
==== Front
J Clin Oncol
J Clin Oncol
jco
JCO
Journal of Clinical Oncology
0732-183X
1527-7755
Wolters Kluwer Health

39038268
JCO.23.02771
10.1200/JCO.23.02771
ORIGINAL REPORTS
Hematologic Malignancy
Curative Strategy for High-Risk Smoldering Myeloma: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Followed by Transplant, KRd Consolidation, and Rd Maintenance
https://orcid.org/0000-0003-2390-1218
Mateos María-Victoria MD, PhD 1
https://orcid.org/0000-0001-7908-0063
Martínez-López Joaquin MD, PhD 2
https://orcid.org/0000-0001-5236-7785
Rodriguez Otero Paula MD, PhD 3
González-Calle Verónica MD, PhD 4 5
Gonzalez Marta Sonia MD 6
https://orcid.org/0000-0001-6804-2221
Oriol Albert MD 7
https://orcid.org/0000-0001-5834-9510
Gutiérrez Norma C. MD, PhD 8 9 10
https://orcid.org/0000-0001-8193-1402
Ríos-Tamayo Rafael MD, PhD 11
https://orcid.org/0000-0002-2534-9239
Rosiñol Laura MD, PhD 12
https://orcid.org/0000-0002-8025-5112
Alvarez Rivas Miguel Angel PhD 13
Bargay Joan MD, PhD 14
https://orcid.org/0000-0002-0565-9133
Gonzalez-Rodriguez Ana Pilar MD, PhD 15
https://orcid.org/0000-0002-2423-822X
Alegre Adrián MD 16
https://orcid.org/0000-0003-4501-9066
Escalante Fernando MD 17
Iñigo Rodríguez María Belén MD 18
https://orcid.org/0000-0002-8354-768X
De La Rubia Javier MD, PhD 19 20 21
https://orcid.org/0000-0003-1559-7607
Teruel Ana Isabel MD, PhD 22
https://orcid.org/0000-0002-4451-1318
de Arriba Felipe MD 23
https://orcid.org/0000-0003-0359-7191
Palomera Luis MD, PhD 24
https://orcid.org/0000-0002-6576-7881
Hernández Miguel T. MD, PhD 25
https://orcid.org/0000-0002-2969-3002
Lopez Jiménez Javier MD, PhD 26
https://orcid.org/0000-0002-1859-9803
Reinoso-Segura Marta MD 27
García Mateo Aránzazu MD, PhD 28
https://orcid.org/0000-0002-5765-0085
Ocio Enrique M. MD, PhD 29
https://orcid.org/0000-0003-1977-3815
Paiva Bruno MD, PhD 30
https://orcid.org/0000-0001-7535-3861
Puig Noemi MD, PhD 31
https://orcid.org/0000-0001-5851-3720
Cedena M. Teresa MD, PhD 32
Bladé Joan MD 33
https://orcid.org/0000-0002-3393-9570
Lahuerta Juan Jose MD, PhD 34
https://orcid.org/0000-0002-9183-4857
San-Miguel Jesus F. MD, PhD 35
on behalf of the Spanish Myeloma Group (GEM-Pethema)
1 Hematology Department, Hospital Universitario de Salamanca-IBSAL, CIBERONC and Centro de Investigación del Cáncer, IBMCC (USAL-CSIC), Salamanca, Spain
2 Hematology Department, Hospital 12 de Octubre, Medicine Department, Medicine School of Complutense University, I+12. CNIO, Madrid, Spain
3 Hematology Department, Cancer Center Clinica Universidad de Navarra (CCUN), Cima, CIBERONC, Pamplona, Spain
4 Hematology Department, Hospital Universitario de Salamanca-IBSAL, CIBERONC, Salamanca, Spain
5 Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
6 Hematology Department, Hospital Clinico Universitario Santiago de Compostela, Santiago de Compostela, Spain
7 Clinical Hematology, Institut Català d’Oncologia and Josep Carreras Research Institute, Hospital Germans Trias I Pujol, Badalona, Spain
8 Hematology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
9 Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain
10 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
11 Unidad de Gammapatías Monoclonales, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
12 Hematology Department, Hospital Clinic, Barcelona, Spain
13 Servicio de Hematología y Hemoterapia, Hospital Universitario Reina Sofía, Córdoba, Spain
14 Hematology Department, Hospital Universitario Son Llatzer, IdISBa (Institut d’Investigació Sanitaria Illes Balears), Palma, Spain
15 Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
16 Hematology Department, University Hospital La Princesa & University Hospital QuironSalud, Autonoma-University, Madrid, Spain
17 Servicio de Hematología, Unidad i+i, Complejo Asistencial Universitario de León, León, Spain
18 Hematology Department, Hospital Clínico San Carlos, Madrid, Spain
19 Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
20 Universidad Católica de Valencia, Valencia, Spain
21 Centro de Investigación Biomédica en Red de Cáncer, CIBERONC CB16/12/00284, Instituto de Salud Carlos III, Madrid, Spain
22 Hematology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
23 Servicio de Hematologia, Hospital Universitario Morales Meseguer, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain
24 Hematology Department, Hospital Clínico Universitario Lozano Blesa, Instituto de Investigación Sanitaria de Aragón, Zaragoza, Spain
25 Hematology Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
26 Hematology Department, Hospital Ramón y Cajal, Madrid, Spain
27 Hematology Department, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain
28 Hematology Department, Complejo Asistencial de Segovia, Segovia, Spain
29 Hematology Department, Hospital Universitario Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
30 Hematology Department, Clinica Universidad de Navarra, Pamplona, Spain
31 Hematology Department, Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain
32 Hematology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain
33 Hematology Department, Hospital Clinic, IDIBARS, Barcelona, Spain
34 Instituto de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain
35 Cancer Center Clinica Universidad de Navarra (CCUN), CIMA, IDISNA, CIBERONC, Pamplona, Spain
María-Victoria Mateos, MD, PhD; e-mail: mvmateos@usal.es.
20 9 2024
22 7 2024
22 7 2024
42 27 32473256
23 12 2023
29 3 2024
17 4 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

PURPOSE

Early treatment of high-risk smoldering myeloma has been shown to delay progression to multiple myeloma (MM). We conducted this trial with curative intention using a treatment approach employed for newly diagnosed patients with MM.

METHODS

Patients with high-risk smoldering myeloma (>50% progression risk at 2 years) and transplant candidates were included and received induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd), six cycles, followed by high-dose melphalan (200 mg/m2) autologous stem-cell transplantation (HDM-ASCT), two KRd consolidation cycles, and Rd maintenance for 2 years. The primary end point was undetectable measurable residual disease (uMRD) rate by next-generation flow after ASCT. Sustained uMRD 4 years after ASCT was the secondary end point.

RESULTS

Between June 2015 and June 2017, 90 patients were included, and 31% met at least one SixtyLightchain MRI (SLiM)-hypercalcemia, renal impairment, anemia, bone disease (CRAB) criterion. After a median follow-up of 70.1 months, 3 months after ASCT, in the intention-to-treat population, 56 (62%) of 90 patients had uMRD, and 4 years later, it was sustained in 29 patients (31%). Five patients progressed to MM, and the 70-month progression rate was 94% (95% CI, 84 to 89). The presence of any SLiM CRAB criteria predicted progression to MM (four of the five patients; hazard ratio, 0.12; 95% CI, 0.14 to 1.13; P = .03). Thirty-six patients showed biochemical progression, and failure to achieve uMRD at the end of treatment predicted it. The 70-month overall survival was 92% (95% CI, 82 to 89). Neutropenia and infections were the most frequent adverse events during treatment, resulting in one treatment-related death. Three second primary malignancies have been reported.

CONCLUSION

Although a longer follow-up is needed, this curative approach is encouraging and more effective than active MM, with 31% of the patients maintaining the uMRD 4 years after HDM-ASCT.

OPEN-ACCESSTRUE
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pmcINTRODUCTION

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of either a serum M-component of at least 3 g/dL or a plasma cell bone marrow (PCBM) infiltration ≥10% with the absence of end-organ damage.1 In 2007, Kyle et al2 published the outcome of 276 patients with SMM, highlighting the heterogeneity of this entity in progression to multiple myeloma (MM) or other diseases: 10% per year over the first 5 years following diagnosis, 3% per year over the next 5 years, and 1.5% per year thereafter.

CONTEXT

Key Objective

To evaluate an approach using carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by high-dose melphalan autologous stem-cell transplantation (HDM-ASCT), KRd consolidation, and lenalidomide maintenance for 2 years with curative intention in patients with high-risk smoldering myeloma.

Knowledge Generated

Of the 90 patients included in the trial, 40 (44%) sustained undetectable measurable residual disease (MRD) 4 years after HDM-ASCT. No safety concerns have been reported.

Relevance (S. Lentzsch)

The data are promising, indicating that almost one third of smoldering multiple myeloma (SMM) patients maintain undetectable MRD for 4 years following HDM-ASCT. However, this non-randomized study cannot fully address the impact of early treatment in SMM. A more extensive follow-up period is necessary to accurately ascertain the operational cure rate 10 years beyond therapy completion, and this study will lay the groundwork for future randomized trials.*

*Relevance section written by JCO Associate Editor Suzanne Lentzsch, MD, PhD.

On the basis of these data, different models have been proposed to predict the risk of progression. The Mayo Clinic and Spanish Myeloma Group (GEM-Pethema) were the first to identify patients at high risk (50% progression risk at 2 years). The Mayo Clinic identified the high-risk subgroup based on serum M protein ≥3 g/dL and BMPC percentage ≥10, whereas the Spanish model was based on the presence of a clonal immunophenotype in ≥95% of plasma cells and immunoparesis.2,3

Although the standard of care for SMM was observation, the Spanish Myeloma Group conducted the QuiRedex trial, the first phase III trial comparing early treatment with lenalidomide plus dexamethasone (Rd) versus observation in 119 patients with high-risk–SMM,4-6 and after a median follow-up of 12.5 years, the median time to progression (TTP) to MM and overall survival (OS) were 2.1 and 8.5 years, respectively, in the observation arm versus 9.5 years and not reached in the Rd arm. Lonial et al7 reproduced the results comparing lenalidomide (R) alone with observation. Several other phase II studies have investigated the efficacy of triplets using Rd as backbone, in combination with elotuzumab, ixazomib, or carfilzomib (K).8-10 Carfilzomib, lenalidomide, and dexamethasone (KRd) followed by R maintenance was evaluated in 54 patients, and the undetectable measurable residual disease (uMRD) complete response (CR) rate was 70.4%. In addition, daratumumab monotherapy was investigated in the Centaurus trial, and although the CR rate was <10%, the median progression-free survival (PFS), including an extension phase, was approximately 80 months. Two phase III randomized trials are ongoing comparing Rd with or without anti CD38 antibodies. The ASCENT trial is also based on D-KRd with encouraging preliminary data.11 Finally, teclistamab has shown promising efficacy in 12 patients.12

The Spanish Myeloma Group, on the basis of the previous studies and the new agents developed in MM, designed a clinical trial with a curative intention. Accordingly, we planned a phase II study with a treatment schedule like that used for newly diagnosed patients with MM eligible for high-dose melphalan autologous stem-cell transplantation (HDM-ASCT). Here, we present the results of the first analysis once all 90 patients completed the planned treatment.

METHODS

Trial Design, Oversight, and Treatment

In this nonrandomized, open-label, multicenter phase II trial, eligible patients received induction therapy with six 4-week induction cycles consisting of intravenous carfilzomib at doses of 20/36 mg/m2 once daily on days 1-2, 8-9, and 15-16; oral lenalidomide 25 mg once daily on days 1 to 21; and dexamethasone 40 mg once a week (KRd). After induction, ASCT was performed with melphalan 200 mg/m2 as conditioning regimen (HDM-ASCT), and peripheral blood stem-cell mobilization using granulocyte colony-stimulating factor as the mobilizer was planned after the fourth induction cycle. Consolidation was scheduled 3 months after ASCT and was based on two 4-week KRd cycles, and subsequently, the patients received maintenance for 2 years with R at a dose of 10 mg on days 1-21 plus dexamethasone at a dose of 20 mg once a week.

The study was approved by the ethics committees of all the participating centers. All the participants provided written informed consent before performing any study-related procedures. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02415413).13

Patients

For eligibility, patients were required to have been diagnosed with high-risk–SMM within 5 years before inclusion in the study. Patients were required to be between age 18 and 70 years and eligible for HDM-ASCT with an Eastern Cooperative Oncology Group performance status of 0-1. The diagnosis of SMM was based on the IMWG criteria published in 2010, and a high risk of progression to MM was defined according to either the Mayo 2008 model or the GEM-Pethema model. It should be highlighted that since the trial was designed in 2013, before implementation of the SixtyLightchain MRI (SLiM)-hypercalcemia, renal impairment, anemia, bone disease criteria, ultra–high-risk SMM presenting one or more of the following markers was included: more than one focal lesion on MRI, clonal PCBM infiltration ≥60%, or ratio of involved/uninvolved sFLC >100.14 However, to evaluate the absence of lytic bone disease, low-dose computerized tomography (CT) or positron emission tomography (PET-CT) was mandatory; if normal, whole-body or dorso/lumbar/pelvis MRI was mandatory to exclude the presence of focal lesions.

End Points and Assessments

The primary end point was uMRD rate 3 months after HDM-ASCT. This end point was defined by the absence of phenotypically abnormal PCs in the BM using EuroFlow standard analysis recommendations to detect MRD in MM (minimum sensitivity of one cell in 105 nucleated cells).15

The secondary end point was sustained uMRD rate at 3 and 5 years after HDM-ASCT. Three years after HDM-ASCT coincided with the SARS-CoV-2 pandemic, the protocol was amended to evaluate the sustained uMRD rate 4 and 5 years after HDM-ASCT. MRD studies were centralized in the three core laboratories of the Spanish GEM-Pethema group.

