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PETHEMA/GEM Cooperative Group., 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.

[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%., [Conclusions] The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.

Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n = 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P = .65), and 3-year overall survival (72% vs 74%, P = .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Background: Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus lowdose dexamethasone (Rd) are standards of care for elderly untreated multiple myeloma patients. Methods: We did a phase 2b, parallel-group, multicentre, open-label randomised trial at 44 hospitals in Spain. We randomly assigned 242 patients (1:1) to receive 9 cycles of VMP followed by 9 cycles of Rd or alternating cycles of VMP and Rd for 18 cycles. The primary endpoints were 18-month progression-free survival and safety profile, which were similar between arms at an initial analysis after a median follow-up of 30·3 months. We did an updated pooled analysis of progression-free and overall survival, overall and by age, cytogenetic risk and minimal residual disease status. Findings: After a median follow-up of 51 months, the median progression-free survival and overall survival were 31·2 and 63·5 months, respectively. The median progression-free survival was 33, 32, and 24 months for patients aged 65-75, 75-80, and >80 years, respectively, (p=0·017); median overall survival was not reached vs 57 vs 33 months (p

This study was supported by the Cooperative Research Thematic Network grant RD12/0036/0061 of the Red de Cancer (Cancer Network of Excellence RTICC); the Subdireccion General de Investigacion Sanitaria (Instituto de Salud Carlos III, Spain) grants PI15/02062 and PI15/01484; the CRIS against Cancer foundation grant 2014/0120; Joan Rodes grant (JR 14/00016); and Undergraduate Fellowship IFI14/00008.

On behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group., [Purpose]: 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 MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative 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., Supported by the Centro de Investigación Biomédica en Red – Area de Oncologia - del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369; CB16/12/00400; CB16/12/00233; CB16/12/00284), formerly named as Cooperative Research Thematic Network (Grants No. RD12/0036/0058, RD12/0036/0048, RD12/0036/0046, and RD12/0036/0061) of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria; funded in part by the European Regional Development Fund (FIS No. 98/1239, 00/10160, 01/0089, 02/0089, 02/0905, G03/136, PI051284, PI06033906/1354, PS09/01897/01370, PI12/01761, PI12/02311, PI13/01469, PI14/01867, G03/136); Sara Borrell (No. CD13/00340); Asociación Española Contra el Cáncer (No. GCB120981SAN); and Federación Española de Enfermedades Raras. Also supported internationally by the Black Swan Research Initiative of the International Myeloma Foundation and the European Research Council 2015 Starting Grant (MYELOMANEXT).

Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

Summary Background Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. Methods Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m 2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m 2 on days 1–4) or daily thalidomide (100 mg), and prednisone (60 mg/m 2 on days 1–4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m 2 on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m 2 on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235. Findings In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. Interpretation Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).

Abstract 309 Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. DNA ploidy is another important prognostic factor with non-hyperdiploid cases being associated with a poor outcome. There are some controversies about whether or not bortezomib-based combinations are able to overcome the poor prognosis of CA. In the VISTA trial, bortezomib plus melphalan and prednisone (VMP) appeared to overcome the poor prognosis of CA in terms of response rate (RR) and survival; however, the number of patients with CA was rather small. Here we report a subanalysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM05MAS65 trial, in order to evaluate the influence of CA by FISH as well as DNA ploidy status on RR and survival. Patients and methods: Patients included in this study were randomized to receive 6 cycles of VMP vs bortezomib, thalidomide and prednisone (VTP) as induction therapy consisting on one 6-week cycle of bortezomib using a bi-weekly schedule (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32) plus either melphalan 9 mg/ m2 on days 1 to 4 or oral daily thalidomide 100 mg, and prednisone 60 mg/ m2 on days 1 to 4; this first cycle was followed by five 5-week cycles of once-weekly bortezomib (1·3 mg/ m2 on days 1, 8, 15 and 22) plus the same doses of MP and TP. After induction therapy, patients were subsequently randomised to maintenance therapy with VP or VT, consisting of one convencional 3-week cycle of bortezomib (1·3 mg/ m2 on days 1, 4, 8 and 11) every 3 months, plus either prednisone 50 mg every other day or thalidomide 50 mg/day, for up to 3 years. FISH analysis for del(13q), t(11;14), t(4;14), t(14;16) and del(17p) was performed at diagnosis according to standard procedures using purified plasma cells, and DNA ploidy status was analysed following induction therapy by multiparametric FCM using propidium Iodide and specific markers for discrimination between myelomatous and normal cells. Result: In 231 out of the 260 patients included in the trial, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 44 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=187 patients without CA, and/or del(13q) and/or t(11;14)). There weren't differences in the rates of CA according to the treatment arm. RR was the same in the high-risk vs standard-risk groups, both after induction (21% vs 27% CR) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter PFS as compared to standard risk both from first (24 versus 33 months, p=0·04, HR 0·6, 95% IC 0·4-0·9) and second randomization (17 versus 27 months, p=0·01, HR 0·5, 95% IC 0·2-0·8). This also translated into shorter OS for high risk patients (3-year OS rate: 55% versus 77% from first randomization, p=0·001, HR 0·4, 95% IC 0·2-0·7) and 60% versus 85% from second randomization, p When we analyzed the influence on survival of the DNA ploidy status (224 patients) by comparing patients with hyperdiploid (132 patients) versus non-hyperdiploid DNA content (92 patients) assessed by FCM, it was found that the former group showed longer OS (77% versus 63% at 3 years, p=0·04), and this difference was more evident in patients treated with VTP (77% versus 53% at 3 years, p=0·02), while no significant differences were observed in the VMP arm. Conclusion: The present schema, particularly after month sixth (using maintenance with bortezomib every 3 months) doesn't overcome the negative prognosis of high-risk cytogenetics in terms of PFS and OS in elderly myeloma patients, and this applied to either patients with t(4;14) or del(17p), and it was independent of the induction treatment arm. Our data also show that non-hyperdiploid cases displayed worse outcome than hyperdiploid patients, particularly under VTP induction treatment. These results suggest that continuous efforts are still required in order to overcome the dismal prognosis of high-risk patients. Disclosures: Mateos: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: VTP is not approved for the treatment of elderly newly diagnosed myeloma patients. VT and VP are not approved for maintenance therapy. Gutierrez:Janssen Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen Cilag: Honoraria; Celgene: Honoraria. Martínez-López:Janssen Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. Hernández:Janssen Cilag: Honoraria. García-Sanz:Janssen Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen Cilag: Honoraria; Celgene: Honoraria.