Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

Abstract

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest

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Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Juan-Jose Lahuerta

Consulting or Advisory Role: Janssen-Cilag, Celgene

Bruno Paiva

Honoraria: Janssen, Celgene

Consulting or Advisory Role: Janssen, Celgene

Research Funding: Celgene (Inst)

Travel, Accommodations, Expenses: Janssen, Celgene

Maria-Belen Vidriales

No relationship to disclose

Lourdes Cordón

No relationship to disclose

Maria-Teresa Cedena

No relationship to disclose

Noemi Puig

Honoraria: Janssen-Cilag, Takeda, Amgen

Consulting or Advisory Role: Janssen-Cilag

Travel, Accommodations, Expenses: Janssen-Cilag

Joaquin Martinez-Lopez

Consulting or Advisory Role: Novartis, Celgene, Janssen, Bristol-Myers Squibb

Speakers’ Bureau: Novartis, Celgene, Janssen, Bristol-Myers Squibb

Research Funding: Novartis, Celgene, Janssen, Bristol-Myers Squibb (Inst)

Laura Rosiñol

Honoraria: Celgene, Janssen

Norma C. Gutierrez

No relationship to disclose

María-Luisa Martín-Ramos

No relationship to disclose

Albert Oriol

Consulting or Advisory Role: Amgen, Janssen-Cilag

Speakers’ Bureau: Amgen, Janssen-Cilag

Ana-Isabel Teruel

No relationship to disclose

María-Asunciín Echeveste

No relationship to disclose

Raquel de Paz

No relationship to disclose

Felipe de Arriba

Honoraria: Janssen, Celgene

Speakers’ Bureau: Janssen, Celgene

Miguel T. Hernandez

No relationship to disclose

Luis Palomera

Honoraria: Janssen-Cilag, Celgene

Consulting or Advisory Role: Celgene, Janssen-Cilag

Rafael Martinez

No relationship to disclose

Alejandro Martin

No relationship to disclose

Adrian Alegre

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

Javier De la Rubia

No relationship to disclose

Alberto Orfao

No relationship to disclose

Maria-Victoria Mateos

Honoraria: Janssen, Celgene

Speakers’ Bureau: Janssen, Celgene

Joan Blade

Honoraria: Celgene, Janssen, Amgen

Research Funding: Janssen (Inst)

Jesus F. San Miguel

Consulting or Advisory Role: Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Takeda, Roche

Figures

Fig 1

(A) PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) GEM (Grupo Español de Mieloma) 2000, (B) GEM2005MENOS65, and (C) GEM2010MAS65 study designs, showing the timing of minimal residual disease (MRD) assessments and numbers of patients included in the present analyses. Data and procedures of all these GEM clinical trials were subject to supervision by a qualified and independent external company. ALO, mini allogeneic stem cell transplant; ASCT, autologous stem cell transplantation; Btz, bortezomib; CR, complete remission; Rd, lenalidomide, dexamethasone; TD, thalidomide, dexamethasone; VBMCP/VBAD, vincristine, carmustine, cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, dexamethasone; VMP, bortezomib, melphalan, prednisone; VT, bortezomib, thalidomide; VTD, bortezomib, thalidomide, dexamethasone.

Fig 2

(A) Progression-free survival (PFS) and (B) overall survival (OS) from time of minimal residual disease (MRD) assessment (9 months after study enrollment) per conventional response assessment: less than partial response (

Fig 3

Forest plots of hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) from time of minimal residual disease (MRD) assessment (9 months after study enrollment) according to achievement of MRD negativity (MRD−) or complete response (CR), among patient subgroups stratified by treatment (transplant v no transplant), International Staging System (ISS) disease stage, and standard-risk versus. high-risk (any t[4;14], t[14;16], and/or del[17p]) cytogenetics by fluorescent in situ hybridization (FISH). (A) PFS by MRD−; (B) PFS by CR achievement; (C) OS by MRD−; (D) OS by CR achievement.

Fig 4

(A) Minimal residual disease (MRD)-negative (MRD−) and MRD-positive (MRD+) rates after induction with vincristine, carmustine, cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and dexamethasone (VBMCP/VBAD), thalidomide and dexamethasone (TD), VBMCP/VBAD followed by two courses of bortezomib (VBMCP/VBAD/Btz), or bortezomib, thalidomide, dexamethasone (VTD) before high-dose therapy and autologous stem cell transplantation (n = 322). MRD− rates after VTD were significantly superior versus other induction regimens. Patients receiving VTD induction displayed trends for superior (B) progression-free survival (PFS) and (C) overall survival (OS) from time of MRD assessment. (D) PFS and (E) OS among transplant-eligible patients in CR after induction, stratified into subgroups who were MRD− before and after HDT/ASCT (MRD– → MRD–), who attained MRD– after HDT/ASCT (MRD+ → MRD–), and who were MRD+ before and after HDT/ASCT (MRD+ → MRD+).

Fig 5

(A) Progression-free survival (PFS) and (B) overall survival (OS) from time of minimal residual disease (MRD) assessment (9 months after study enrollment) among patients with baseline monoclonal gammopathy of undetermined significance (MGUS)-like versus multiple myeloma–like bone marrow phenotypic profiles, according to MRD status. MM, multiple myeloma; MRD–, MRD-negative; MRD+, MRD-positive.