Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

Pieter Sonneveld; Meletios A Dimopoulos; Meral Beksac; Bronno van der Holt; Sara Aquino; Heinz Ludwig; Sonja Zweegman; Thilo Zander; Elena Zamagni; Ruth Wester; Roman Hajek; Lucia Pantani; Luca Dozza; Francesca Gay; AnneMaria Cafro; Luca De Rosa; Annamaria Morelli; Henrik Gregersen; Nina Gulbrandsen; Petra Cornelisse; Rosella Troia; Stefania Oliva; Vincent van de Velden; KaLung Wu; Paula F Ypma; Gerard Bos; Mark-David Levin; Luca Pour; Christoph Driessen; Annemiek Broijl; Alexandra Croockewit; Monique C Minnema; Anders Waage; Cecilie Hveding; Niels W C J van de Donk; Massimo Offidani; Giuseppe A Palumbo; Andrew Spencer; Mario Boccadoro; Michele Cavo

doi:10.1200/JCO.21.01045

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

Pieter Sonneveld^*, Meletios A Dimopoulos, Meral Beksac, Bronno van der Holt, Sara Aquino, Heinz Ludwig, Sonja Zweegman, Thilo Zander, Elena Zamagni, Ruth Wester, Roman Hajek, Lucia Pantani, Luca Dozza, Francesca Gay, AnneMaria Cafro, Luca De Rosa, Annamaria Morelli, Henrik Gregersen, Nina Gulbrandsen, Petra CornelisseRosella Troia, Stefania Oliva, Vincent van de Velden, KaLung Wu, Paula F Ypma, Gerard Bos, Mark-David Levin, Luca Pour, Christoph Driessen, Annemiek Broijl, Alexandra Croockewit, Monique C Minnema, Anders Waage, Cecilie Hveding, Niels W C J van de Donk, Massimo Offidani, Giuseppe A Palumbo, Andrew Spencer, Mario Boccadoro, Michele Cavo

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial.

PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS).

RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable.

CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Original language	English
Pages (from-to)	3613-3622
Number of pages	10
Journal	Journal of Clinical Oncology
Volume	39
Issue number	32
DOIs	https://doi.org/10.1200/JCO.21.01045
Publication status	Published - 10 Nov 2021

Keywords

Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols/administration & dosage
Bortezomib/administration & dosage
Consolidation Chemotherapy
Dexamethasone/administration & dosage
Europe
Humans
Lenalidomide/administration & dosage
Maintenance Chemotherapy
Middle Aged
Multiple Myeloma/drug therapy
Neoplasm Staging
Neoplasm, Residual
Progression-Free Survival
Time Factors
Young Adult
DEXAMETHASONE
CONSENSUS
INDUCTION
THERAPY
IMPROVES
STEM-CELL TRANSPLANTATION
OPEN-LABEL
BORTEZOMIB
OUTCOMES
LENALIDOMIDE MAINTENANCE

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10.1200/JCO.21.01045

Cite this

Sonneveld, P., Dimopoulos, M. A., Beksac, M., van der Holt, B., Aquino, S., Ludwig, H., Zweegman, S., Zander, T., Zamagni, E., Wester, R., Hajek, R., Pantani, L., Dozza, L., Gay, F., Cafro, A., De Rosa, L., Morelli, A., Gregersen, H., Gulbrandsen, N., ... Cavo, M. (2021). Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. Journal of Clinical Oncology, 39(32), 3613-3622. https://doi.org/10.1200/JCO.21.01045

@article{37b7a8fcd238427cb05868bd1196d880,

title = "Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma",

abstract = "PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial.PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS).RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable.CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.",

keywords = "Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Bortezomib/administration & dosage, Consolidation Chemotherapy, Dexamethasone/administration & dosage, Europe, Humans, Lenalidomide/administration & dosage, Maintenance Chemotherapy, Middle Aged, Multiple Myeloma/drug therapy, Neoplasm Staging, Neoplasm, Residual, Progression-Free Survival, Time Factors, Young Adult, DEXAMETHASONE, CONSENSUS, INDUCTION, THERAPY, IMPROVES, STEM-CELL TRANSPLANTATION, OPEN-LABEL, BORTEZOMIB, OUTCOMES, LENALIDOMIDE MAINTENANCE",

author = "Pieter Sonneveld and Dimopoulos, {Meletios A} and Meral Beksac and {van der Holt}, Bronno and Sara Aquino and Heinz Ludwig and Sonja Zweegman and Thilo Zander and Elena Zamagni and Ruth Wester and Roman Hajek and Lucia Pantani and Luca Dozza and Francesca Gay and AnneMaria Cafro and {De Rosa}, Luca and Annamaria Morelli and Henrik Gregersen and Nina Gulbrandsen and Petra Cornelisse and Rosella Troia and Stefania Oliva and {van de Velden}, Vincent and KaLung Wu and Ypma, {Paula F} and Gerard Bos and Mark-David Levin and Luca Pour and Christoph Driessen and Annemiek Broijl and Alexandra Croockewit and Minnema, {Monique C} and Anders Waage and Cecilie Hveding and {van de Donk}, {Niels W C J} and Massimo Offidani and Palumbo, {Giuseppe A} and Andrew Spencer and Mario Boccadoro and Michele Cavo",