Patients missing an MRD evaluation were considered to have detectable MRD. For the analysis of the sustained uMRD rate, patients were considered negative if they were negative after HDM-ASCT and maintained the negative status at 4 and 5 years after HDM-ASCT. According to the intention-to-treat (ITT) principle, patients who were positive after transplant, missed the follow-up evaluation, or had a detectable MRD evaluation 4 and 5 years after transplant were considered to have nonsustained MRD.

Other secondary end points were response rates after the different phases of treatment assessed according to the IMWG criteria.15 TTP to symptomatic disease, PFS, and OS were also evaluated and defined as follows: TTP as the time since inclusion in the trial to the development of symptomatic MM defined by the presence of end-organ damage; PFS as the time since inclusion in the trial to the development of either symptomatic MM or death, whatever occurs first; and OS as the time from inclusion to death of any cause. Time to biochemical progression (TTBP) was defined as the time since inclusion in the trial to biochemical progression defined by biochemical relapse/progressive disease according to the IMWG criteria; of note, under this term, we also included ultrasensitive MRD relapse defined by the reappearance of MRD confirmed at least 2 months apart. Patients experiencing biochemical progression had the opportunity to receive rescue therapy with daratumumab in combination with pomalidomide and dexamethasone (DPd). This approach was included as an amendment to the protocol for a separate analysis.

The safety profile was also evaluated across the different phases of treatment by evaluating the incidence, severity, and type of adverse events (AEs) that were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Statistical Analysis

The rate of uMRD 3 months after HDM-ASCT was the primary end point, carried out in the ITT population, which included all enrolled patients who had begun treatment.

For the calculation of the sample size, there were no previous data with this approach for SMM. As the treatment schedule was similar to that used in newly diagnosed MM, we considered 34% of uMRD after HDM-ASCT as control based on our results of 206 patients treated with a similar schedule.16 We hypothesized that the percentage of patients with uMRD after HDM-ASCT would increase by up to 50%. The chosen parameters were α = .05 and β = .11. The sample size was calculated using PASS software, given that the required number of patients was 82, and if we assume a dropout rate of 10%, 90 patients should be included in the study. A subanalysis was planned to evaluate the percentage of patients with uMRD 3 and 5 years after HDM-ASCT; however, because of the COVID-19 pandemic, the time point changed to uMRD 4 years after transplantation.

The Kaplan-Meier method was used to characterize event time distributions, and the corresponding treatment hazard ratio was estimated using a stratified Cox regression model to compare outcomes based on baseline characteristics and MRD status. To address the immortal time bias, the analyses conducted to evaluate the impact of achieving uMRD sustained over time were landmarked at the end of maintenance.

RESULTS

Patients and Treatment

Between June 2015 and June 2017, 126 patients were screened, of which 36 were screening failures, with the most frequent reason being the presence of lytic lesions on CT or PET/CT. Ninety patients started treatment, and the disposition of the patients in this study is shown in Figure 1. Baseline demographic and disease characteristics are shown in Table 1.

FIG 1. Disposition of patients. ASCT, autologous stem-cell transplantation; CT, computed tomography; IC, informed consent; MDE, myeloma-defining event; SMM, smoldering multiple myeloma.

TABLE 1. Baseline Characteristics of the Patients Included in the Study

Characteristic	All Patients (N = 90)	
Median age (range), years	59 (33-70)	
Serum/urine, median (range)
M-component (g/dL/g/24 h urine)	2.77 (0-8.6)/0.43 (0-7.2)	
Plasma cell bone marrow infiltration, median (range), %	22 (10-80)	
Time from diagnosis of the precursor disease to being high-risk SMM, median (range)	1.7 (0.03-59.80)	
High-risk model, No. (%)		
 Mayo clinic only	19 (21)	
 Spanish only	48 (53)	
 Both	26 (27)	
 SLiM-CRAB criteria, No. (%)	28 (31)	
 sFLC >100	18 (20)	
 >1 focal lesion in MRI	9 (10)	
 ≥60% PCBMI	7 (8)	
 PET + w/o lytic lesions, No. (%)	5 (6)	
Cytogenetic abnormalities, No. (%)		
 Standard risk	54 (63)	
 High-risk (t(4;14), t(14;16), del17)	26 (29)	
 High-risk (t(4;14), t(14;16), del17, 1q abnormalities)	51 (57)	
 Unknown	5 (6)	
Abbreviations: CRAB, hypercalcemia, renal impairment, anemia, bone disease; dL, deciliter; g, grams; MRI, magnetic resonance imaging; PCBMI, plasma cell bone marrow infiltration; PET, positron emission tomography; sFLC, serum-free Light Chain; SLiM, SixtyLightchain MRI; SMM, smoldering multiple myeloma; t, translocation; w/o, without.

The cutoff date for analysis was October 2022; all patients had completed the treatment phase, and the median follow-up time was 70.1 (range, 28.4-89.9) months.

Efficacy

According to the ITT analysis, 3 months after HDM-ASCT, 56 (62%) of 90 patients had uMRD. At the end of the treatment phase, after completing maintenance therapy, 48 patients (53%) had uMRD, and 4 years after HDM-ASCT, the sustained uMRD rate was 31% (Appendix Table A1, online only)

The overall response rate (ORR) and different response categories across the different phases of the study are presented in Table 2. No significant differences were observed between high-risk and SMM with any SLiM criteria in terms of serological responses, but the uMRD rate at the end of maintenance was higher in high-risk (59%) compared with those with any SLiM criteria (39%; Appendix Table A2).

TABLE 2. Response Rates Observed Across the Different Phases of the Study in the Intention-To-Treat Patient Population

Response Category	Induction (N = 90)	HDM-ASCT (N = 90)	Consolidation (N = 90)	Maintenance (N = 90)	
ORR, No. (%)	85 (94)	82 (91)	85 (94)	80 (95)	
≥Complete remission, No. (%)	37 (41)	54 (60)	64 (70)	58 (64)	
VGPR, No. (%)	35 (39)	17 (19)	14 (16)	9 (10)	
PR, No. (%)	13 (14)	11 (12)	7 (8)	3 (3)	
SD, No. (%)	1 (1)	1 (1)	—	—	
Progressive disease, No. (%)	2 (3)a	—	—	7 (7)b	
Biochemical progression, No. (%)	2 (2)	—	—	7 (7)	
Not evaluable,c No. (%)	2 (3)	7(8)	5 (5)	13 (14)	
Undetectable measurable residual disease by NGF and 10−5, No. (%)		56 (62)		48 (53)	
Abbreviations: HDM-ASCT, high-dose melphalan autologous stem-cell transplantation; NGF, next-generation flow; ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good partial response.

a Two patients biochemically progressed during induction and one of them progressed to myeloma.

b Seven patients biochemically progressed during maintenance and one of them progressed to myeloma.

c The patients not evaluable included early discontinuations before each phase of treatment for several reasons included in the flow chart.

Time-To-Event End Points

Overall, 36 patients had biochemical progression (40%), nine during the treatment period (Table 2) and 27 during the follow-up period once they had finalized the treatment. These biochemical relapses included eight patients (9%) with biochemical progression, 20 patients (22%) with biochemical relapse from complete remission, and eight patients (9%) with ultrasensitive MRD relapse. The 70-month TTBP was 59% (95% CI, 66 to 76; Fig 2A). Eleven (25%) of 43 patients who completed the maintenance and achieved uMRD experienced biochemical progression versus 15 (55%) of 27 patients in whom the MRD was detectable (hazard ratio [HR], 0.29 [95% CI, 0.13 to 0.66]; P = .003; Fig 2B).

FIG 2. Kaplan-Meier estimates of (A) time to biochemical progression and (B) landmark time to biochemical progression by MRD status at the end of maintenance. MRD, measurable residual disease.

The analysis of other baseline characteristics showed that the presence of at least one high-risk cytogenetic abnormality (HRCA) according to the IMWG resulted in a higher risk of biochemical progression (70 months TTBP: 38% v 67%, HR, 0.42 [95% CI, 0.22 to 0.81]; P = .01), and the same effect was maintained when abnormalities of 1q were included (70 months TTBP: 45% v 75%, HR, 0.40 [95% CI, 0.18 to 0.85]; P = .018; Appendix Figs A1A and A1B). The presence of any SLiM criteria showed a trend to a higher risk of biochemical progression (12 [38.7%] of 31 patients) compared with those without (18 [30.5%] of 59 patients), but the difference was not statistically significant.

In the case of biochemical progression, patients were offered to be included in a subsequent trial with daratumumab plus pomalidomide and dexamethasone (D-Pd). Twenty-one patients have so far been included.

Overall, five patients progressed to MM, two during the treatment phase and three during follow-up. In four patients, the progression was first biochemical. The 70-month TTP was 94% (95% CI, 84 to 89; Fig 3A). As mentioned above, 28 patients presented with any one SLiM biomarker. Although their response rate was not different from that observed in the standard high-risk–SMM population (Appendix Table A2), the presence of any SLiM biomarker predicted progression to MM (HR, 0.10 [95% CI, 0.01 to 0.96]; P = .046; Fig 3B).

FIG 3. Kaplan-Meier estimates of (A) TTP to myeloma; (B) TTP to myeloma by the presence of any SLiM-CRAB criteria; and (C) OS in the ITT population, which included all patients who started treatment. CRAB, hypercalcemia, renal impairment, anemia, bone disease; ITT, intention-to-treat; MRI, magnetic resonance imaging; OS, overall survival; SliM, SixtyLightchain MRI; TTP, time to progression.

Seven patients died: three due to progressive disease, one due to early death from respiratory infection and treatment-related disease, two because of second primary malignancies, and one because of cardiac arrest at home. The 70-month OS rate was 92% (95% CI, 82 to 89; Fig 3C).

Safety

During the induction phase, three (3%) and five (5%) patients developed grade 3 to 4 neutropenia and thrombocytopenia, respectively. Grade 3 to 4 infections occurred in nine patients (10%), skin rash in eight patients (9%), and G3 cardiac failure was the only cardiologic event reported, presenting in one patient.

Peripheral blood stem-cell collection was planned after the fourth induction cycle, but two patients had previously discontinued treatment; therefore, the process was performed in 88 patients. Only six patients (7%) required plerixafor as a mobilizer. After a median of one apheresis, the mean number of CD34+ cells collected was 4 × 106/kg ± 2.7 × 106/kg. There were two mobilization failures that proceeded directly to consolidation. HDM followed by ASCT was performed in 83 patients, and all but one were engrafted. Neither transplant-related mortality nor other relevant toxicities were reported.

Eighty-one patients proceeded to consolidation, and eight patients (9%) developed grade 3 to 4 neutropenia and thrombocytopenia. Four patients (5%) developed grade 3 to 4 infections. During maintenance therapy, grade 3 to 4 neutropenia was reported in 20% of patients, and 9% developed any grade 3 to 4 infections (Table 3).

TABLE 3. Safety Profile Through the Different Phases of the Protocol

Adverse Event (N = 90)	Induction
Overall/G3-4, No. (%)	Consolidation
Overall/G3-4, No. (%)	Maintenance
Overall/G3-4, No. (%)	
Hematologic		
 Neutropenia	9 (10)/3 (3)	14 (16)/8 (9)	28 (31)/21 (23)	
 Thrombocytopenia	11 (12)/4 (4)	14 (16)/7 (8)	13 (14)/3 (3)	
 Anemia	11 (12)/—	8 (9)/—	8 (9)/—	
Nonhematologic		
 General symptomatology	20 (22)/2 (2)	4 (5)/—	23 (25)/1 (1)	
 G-I toxicity	19 (21)/2 (2)	5 (6)/—	23 (25)/6 (7)	
  Skin rash	20 (22)/8 (9)	1 (1)/—	1 (1)/—	
 Infections	22 (24)/9 (10)a	11 (12)/5 (6)	32 (36)/8 (9)	
 Cardiac events	1 (1)/1 (1)	—/—	1 (1)/—	
 SPM			3 (4)b	
Abbreviations: G, Grade; G-I, Gastro International; SPM, second primary malignancies.

a Infection was G5 in one patient who died because of massive ischemic stroke after a respiratory infection.

b The three second primary malignancies were lung cancer, prostate cancer, and myelodysplastic syndrome.

Overall, nine patients discontinued treatment early because of toxicity: one patient during induction due to respiratory infection complicated with massive ischemic stroke resulted in the only treatment-related death; one patient after ASCT because of nonengraftment; seven patients during maintenance mainly because of neutropenia and gastrointestinal toxicity; and one patient who suffered cardiac arrest at home, which was considered nonrelated.

Three patients (3%) developed second primary malignancies: prostate cancer in a patient with a history of prostate hyperplasia who remained alive; lung cancer in another patient with multiple additional risk factors who died with uMRD; and myelodysplastic syndrome in the third patient, who had no known risk factors but died. This latter case occurred under the rescue therapy the patient was receiving because of progression to active MM, whereas the two solid second primary malignancies emerged during the maintenance period.

DISCUSSION

This clinical trial was designed pursuing the goal of cure for high-risk–SMM through an intensive treatment approach.

The primary end point was the uMRD rate 3 months after HDM-ASCT, which was achieved in 62% of the patients using the ITT analysis, and the trial met its primary end point. We evaluated the sustained uMRD rate planned at 3 and 5 years after ASCT but modified at 4 years because of COVID-19; 28 patients (31%) achieved this goal in the ITT population. We hypothesized that this rate could be 50% after 3 years of ASCT, but the assumption was empirical. Continuous follow-up in this group is required to see if sustained uMRD can be considered as surrogate for cure.

In line with this, Hill et al10 have recently shown the results of 54 patients with high-risk–SMM treated with KRd eight cycles, followed by R maintenance for 24 months, a similar design but without ASCT. The primary end point was uMRD CR rate at the end of induction, and it was 70%; the sustained uMRD over 2 years was 39%. In our study, uMRD in clinical remission patients after induction was 67% and 88% after consolidation. The sustained uMRD at 4 years was 31%. Both studies indicate that this approach is very effective in patients with high-risk–SMM.

The ASCENT trial is also pursuing a curative objective in high-risk–SMM, but the approach was based on D-KRd, fixed duration as well, and without ASCT.11 The follow-up was shorter, 26 months, but the 64% stringent complete response (sCR)/CR rate was similar to that of ours.

An alternative of particular interest for frail high-risk–SMM or with comorbidities would be the use of a gentle treatment with Rd, evaluated in the QuiRedex trial, which led to a median TTP of 9.5 years.5

To explore the value of early intervention, we also wanted to compare the efficacy of the current trial in SMM with other similar trials but conducted in NDMM. In the phase III randomized Perseus study, D-VRd and VRd as part of the induction and consolidation after HDM-ASCT resulted in an uMRD rate after consolidation of 57.5% and 32.5%, respectively, and these rates are not superior to our data.17 In the ISKIA study, in which carfilzomib is the proteasome inhibitor, the uMRD rates after induction and consolidation with isatuximab-KRd or KRd following ASCT were 77% and 67%, respectively, and these data are not very different from ours, especially in the arm without monoclonal antibody.18 As far as uMRD evaluation over time in other trials, the phase II randomized Griffin study reported 44% of uMRD sustained at 1 year after D-VRD, HDM-ASCT, D-VRD, and DR maintenance,19 and in the FORTE study, KRd followed by ASCT and KRd consolidation followed by maintenance with KR or R, the sustained uMRD rate at 1 year was 47%.20 These results appear to be inferior to the 65% uMRD rate at 1 year in our study in the ITT population (data not shown). Overall, these data suggest that the sustained uMRD rate is higher in high-risk–SMM than in MM upon treatment with similar approaches, and therefore, the probabilities for operational cure would increase with early intervention. In our study, the only feature predicting progression to MM was the presence of any SLiM biomarker, now incorporated into the definition of MM, which would reinforce this hypothesis.

We decided to evaluate TTBP because of the nature of this disease, without myeloma-defining events, and because we observed that most biochemical relapses occurred after maintenance ended. Interestingly, failure to achieve uMRD at the end of maintenance predicted biochemical progression. Thus, a potential strategy could be to intensify or prolong maintenance to eradicate residual tumor cells.

A potential limitation is the MRD sensitivity level established here, specifically 10−5. To overcome this limitation, we also evaluated MRD at a sensitivity level of 10−6 as an exploratory objective, and 4 years after HDM-ASCT, 24 patients had sustained negative MRD and had not yet progressed. Another limitation is the frequency of MRD assessment according to the IMWG, that is, annual. Biochemical progression was detected in only eight patients using MRD, and new sensitive techniques, such as next blood flow and mass spectrometry, will allow to monitor MRD more frequently in peripheral blood.

The safety profile was acceptable. After the induction and consolidation phases, the incidence of G3-4 neutropenia was comparable (3% and 9%, respectively) with that reported in the ASCENT trial with D-KRd (10%) and slightly inferior compared with that reported in the Hill's trial (22%,) but patients received eight cycles.10 In the ASCENT trial, four patients presented with pneumonia; in the Hill's study, three presented with pneumonia; and in our study, two presented with pneumonia. During maintenance, G3-4 neutropenia (20%) and infections (9%) were the most frequent investigator-based lenalidomide-related AEs, like the rates reported by Hill et al (17% of G3-4 neutropenia with infections not reported). Three patients developed SPMs, a figure that is not different from the four cases reported in the Hill's study, although we cannot exclude that the genotoxic effect of melphalan could have influenced more aggressive tumors and the role of HDM can be questionable.

Despite this and another data, the role of early treatment continues to be a matter of debate, and there is a phase III randomized study comparing daratumumab single agent with observation based on the positive data reported with daratumumab monotherapy in the CENTAURUS study.21 There are two phase III trials ongoing with registrational purposes comparing Rd ± anti-CD38 monoclonal antibodies. Moreover, immunotherapy approaches targeting B-cell maturation antigen (BCMA) through chimeric antigen receptor T lymphocytes (CAR-T) or CD3 bispecific monoclonal antibodies are also planned for high-risk–SMM, and very encouraging data have been reported in a preliminary study with teclistamab in this population (100% of uMRD after two cycles of treatment).12

In summary, our curative approach for high-risk–SMM with a schedule comparable with that used in newly diagnosed patients with MM seems to be encouraging, with nearly one third of the patients maintaining MRD as undetectable 4 years after HDM-ASCT. However, a longer follow-up period is required to show the true operational cure rate at 10 years beyond the end of therapy.

PRIOR PRESENTATION

SUPPORT

CLINICAL TRIAL INFORMATION

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.23.02771.

AUTHOR CONTRIBUTIONS

Conception and design: María-Victoria Mateos, Jesús F. San-Miguel

Provision of study materials or patients: Joaquin Martínez-López, Paula Rodriguez Otero, Verónica González-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutiérrez, Rafael Ríos-Tamayo, Laura Rosiñol, Miguel Angel Alvarez Rivas, Joan Bargay, Ana Pilar Gonzalez-Rodriguez, Adrián Alegre, Fernando Escalante, María Belén Iñigo Rodríguez, Javier De La Rubia, Ana Isabel Teruel, Felipe de Arriba, Luis Palomera, Miguel T. Hernández, Javier Lopez Jiménez, Marta Reinoso-Segura, Aránzazu García Mateo, Enrique M. Ocio, Bruno Paiva, Noemi Puig, M. Teresa Cedena, Joan Bladé, Juan Jose Lahuerta

Collection and assembly of data: María-Victoria Mateos, Joaquin Martínez-López, Paula Rodriguez Otero, Verónica González-Calle, Marta Sonia Gonzalez, Albert Oriol, Norma C. Gutiérrez, Rafael Ríos-Tamayo, Laura Rosiñol, Miguel Angel Alvarez Rivas, Joan Bargay, Ana Pilar Gonzalez-Rodriguez, Adrián Alegre, Fernando Escalante, María Belén Iñigo Rodríguez, Javier De La Rubia, Ana Isabel Teruel, Felipe de Arriba, Luis Palomera, Miguel T. Hernández, Javier Lopez Jiménez, Marta Reinoso-Segura, Aránzazu García Mateo, Enrique M. Ocio, Bruno Paiva, Noemi Puig, M. Teresa Cedena, Joan Bladé, Juan Jose Lahuerta

Data analysis and interpretation: María-Victoria Mateos, Joaquin Martínez-López, Laura Rosiñol, Javier De La Rubia, Bruno Paiva, Noemi Puig, M. Teresa Cedena, Joan Bladé, Juan Jose Lahuerta, Jesus F. San-Miguel

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Curative Strategy for High-Risk Smoldering Myeloma: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Followed by Transplant, KRd Consolidation, and Rd Maintenance

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. 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/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

APPENDIX

TABLE A1. Undetectable Measurable Residual Disease Across the Different Phases of Therapy, Including the Sustained uMRD 4 Years After ASCT in the Intention-To-Treat Population

Response Category	Induction (N = 90), No. (%)	HDM-ASCT (N = 90), No. (%)	Consolidation (N = 90), No. (%)	Maintenance (N = 90), No. (%)	4 years after ASCT (N = 90), No. (%)	
Undetectable measurable residual disease by NGF and 10−5	36 (42)	56 (62)	61 (68%)	48 (53)	28 (31)	
Abbreviations: HDM-ASCT, high-dose melphalan autologous stem-cell transplantation; NGF, next-generation flow.

TABLE A2. Response Rates in Patients Included in the Study by the Presence of Any SLiM CRAB Criteria

Response Category	Induction	HDM-ASCT	Consolidation	Maintenance	
High Risk (n = 62), No. (%)	Ultra High Risk (n = 28), No. (%)	High Risk (n = 62), No. (%)	Ultra High Risk (n = 28), No. (%)	High Risk (n = 62), No. (%)	Ultra High Risk (n = 28), No. (%)	High Risk (n = 62), No. (%)	Ultra High Risk (n = 28), No. (%)	
ORR	59 (95)	26 (93)	57 (92)	25 (89)	59 (95)	26 (93)	61 (98)	19 (68)	
≥Complete remission	26 (42)	11 (39)	38 (61)	16 (57)	44 (71)	20 (71)	42 (68)	16 (57)	
VGPR	25 (40)	10 (36)	12 (19)	5 (18)	11 (12)	3 (11)	8 (13)	1 (4)	
PR	8 (13)	5 (18)	7 (11)	4 (14)	4 (6)	3 (11)	1 (2)	2 (7)	
SD	1 (2)	—	1 (2)	—	—	—	—	—	
Progressive disease	1 (2)	1 (4)a	—	—	—	—	3 (5)	4 (14)b	
Biochemical progression	1 (2)	1 (4)					3 (5)	4 (14)	
Not evaluablec	1 (2)	1 (4)	4 (6)	3 (11)	4 (6)	1 (4)	8 (13)	5 (18)	
Undetectable measurable residual disease by NGF and 10−5d	23/62 (37)	13/28 (46)	41/62 (66)	15/28 (54)	43/62 (69)	18/28 (64)	37/62 (59)	11/28 (39)	
Abbreviations: CRAB, hypercalcemia, renal impairment, anemia, bone disease; HDM-ASCT, high-dose melphalan autologous stem-cell transplantation; MRI, magnetic resonance imaging; ORR, overall response rate; PR, partial response; SD, stable disease; SLiM, SixtyLightchain MRI; VGPR, very good partial response.

a This patient progressed biochemically and subsequently to myeloma.

b Four patients biochemically progressed and one of them progressed to myeloma.

c The reasons for not being evaluable are represented in the flow chart.

d This rate is evaluated in the intention-to-treat population.

FIG A1. (A) Time to biochemical progression by the presence of HRCAs according to the International Myeloma Working Group [t(4;14), t(14;16) and/or del(17/17p). (B) Time to biochemical progression by the presence of HRCAs according to the International Myeloma Working Group [t(4;14), t(14;16) and/or del(17/17p)] plus abnormalities on 1q chromosome. HRCA, high-risk cytogenetic abnormalities; TTBP, time to biochemical progression.

Presented at the 61st American Society of Hematology (ASH) Annual Meeting, Orlando, FL, December 6-10, 2019; the 63rd ASH Annual Meeting, Atlanta, GA, December 11-14, 2021; and the 64th ASH Annual Meeting, New Orleans, LA, December 10-13, 2022.

Supported by the Pethema Foundation. The manufacturers of carfilzomib (Amgen) and lenalidomide (Celgene BMS, Summit, NJ, USA) supplied the drugs at no charge and provided financial support, but were not involved in the analysis, interpretation, or decision to publish the trial. This study was also supported by the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria, Spain (FIS: PI21/01917; PI21/01751; PI21/01816).

NCT02415413

María-Victoria Mateos

Honoraria: Janssen-Cilag, Celgene, Amgen, GlaxoSmithKline, AbbVie/Genentech, Sanofi, Pfizer

Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, GlaxoSmithKline, Pfizer, Regeneron, Roche/Genentech, Stemline Therapeutics, Kite, a Gilead company

Joaquin Martínez-López

Honoraria: Janssen Oncology, BMSi

Research Funding: Bristol Myers Squibb/Celgene (Inst)

Paula Rodriguez Otero

Honoraria: Janssen, Celgene, Sanofi, AbbVie, GlaxoSmithKline, Pfizer, H3 Biomedicine, Roche/Genentech, Regeneron

Consulting or Advisory Role: Janssen, Sanofi, GlaxoSmithKline, Pfizer, BMS, AbbVie, Roche

Speakers' Bureau: BMS, Janssen, GlaxoSmithKline, Sanofi

Travel, Accommodations, Expenses: Pfizer

Verónica González-Calle

Consulting or Advisory Role: Janssen

Speakers' Bureau: Janssen, Pfizer, GlaxoSmithKline, Bristol Myers Squibb/Celgene

Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline

Marta Sonia Gonzalez

Consulting or Advisory Role: Janssen Oncology, Sanofi, Amgen, Pfizer, Menarini

Speakers' Bureau: Janssen Oncology

Travel, Accommodations, Expenses: Sanofi, Janssen Oncology, Pfizer

Albert Oriol

Consulting or Advisory Role: Janssen, Amgen, Sanofi, GlaxoSmithKline, Bristol Myers Squibb/Celgene

Speakers' Bureau: Amgen, Sanofi, GlaxoSmithKline, Bristol Myers Squibb/Celgene, Janssen

Norma C. Gutiérrez

Honoraria: Amgen, Sanofi

Travel, Accommodations, Expenses: AbbVie, Kite, a Gilead company

Rafael Ríos-Tamayo

Consulting or Advisory Role: Sanofi/Aventis, GlaxoSmithKline, Menarini

Laura Rosiñol

Honoraria: Janssen-Cilag, Celgene, Amgen, Takeda, GlaxoSmithKline, Sanofi

Consulting or Advisory Role: Janssen-Cilag, Amgen, Sanofi, GlaxoSmithKline, Takeda, Bristol Myers Squibb Foundation

Miguel Angel Alvarez Rivas

Speakers' Bureau: GlaxoSmithKline, Janssen Oncology, Sanofi, Amgen

Travel, Accommodations, Expenses: Sanofi, Janssen Oncology

Joan Bargay

Consulting or Advisory Role: Bristol Myers Squibb/Celgene, Janssen

Speakers' Bureau: Janssen Oncology, Bristol Myers Squibb/Celgene

Ana Pilar Gonzalez-Rodriguez

Consulting or Advisory Role: Swedish Orphan Biovitrum, Jazz Pharmaceuticals, Janssen, Sanofi

Speakers' Bureau: Alexion Pharmaceuticals, Janssen, Takeda, Sanofi

Adrián Alegre

Consulting or Advisory Role: Janssen, Amgen, Sanofi, Oncopetides, Bristol Myers Squibb/Celgene, GlaxoSmithKline

Speakers' Bureau: Janssen, AMGEN, Bristol Myers Squibb/Celgene, Sanofi

Research Funding: Janssen-Ortho (Inst), Sanofi (Inst), GlaxoSmithKline (Inst)

Travel, Accommodations, Expenses: Janssen

Fernando Escalante

Consulting or Advisory Role: Janssen Oncology, Amgen, GlaxoSmithKline, BeiGene, Sanofi

Speakers' Bureau: Janssen Oncology, GlaxoSmithKline

Travel, Accommodations, Expenses: BeiGene, Janssen Oncology, Amgen

Javier De La Rubia

Consulting or Advisory Role: GlaxoSmithKline, Sanofi, Janssen Oncology, Karyopharm Therapeutics, Sanofi, Pfizer, Menarini

Speakers' Bureau: Amgen, Bristol Myers Squibb

Expert Testimony: Amgen, Celgene, Janssen, Sanofi, GlaxoSmithKline, Karyopharm Therapeutics, Pfizer

Travel, Accommodations, Expenses: Amgen, Janssen, Sanofi, Bristol Myers Squibb, GlaxoSmithKline

Felipe de Arriba

Honoraria: Janssen, Bristol Myers Squibb (Celgene), Sanofi, GlaxoSmithKline, Amgen

Consulting or Advisory Role: Janssen, GlaxoSmithKline, Sanofi, Bristol Myers Squibb/Celgene, Amgen

Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen

Luis Palomera

Honoraria: Janssen-Cilag

Consulting or Advisory Role: Celgene, Janssen-Cilag, Amgen

Miguel T. Hernández

Consulting or Advisory Role: Janssen, Sanofi/Aventis, Celgene/Bristol Myers Squibb, GlaxoSmithKline

Speakers' Bureau: Janssen, Celgene/Bristol Myers Squibb, GlaxoSmithKline

Javier Lopez Jiménez

Consulting or Advisory Role: Roche/Genentech, AbbVie, Janssen Oncology, Gilead Sciences, BeiGene, Celgene

Speakers' Bureau: Roche/Genentech, AbbVie, Pfizer

Research Funding: Roche/Genentech, AbbVie, BeiGene, Janssen-Ortho, Bristol Myers Squibb/Medarex

Travel, Accommodations, Expenses: Gilead Sciences, Janssen Oncology, AbbVie

Marta Reinoso-Segura

Honoraria: Janssen, Amgen, GlaxoSmithKline

Enrique M. Ocio

Honoraria: Amgen, Bristol Myers Squibb, Janssen, Takeda, Sanofi, GlaxoSmithKline, Oncopeptides, Pfizer, Regeneron, AbbVie

Consulting or Advisory Role: Amgen, Janssen, Oncopeptides, Takeda, Sanofi, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Pfizer, AbbVie, Menarini

Speakers' Bureau: Janssen-Cilag

Research Funding: GlaxoSmithKline

Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline, BMS, Lilly

Bruno Paiva

Honoraria: Bristol Myers Squibb, Celgene, Janssen-Cilag, Takeda, Sanofi, Roche/Genentech, Adaptive Biotechnologies, Amgen, GlaxoSmithKline

Consulting or Advisory Role: Celgene, Janssen-Cilag, Sanofi, Takeda

Speakers' Bureau: Celgene

Research Funding: Celgene (Inst), Janssen-Cilag (Inst), Sanofi (Inst), Takeda (Inst), Roche/Genentech (Inst), GlaxoSmithKline (Inst), BeiGene (Inst)

Travel, Accommodations, Expenses: GlaxoSmithKline

Noemi Puig

Honoraria: Amgen, Celgene, Janssen, Takeda, The Binding Site, Sanofi, Pfizer

Consulting or Advisory Role: Amgen, Celgene, Janssen, Takeda, The Binding Site, Sanofi, Pfizer

Speakers' Bureau: Celgene

Research Funding: Celgene, Janssen, Amgen, Takeda, Pfizer (Inst)

Travel, Accommodations, Expenses: Amgen, Celgene, Janssen, Takeda, The Binding Site, Pfizer

M. Teresa Cedena

Honoraria: Janssen, Sobi

Joan Bladé

Honoraria: Janssen, Celgene, Amgen, Takeda, Oncopeptides

Juan Jose Lahuerta

Travel, Accommodations, Expenses: GlaxoSmithKline

Jesus F. San-Miguel

Consulting or Advisory Role: Amgen (Inst), Celgene (Inst), Takeda (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Novartis (Inst), Sanofi (Inst), Janssen (Inst), Roche (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Karyopharm Therapeutics (Inst), Secura Bio (Inst), Regeneron (Inst), Haemalogix (Inst), Pfizer (Inst), Kite, a Gilead company (Inst)

No other potential conflicts of interest were reported.

María-Victoria Mateos

Honoraria: Janssen-Cilag, Celgene, Amgen, GlaxoSmithKline, AbbVie/Genentech, Sanofi, Pfizer

Consulting or Advisory Role: Takeda, Janssen-Cilag, Celgene, Amgen, AbbVie, GlaxoSmithKline, Pfizer, Regeneron, Roche/Genentech, Stemline Therapeutics, Kite, a Gilead company

Joaquin Martínez-López

Honoraria: Janssen Oncology, BMSi

Research Funding: Bristol Myers Squibb/Celgene (Inst)

Paula Rodriguez Otero

Honoraria: Janssen, Celgene, Sanofi, AbbVie, GlaxoSmithKline, Pfizer, H3 Biomedicine, Roche/Genentech, Regeneron

Consulting or Advisory Role: Janssen, Sanofi, GlaxoSmithKline, Pfizer, BMS, AbbVie, Roche

Speakers' Bureau: BMS, Janssen, GlaxoSmithKline, Sanofi

Travel, Accommodations, Expenses: Pfizer

Verónica González-Calle

Consulting or Advisory Role: Janssen

Speakers' Bureau: Janssen, Pfizer, GlaxoSmithKline, Bristol Myers Squibb/Celgene

Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline

Marta Sonia Gonzalez

Consulting or Advisory Role: Janssen Oncology, Sanofi, Amgen, Pfizer, Menarini

Speakers' Bureau: Janssen Oncology

Travel, Accommodations, Expenses: Sanofi, Janssen Oncology, Pfizer

Albert Oriol

Consulting or Advisory Role: Janssen, Amgen, Sanofi, GlaxoSmithKline, Bristol Myers Squibb/Celgene

Speakers' Bureau: Amgen, Sanofi, GlaxoSmithKline, Bristol Myers Squibb/Celgene, Janssen

Norma C. Gutiérrez

Honoraria: Amgen, Sanofi

Travel, Accommodations, Expenses: AbbVie, Kite, a Gilead company

Rafael Ríos-Tamayo

Consulting or Advisory Role: Sanofi/Aventis, GlaxoSmithKline, Menarini

Laura Rosiñol

Honoraria: Janssen-Cilag, Celgene, Amgen, Takeda, GlaxoSmithKline, Sanofi

Consulting or Advisory Role: Janssen-Cilag, Amgen, Sanofi, GlaxoSmithKline, Takeda, Bristol Myers Squibb Foundation

Miguel Angel Alvarez Rivas

Speakers' Bureau: GlaxoSmithKline, Janssen Oncology, Sanofi, Amgen

Travel, Accommodations, Expenses: Sanofi, Janssen Oncology

Joan Bargay

Consulting or Advisory Role: Bristol Myers Squibb/Celgene, Janssen

Speakers' Bureau: Janssen Oncology, Bristol Myers Squibb/Celgene

Ana Pilar Gonzalez-Rodriguez

Consulting or Advisory Role: Swedish Orphan Biovitrum, Jazz Pharmaceuticals, Janssen, Sanofi

Speakers' Bureau: Alexion Pharmaceuticals, Janssen, Takeda, Sanofi

Adrián Alegre

Consulting or Advisory Role: Janssen, Amgen, Sanofi, Oncopetides, Bristol Myers Squibb/Celgene, GlaxoSmithKline

Speakers' Bureau: Janssen, AMGEN, Bristol Myers Squibb/Celgene, Sanofi

Research Funding: Janssen-Ortho (Inst), Sanofi (Inst), GlaxoSmithKline (Inst)

Travel, Accommodations, Expenses: Janssen

Fernando Escalante

Consulting or Advisory Role: Janssen Oncology, Amgen, GlaxoSmithKline, BeiGene, Sanofi

Speakers' Bureau: Janssen Oncology, GlaxoSmithKline

Travel, Accommodations, Expenses: BeiGene, Janssen Oncology, Amgen

Javier De La Rubia

Consulting or Advisory Role: GlaxoSmithKline, Sanofi, Janssen Oncology, Karyopharm Therapeutics, Sanofi, Pfizer, Menarini

Speakers' Bureau: Amgen, Bristol Myers Squibb

Expert Testimony: Amgen, Celgene, Janssen, Sanofi, GlaxoSmithKline, Karyopharm Therapeutics, Pfizer

Travel, Accommodations, Expenses: Amgen, Janssen, Sanofi, Bristol Myers Squibb, GlaxoSmithKline

Felipe de Arriba

Honoraria: Janssen, Bristol Myers Squibb (Celgene), Sanofi, GlaxoSmithKline, Amgen

Consulting or Advisory Role: Janssen, GlaxoSmithKline, Sanofi, Bristol Myers Squibb/Celgene, Amgen

Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen

Luis Palomera

Honoraria: Janssen-Cilag

Consulting or Advisory Role: Celgene, Janssen-Cilag, Amgen

Miguel T. Hernández

Consulting or Advisory Role: Janssen, Sanofi/Aventis, Celgene/Bristol Myers Squibb, GlaxoSmithKline

Speakers' Bureau: Janssen, Celgene/Bristol Myers Squibb, GlaxoSmithKline

Javier Lopez Jiménez

Consulting or Advisory Role: Roche/Genentech, AbbVie, Janssen Oncology, Gilead Sciences, BeiGene, Celgene

Speakers' Bureau: Roche/Genentech, AbbVie, Pfizer

Research Funding: Roche/Genentech, AbbVie, BeiGene, Janssen-Ortho, Bristol Myers Squibb/Medarex

Travel, Accommodations, Expenses: Gilead Sciences, Janssen Oncology, AbbVie

Marta Reinoso-Segura

Honoraria: Janssen, Amgen, GlaxoSmithKline

Enrique M. Ocio

Honoraria: Amgen, Bristol Myers Squibb, Janssen, Takeda, Sanofi, GlaxoSmithKline, Oncopeptides, Pfizer, Regeneron, AbbVie

Consulting or Advisory Role: Amgen, Janssen, Oncopeptides, Takeda, Sanofi, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Pfizer, AbbVie, Menarini

Speakers' Bureau: Janssen-Cilag

Research Funding: GlaxoSmithKline

Travel, Accommodations, Expenses: Janssen, GlaxoSmithKline, BMS, Lilly

Bruno Paiva

Honoraria: Bristol Myers Squibb, Celgene, Janssen-Cilag, Takeda, Sanofi, Roche/Genentech, Adaptive Biotechnologies, Amgen, GlaxoSmithKline

Consulting or Advisory Role: Celgene, Janssen-Cilag, Sanofi, Takeda

Speakers' Bureau: Celgene

Research Funding: Celgene (Inst), Janssen-Cilag (Inst), Sanofi (Inst), Takeda (Inst), Roche/Genentech (Inst), GlaxoSmithKline (Inst), BeiGene (Inst)

Travel, Accommodations, Expenses: GlaxoSmithKline

Noemi Puig

Honoraria: Amgen, Celgene, Janssen, Takeda, The Binding Site, Sanofi, Pfizer

Consulting or Advisory Role: Amgen, Celgene, Janssen, Takeda, The Binding Site, Sanofi, Pfizer

Speakers' Bureau: Celgene

Research Funding: Celgene, Janssen, Amgen, Takeda, Pfizer (Inst)

Travel, Accommodations, Expenses: Amgen, Celgene, Janssen, Takeda, The Binding Site, Pfizer

M. Teresa Cedena

Honoraria: Janssen, Sobi

Joan Bladé

Honoraria: Janssen, Celgene, Amgen, Takeda, Oncopeptides

Juan Jose Lahuerta

Travel, Accommodations, Expenses: GlaxoSmithKline

Jesus F. San-Miguel

Consulting or Advisory Role: Amgen (Inst), Celgene (Inst), Takeda (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Novartis (Inst), Sanofi (Inst), Janssen (Inst), Roche (Inst), AbbVie (Inst), GlaxoSmithKline (Inst), Karyopharm Therapeutics (Inst), Secura Bio (Inst), Regeneron (Inst), Haemalogix (Inst), Pfizer (Inst), Kite, a Gilead company (Inst)

No other potential conflicts of interest were reported.
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