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Purpose: Recent studies describe inferior outcomes in newly diagnosed multiple myeloma (NDMM) patients with t(11;14) treated with novel agents., Materials and Methods: We analyzed 240 NDMM transplant eligible (TE) patients who received triplet induction regimen in the GEM05MENOS65 (bortezomib, thalidomide and dexamethasone - VTD) and GEM2012 (bortezomib, lenalidomide and dexamethasone - VRD) clinical trials., Results: t(11;14) and standard risk (SR) non-t(11;14) were prevalent in 51 (21%) and 189 (79%) patients, respectively. Patients with t(11;14) treated with VTD had a lower overall response rate (ORR) (84% vs. 97%, P = .044) and lower negative minimal residual disease (MRD) (7.7% vs 35.1%, P = .049) after induction, as compared to SR non-t(11;14), while there were no differences in ORR (87% vs. 89%) or negative MRD (13.2% vs. 24.4%, P = .2) for these 2 subgroups in patients treated with VRD. The presence of t(11;14) impacted negatively on PFS in patients with VTD (hazard ratio 2.70; P = .005), while no differences were observed in those treated with VRD., Conclusion: TE NDMM patients harboring t(11;14) had an inferior outcome compared with SR patients when receiving induction therapy with VTD while no differences were observed when receiving a lenalidomide containing regimen., Competing Interests: Disclosure A.O. has received honoraria for lectures from and serves on the advisory boards of Janssen, Bristol Myers Squibb-Celgene, Amgen, GlaxoSmithKline, Sanofi, and Pfizer. J.S.M. has received honoraria and consulting services fee from and served on the advisory boards of AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Haemalogix, Janssen, Karyopharm, Merck Sharp & Dohme, Novartis, Takeda, Regeneron, Roche, Sanofi, SecuraBio, and Clínica Universitaria de Navarra. J.J.L. has received consultancy fees and/or has participated on advisory board of BMS, Sanofi, Amgen and Janssen; and has received travel expenses from Celgene and Pfizer. L.R.: honoraria for lectures and advisory boards from Janssen, BMS-Celgene, Amgen, Takeda, Sanofi, GSK, Menarini. J.B.: honoraria for lectures and advisory boards from Janssen, BMS-Celgene, Amgen, Takeda, Oncopeptides. J.dl.R.: honoraria for lectures and advisory boards from Janssen, BMS-Celgene, GSK, Pfizer, Amgen, Menarini, Sanofi. L.P: honoraria for lectures and advisory boards from Janssen, Amgen, Sanofi, GSK. M.V.M.: honoraria derived from lectures and participation in advisory boards for Johnson and Johnson, Celgene-BMS, GSK, Sanofi, Pfizer, Stemline-Menarini, Kite, Regeneron, and Amgen. R.R.T.: Honoraria for lectures and advisory board from Amgen BMS, GSK Janssen, Sanofi, and The Binding Site. M.J.C.: honoraria derived from lectures and participation in advisory boards: Celgene-BMS, GSK, Sanofi, Pfizer, Amgen, Novartis, JAZZ Pharmaceuticals, and Astellas Pharma. A.S.: honoraria from Takeda, BMS/Celgene, MSD, Janssen, Amgen, Novartis, Gilead Kite, Sanofi, Roche, GenMab, Abbvie, Jazz Pharmaceuticals, consultancy from Takeda, BMS/Celgene, Novartis, Janssen, Gilead, Sanofi, GenMab, Abbvie, speaker's Bureau for Takeda and research support from Takeda. M.B.I.: honoraria derived from lectures and participation in advisory boards for Janssen, Celgene-BMS, GSK, Sanofi and Amgen. F.d.A.: honoraria for lectures and advisory boards from Janssen, Bristol-Myers-Squibb (Celgene), Amgen, GlaxoSmithKline, Sanofi and Takeda. N.C.G.: honoraria from Janssen and Amgen, and travel grants from Gilead. The remaining authors have nothing to disclose., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In multiple myeloma (MM), measurable residual disease (MRD) is assessed in bone marrow (BM). However, less invasive evaluation of peripheral residual disease (PRD) in blood could be advantageous and less cumbersome. We investigated the prognostic value of PRD monitoring after 24 cycles of maintenance in 138 transplant-eligible patients with MM enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials. PRD was assessed using next-generation flow (NGF) and mass spectrometry (MS). Positive PRD by NGF in 16/138 (11.5%) patients was associated with a 13-fold increased risk of progression and/or death; median progression-free survival (PFS) and overall survival (OS) were 2.5 and 47 months, respectively. Considering patients' MRD status in BM as the reference, PRD detection using NGF showed positive and negative predictive values of 100% and 73%, respectively. Presence of PRD helped identifying patients at risk of imminent progression among those with positive MRD in BM. Patients with undetectable PRD according to both NGF and MS showed 2-year PFS and OS rates of 97% and 100%, respectively. In multivariate analyses including the Revised International Staging System and the complete remission status, only MRD in BM and PRD by NGF showed independent prognostic value for PFS. This study supports the use of less invasive PRD monitoring during maintenance or observation in transplant-eligible patients with MM.

The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10 -6 was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Antiapoptotic Bcl-2 family proteins are involved in myeloma cell survival. To date, their expression in multiple myeloma (MM) patients has mostly been analyzed at the RNA level. In the present study, we quantified for the first time the protein expression of the Bcl2-family members using a capillary electrophoresis immunoassay in 120 newly diagnosed MM patients, aged ≤65 years, treated in the context of the PETHEMA/GEM2012 study. We found that the pattern of expression of Bcl-2 family proteins was highly heterogeneous among patients. Although cases with t(11;14) had significantly higher levels of Bcl-2/Bcl-xL and Bcl-2+Bim+Bax/Bcl-xL ratios than those without t(11;14), the presence of this translocation was not synonymous with such high levels of expression. Conversely, some patients with other genetic alterations also showed higher levels of those ratios. Survival analysis revealed that the high expression of Bad and Puma proteins was associated with significantly longer overall survival ( p  = 0.001 and p  < 0.001, respectively). Bcl-2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies., Competing Interests: Cristina De Ramón has received travel grants from Beigene. Ramón García‐Sanz has received personal fees from Amgen, Janssen, Takeda, and Pfizer, honoraria from Pharmacyclics, research funding from Hospira, and travel accommodation from Celgene, unconnected with the submitted work. Bruno Paiva has received research funding from Bristol Myers Squibb/Celgene, Roche, and Sanofi and has served as a consultant or advisor for Adaptive, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Kite, Roche, Sanofi, and Takeda. Noemi Puig has received honoraria from Amgen, Celgene, Janssen, Takeda, and The Binding Site, funding from Celgene, Janssen, Amgen, and Takeda, and travel grants from Amgen Celgene, Janssen, and Takeda. Laura Rosiñol has received consulting fees from Amgen, BMS/Celgene, Sanofi, Janssen, Takeda, GSK, and Karyofarm. Joaquín Martínez‐López has received honoraria and consulting fees from BMS/Celgene, Incyte, Janssen, Novartis, Sanofi, and Roche. Joan Bladé has received honoraria from Celgene, Janssen, and Amgen. Jesús F. San Miguel has consulting and advisory roles with Amgen, Bristol‐Myers Squibb, Celgene, Janssen, MSD, Novartis, Takeda, and Roche. María V. Mateos has served on speakers bureaus and advisory boards for AbbVie, Adaptive, Amgen, Celgene, GlaxoSmithKline, Janssen, Mundipharma, Oncopeptides, PharmaMar, Roche, Seattle Genetics, and Takeda. Norma C. Gutiérrez has received honoraria from Janssen and Amgen, and travel grants from Gilead. All the other authors have no conflicts of interest to disclose., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

This study examines the impact of cytogenetic abnormalities and their co-segregation on the prognosis of newly diagnosed multiple myeloma patients. The analysis included 1304 patients from four different GEM-PETHEMA clinical trials. Genetic alterations, such as t(4;14), t(14;16), del(17p), +1q, and del(1p), were investigated using FISH on CD38 purified plasma cells. The frequency of genetic alterations detected were as follows: del(17p) in 8%, t(4;14) in 12%, t(14;16) in 3%, +1q in 43%, and del(1p) in 8%. The median follow-up was 61 months, and the median progression-free survival (PFS) and overall survival (OS) were 44 months and not reached, respectively. Consistent with previous reports, the presence of t(4;14) was associated with shorter PFS and OS. In our series, the presence of t(14;16) did not impact survival, maybe due to limitations in sample size. Del(17p) was linked to poor prognosis using a cut-off level of ≥20% positive cells, without any impact of higher cut-off in prognosis, except for patients with clonal fraction ≥80% who had a dismal outcome. Cosegregation of cytogenetic abnormalities patients worsened the prognosis in t(4;14) patients but not in patients with del(17p), which retained its adverse prognosis even as a solitary abnormality. Gain(1q) was associated with significantly shorter PFS and OS, while del(1p) affected PFS but not OS. Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment., Competing Interests: Veronica González‐Calle: Consulting or Advisory Role: Janssen. Speakers' Bureau: Janssen, GlaxoSmithKline, Pfizer, Bristol Myers Squibb/Celgene. Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline. Paula Rodriguez‐Otero declares honoraria derived from Consulting or advisory board role: Celgene‐BMS, Janssen, Roche, Abbvie, Pfizer, GSK, Sanofi, H3Biomedicine. Steering committee member: Celgene‐BMS, Regeneron, Janssen Speaker's bureau: Janssen, Celgene‐BMS, GSK, Sanofi, Abbvie. Travel grant: Pfizer, and is an Editor of HemaSphere. Miguel T. Hernández: Consulting or Advisory Role: Janssen, Sanofi/Aventis, Celgene/Bristol Myers Squibb, GlaxoSmithKline. Speakers' Bureau: Janssen, Celgene/Bristol Myers Squibb, GlaxoSmithKline. Research Funding: Celgene/Bristol Myers Squibb (Inst). Laura Rosiñol reports honoraria from Janssen, Celgene, Amgen, and Takeda. Joaquin Martínez‐López declares honoraria from consulting activities from Astellas Pharma, BMS, F. Hoffman‐La Roche, Janssen, Novartis, Sanofi. Research grant from BMS. Ana P. González‐Rodríguez reports honoraria from Janssen, Celgene, Takeda, and Amgen. JdlR is a consultant for Bristol‐Meyers Squibb, GlaxoSmithKline, Janssen, Menarini, Pfizer, Sanofi, and Takeda and is on the advisory board of GlaxoSmithKline, Janssen, Pfizer, and Sanofi. Maria V. Mateos: declares honoraria derived from lectures and advisory roles at Amgen, Celgene, BMS, GSK, Janssen, Pfizer, Regeneron, Sanofi, and Takeda. Anna Sureda reports consultancy for BMS, Celgene, Gilead, Janssen, MSD, Novartis, Sanofi, Takeda, and GSK; speakers bureau for Takeda; travel grants from BMS, Celgene, Janssen, Roche, Sanofi, and Takeda; research support from Takeda and BMS. Albert Oriol declares consultant activities from Amgen, Celgene, BMS, GSK, Janssen, and Sanofi. EMO reports consulting or an advisory role for Amgen, AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Menarini‐Stemline, Mundipharma, Oncopeptides, Sanofi, Secura Bio, and Takeda; meeting and/or travel expenses from Bristol Myers Squibb, GlaxoSmithKline, Janssen, Lilly, and Sanofi; and honoraria from Amgen, Asofarma, Bristol Myers Squibb, GlaxoSmithKline, Janssen, MSD, Pfizer, Sanofi, and Takeda. Joan Bargay: honoraria for lectures and advisory boards from Janssen, BMS‐Celgene, Amgen, Takeda, Oncopeptides. Juan J. Lahuerta: Consulting or Advisory Role: Celgene, Amgen, Janssen‐Cilag, Sanofi. Travel, Accommodations, Expenses: Celgene, Pfizer. Jesus F. San Miguel declares consulting activities from Abbvie, Amgen, BMS, Celgene, F. Hoffman‐La Roche, GSK, HaemaLogiX, KaryoPharm, Merck, Novartis, Pfizer, Regeneron, Sanofi‐Aventis, Takeda, and SecuraBio. Maria V. Mateos: honoraria for lectures and advisory boards from Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, Pfizer, Regeneron, Roche, Sanofi, Oncopeptides; The remaining authors declare no competing interests relative to this work., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Abstract: Quantitative immunoprecipitation 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 postinduction, transplant, consolidation and after 24 cycles of maintenance. At each time point, both NGF and QIP-MS were able to segregate 2 groups of patients with significantly different progression-free survival; 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 with sustaining or converting to MRD positivity. Reemergence of MRD by QIP-MS was associated with high risk of imminent clinical progression. In conclusion, MRD evaluation by NGF and MS achieves 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 highly sensitive response assessment in MM. The trials were registered at www.clinicaltrials.gov as #NCT01916252 (GEM2012MENOS65) and at EudraCT as #2012-005683-10; and as #NCT02406144 (GEM2014MAIN) and at EudraCT as 2014-00055410., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

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 next-generation flow cytometry (NGF) identified cases with a significantly shorter median progression-free survival (mPFS) (MS: not reached vs. 1.4 years, P=0.001; NGF: not reached vs. 2 years, P=0.0002) but reaching complete response (CR) + stringent CR (sCR) did not discriminate between 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 an mPFS not yet reached versus 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 International Myeloma Working Group do not seem to be useful for monitoring treatment in HRsMM patients; 2) MS could be used as a valuable, non-invasive, clinical 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 to identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (clinicaltrials.gov identifier: 02415413).

Information on the prognostic value of immunoparesis (IP) recovery in multiple myeloma (MM) patients has been only generated in some observational and retrospective studies. We have evaluated the prognostic impact of IP recovery and its association with minimal residual disease (MRD) in a series of 113 newly diagnosed transplant-ineligible (NDTI) patients, that received fix duration treatment (18 cycles of VMP/lenalidomide-dexamethasone) within the PETHEMA/GEM2010MAS65 trial and who achieved CR or VGPR. Immunoglobulin levels were measured at diagnosis, at the end of treatment (after cycle 18th) and during subsequent follow up whereas MRD was analyzed only at the end of the treatment (after cycle 18th). We found that patients who had IP at diagnosis and recovered it during or after treatment had longer progression free survival (PFS) [p < 0.001; HR 0.32 (0.19-0.52)] and longer overall survival (OS) [p = 0.007; HR 0.40 (0.20-0.80)] compared to those who failed to recover it. When we analyzed IP recovery in MRD negative patients, we found that those cases with IP recovery had longer PFS [p = 0.007; HR 0.31 (0.13-0.76)] and longer OS [p = 0.012; HR 0.21 (0.06-0.80)] as compared to MRD negative patients but without IP recovery. In conclusion, IP recovery confers better prognosis in NDTI-MM patients with fixed duration treatment who achieve CR or VGPR and the prognostic value of MRD can be complemented when combined with IP recovery., Competing Interests: Declarations. Ethical approval: The review board or independent ethics committee of each participating center approved the study. This trial was registered at www.clinicaltrials.gov with the number #NCT01237249. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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/m 2 ) 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.

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.

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with minimal residual disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA /GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next-generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression-free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (95% confidence interval [CI]: 0.21-0.81; P=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (95% CI: -0.04 to 0.14; P<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after 1 year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment (clinicaltrials gov. Identifiers: NCT01916252 and NCT02406144).

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting., (© 2024. The Author(s).)

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.

Abstract: The role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

From November 2014 to May 2017, 332 patients homogeneously treated with bortezomib, lenalidomide, and dexamethasone (VRD) induction, autologous stem cell transplant, and VRD consolidation were randomly assigned to receive maintenance therapy with lenalidomide and dexamethasone (RD; 161 patients) vs RD plus ixazomib (IRD; 171 patients). RD consisted of lenalidomide 15 mg/d from days 1 to 21 plus dexamethasone 20 mg/d on days 1 to 4 and 9 to 12 at 4-week intervals, whereas in the IRD arm, oral ixazomib at a dose of 4 mg on days 1, 8, and 15 was added. Therapy for patients with negative measurable residual disease (MRD) after 24 cycles was discontinued, whereas those who tested positive for MRD remained on maintenance with RD for 36 more cycles. After a median follow-up of 69 months from the initiation of maintenance, the progression-free survival (PFS) was similar in both arms, with a 6-year PFS rate of 61.3% and 55.6% for RD and IRD, respectively (hazard ratio, 1.136; 95% confidence interval, 0.809-1.603). After 2 years of maintenance, treatment was discontinued in 163 patients with negative MRD, whereas 63 patients with positive MRD continued with RD therapy. Maintenance discontinuation in patients tested negative for MRD resulted in a low progression rate (17.2% at 4 years), even in patients with high-risk features. In summary, our results show the efficacy of RD maintenance and support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years. This trial was registered at www.clinicaltrials.gov as #NCT02406144 and at EudraCT as 2014-00055410., (© 2023 by The American Society of Hematology.)

Objective: Providing the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM., Methods: An integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04)., Results: The primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (≥ VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the ≥ VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04)., Conclusion: These results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658)., Competing Interests: LR and JL report honoraria from Janssen; Celgene, a Bristol-Myers Squibb Company; Takeda; and Amgen. AO reports consultancy and speakers bureau with Amgen; Janssen; Takeda; and Celgene, a Bristol-Myers Squibb Company. RR reports consultancy with Amgen; Celgene, a Bristol-Myers Squibb Company; Janssen; and Takeda. CH reports honoraria from Celgene, a Bristol-Myers Squibb Company; Janssen; Takeda; and Amgen. AS reports honoraria from Bristol Myers Squibb, Takeda, Sanofi, Merck, and Roche; consultancy with Bristol Myers Squibb, Takeda, and Merck; and speakers bureau with Takeda. M-VM reports honoraria and membership on advisory boards with Janssen; Celgene, a Bristol-Myers Squibb Company; Amgen; Takeda; AbbVie; GlaxoSmithKline; EDO; PharmaMar; and Adaptive. MM reports honoraria, membership on advisory boards, and financial support with Celgene, a Bristol-Myers Squibb Company; Janssen; and Takeda and honoraria and membership on advisory boards with Amgen. JS-M reports consultancy with Bristol Myers Squibb; Celgene, a Bristol-Myers Squibb Company; Novartis; Takeda; Amgen; MSD; Janssen; and Sanofi and membership on board of directors or advisory committees with Takeda. KB reports honoraria and consultancy with Celgene, a Bristol-Myers Squibb Company; Amgen; Janssen; and Takeda. MG reports employment with Celgene, a Bristol-Myers Squibb Company. JB reports honoraria from Janssen; Celgene, a Bristol-Myers Squibb Company; and Amgen. PM reports honoraria from Celgene, a Bristol-Myers Squibb Company; Janssen; Takeda; AbbVie; and Amgen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Celgene, a Bristol-Myers Squibb Company. Author MG was employed by the funder and involved in study design, collection, analysis, or interpretation of data and writing the article and deciding to submit the article for publication., (Copyright © 2023 Rosiñol, Hebraud, Oriol, Colin, Ríos Tamayo, Hulin, Blanchard, Caillot, Sureda, Hernández, Arnulf, Mateos, Macro, San-Miguel, Belhadj, Lahuerta, Garelik, Bladé and Moreau.)

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.

Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27 - and CD27 + T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations., (© 2023. Springer Nature Limited.)

Monoclonal gammopathies (MGs) are a wide range of diseases that may evolve or progress over time. Comorbidity plays a critical role in this setting. The co-occurrence of two MGs is not a rare event. The evidence on the association of systemic light chain (AL) amyloidosis and multiple myeloma (MM) is scarce and controversial. Herein we aim to address this topic in a large series of patients of a referral center. All consecutive AL amyloidosis patients treated at our center from January 2005 to April 2023 were prospectively enrolled in a clinical and epidemiological registry. 141 patients diagnosed with AL amyloidosis were included, of which 7 (5%) had localized whereas 134 presented with systemic disease. The heart was the most frequently affected organ (90.3%). 25 patients (18.7%) fulfilled the IMWG diagnostic criteria of MM (AL/MM). Time-dependent association between AL and MM showed that the synchronous pattern is more frequent than the appearance of a second primary malignancy. The diagnostic delay was six months (m). Patients with AL/MM had a poorer median overall survival (OS) than AL-only patients (35.5 m, CI 95% 0-88.9, vs. 52.6 m, CI 95% 16.7-88.5), but this difference was not statistically significant. The prognosis in AL is dominated by the heart involvement, which is massive in this series. In our Cox regression model, only three prognostic variables remain as independent prognostic factors: age, N-terminal pro-brain natriuretic peptide (≥8500 ng/L), and undergoing an autologous stem cell transplant, whereas left ventricular ejection fraction shows a marginal effect. More and large studies focusing on the AL/MM association are needed to uncover the characteristics and prognostic impact of this association.

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.

Much attention has been paid to the health benefits of including fruits and vegetables in the diet. However, for the compounds responsible for this beneficial effect to be effective at the level of the human organism, they must be available for absorption after digestion. In this sense, in vivo studies are needed to demonstrate the bioavailability of these compounds and their physiological activity. In order to provide information in this regard, this study collects data on the levels of vitamin C (VC) and naringenin (NAG) in the blood serum of the 11 volunteer participants in this trial, before and after consuming two different grapefruit juices. The juices were prepared by rehydrating the grapefruit powder obtained by freeze-drying (FD) the fruit puree or by spray-drying (SD) the liquefied grapefruit. No significant differences ( p > 0.05) neither by juice nor by participant were observed in any case. The mean relative increase of VC, NAG and the radical scavenging ability (RSA) in blood serum due to grapefruit juices intake was 12%, 28% and 26%, respectively. Just VC showed a positive and significant Pearson's correlation with RSA. The mean bioavailability of VC was quantified as 1.529 ± 0.002 mg VC/L serum per 100 mg of VC ingested., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Despite a lack of evidence, a bone marrow aspirate differential of 500 cells is commonly used in the clinical setting. We aimed to test the performance of 200-cell counts for daily hematological workup. In total, 660 consecutive samples were analyzed recording differentials at 200 and 500 cells. Additionally, immunophenotype results and preanalytical issues were also evaluated. Clinical and statistical differences between both cutoffs and both methods were checked. An independent control group of 122 patients was included. All comparisons between both cutoffs and both methods for all relevant types of cells did not show statistically significant differences. No significant diagnostic discrepancies were demonstrated in the contingency table analysis. This is a real-life study, and some limitations may be pointed out, such as a different sample sizes according to the type of cell in the immunophenotype analysis, the lack of standardization of some preanalytical events, and the relatively small sample size of the control group. The comparisons of differentials by morphology on 200 and 500 cells, as well as by morphology (both cutoffs) and by immunophenotype, are equivalent from the clinical and statistical point of view. The preanalytical issues play a critical role in the assessment of bone marrow aspirate samples.

The reuse of food by-products is crucial for the well-being of the planet. Considering the high content of nutrients and other bioactive compounds in many of them, investigating their suitability for use as human food ingredients is an interesting challenge. In this study, in addition to the proximate composition, phenol content and antioxidant activity (AOA = 3.2 mmol Trolox equivalent (TE)/100 g, db) of orange juice powder by-product (CoP), different in vitro properties related to carbohydrate metabolism have been characterised. Specifically, the glycaemic index (GI), the glycaemic load (GL), the glucose dialysis retardation index (GDRI = 13.6%), the glucose adsorption capacity (GAC = 22.5 mM) and the inhibition capacity of α-amylase (α-A = 46.9%) and α-glucosidase (α-G = 93.3%) of powdered orange juice waste have been determined and related to fibre and phenolics composition. Taking advantage of the high fibre content of the by-product (36.67%), its GL was calculated for a CoP dose that allows labelling the food to which it is added as a source of fibre. The low GI value (24.4%) and the low GL (0.918 g available carbohydrates per serving) allowed us to conclude that the product studied could be an interesting opportunity for the food industry to offer it as a healthy food ingredient to be included in the diet, especially for those suffering from type 2 diabetes mellitus. Of the total phenolic compounds (TP = 509 mg equivalent of gallic acid (GAE)/100 g, db), 68% were found in free fraction (FP), and their contribution to the total AOA was 40.6%, while this was 54.9% for the 32% of phenols bound to plant tissues (BP).

Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged.

Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival ( p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes ( p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients.

Purpose: Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+., Patients and Methods: The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated., Results: In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value., Conclusion: The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.

Background: Smoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation., Methods: The QuiRedex phase 3 trial initiated in 2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363)., Findings: After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18-0.44, p &lt; 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96)., Interpretation: This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS., Funding: Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined., Patients and Methods: CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment., Results: CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS., Conclusion: Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.

Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC])., Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a "resistance" parameter that reflects the stagnation in the response after an initial descent., Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P = .02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P = .02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P < .002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics., Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Monitoring of the monoclonal protein (M-protein) by electrophoresis and/or immunofixation (IFE) has long been used to assess treatment response in multiple myeloma (MM). However, with the use of highly effective therapies, the M-protein becomes frequently undetectable, and more sensitive methods had to be explored. We applied IFE and mass spectrometry (EXENT&FLC-MS) in serum samples from newly diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 obtained at baseline (n = 223), and after induction (n = 183), autologous stem cell transplantation (n = 173), and consolidation (n = 173). At baseline, the isotypes identified with both methods fully matched in 82.1% of samples; in the rest but 2 cases, EXENT&FLC-MS provided additional information to IFE with regards to the M-protein(s). Overall, the results of EXENT&FLC-MS and IFE were concordant in >80% of cases, being most discordances due to EXENT&FLC-MS+ but IFE- cases. After consolidation, IFE was not able to discriminate 2 cohorts with different median progression-free survival (PFS), but EXENT&FLC-MS did so; furthermore, among IFE- patients, EXENT&FLC-MS identified 2 groups with significantly different median PFS (P = .0008). In conclusion, compared with IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients' outcome. This trial was registered at www.clinicaltrials.gov as #NCT01916252., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma., Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial., Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years., Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma. See related commentary by Pawlyn and Davies, p. 2482., (©2022 American Association for Cancer Research.)

Loss and/or mutation of the TP53 gene are associated with short survival in multiple myeloma, but the p53 landscape goes far beyond. At least 12 p53 protein isoforms have been identified as a result of a combination of alternative splicing, alternative promoters and/or alternative transcription site starts, which are grouped as α, β, γ, from transactivation domain (TA), long, and short isoforms. Nowadays, there are no studies evaluating the expression of p53 isoforms and its clinical relevance in multiple myeloma (MM). We used capillary nanoimmunoassay to quantify the expression of p53 protein isoforms in CD138-purified samples from 156 patients with newly diagnosed MM who were treated as part of the PETHEMA/GEM2012 clinical trial and investigated their prognostic impact. Quantitative real-time polymerase chain reaction was used to corroborate the results at RNA levels. Low and high levels of expression of short and TAp53β/γ isoforms, respectively, were associated with adverse prognosis in MM patients. Multivariate Cox models identified high levels of TAp53β/γ (hazard ratio [HR], 4.49; p < .001) and high-risk cytogenetics (HR, 2.69; p < .001) as independent prognostic factors associated with shorter time to progression. The current cytogenetic-risk classification was notably improved when expression levels of p53 protein isoforms were incorporated, whereby high-risk MM expressing high levels of short isoforms had significantly longer survival than high-risk patients with low levels of these isoforms. This is the first study that demonstrates the prognostic value of p53 isoforms in MM patients, providing new insights on the role of p53 protein dysregulation in MM biology., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The International Staging System (ISS) and the Revised International Staging System (R-ISS) are commonly used prognostic scores in multiple myeloma (MM). These methods have significant gaps, particularly among intermediate-risk groups. The aim of this study was to improve risk stratification in newly diagnosed MM patients using data from three different trials developed by the Spanish Myeloma Group. For this, we applied an unsupervised machine learning clusterization technique on a set of clinical, biochemical and cytogenetic variables, and we identified two novel clusters of patients with significantly different survival. The prognostic precision of this clusterization was superior to those of ISS and R-ISS scores, and appeared to be particularly useful to improve risk stratification among R-ISS 2 patients. Additionally, patients assigned to the low-risk cluster in the GEM05 over 65 years trial had a significant survival benefit when treated with VMP as compared with VTD. In conclusion, we describe a simple prognostic model for newly diagnosed MM whose predictions are independent of the ISS and R-ISS scores. Notably, the model is particularly useful in order to re-classify R-ISS score 2 patients in 2 different prognostic subgroups. The combination of ISS, R-ISS and unsupervised machine learning clusterization brings a promising approximation to improve MM risk stratification., (© 2022. The Author(s).)

Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0-2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies., (© 2022. The Author(s).)

Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single-cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P = .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www.clinicaltrials.gov as #NCT01916252 and #NCT02406144., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alonso and Lahuerta.)

The increase in the number of therapeutic alternatives for both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients has widened the clinical scenario, leading to a level of complexity that no algorithm has been able to cover up to date. At present, this complexity increases due to the wide variety of clinical situations found in MM patients before they reach the status of relapsed/refractory disease. These different backgrounds may include primary refractoriness, early relapse after completion of first-line therapy with latest-generation agents, or very late relapse after chemotherapy or autologous transplantation. It is also important to bear in mind that many patient profiles are not fully represented in the main randomized clinical trials (RCT), and this further complicates treatment decision-making. In RRMM patients, the choice of previously unused drugs and the number and duration of previous therapeutic regimens until progression has a greater impact on treatment efficacy than the adverse biological characteristics of MM itself. In addition to proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and corticosteroids, a new generation of drugs such as XPO inhibitors, BCL-2 inhibitors, new alkylators and, above all, immunotherapy based on conjugated anti-BCMA antibodies and CAR-T cells, have been developed to fight RRMM. This comprehensive review addresses the fundamentals and controversies regarding RRMM, and discusses the main aspects of management and treatment. The basis for the clinical management of RRMM (complexity of clinical scenarios, key factors to consider before choosing an appropriate treatment, or when to treat), the arsenal of new drugs with no cross resistance with previously administered standard first line regimens (main phase 3 clinical trials), the future outlook including the usefulness of abandoned resources, together with the controversies surrounding the clinical management of RRMM patients will be reviewed in detail., (© 2021. The Author(s).)

Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies., (© 2021 by The American Society of Hematology.)

Background: Whereas, in most patients with multiple myeloma (MM), achieving undetectable MRD anticipates a favorable outcome, some others relapse shortly afterwards. Although one obvious explanation for this inconsistency is the use of nonrepresentative marrow samples due to hemodilution, there is no guidance on how to evaluate this issue., Methods: Since B-cell precursors, mast cells and nucleated red blood cells are normally absent in peripheral blood, we analyzed them in 1404 bone marrow (BM) aspirates obtained in numerous disease settings and in 85 healthy adults (HA)., Results: First, we confirmed the systematic detection of the three populations in HA, as well as the nonreduced numbers with aging. Pairwise comparisons between HA and MM patients grouped according to age and treatment showed significant variability, suggesting that hemodilution should be preferably evaluated with references obtained from patients treated with identical regimens. Leveraging the MRD results from 118 patients, we showed that a comparison with HA of similar age could also inform on potential hemodilution., Conclusions: Our study supports the routine assessment of BM cellularity to evaluate hemodilution, since reduced BM-specific cell types as compared to reference values (either treatment-specific or from HA if the former are unavailable) could indicate hemodilution and a false-negative MRD result.

Introduction: Treatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations., Patients and Methods: A real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy., Results: Overall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease., Conclusion: Our results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients., (Copyright © 2021. Published by Elsevier Inc.)

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.

Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252., (© 2021 by The American Society of Hematology.)

The search for biomarkers based on the mechanism of drug action has not been thoroughly addressed in the therapeutic approaches to multiple myeloma (MM), mainly because of the difficulty in analyzing proteins obtained from purified plasma cells. Here, we investigated the prognostic impact of the expression of 12 proteins involved in the mechanism of action of bortezomib, lenalidomide, and dexamethasone (VRD), quantified by capillary nanoimmunoassay, in CD138-purified samples from 174 patients with newly diagnosed MM treated according to the PETHEMA/GEM2012 study. A high level of expression of 3 out of 5 proteasome components tested (PSMD1, PSMD4, and PSMD10) negatively influenced survival. The 5 analyzed proteins involved in lenalidomide's mode of action were associated with time to progression (TTP); low levels of cereblon and IRF4 protein and high levels of Ikaros, AGO2, and Aiolos were significantly associated with shorter TTP. Although the glucocorticoid receptor (GCR) level by itself had no significant impact on MM prognosis, a high XPO1 (exportin 1)/GCR ratio was associated with shorter TTP and progression-free survival (PFS). The multivariate Cox model identified high levels of PSMD10 (hazard ratio [HR] TTP, 3.49; P = .036; HR PFS, 5.33; P = .004) and Ikaros (HR TTP, 3.01, P = .014; HR PFS, 2.57; P = .028), and low levels of IRF4 protein expression (HR TTP, 0.33; P = .004; HR PFS, 0.35; P = .004) along with high-risk cytogenetics (HR TTP, 3.13; P < .001; HR PFS, 2.69; P = .002), as independently associated with shorter TTP and PFS. These results highlight the value of assessing proteins related to the mechanism of action of drugs used in MM for predicting treatment outcome., (© 2020 by The American Society of Hematology.)

PD1 expression in CD4 + and CD8 + T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8 + effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.

Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile.