Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 https://doi.org/10.1038/s41408-019-0176-x Blood Cancer Journal ARTICLE Open Access Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature Paula Rodríguez-Otero1, María Victoria Mateos2, Joaquín Martínez-López3, Miguel-Teodoro Hernández4, Enrique M. Ocio2, Laura Rosiñol5, Rafael Martínez6, Ana-Isabel Teruel7, Norma C. Gutiérrez2, Joan Bargay8, Enrique Bengoechea9, Yolanda González10, Jaime Pérez de Oteyza11, Mercedes Gironella12, Jorge M. Nuñez-Córdoba13, Cristina Encinas14, Jesús Martín15, Carmen Cabrera16, Luis Palomera17, Felipe de Arriba18, María Teresa Cedena3, Noemí Puig2, Albert Oriol19, Bruno Paiva1, Joan Bladé6, Juan José Lahuerta4 and Jesús F. San Miguel1 Abstract Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post- treatment biomarkers helpful in predicting the likelihood of disease control at 5 years. Introduction unprecedent rates (10–40%) of 10-year overall survival Treatment of multiple myeloma (MM) has significantly (OS)2–4; the percentage of elderly patients reaching dis- improved in the last decade but the outcome remain ease control at 5 years and the characteristics of such significantly poorer in elderly patients1. Thus, while patients is less well established. Moreover, in the non- approximately 34–60% of transplant-eligible cases remain transplant-eligible population, definition of long-term progression free at 5 years2–4 and this has resulted in disease control could be different, since patients that are free from relapse beyond 5 years, could eventually die for reasons other than progressive disease. Thus, achieving Correspondence: Jesús F. San Miguel (sanmiguel@unav.es) 1 Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona, Spain disease control beyond 5 years would be a most relevant 2 Complejo Asistencial Universitario de Salamanca, Instituto de Investigación endpoint, since elderly patients usually have fewer options Biomédica de Salamanca, Salamanca, Spain for subsequent lines of therapy, and a prolonged first Full list of author information is available at the end of the article. These authors contributed equally: Paula Rodríguez-Otero, María Victoria Mateos © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 Page 2 of 6 response will translate not only into a longer survival but Patients and methods also in improved quality of life. Study design Several studies have searched for relevant prognostic Four hundred ninety-eight newly diagnosed elderly and factors associated with prolonged survival in elderly MM. symptomatic MM patients (aged 65 years or older) were Thus, in addition to a fit status, according to geriatric included in two prospective Spanish trials: GEM2005- assessment5, and absence of high-risk cytogenetic MAS65 and GEM2010MAS6519–22. Patients with a abnormalities (HR CAs)6, both the International Staging follow-up shorter than 5 years (n = 22) or who died System (ISS) and the Revised-ISS (R-ISS)7,8 clearly iden- without progression (n = 41) were censored from the tified that ISS 1 and R-ISS 1 patients enjoy a significantly analysis and, accordingly, 435 patients were evaluated in longer progression-free survival (PFS) and OS. Additional this post-hoc study. All patients were diagnosed according conventional factors such as normal hemoglobin (Hb), to the IMWG criteria23. Data cut-off was 20 February creatinine, and beta-2-microglobulin (B2M) levels, age 2018. All patients provided written informed consent below 80 years and normal lactate dehydrogenase (LDH) before screening. Data were monitored by an external levels, as well as, low percentage of S-phase bone marrow contract research organization and centrally re-assessed. (BM) plasma cells (PCs), have been identified as pre- Median follow-up was 92.6 months (range: dictors for longer PFS and OS9–11. Nevertheless, none of 0.3–132.9 months) and 61.7 (range: 1.6–81.1 months) for these studies have specifically focused on the identifica- the GEM2005MAS65 and the GEM2010MAS65 studies, tion of the characteristics of the patients' cohort that respectively. The endpoint of this study was defined as achieve a long-term disease control (PFS > 5 years). time to progression at 5 years or longer since diagnosis, in Depth of response is also associated with prolonged patients with a follow-up of at least 5 years. survival in elderly patients. Thus, complete response The GEM05MAS65 trial included 259 patients rando- (CR) defined by conventional criteria translates into mized to receive upfront induction treatment with either longer PFS and OS12–14. More recently, it has been bortezomib, melphalan, and prednisone (VMP), or bor- shown that the achievement of sustained minimal resi- tezomib, thalidomide, and prednisone (VTP)16. VMP dual disease negativity clearly predict for a longer PFS induction therapy consisted of six cycles: one cycle of and OS in non-transplant candidate patients15. How- intravenous bortezomib given twice per week for 6 weeks ever, there is a small subset of MM patients that despite (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus persistence of the disease enjoy long-term disease con- oral melphalan 9 mg/m2 and prednisone 60 mg/m2 on trol, underlying the need of new tools to identify these days 1–4, followed by five cycles of bortezomib once per long-term survivors. week for 5 weeks (1.3 mg/m2 on days 1, 8, 15, and 22) plus Interestingly, it has been reported that patients with a the same doses of melphalan and prednisone. VTP previous diagnosis of monoclonal gammopathy of induction therapy consisted of the same schedule of unknown significance (MGUS) or smoldering MM bortezomib and prednisone plus oral, continuous, thali- (SMM) have a more prolonged survival16. However, domide at a dose of 100 mg per day instead of melphalan. although it is well known that all MM evolve from a Patients from each arm completing the six induction prior MGUS, in most patients presenting with active cycles were then randomly assigned to maintenance disease no information on a previous MGUS-status is therapy with either bortezomib and thalidomide (VT) or available. Noteworthy, both the Arkansas17 and the bortezomib and prednisone (VP). Maintenance consisted Spanish groups18 have reported, by using gene expres- of one conventional cycle of bortezomib (1.3 mg/m2 on sion profiling (GEP) and multiparameter flow cytometry days 1, 4, 8, and 11) every 3 months, plus either oral (MFC) techniques, respectively, that an MGUS sig- prednisone (50 mg every other day) or oral thalidomide nature, associated with low-risk features and superior (50 mg per day), for up to 3 years. survival, can be identified in a fraction of patients with In the GEM010MAS65, 239 patients were randomly active MM. assigned 1:1 to receive both VMP and lenalidomide in Here, we evaluated a large series of 498 transplant- combination with low-dose dexamethasone (Rd) in a ineligible MM patients enrolled in two consecutive sequential or alternating manner, for 18 cycles17. VMP Spanish clinical trials, treated with first-generation novel therapy comprised nine cycles: one 6-week cycle of IV agent-based combinations and with mature follow-up. bortezomib using a conventional twice-weekly schedule Our aims were to (i) determine the percentage of elderly (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus patients with disease control at 5 years after treatment oral melphalan (9 mg/m2) and oral prednisone (60 mg/ initiation, (ii) analyze whether this translates into a sub- m2) on days 1–4, followed by eight 4-week cycles of once- stantial benefit in OS, and (iii) define an optimal set of weekly IV bortezomib (1.3 mg/m2 on days 1, 8, 15, and 22) biomarkers to estimate the odds of achieving disease plus the same doses of melphalan and prednisone. Rd control at 5 years. treatment consisted of nine cycles of oral lenalidomide Blood Cancer Journal Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 Page 3 of 6 25 mg daily on days 1–21 of each 28-day cycle plus