Measurable Residual Disease by Mass Spectrometry and Next-Generation Flow to Assess Treatment Response in Myeloma.

Quantitative immuneprecipitation mass-spectrometry (QIP-MS) allows the identification of the M-protein in patients with multiple myeloma (MM) otherwise in complete response, and could be considered suitable for measurable residual disease (MRD) evaluation in peripheral blood. In the context of the GEM2012MENOS65 and GEM2014MAIN trials, we compared the performance of QIP-MS in serum with next-generation flow (NGF) cytometry in bone marrow to assess MRD in paired samples obtained post-induction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate two groups of patients with significantly different progression-free survival (PFS); when the evolution of the results obtained with either method was considered, maintaining or converting to MRD negativity was associated with longer survival, significantly better when compared to sustaining or converting to MRD positivity. Of note, reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieve similar prognostic value based in single time point assessments and kinetics. Thus, the minimally-invasive nature of MRD monitoring by MS represents a breakthrough in high-sensitive response assessment in MM. GEM2012MENOS65: #NCT01916252 and EudraCT as #2012-005683-10. GEM2014MAIN: #NCT02406144 and at EudraCT as 2014-00055410.

Curative Strategy for High-Risk Smoldering Myeloma: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Followed by Transplant, KRd Consolidation, and Rd Maintenance.

PURPOSE: Early treatment of high-risk smoldering myeloma has been shown to delay progression to multiple myeloma (MM). We conducted this trial with curative intention using a treatment approach employed for newly diagnosed patients with MM. METHODS: Patients with high-risk smoldering myeloma (>50% progression risk at 2 years) and transplant candidates were included and received induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd), six cycles, followed by high-dose melphalan (200 mg/m2) autologous stem-cell transplantation (HDM-ASCT), two KRd consolidation cycles, and Rd maintenance for 2 years. The primary end point was undetectable measurable residual disease (uMRD) rate by next-generation flow after ASCT. Sustained uMRD 4 years after ASCT was the secondary end point. RESULTS: Between June 2015 and June 2017, 90 patients were included, and 31% met at least one SixtyLightchain MRI (SLiM)-hypercalcemia, renal impairment, anemia, bone disease (CRAB) criterion. After a median follow-up of 70.1 months, 3 months after ASCT, in the intention-to-treat population, 56 (62%) of 90 patients had uMRD, and 4 years later, it was sustained in 29 patients (31%). Five patients progressed to MM, and the 70-month progression rate was 94% (95% CI, 84 to 89). The presence of any SLiM CRAB criteria predicted progression to MM (four of the five patients; hazard ratio, 0.12; 95% CI, 0.14 to 1.13; P = .03). Thirty-six patients showed biochemical progression, and failure to achieve uMRD at the end of treatment predicted it. The 70-month overall survival was 92% (95% CI, 82 to 89). Neutropenia and infections were the most frequent adverse events during treatment, resulting in one treatment-related death. Three second primary malignancies have been reported. CONCLUSION: Although a longer follow-up is needed, this curative approach is encouraging and more effective than active MM, with 31% of the patients maintaining the uMRD 4 years after HDM-ASCT.

Single-point and kinetics of peripheral residual disease by mass spectrometry to predict outcome in patients with high risk smoldering multiple myeloma included in the GEM-CESAR trial.

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).

Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells.

Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM.

Mass Spectrometry as Alternative Method to Identify and Monitor Non-Secretory Progressive Disease in Patients with Multiple Myeloma.

INTRODUCTION: After receiving different lines of treatment, multiple myeloma patients tend to present with less secretory and more frequent extramedullary disease. These features make treatment monitoring and follow-up very complex since they have to be based on the use of imaging methods and/or bone marrow aspirations or biopsies. OBJECTIVE: To present the case of a patient with myeloma progressing with non-secretory bone disease and to discuss the potential impact of mass spectrometry as a new highly sensitive method able to identify the monoclonal protein (MP) in the serum of these types of patients. MATERIALS AND METHODS: Informed consent was signed by the patient prior to receiving each line of treatment. The clinical information and images were obtained from anonymized electronic files. The mass spectrometry was performed with the Immunoglobulin Isotypes (GAM) assay for the mass spectrometry EXENT® Analyser Technology from Binding Site, part of Thermofisher. RESULTS: A 73-year-old male with IgG kappa multiple myeloma progressing with a new lytic lesion after receiving 14 cycles of Talquetamab as a third line of therapy who, due to the non-secretory nature of the disease at this point, could not be enrolled in a clinical trial, thus limiting his therapeutic options. The mass spectrometry was able to identify and quantify the presence of the patient's MP when the serum protein electrophoresis and immunofixation were still negative and therefore could have been used to confirm the progression, to permit the inclusion of the patient in a clinical trial and to further monitor the disease response. CONCLUSIONS: The higher sensitivity of the mass spectrometry methods to detect the MP in patients with myeloma and other monoclonal gammopathies translates into better identification of the disease progression, permits the inclusion of more patients in clinical trials and facilitates treatment monitoring.