note = "Funding Information: Supported by the Dutch Cancer Society (grant 2010-4798), by the European Myeloma Network, and by unrestricted grants from Celgene and Janssen. Funding Information: Funding for this study was provided by the Dutch National Cancer Society and by Janssen and Celgene. The study was performed as an independent, investigator-sponsored study. All patients provided written informed consent and the study was approved by the independent ethics committee or institutional review board of each participating hospital. Funders had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. The corresponding author had full access to the data and carried the final responsibility for the submission of the manuscript. Publisher Copyright: {\textcopyright} 2021 by American Society of Clinical Oncology.",

year = "2021",

month = nov,

day = "10",

doi = "10.1200/JCO.21.01045",

language = "English",

volume = "39",

pages = "3613--3622",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "32",

}

Sonneveld, P, Dimopoulos, MA, Beksac, M, van der Holt, B, Aquino, S, Ludwig, H, Zweegman, S, Zander, T, Zamagni, E, Wester, R, Hajek, R, Pantani, L, Dozza, L, Gay, F, Cafro, A, De Rosa, L, Morelli, A, Gregersen, H, Gulbrandsen, N, Cornelisse, P, Troia, R, Oliva, S, van de Velden, V, Wu, K, Ypma, PF, Bos, G, Levin, M-D, Pour, L, Driessen, C, Broijl, A, Croockewit, A, Minnema, MC, Waage, A, Hveding, C, van de Donk, NWCJ, Offidani, M, Palumbo, GA, Spencer, A, Boccadoro, M & Cavo, M 2021, 'Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma', Journal of Clinical Oncology, vol. 39, no. 32, pp. 3613-3622. https://doi.org/10.1200/JCO.21.01045

TY - JOUR

T1 - Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

AU - Sonneveld, Pieter

AU - Dimopoulos, Meletios A

AU - Beksac, Meral

AU - van der Holt, Bronno

AU - Aquino, Sara

AU - Ludwig, Heinz

AU - Zweegman, Sonja

AU - Zander, Thilo

AU - Zamagni, Elena

AU - Wester, Ruth

AU - Hajek, Roman

AU - Pantani, Lucia

AU - Dozza, Luca

AU - Gay, Francesca

AU - Cafro, AnneMaria

AU - De Rosa, Luca

AU - Morelli, Annamaria

AU - Gregersen, Henrik

AU - Gulbrandsen, Nina

AU - Cornelisse, Petra

AU - Troia, Rosella

AU - Oliva, Stefania

AU - van de Velden, Vincent

AU - Wu, KaLung

AU - Ypma, Paula F

AU - Bos, Gerard

AU - Levin, Mark-David

AU - Pour, Luca

AU - Driessen, Christoph

AU - Broijl, Annemiek

AU - Croockewit, Alexandra

AU - Minnema, Monique C

AU - Waage, Anders

AU - Hveding, Cecilie

AU - van de Donk, Niels W C J

AU - Offidani, Massimo

AU - Palumbo, Giuseppe A

AU - Spencer, Andrew

AU - Boccadoro, Mario

AU - Cavo, Michele

N1 - Funding Information: Supported by the Dutch Cancer Society (grant 2010-4798), by the European Myeloma Network, and by unrestricted grants from Celgene and Janssen. Funding Information: Funding for this study was provided by the Dutch National Cancer Society and by Janssen and Celgene. The study was performed as an independent, investigator-sponsored study. All patients provided written informed consent and the study was approved by the independent ethics committee or institutional review board of each participating hospital. Funders had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. The corresponding author had full access to the data and carried the final responsibility for the submission of the manuscript. Publisher Copyright: © 2021 by American Society of Clinical Oncology.

PY - 2021/11/10

Y1 - 2021/11/10

N2 - PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial.PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS).RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable.CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

AB - PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial.PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS).RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable.CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

KW - Adolescent

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage

KW - Bortezomib/administration & dosage

KW - Consolidation Chemotherapy

KW - Dexamethasone/administration & dosage

KW - Europe

KW - Humans

KW - Lenalidomide/administration & dosage

KW - Maintenance Chemotherapy

KW - Middle Aged

KW - Multiple Myeloma/drug therapy

KW - Neoplasm Staging

KW - Neoplasm, Residual

KW - Progression-Free Survival

KW - Time Factors

KW - Young Adult

KW - DEXAMETHASONE

KW - CONSENSUS

KW - INDUCTION

KW - THERAPY

KW - IMPROVES

KW - STEM-CELL TRANSPLANTATION

KW - OPEN-LABEL

KW - BORTEZOMIB

KW - OUTCOMES

KW - LENALIDOMIDE MAINTENANCE

U2 - 10.1200/JCO.21.01045

DO - 10.1200/JCO.21.01045

M3 - Article

C2 - 34520219

SN - 0732-183X

VL - 39

SP - 3613

EP - 3622

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 32

ER -