oral In both models, the R-ISS was included instead of ISS, dexamethasone 40 mg weekly, on days 1, 8, 15, and 22. LDH, and HR CAs in order to avoid redundancy. A The following characteristics, documented at diagnosis, landmark analysis at 6 and 12 months has been performed were analyzed: age, gender, Hb, serum creatinine levels, including all patients. Crude survival analysis was assessed B2M, albumin, PC infiltration, LDH, type of monoclonal using log-rank test. Kaplan–Meier survival analysis was component, presence of urine light chains, extramedullary carried out for each group category. All statistical analyses disease, clinical staging according to the ISS and R-ISS, were carried out using Stata 12.1. plus chromosomal abnormalities defining high-risk patients: t(4;14) and/or t(14;16) and/or del(17p). Results In addition, an immunophenotypic algorithm to deter- The median PFS for the whole population included in mine if patients had MGUS-like vs MM-like profiles was the GEM05MAS65 and GEM2010MAS65 (n = 498) was used by comparing the relative frequency of BM PCs plus 31.4 month (95% confidence inerval (CI), 28.28–34.36), the percentage of clonal and normal PCs within the whole being 28.3 months (95% CI, 24.8–32.9) and 34.3 months BM PC compartment for each patient, plotted against a (95% CI, 29.6–39.1) in each trial, respectively. The median database containing information on the same three OS was 57.3 months (95% CI, 49.1–65.4), being parameters from a total of 1774 patients, including 497 51.6 months (95% CI, 42.9–61.1) and 68.2 months (95% MGUS and 1277 newly diagnosed MM enrolled in the CI, 49.1–NR) for patients included in the GEM05MAS65 GEM2000 (N = 486) plus GEM2005MENOS65 (N = 330) and GEM2010MAS65 trials, respectively. protocols for transplant-eligible cases, and the Four hundred thirty-five newly diagnosed transplant- GEM2005MENOS65 (N = 239) plus GEM2010MAS65 ineligible MM patients were analyzed in this post-hoc (N = 222) protocols for transplant-ineligible patients. study. Eighty-one out of 435 patients (18.6%) were alive Based on those three parameters and the automatic and without disease progression during the first 5 years of population separator (APS) representation of the Infinicyt initiating treatment and this group of patients has been software (Cytognos, Salamanca, Spain), two reference identified as the long-term disease-free survivor group. groups corresponding to MGUS and MM emerged; each The remaining 354 patients have progressed in the first 5 patient falling into the MGUS reference being classified as years after the diagnosis. The proportion of patients alive MGUS-like (Supplementary Figure 1)18. at 10 years in the long-term disease-free survivor group Fluorescence in situ hybridization (FISH) on CD138- was 60.8% (95% CI, 35.4%–78.8%) as compared purified PCs and immunophenotyping were performed with 11.8% (95% CI, 5.9%–19.8%) (p < 0.001), respectively centrally at diagnosis following standard procedures6. (Fig. 1). Responses were evaluated according to the European Results of the univariate analyses are summarized in Group for Blood and Marrow Transplantation24 and Table 1. Baseline variables significantly associated with IMWG25 criteria. long-term PFS were, ISS 1 (35% vs 22.3%; p = 0.036), R- ISS 1 (30% vs 16.6%, p = 0.002), Hb ≥ 12 g/dl (34.6% vs Statistical analysis 17.8%, p = 0.001), normal LDH (97.5% vs 87.6%, p = The endpoint of this study was defined as time to 0.009), and absence of HR CAs (91% vs 80.9%, p = 0.04). progression at 5 years or longer since diagnosis, in patients with a follow-up of at least 5 years. The baseline characteristics of the patients are pre- sented as mean and standard deviation (SD) for con- tinuous variables and as proportions for categorical variables. Univariate analysis was performed using the chi-squared or Fisher’s exact test, as appropriate, for independent variables. Multivariate analysis was per- formed using a forward-stepwise model. Variable selec- tion to be tested in the multivariate analysis was carried out using an automated selection method (forward-step- wise). Two significance levels were specified in the (HR 0.09; 95% CI 0.05 – 0.16, p=0.000) forward-stepwise procedure: 10% for predictor addition to the model, and 20% for predictor removal from the model. A first model including all the baseline variables was performed and a second model including depth of Fig. 1 Kaplan–Meier curves of overall survival in long-term response based on conventional and minimal residual survivor group as compared with the remainder disease evaluation was conducted using the same criteria. Blood Cancer Journal Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 Page 4 of 6 Table 1 Distribution of the main characteristic between Table 2a Multivariate analysis including baseline the long-term survival group and the remainder variables population (univariate analysis) Odds ratio 95% CI p-Value Variable Long-term survival, Remainder, n (%) p-Value n (%) MGUS-like profile 4.18 1.55–11.26 0.005 Age n = 81 n = 354 p = n.s. Hb ≥ 12 g/dl 2.74 1.53–4.89 0.001 <75 years 56 (69.1) 224 (63.2) Gender n = 81 n = 354 p = n.s. MGUS monoclonal gammopathy of unknown significance, Hb hemoglobin, 95% CI 95% confidence interval Male 46 (56.8) 178 (50.3) Protocol n = 81 n = 354 p = n.s. GEM05MAS65 44 (54.3) 206 (58.2) Table 2b Multivariate analysis including depth of GEM2010MAS65 37 (45.7) 148 (41.8) response measured by complete response and MRD Durie stage n = 81 n = 352 p = n.s. negativity rates I 12 (14.8) 29 (8.2) II 42 (51.8) 168 (47.8) Odds ratio 95% CI p-Value III 27 (33.3) 155 (44) ISS n = 80 n = 350 p = 0.036 MGUS-like profile 7.48 2.46–22.74 0.000 ISS 1 28 (35) 78 (22.3) Hb ≥ 12 g/dl 2.27 1.22–4.22 0.009 ISS 2 33 (41.2) 151 (43.1) MRD negativity 5.18 2.77–9.69 0.000 ISS 3 19 (23.8) 121 (34.6) R-ISS n = 80 n = 350 p = 0.002 MGUS monoclonal gammopathy of unknown significance, Hb hemoglobin, MRD R-ISS 1 24 (30) 58 (16.6) negativity minimal residual disease negativity detected by flow cytometry R-ISS 2 55 (68.8) 256 (73.1) R-ISS 3 1 (1.2) 36 (10.3) The multivariate logistic regression analysis showed that Hemoglobin (g/dl) n = 81 n = 354 p = 0.001 the probability of long-term disease control was asso- Hb ≥ 12 g/dl 28 (34.6) 63 (17.8) ciated with two independent baseline factors (Table 2a): Creatinine (mg/dl) n = 81 n = 354 p = n.s. the presence of an Hb ≥ 12 g/dl (OR 2.74; 95% CI, Creat < 1.1 54 (66.7) 242 (68.4) LDH n = 81 n = 348 p = 0.009 1.53–4.89, p = 0.001), and the presence of an MGUS-like Normal 79 (97.5) 305 (87.6) profile in the BM PCs (OR 4.18; 95% CI, 1.5–11.3, p = Cytogenetics n = 75 n = 335 p = 0.04 0.005). When incorporating depth of response and Standard risk 68 (91) 271 (80.9) patients’ MRD status into the model, three variables were Response n = 81 n = 327 p = 0.001 found to be independently associated with the probability CR (sCR + CR IF-) 47 (58) 109 (33.3) of 5-year PFS (Table 2b): the presence of an MGUS-like VGPR 27 (33.3) 161 (49.2) profile (OR 7.48; 95% CI, 2.46–22.74, p < 0.001); the MRD PR 4 (4.9) 45 (13.8) negativity (OR 5.18; 95% CI, 2.77–9.69, p < 0.001), and the SD 3 (3.7) 11 (3.4) Hb ≥ 12 g/dl (OR 2.27; 95% CI, 1.22–4.22, p = 0.009). PD 0 (0) 1 (0.3) Moreover, after performing a landmark analysis at 6 and BM signature n = 77 N = 323 p < 0.001 12 months including all patients (n = 498), the three MGUS-like profile 12 (15.6) 12 (3.7) MM-like profile 68 (84.4) 311 (96.3) variables significantly associated with long-term survival MRD n = 81 n = 354 p < 0.001 remain the same (Hb > 12, MGUS-like profile and MRD Negative 35 (41.9) 35 (9.9) negativity). Focusing on the 24 patients with an MGUS-like sig- n.s. not statistically significant, MRD minimal residual disease, CR complete response, sCR stringent complete response, CR IF- complete response with nature, 50% of these patients displayed a long-term dis- negative immunofixation, VGPR very good partial response, PR partial response, ease-free