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

ABSTRACT: The efficacies of chimeric antigen receptor T cells (CAR-Ts) 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-Ts and 37 received BiAbs. CAR-Ts produced a higher overall response rate (ORR) than BiAbs (97.1% vs 56.8%, P = .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 = .090), whereas overall survival (OS) was significantly longer in the CAR-T than in the BiAbs group (49.2 vs 22.6 months; P = .021). BiAbs after CAR-Ts yielded a higher ORR and longer PFS2 than did nonredirecting T-cell therapies after CAR-Ts (ORR: 87.5% vs 50.0%; PFS2: 22.9 vs 12.4 months). By contrast, BiAbs after BiAbs resulted in an ORR of 33% and PFS2 of 8.4 months, which was similar to that produced by the nonredirecting T-cell therapies (ORR: 28.6%; PFS2: 8.1 months). Although this is a pooled analysis of different trials with different products and the patient profile is different for CAR-Ts and BiAbs, both were effective therapies for TCR myeloma. However, in our experience, although the PFS was similar with the 2 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.

A Simple Frailty Score Predicts Survival and Early Mortality in Systemic AL Amyloidosis.

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.

Outcomes of Modified Mayo Stage IIIa and IIIb Cardiac Light-Chain Amyloidosis: Real-World Experience in Clinical Characteristics and Treatment-67 Patients Multicenter Analysis.

Light-chain amyloidosis (AL) is a rare multisystem disorder characterized by the deposition of misfolded amyloid fibrils derived from monoclonal immunoglobulin light chains in various organs. One of the most common organs involved in AL is the heart, with 50-70% of patients clinically symptomatic at diagnosis. We conducted a multi-center, retrospective analysis of 67 patients diagnosed between July 2012 and August 2022 with the European 2012 modification of Mayo 2004 stage III cardiac AL. The most important factors identified in the univariate Cox analysis contributing to a longer OS included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1, New York Heart Association functional classification (NYHA FC) ≤ 2, the use of autologous stem cell transplantation (ASCT) after induction treatment, achieving a hematological response (≥very good partial response) and cardiac (≥partial response) response after first-line treatment. The most important prognostic factors with the most significant impact on OS improvement in patients with modified Mayo stage III cardiac AL identified by multivariate Cox analysis are ECOG PS ≤ 1, NYHA FC ≤ 2, and achieving hematological response ≥ VGPR and cardiac response ≥ PR after first-line treatment.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Selinexor, daratumumab, bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the phase II, nonrandomized, multicenter GEM-SELIBORDARA study.

The treatment landscape for multiple myeloma has significantly evolved in the last decade. Notwithstanding, a large proportion of patients continue to relapse and novel combinations continue to be needed. In this phase II study, selinexor, a first-in-class inhibitor of exportin-1 was evaluated in combination with standard daratumumab-bortezomib-dexamethasone (DVd), for the treatment of relapsed and refractory multiple myeloma (RRMM). The aim of the trial was to assess the efficacy and safety of the combination of selinexor with DVd (S-DVd). A total of 57 patients were enrolled in the two parts of the study. Part 1 enrolled a heavily pretreated population with at least three prior lines (PL) of therapy and part 2 enrolled an early relapse population with at least one PL of therapy. The primary endpoint was complete response (CR) rate in part 2 and overall response rate (ORR) in part 1. In the latter, 24 patients were treated with a median of three PL. Overall response rate (ORR) was 50% with two CR. Median progression- free survival (PFS) was 7 months. In part 2, 33 patients were enrolled, with a median of one PL. ORR was 82% and CR or better was 33%. Median PFS was 24 months. In lenalidomide-refractory patients, a median PFS of 22.1 months was observed. Thrombocytopenia was the most common hematological adverse event (69%; grade 3-4: 34%) and nausea, the most frequent non-hematological adverse event (38%; grade 3-4: 6%). Sixty-two percent of the patients required dose modifications. In summary, although the primary endpoint of the study was not met, the combination of S-DVd showed encouraging clinical efficacy with a generally manageable safety profile representing a potential option for the treatment of RRMM patients.

Assessment of the psychometric properties of the Spanish version of EORTC QLQ-MY20 and evaluation of health-related quality of Life outcomes in patients with relapsed and/or refractory multiple myeloma in the real-world setting in Spain: results from the CharisMMa study.

We evaluated the psychometric properties of the Spanish version of the European Organization for Research and Treatment of Multiple Myeloma (MM) specific quality-of-life (QoL) questionnaire module (QLQ-MY20) in relapsed/refractory MM (RRMM) patients. This was an observational, cross-sectional, multicenter study using EORTC QLQ-C30 and QLQ-MY20 in RRMM patients (ClinicalTrials.gov ID NCT03188536). We assessed the non-response rate, ceiling/floor effects, internal consistency, test-retest reliability, and validity. The study included 276 patients (53.3% males, mean [SD] age of 67.4 [10.5] years). The EORTC QLQ-MY20 showed a low non-response rate, very low ceiling and floor effects, and good internal consistency. The test-retest reliability assessment revealed good temporary stability, the construct validity analysis stated four main factors similar to the ones of the original version, and the criterion validity assessment showed no differences between groups. In conclusion, the Spanish version of EORTC QLQ-MY20 is a reliable and valid tool for assessing QoL in RRMM patients.

Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma. METHODS: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 106 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11. FINDINGS: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19. INTERPRETATION: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach. FUNDING: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich.

Clonal architecture and evolutionary history of Waldenström's macroglobulinemia at the single-cell level.

To provide insight into the subclonal architecture and co-dependency 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; 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.

Real-World Health Care Services Utilization Associated With the Management of Patients With Relapsed and Refractory Multiple Myeloma in Spain: The CharisMMa Study.

BACKGROUND: Most patients with multiple myeloma (MM) relapse or become refractory, resulting in high health care costs. However, real-world data regarding the utilization of health care services among the relapsed/refractory MM (RRMM) population are scarce. METHODS: Observational, cross-sectional, multicenter study of the utilization of health care services by RRMM patients who had relapsed within the previous 6 months in Spain in a real-world setting. Data were collected from the clinical records and during a single structured interview and included sociodemographic and clinical characteristics at last relapse, the treatment and health care services nature, and were presented using descriptive statistics. RESULTS: The 276 patients enrolled (53.3% males), with a mean [SD] age of 67.4 [10.5] years, had experienced their most recent relapse a median (IQR) of 1.61 (0.74, 3.14) months before entering the study. Patients lived a median (IQR) of 9.0 (3.0, 30.0) km away from the hospital and visited the hospital a median (IQR) of 3.0 (2.0, 5.0) times/month to receive treatment for their most recent relapse. They spent a median (IQR) of 15.84 (5.0, 42.0) euros/month on transportation. Since their most recent relapse, most patients had been admitted to a hospital unit (n = 155, 56.2%), had required ≥1 diagnostic tests (n = 227, 82.2%), and had consulted the hematologist (n = 270, 97.8%) a mean (SD) of 5.5 (5.4) times. In half of the visits, patients were accompanied by an actively working caregiver (n = 112, 54.4%). CONCLUSIONS: RRMM treatments are associated with a high utilization of health care services and pose a significant burden for patients and caregivers. TRIAL REGISTRATION NUMBER: NCT03188536.

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.

Definition and Clinical Significance of the Monoclonal Gammopathy of Undetermined Significance-Like Phenotype in Patients With Monoclonal Gammopathies.

PURPOSE: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated. PATIENTS AND METHODS: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis. RESULTS: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival. CONCLUSION: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Single-Cell DNA Sequencing and Immunophenotypic Profiling to Track Clonal Evolution in an Acute Myeloid Leukemia Patient.

Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an NPM1-mutated AML patient with an initial low ratio of FLT3-ITD (low-risk ELN-2017), treated with midostaurin combined with standard chemotherapy as front-line treatment, and with salvage therapy plus gilteritinib following allogenic stem cell transplantation after relapse. Simultaneous single-cell DNA sequencing and cell-surface immunophenotyping was used in diagnostic and relapse samples to understand the clinical scenario of this patient and to reconstruct the clonal composition of both tumors. Four independent clones were present before treatment: DNMT3A/DNMT3A/NPM1 (63.9%), DNMT3A/DNMT3A (13.9%), DNMT3A/DNMT3A/NPM1/FLT3 (13.8%), as well as a wild-type clone (8.3%), but only the minor clone with FLT3-ITD survived and expanded after therapy, being the most represented one (58.6%) at relapse. FLT3-ITD was subclonal and was found only in the myeloid blast population (CD38/CD117/CD123). Our study shows the usefulness of this approach to reveal the clonal architecture of the leukemia and the identification of small subclones at diagnosis and relapse that may explain how the neoplastic cells can escape from the activity of different treatments in a stepwise process that impedes the disease cure despite different stages of complete remission.