Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial

Mateos, María‐Victoria; Hernández, Miguel‐Teodoro; Giraldo, Pilar; Rubia, Javier de la; Arriba, Felipe de; Corral, Lucía López; Rosiñol, Laura; Paiva, Bruno; Palomera, Luis; Bargay, Joan; Oriol, Albert; Prósper, Felipe; López, Javier; Arguiñano, José-María; Quintana, Nuria; García, J. Coullaut-Valera; Bladé, Joan; Lahuerta, Juan-José; Miguel, Jesús F. San

doi:10.1016/s1470-2045(16)30124-3

Cited by 153 publications

(106 citation statements)

References 27 publications

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“…Early studies in SMM failed to show an advantage to preventive intervention, but were limited by lack of power, safe and effective drugs, and a risk‐adapted strategy 163,164 . A randomized trial conducted in Spain found that patients with high risk SMM had significant prolongation of PFS and OS with Rd compared with observation 90,165 .…”

Section: Smoldering Multiple Myelomamentioning

confidence: 99%

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

2020

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Disease overview: Multiple myeloma accounts for approximately 10% of hematologic malignancies.Diagnosis: The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). Risk stratification:The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma.Risk-adapted initial therapy: In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd).Maintenance therapy: After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma.Management of refractory disease: Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.

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Section: Smoldering Multiple Myelomamentioning

confidence: 99%

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

2020

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“…7 A recent randomized clinical trial by the Spanish Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) myeloma group demonstrated improved time to progression to overt myeloma and overall survival (OS) with early initiation of lenalidomide and dexamethasone therapy compared with patients managed with standard observation. 12,13 Despite the increasing interest in treatment studies that focus on high-risk smoldering myeloma, only limited information is available regarding the genetic profiles for this disease, but preliminary studies have suggested comparable mutational load and copy number profiles of myeloma cells in patients with either smoldering myeloma or MM. 14,15 We previously reported results from 2 prospective studies that included patients with either high-risk smoldering myeloma or newly diagnosed MM.…”

Section: Introductionmentioning

confidence: 99%

Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma

et al. 2017

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Early results of a prospective phase 2 clinical trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance in high-risk smoldering myeloma showed promising results that were previously published. Here, we provide novel insights into the genetic landscape of high-risk smoldering myeloma and information on sustained minimal residual disease (MRD) negativity with an expanded cohort of patients. Eighteen patients with high-risk smoldering myeloma were enrolled between 29 May 2012, and 14 January 2014. We included patients with newly diagnosed multiple myeloma enrolled in a parallel trial who received the same therapy (reference group). The overall response rate was 100%. With median potential follow-up of 43.3 months, 10 (63%) remain in MRD negativity, and the estimated 4-year progression-free and overall survival rates are 71% and 100%, respectively. Importantly, we report differences in mutational patterns in patients with high-risk smoldering myeloma and newly diagnosed multiple myeloma, reflected in a lower frequency of mutations in significant myeloma genes (6.6% vs 45%) and pathway genes (6.6% vs 25%). Treatment with carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance was associated with a 100% response rate and 63% MRD negativity with a safety profile consistent with previous reports for this regimen. This study had a small numbers of participants, but there seemed to be important differences in the genetic landscape of patients with high-risk smoldering myeloma and those with newly diagnosed multiple myeloma, suggestive of a more treatment-responsive biology in early disease.

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“…Although Ld delayed the development of active MM, a higher proportion of patients in the Ld arm experienced AEs compared with the observation cohort, including one grade 5 AE (Mateos et al , 2013). A long-term follow-up of this study, with a median follow-up of 75 months, showed that, as of June 2015, the median time to progression was not reached in the Ld group ( versus 23 months in the observation group; P < 0·0001) (Mateos et al , 2016). …”

Section: Discussionmentioning

confidence: 74%

Elotuzumab monotherapy in patients with smouldering multiple myeloma: a phase 2 study

et al. 2018

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Summary Smouldering multiple myeloma (SMM) is associated with increased risk of progression to multiple myeloma within 2 years, with no approved treatments. Elotuzumab has been shown to promote natural killer (NK) cell stimulation and antibody-dependent cellular cytotoxicity (ADCC) in vitro. CD56dim (CD56dim/CD16+/CD3−/CD45+) NK cells represent the primary subset responsible for elotuzumab-induced ADCC. In this phase II, non-randomized study (NCT01441973), patients with SMM received elotuzumab 20 mg/kg intravenously (cycle 1: days 1, 8; monthly thereafter) or 10 mg/kg (cycles 1, 2: weekly; every 2 weeks thereafter). The primary endpoint was the relationship between baseline proportion of bone marrow-derived CD56dim NK cells and maximal M protein reduction; secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). Fifteen patients received 20 mg/kg and 16 received 10 mg/kg; combined data are presented. At database lock (DBL, September 2014), no association was found between baseline CD56dim NK cell proportion and maximal M protein reduction. With minimum 28 months’ follow-up (DBL: January 2016), ORR (90% CI) was 10% (2·7–23·2) and 2-year PFS rate was 69% (52–81%). Upper respiratory tract infections occurred in 18/31 (58%) patients. Four (13%) patients experienced infusion reactions, all grade 1–2. Elotuzumab plus lenalidomide/dexamethasone is under investigation for SMM.

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Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial

Cited by 153 publications

References 27 publications

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma

Elotuzumab monotherapy in patients with smouldering multiple myeloma: a phase 2 study

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