The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day ؉100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n ‫؍‬ 140) and GEM2005 < 65y (n ‫؍‬ 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P ‫؍‬ .002) and persistent minimal residual disease by multiparameter flow cytometry at day ؉100 after HDT/ASCT (hazard ratio 8.0; P ‫؍‬ .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated. (Blood. 2012;119(3):687-691) IntroductionThe incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents in the treatment of young patients with multiple myeloma (MM) has markedly improved the achievement of complete response (CR). 1,2 There are now extensive data in the setting of HDT/ASCT showing that achievement of CR is associated with prolonged survival. 3 Although this is well accepted, the long-term clinical outcome of MM patients who achieve CR is still heterogeneous, 4 and 2 important observations must be made: (1) some patients who revert to a monoclonal gammopathy of undetermined significance (MGUS) stage after therapy experience similar prolonged survival as patients in CR 5 ; and (2) a small fraction of patients unexpectedly lose their CR status during the first year after HDT/ASCT and experience a dismal survival rate. 6,7 In fact, survival of patients with unsustained CR is even poorer than for those not achieving CR. 6,7 Herein, we sought to identify prognostic markers predictive of unsustained CR after HDT/ASCT. MethodsThe study included 241 MM patients diagnosed according to International Myeloma Working Group criteria. 8 Patients were included in 2 consecutive PETHEMA/GEM (Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma) trials: GEM2000 (VBMCP [vincristine, carmustine, melphalan, cyclophosphamide, and prednisone]/VBAD [vincristine, carmustine, doxorubicin, and dexamethasone] followed by HDT/ASCT and 2 years of maintenance with interferon and prednisone; n ϭ 140) and GEM2005 Ͻ 65y (randomized induction with the same chemotherapy plus bortezomib in the last 2 cycles or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT, and 3 years of maintenance with interferon-␣2b or thalidomide or thalidomide/bortezomib; n ϭ 101). All case subjects were in CR at day ϩ100 after HDT/ASCT, def...

PURPOSE Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10−6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial. RESULTS Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%. CONCLUSION The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Juan-Jose Lahuerta AbstractPurpose-To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM).Patients and Methods-Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months.Results-Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRDnegative rates after different induction regimens anticipated prolonged PFS. Among 34 MRDnegative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%.Conclusion-Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.