survival, as compared with 17.3% of the SD stable disease, PD progressive disease, Hb hemoglobin, Creat creatinine, ISS International Staging System, R-ISS revised International Staging System, LDH remaining MM patients. The proportion of patients alive lactate deshydrogenase at 10 years with an MGUS-like profile was 40.5% (95% CI, 9.4–70.7) as compared with 20.3% (95% CI, 12.7–29.2) in the MM-like population (p = 0.07). Similarly, for PFS, the Moreover, patients in the long-term disease-free survivor proportion of patients alive and without disease progres- group presented more frequently an MGUS-like profile sion at 10 years in the MGUS-like group was 40.2% (95% (15.6 % vs 3.7%, p < 0.001). In addition, quality of response CI, 20.5–59.1) as compared with 5.7% (95% CI, 2.8–10.1) measure by both the proportion of complete remissions among the MM-like patients (p = 0.001). Disease (CRs) (58% vs 33.3%, p = 0.001), and MRD-negative cases response has been evaluated in 21 out of 24 patients with (41.9% vs 9.9%, p < 0.001) were also higher in the long- MGUS-like profile and 90% of the patients achieved a term PFS group. favorable response (10 CR and 9 VGPR). No differences in Blood Cancer Journal Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 Page 5 of 6 outcome were observed between VGPR and CR cases (p- MGUS-like profile was first shown by the Arkansas group value for OS 0.78) among the MGUS-like profile patients. using a gene expression signature based on 52 genes17. Interestingly, as suggested by the multivariate analysis, the From 214 patients with MM, 27% were found to have an impact of the MGUS-like signature on long-term survival MGUS-like signature, and it was associated with low-risk is independent on the MRD status, since only 16.7% of clinical and molecular features and superior survival. these patients achieved MRD negativity, as compared with Moreover, the MGUS-like signature was also seen in PCs 46.15% patients in the long-term survival group with a from 15 of 20 patients surviving >10 years after auto- MM-like profile (p = 0.057). transplantation. By using MFC, Paiva et al.18 had shown that 59 out of 689 transplant candidate MM patients (8%) Discussion displayed an MGUS-like profile. Despite achieving similar In the transplant setting, it has been clearly shown that CR rates after high-dose therapy vs other MM patients, improving the median PFS beyond 5 years resulted in MGUS-like cases had very long time to progression and median OS of 8–12 years2–4. However, it is not so well OS (~60% at 10 years; p < 0.001). Although, MGUS-like established if disease control at 5 years in elderly MM has signature does not necessarily drive a long time to pro- a similar impact in OS. Indeed, in this setting it may be gression, our data indicate that this biomarker can con- even more relevant, since many elderly patients will only tribute to identify a subset of symptomatic MM patients receive 2–3 lines of therapy, and accordingly, a prolonged with an excellent outcome, independently of the depth of initial response could translate both in a prolonged sur- response. Overall, these data could also imply that treat- vival, similar to that of elderly healthy individuals, and an ing patients before massive disease dissemination and improved quality of life. The definition of long-term dis- niche occupancy in BM confers favorable prognosis. ease control used in the present study (PFS beyond 5 Although the depth of response is not predictable at the years) is quite challenging since it is equivalent to the time of diagnosis, it was shown to be a significant pre- median OS reported in the VISTA26 and FIRST trials27 dictive marker of long-term disease control when mea- based on VMP (OS: 56 months) or continuous sured with conventional methods (CR) or, particularly, by Lenalidomide-dexamethasone (OS: 59 months) treat- MFC (MRD negativity). Noteworthy, our study highlights ments, respectively. Upon considering VRD as a new that the prognostic impact of