoglobulin recovery at different time points using a landmark approach. One year after transplant, when B-cell reconstitution is expected to be completed, among 169 patients alive and progression free, 88 patients (52%) showed immunoglobulin recovery and 81 (48%) did not. Interestingly, the group with immunoglobulin recovery had a significantly longer median progression-free survival than the group with persistent immunoparesis (median 60.4
27.9 months, respectively; Hazard Ratio: 0.45, 95%Confidence Interval: 0.31-0.66;
<0.001), and improved overall survival (11.3 vs. 7.3 years; Hazard Ratio: 0.45, 95%Confidence Interval: 0.27-0.74;
=0.002). Furthermore, the percentage of normal plasma cells detected by flow cytometry in the bone marrow assessed at day 100 after transplantation was associated with the immunoglobulin recovery at that time and may predict immunoglobulin recovery in the subsequent months: nine months and one year. In conclusion, the recovery of polyclonal immunoglobulins one year after autologous transplantation in myeloma patients is an independent long-term predictor marker for progression and survival.
To provide insight into the subclonal architecture and codependency patterns of the alterations in Waldenström's macroglobulinemia (WM), we performed single-cell mutational and protein profiling of ...eight patients. A custom panel was designed to screen for mutations and copy number alterations at the single-cell level in samples taken from patients at diagnosis (n=5) or at disease progression (n=3). Results showed that in asymptomatic WM at diagnosis, MYD88L265P was the predominant clonal alteration, while other events, if present, were secondary and subclonal to MYD88L265P. In symptomatic WM, clonal diversity was more evident, uncovering combinations of alterations that synergized to promote clonal expansion and dominance. At disease progression, a dominant clone was observed, sometimes accompanied by other less complex minor clones, which could be consistent with a clonal selection process. Clonal diversity was also reduced, probably due to the effect of treatment. Finally, we combined protein expression with mutational analysis to map somatic genotype with the immunophenotype. Our findings provide a comprehensive view of the clonality of tumor populations in WM and how clonal complexity can evolve and impact disease progression.
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.
Monoclonal gammopathy of unknown significance (MGUS) is the most frequent plasma cell disorder that commonly affects elderly patients. Although it is an asymptomatic condition, as well as smoldering ...myeloma (SMM), the risk of progression to multiple myeloma requiring therapy or other B-cell disorders varies greatly for individual patients, remaining low for MGUS (1% per year), while higher and not uniform for SMM patients (10% per year). This scenario implies some special considerations regarding assessment and follow-up, especially in the elderly. In this review, we provide the updated diagnostic criteria of monoclonal gammopathies proposed by the International Myeloma Working Group (IMGW); the current recommendations for the assessment of asymptomatic plasma cell disorders, with some concerns about the need of geriatric evaluation in the elderly population, the importance of distinguishing myeloma-related symptomatology from signs or symptoms caused by multiple chronic conditions typically found in the elderly. Finally, the identification of predictor markers of progression has enabled a proposal of risk-adapted follow-up strategies in MGUS and SMM that should be implemented in clinical practice. Although the standard of care is observation for MGUS and SMM patients as well, a recent randomized trial targeting high-risk SMM showed the clinical benefit of early intervention. The change of the treatment paradigm is also very promising and feasible for elderly patients, as long as a comprehensive geriatric assessment is conducted to optimize early treatment and reach maximum benefit with minimum toxicity, in other words, to ensure a better quality of life for these patients.
•The prevalence of monoclonal gammopathies increases with age.•In the elderly, some comorbidities can mimic myeloma-related symptomatology.•It is crucial to establish the differential diagnosis to not overtreat MGUS/SMM.•Geriatric assessment may improve the management of MGUS/SMM elderly patients.•Further investigation is required to define the optimal treatment in high-risk SMM.
(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 (
< 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 (
< 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.
Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming ...these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia 12% vs 19% and infections 30% vs 25%, similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 72% vs 22/40 55%, p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the ...high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial.
We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes.
At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% 95% confidence interval (CI), 89.5-100; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse.
Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.
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