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...

One hundred ten patients with multiple myeloma (MM) failing to achieve at least nearcomplete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)-identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P ‫؍‬ .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P ‫؍‬ .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantationrelated mortality (16% vs 5%, P ‫؍‬ .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. IntroductionAutologous stem cell transplantation (ASCT) has become the standard of care in the up-front therapy for younger patients with multiple myeloma (MM). [1][2][3] In 2 randomized trials, double ASCT was superior to a single transplantation in patients failing to achieve complete remission (CR) or very good partial response after the first transplantation. 4,5 However, despite tandem ASCT, patients continue to relapse and there is no survival plateau. Allogeneic stem cell transplantation is the best potential curative approach. 6,7 However, a transplantation-related mortality (TRM) rate of 30% to 50% constitutes its major limitation. [6][7][8] The use of dose-reduced intensity conditioning (allo-RIC) has reduced the TRM to 10% to 20%. 9-15 Interestingly, promising results with autograft followed by an allo-RIC have been reported. 11,13 However, only 2 trials comparing the efficacy of double ASCT versus a single autograft followed by an allo-RIC have been published and they show contradictory results. 14,15 We report the results achieved with a second ASCT versus allo-RIC in chemosensitive patients failing to achieve CR or near-complete remission (nCR) after a first ASCT. Methods Patients and treatment planPatients diagnosed with symptomatic MM between October 1, 1999, and December 31, 2004, who were younger than 70 years were included in the Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM)-2000 trial. They received 6 cycles of vincristine, carmustine (BCNU), melphalan, cyclophosphamide, prednisone (VBMCP)/vincristine, BCNU, adriamycin, dexamethasone (VBAD) chemotherapy 16 followed by a first ASCT. Patients failing to achieve CR or nCR (ie, persistence of a serum or urine M-protein on the electrophoretic pattern) were scheduled to receive either a secondASCT conditioned with CVB (cyclophosphamide, etoposide, BCNU) or melphalan (MEL)-200 or an allo-RIC conditioned with fludarabine 2...

Key PointsVRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.

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.