Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P ‫؍‬ .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD ؊ immunofixation-negative (IFx ؊ ) patients and MRD ؊ IFx ؉ patients had significantly longer PFS than MRD ؉ IFx ؊ patients. Multivariate analysis identified MRD status by MFC at day 100 after ASCT as the most important independent prognostic factor for PFS (HR ‫؍‬ 3.64, P ‫؍‬ . IntroductionIn most hematologic malignancies, response to front-line therapy is a good predictor of prognosis, with the longest survival seen in patients achieving an optimal response. This paradigm is represented by chronic myeloid leukemia (CML), in which hematologic, cytogenetic, and molecular remissions define progressively better response to therapy. In consequence, investigations to define these levels of remission are mandatory in routine clinical practice for treatment stratification and assessment of prognosis. 1 The situation is similar for other malignancies such as acute promyelocytic leukemia (APL) or acute lymphoblastic leukemia (ALL). 2,3 For this reason, there are continuous efforts to improve the sensitivity of the methods used to assess response to therapy, mainly through the introduction and refinement of both molecular and immunophenotyping approaches, as well as imaging techniques.Multiple myeloma (MM) should be no exception to this paradigm. For many years, the major goal of MM therapy was to achieve partial response (PR) or disease stabilization. 4,5 With the introduction of high-dose therapy plus autologous stem cell transplantation (HDT/ASCT), the new goal became the achievement of complete response (CR), defined as absence of M-protein by immunofixation (IFx) and less than 5% plasma cells (PCs) in bone marrow (BM). 6,7 More recently, the International Myeloma Working Group proposed a new response category of "stringent CR," which requires normalization of the free light chain ratio and the absence of residual clonal cells in the BM by immunohistochemistry or immunofluorescence. 8 As noted previously, the assessment of minimal residual disease (MRD), residual tumor cells persisting after therapy, is part of the standard of care in many hematologic malignancies, whereas in MM this is still considered investigational. Thus, MRD studies in MM have involved mainly small series of patients or have...

In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P ‫؍‬ .004) or with VBMCP/ VBAD/B (46% vs 38%, P ‫؍‬ .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher preand posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no.

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.

To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression.