ABSTRACT:In retrospective studies, autologous stem cell transplantation (ASCT) conditioning with intravenous busulfan and melphalan (BUMEL) led to longer progression-free survival (PFS) than melphalan alone (MEL200). We compared long-term outcomes of BUMEL vs MEL200 in the context of intensified bortezomib, lenalidomide, and dexamethasone (VRD) induction and consolidation therapies. GEM12 was a phase 3 trial for patients with newly diagnosed multiple myeloma (NDMM) eligible for ASCT including 6 reinforced VRD cycles followed by ASCT conditioned with BUMEL or MEL200 and 2 VRD consolidation cycles. The primary end point was PFS. Subgroup analyses were based on International Staging System (ISS) stages and high-risk genetic abnormalities. Patients were randomized with an open-label 2 × 2 factorial design and 1:1:1:1 allocation ratio to ensure the balance between the GEM12 and the subsequent phase 3 GEM14 trial. Between 2013 and 2015, 458 patients were randomized (BUMEL, n = 230; MEL200, n = 228). The 10⁻⁶ MRD-negative rate was 63%, 68% for BUMEL vs 58% for MEL200 (odds ratio, 1.51; P = .035). The median PFS was 89 months for BUMEL and 73.1 for MEL200 (hazard ratio, 0.89 [95% confidence interval, 0.70-1.14]; P = .3). BUMEL showed benefit for patients with ISS stages II or III, t(14;16), and del(1p). For subcohorts ISS stages II or III treated with BUMEL and ISS I treated with MEL200 the median PFS was 96.5 months (95% confidence interval, 76 to not estimable). No safety concerns were observed. After a median follow-up of 8.4 years, GEM2012 demonstrated one of the longest PFS values reported in patients with NDMM, with significant differences favoring BUMEL in advanced ISS stages. The trial was registered at www.ClinicalTrials.gov as #NCT01916252 and at European Union Drug Regulating Authorities Clinical Trials as EudraCT 2012-005683-10.

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.

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.

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.

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).

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.

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.

Introduction. Immunoparesis (IP) or the suppression of uninvolved immunoglobulins (Ig) is a very common finding in multiple myeloma (MM) patients at diagnosis that confers worse prognosis. In addition to classic total Ig, IP can be measured by the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC). Previously, we have reported that recovery of uHLC IP in a single time point (at first year of maintenance) is an independent prognostic factor in newly diagnosed MM transplant eligible (NDMM-TE) patients with intensive treatment within a clinical trial, without significant prognostic value for recovery from classic IP in that setting. Moreover, recovery of uHLC IP affords complementary information to single time point minimal residual disease (MRD) for risk stratification. Although, negative sustained MRD is the most important evolutive favorable prognostic factor in MM, some patients relapse despite achieving negative sustained MRD. Aim. To evaluate the prognostic value of sustained uHLC IP recovery during maintenance treatment, measured by progression free survival (PFS), within a clinical trial of NDMM TE patients with intensive treatment and its potential association with sustained MRD. Patients & Methods. Patients with newly diagnosed MM enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycle VRD-GEM induction, autologous hematopoietic stem cell transplantation conditioned by melphalan or busulfan plus melphalan and consolidation with two more cycles of VRD-GEM. Afterwards, patients were enrolled in the PETHEMA/GEM2014MAIN clinical trial that randomly assigned them to maintenance with lenalidomide and low-dose dexamethasone (Rd) or Rd plus ixazomib for two years. After two years, patients who achieved negative MRD stopped the treatment and patients who did not achieve MRD negativity received three more years of Rd. We analyzed uHLC in a central laboratory at diagnosis and at the first and second year of maintenance. We consider IP at diagnosis when uHLC were under lower limit of normality (LLN) and recover IP when suppressed uHLC at diagnosis reach at least LLN plus 10%. Sustained uHLC IP recovery was defined as IP recovery in the first year of maintenance that persists in the second year of maintenance. MRD was analyzed by next generation flow cytometry (sensitivity level 2x10 -6) after consolidation and at the first and second year of maintenance. Sustained MRD was defined as a negative MRD for at least 12 months that remains negative at the second year of maintenance. In the PETHEMA/GEM2012MENOS65 trial, 458 patients were included of which 332 patients entered the PETHEMA/GEM2014MAIN clinical trial. We included in this study 137 patients, those who reached the second year of maintenance without relapse and had samples available at any of the three time points for the uHLC analysis. Results. We found uHLC IP in 93.7% of patients (119/127) at diagnosis, 28.1% of patients (34/121) at first year of maintenance and 46.8% of patients (51/109) at second year of maintenance. After the second year of maintenance, we found recovery from uHLC IP present at diagnosis in 48.4% of patients (46/95). Patients that recovered from uHLC IP after second year of maintenance had better PFS (p=0.015) with hazard ratio (HR) 0.27 (CI95% 0.09 - 0.84). Patients with sustained recovery from uHLC IP had better prognosis than patients without recovery at first year of maintenance [p=0.010; HR 0.16 (CI95% 0.03 - 0.78)] and patients with IP recovery at first year who lose it at second year of maintenance [p=0.002: HR 0.12 (CI95% 0.02 - 0.59)] ( Figure 1). Only five patients without recovery at first year had uHLC IP recovery at second year of maintenance, but with similar PFS than patients without recovery at both time points (p=0.441). Sustained negative MRD for at least 12 months was present in 87/136 (64%) of patients, however we had data of IP recovery evolution in only 54 of these patients, of which 28 had sustained IP recovery. Patients with sustained negative MRD and sustained IP recovery had longer PFS than patients with sustained negative MRD without sustained IP recovery [p=0.025; HR 0.13 (CI95% 0.02 - 0.98)] ( Figure 2). Conclusions. Sustained recovery of uHLC IP during maintenance in NDMM-TE patients with intensive treatment is a prognostic factor complementary to sustained negative MRD. Combination of both factors identify patients with very good prognosis.