a MGUS-like signature, is standard of care, the median PFS reported for patients even more relevant than to achieve MRD negativity for above the age of 65 (35 months) is clearly inferior to the 5 predicting long-term disease control (HR of 7.09 and 4.87, years here proposed28. Taken together, it should be respectively). Although MRD is becoming a most valuable assumed that despite substantial improvement in the treatment endpoint and a surrogate marker for survival, treatment of MM, the proportion of elderly patients the fact that MGUS-like and MRD are independent achieving long-term disease control (i.e.: > 5 years PFS) is confirms that for some patients the achievement of an limited and factors identifying this population upfront are MRD-negative status is not imperative for attaining long- lacking. term disease control. In our series, only 18.6% out of 435 elderly patients In summary, we identified that the combination of three entered in this category, and 61% of them achieved an OS biomarkers (normal Hb, MGUS-like signature, and MRD of more than 10 years, accordingly they will reach a life negativity) can help to define elderly MM patients expectancy similar to the normal population. As expected, achieving long-term disease control. Although these this patients' cohort is characterized by the presence of findings will be validated in our next GEM2017FIT trial low-risk clinical features (R-ISS 1, normal Hb, and LDH). for elderly newly diagnosed MM patients, our results The ISS, particularly the revised version (R-ISS), that show that the presence of a MGUS-like signature in the include the cytogenetic information, is a powerful tool in BM at diagnoses is the most powerful predictor for long- discriminating risk subgroups, but their predictive value term disease-free survival, becoming an important prog- for 5-year disease control is not established. By contrast, nostic biomarker. the emergence of normal Hb levels as a strong predictor Acknowledgements of long-term disease control was surprising and could This study was supported by the Centro de Investigación Biomédica en Red— reflect a lower BM infiltration and potentially a better Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/ tolerance to treatment. But the most relevant biomarker 00369 and CB16/12/00377), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS no. PS09/01897/01370, PI12/01761, PI12/02311, for predicting long-term disease control upfront was the PI13/01469, PI14/01867, G03/136, CD13/00340), Asociación Española Contra el presence of an MGUS-like signature defined by auto- Cáncer (GCB120981SAN) and the European Research Council (ERC) 2015 mated MFC and characterized by a low number of bone Starting Grant (MYELOMANEXT). BM PCs together with a relative preservation in the per- Author details centage of normal vs clonal PCs within the whole BM PC 1 Clínica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona, Spain. compartment. The favorable outcome of patients with an 2 Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Blood Cancer Journal Rodríguez-Otero et al. Blood Cancer Journal (2019)9:36 Page 6 of 6 Biomédica de Salamanca, Salamanca, Spain. 3Hospital Universitario 12 de deletion as a unique abnormality is not associated with adverse prognosis. Octubre, Instituto de Investigación 12 de Octubre, CIBERONC, Madrid, Spain. Leukemia 21, 143–150 (2007). 4 Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain. 5Hospital 7. Palumbo, A. et al. Revised International Staging System for multiple myeloma: Clinic I Provincial, Institud’Investigacions Biomèdiques August Pi i Sunyer a report from International Myeloma Working Group. J. Clin. Oncol. 33, (IDIBAPS), Barcelona, Spain. 6Hospital Clínico San Carlos, Madrid, Spain. 2863–2869 (2015). 7 Hospital Clínico de Valencia, Valencia, Spain. 8Hospital Son Llatzer, Palma de 8. Greipp, P. R. et al. International Staging System for multiple myeloma. J. Clin. Mallorca, Spain. 9Hospital de Donostia, San Sebastian, Spain. 10Institut Oncol. 23, 3412–3420 (2005). d’Oncologia Dr. Josep Trueta, Girona, Spain. 11Hospital de Madrid Sanchinarro, 9. Ludwig, H. et al. Myeloma in patients younger than age 50 years presents Universidad CEU San Pablo, Madrid, Spain. 12Hospital Vall d’Hebron, Barcelona, with more favorable features and shows better survival: an analysis of 10 549 Spain. 13Research Support Service, Central Clinical Trials Unit, University Clinic patients from the International Myeloma Working Group. Blood 111, of Navarra, Pamplona, Spain. 14Hospital General Universitario Gregorio 4039–4047 (2008). Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 10. Stella-Holowiecka, B. et al. Beta-2-microglobulin level predicts outcome fol- Madrid, Spain. 15Hospital General Virgen del Rocío, Sevilla, Spain. 16Hospital San lowing autologous hematopoietic stem cell transplantation in patients with Pedro de Alcántara, Cáceres, Spain. 17Hospital Clínico Universitario Lozano multiple myeloma. Transplant. Proc. 39, 2893–2897 (2007). Blesa, Zaragoza, Spain. 18Servicio de Hematología y Oncología Médica, Hospital 11. San Miguel, J. F. et al. A new staging system for multiple myeloma based on Universitario Morales Meseguer, IMIB-Arrixaca, Universidad de Murcia, Murcia, the number of S-phase plasma cells. Blood 85, 448–455 (1995). Spain. 19Insitut Català d’Oncologia, Institut Josep Carreras, Hospital German 12. Harousseau, J. L. et al. Superior outcomes associated with complete response Trias i Pujol, Badalona, Barcelona, Spain in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan- Conflict of interest prednisone versus melphalan-prednisone. Blood 116, 3743–3750 (2010). P.R.-O.: has served on the speaker’s bureau and as a member of advisory 13. Gay, F. et al. Complete response correlates with long-term progression-free boards for Janssen, Celgene, BMS, and Takeda. M.V.M.: has declared and overall survival in elderly myeloma treated with novel agents: analysis of consultancy for: Janssen, Celgene, Takeda, and Amgen. E.M.O.: has declared 1175 patients. Blood 117, 3025–3031 (2011). consultancy for or honoraria from: Mundipharma, Celgene, Amgen, Novartis, 14. Kyle, R. A. et al. Complete response in multiple myeloma: clinical trial E9486, an Takeda, AbbVie, BMS, and Janssen. B.P.: has declared grants from Celgene, Eastern Cooperative Oncology Group study not involving stem cell trans- EngMab, Sanofi, and Takeda, and received honoraria for lectures and plantation. Cancer 106, 1958–1966 (2006). advisory boards from Amgen, BMS, Celgene, Janssen, Takeda, Sanofi, and 15. Lahuerta, J. J. et al. Depth of response in multiple myeloma: a pooled analysis Novartis. J.F.S.M.: received honoraria as part of Advisory boards from of three PETHEMA/GEM clinical trials. J. Clin. Oncol. 35, 2900–2910 (2017). Celgene, Novartis, Millenium, Janssen, Amgen, MSD, Sanofi, and BMS. A.O.: 16. Sigurdardottir, E. E. et al. The role of diagnosis and clinical follow-up of has served as a member of advisory boards for Janssen and Celgene. J.B.: monoclonal gammopathy of undetermined significance on survival in mul- received honoraria for lectures and advisory boards from Celgene and tiple myeloma. JAMA Oncol. 1, 168–174 (2015). Janssen and grant support from Janssen. L.R.: received honoraria from 17. Zhan, F. et al. Gene-expression signature of benign monoclonal gammopathy Janssen and Celgene. The remaining authors declare that they have no evident in multiple myeloma is linked to good prognosis. Blood 109, 1692 conflict of interest. (2007). 18. Paiva, B. et al. A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. Leukemia 27, 2056–2061 Publisher’s note (2013). Springer Nature remains neutral with regard to jurisdictional claims in 19. Mateos, M. V. et al. Sequential vs alternating administration of VMP and Rd in published maps and institutional affiliations. elderly patients with newly diagnosed MM. Blood 127, 420–425 (2016). 20. Mateos, M. V. et al. 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