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.

Key Points EXENT&FLC-MS is more sensitive than IFE in detecting the M-protein of MM patients in serum, both at baseline and during treatment monitoring. EXENT&FLC-MS is more accurate than IFE to predict patients’ outcome.

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.

IntroductionResponse 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 MethodsWe 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.ResultsTwo 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.ConclusionThis 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.

Abstract: These proceedings from the First Gulf Cardiac Amyloidosis Summit held in June 2021 aimed to increase awareness of cardiac amyloidosis among the wider medical community in the region. Although the clinical presentation of cardiac amyloidosis is highly variable, a number of ‘red flags’ have been identified to raise suspicion of the disease and prompt further investigation. Accurate diagnosis of cardiac amyloidosis is challenging and relies on the integration of clinical, imaging and laboratory investigations. Recent imaging techniques, including bone scintigraphy together with a complete serum and urine workup, allow, in the majority of patients, accurate non-invasive diagnosis without the need for confirmatory endomyocardial biopsies. Early differential diagnosis between light-chain (AL) amyloidosis and amyloid transthyretin amyloidosis (ATTR) is critical for timely delivery of appropriate therapy. AL amyloidosis is a medical emergency requiring chemotherapy and supportive care. Treatment for ATTR-amyloidosis is most effective when administered early, before development of significant symptoms or cardiac dysfunction. Optimal management of patients involves close collaboration between multidisciplinary specialists, which may include hematologists, cardiologists, and other subspecialists, ideally at a designated specialty center with interest and expertise in amyloidosis.

Belantamab mafodotin (BM) is a new anti-BCMA antibody–drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP). We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs). Thirty-three patients were included with a median of 70 years of age (range, 46–79 years). Median time from diagnosis was 71 months (range, 10–858 months). Median prior lines was 5 (range, 3–8 lines); 90

Introduction: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with multiple myeloma (MM). Up to 10% of them may develop a thrombotic complication, being the risk higher during the first year of diagnosis. Currently, the use of thromboprophylaxis is based on risk scales according to logistic regression that generally are not validated and present modest predictive values. Machine learning (ML) algorithms identifies patterns that help us predict risk factors in a given disease. Numerous studies have shown that ML improves outcome prediction over traditional multivariate analysis models. To optimize VTE management in MM patients, thrombotic risk assessment models (RAM) will be generated in order to predict VTE development in MM patients (VTE-MM). To test our objective, we retrospectively analyzed a total of 133 patients with MM from 5 Spanish hospitals between January 2014 and December 2018. MM cohort was enriched with a total of 45 VTE patients in order to help machine learning algorithms and solving the imbalance problem. To build our predictive models, 131 clinical and biological variables were included. Variables with more than 25% of missing data were removed. Feature pre-filtering was carried out using unsupervised Boruta algorithm. Subsequently, the supervised Artifitial Neural Network (ANN) algorithm (80% training and 20% test) was applied on an input layer of 10 dimensions. To evaluate our ML model, we performed 10-fold cross validation. A confusion matrix was also used in the testing sets to evaluate the accuracy of the model. Parallelly, a univariate logistic regression (ULR) analysis was performed to identify significant variables (P<0.05) to entering into a multiple logistic regression (MLR) model. To determine a score for each independent variable, we used beta coefficients. The model was validated and evaluated applying leave-one-out method and ROC curve respectively. All analyses were carried out in R 3.6.3 and SPSS 26.0. Among VTE-MM (median age 67y, RIQ=60-74), 53% were men, mostly with ECOG >1, BMI 28 kg/m2 (RIQ 24-32), 53% had IgG and 45% of VTE-MM had revised international staging system (R-ISS) high at diagnosis. PE was the most frequent event (55%), occurring after diagnosis or 1st line of treatment. (Table 1). Boruta significantly selected 10 features (Fig.1A) and ANN algorithm demonstrated an AUC of 0.82 (Fig.1B and 1C). ML model selected young patients with previous surgeries, CVC before VTE, acute infections and with a high R-ISS as risk predictor factors. Multivariate-derived model were constructed with 8 ULR-derived variables (Fig 1D) and showed an AUC of 0.82 (Fig 1E). MLR model highlighted age (> 65y) as a protective factor (score of -4, CI: 0.003-0.308) (Fig 1D). Deep analysis of this group showed women as the higher risk patients (p=0.02). Conclusion: Both RAM models are good predictors of VTE in MM. They share 4 variables. Among them, young adult MM women seem to have more risk to develop VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction. Immunoparesis (IP) is defined as the suppression of uninvolved immunoglobulins (Ig) and is a very frequent finding in multiple myeloma (MM) patients at diagnosis. The classical and most common way to measure it is by nephelometry of other immunoglobulins (classic IP), but also in recent years we can measure the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC). Recovery of classic IP have been reported as a good prognosis factor in some studies, but these are observational retrospective works with non-homogeneous treatment and most of them with a non-continuous treatment. Recovery of uHLC IP have not been correctly studied as far as we know. Minimal residual disease (MRD) has become in the last years probably the most important prognosis factor during evolution. Aim. Evaluate the prognostic value of IP recovery by classic Ig and uHLC, in terms of progression free survival (PFS), within a clinical trial of newly diagnosed MM transplant-eligible (NDMM TE) patients with intensive continuous treatment and evaluate the association with MRD. Patients & Methods. Patients with newly diagnosed MM enrolled in the PETHEMA/GEM2012MENOS65 trial received six cycle VRD-GEM induction, autologous hematopoietic stem cell transplantation conditioned by melphalan or busulfan plus melphalan and consolidation with two more cycles of VRD-GEM. Afterward, patients were enrolled in the PETHEMA/GEM2014MAIN clinical trial that randomly assigned them to maintenance with lenalidomide and low-dose dexamethasone (Rd) or Rd plus ixazomib. We analyze classic Ig and uHLC in a centralized laboratory at diagnosis, after consolidation treatment and at the first year of maintenance. We consider IP at diagnosis when one or more uninvolved classic Ig or uHLC were under lower limit of normality (LLN) and Recover IP when one or all classic Ig who were suppressed at diagnosis or suppressed uHLC at diagnosis reach at least LLN plus 10%. MRD was analyzed by next generation flow cytometry after consolidation (sensitivity level ≥10-5). High risk cytogenetics was defined as del17p, t(4;14), t(14;16) and/or +1q21. We included in this study 245 patients with samples available at any of the three time points for the analysis. Results. At diagnosis we found classic IP in 86,7% of patients (203/234) and uHLC IP in 94,5% of patients (191/202). No difference in PFS was found between patients with or without IP at diagnosis for both methods. After consolidation we found recovery of classic IP in 42,4% of patients (87/205) and recovery of uHLC in 49,2% of patients (89/181). We also found no differences in PFS between patients who recover or not recover IP for both methods. After the first year of maintenance, we found recovery of classic IP in 53,8% (77/143) and recovery of uHLC in 63,2% of patients (84/133). We found no differences for recovery of classic IP, but patients with recovery of uHLC IP after one year of maintenance had better PFS (p=0,008) with hazard ratio 0,42 (Figure 1A). When we include recover uHLC IP with MRD after consolidation and high-risk cytogenetics at diagnosis in a multivariate analysis for PFS we confirm that all three variables maintain their independent prognosis value for PFS. We stratified patients in three categories according to post-consolidation MRD status and uHLC recovery after one year of maintenance. As we can see in Figure 1B patients with both favorable factors (MRD negative and recover IP) had better PFS (p=0,001) than patients with both unfavorable factors (MRD positive and no recover IP). Patients with only one favorable factor (MRD negative or recover IP) seems to have an intermediate risk status but differences within the other groups were not statistically significative (p=0,091 and p=0,054 respectively). Conclusions. Recovery of uHLC IP after one year of maintenance is an independent prognostic factor for PFS in NDMM TE patients and intensive continuous treatment. Classic Ig are less sensitive than uHLC for measure immune reconstitution in this scenario. Immune reconstitution, measured as recovery of uHLC IP, may provide complementary prognostic value to MRD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal