Maintenance Treatment and Survival in Patients With Myeloma

Gay, Francesca; Jackson, Graham; Rosiñol, Laura; Holstein, Sarah A.; Moreau, Philippe; Spada, Stefano; Davies, Faith E.; Lahuerta, Juan José; Leleu, Xavier; Bringhen, Sara; Evangelista, Andrea; Hulin, Cyrille; Panzani, Ugo; Cairns, David A.; Raimondo, Francesco Di; Macro, Margaret; Liberati, Anna Marina; Pawlyn, Charlotte; Offidani, Massimo; Spencer, Andrew; Hájek, Roman; Terpos, Evangelos; Morgan, Gareth J.; Bladé, Joan; Sonneveld, Pieter; Miguel, Jesús F. San; McCarthy, Philip L.; Ludwig, Heinz; Boccadoro, Mario; Mateos, María‐Victoria; Attal, Michel

doi:10.1001/jamaoncol.2018.2961

Cited by 74 publications

(42 citation statements)

References 56 publications

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“…The hazard ratio (HR) for progression or death was 0.72, which is similar to data from the Nordic/ German group on bortezomib in this setting [3]. In light of a recent meta-analysis investigating different maintenance regimens, lenalidomide still shows substantially better survival data and should remain standard of care [4].…”

Section: Newly Diagnosed Transplant Eligiblesupporting

confidence: 72%

ASH 2018—Highlights in Multiple Myeloma

Jeryczynski

Krauth

2019

memo

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More than 900 abstracts on multiple myeloma were presented at this year's ASH in San Diego. Several trials explored the addition of the monoclonal antibody daratumumab to established treatment regimens in both newly diagnosed as well as relapsed and refractory multiple myeloma. A long-awaited study tried to evaluate the role of double autologous stem cell transplant in multiple myeloma in newly diagnosed transplant eligible multiple myeloma. In relapsed and refractory multiple myeloma updates from several large trials like CAS-TOR and POLLUX were presented. Another spotlight were lenalidomide-refractory patients, an important patient group that is emerging as an increasingly challenging collective. Finally, abstracts on several novel agents like selinexor, venetoclax, isatuximab, melflufen and AMG420 were presented. Although still very preliminary, these data are already quite promising and illustrate the ever-changing treatment landscape in multiple myeloma.

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Section: Newly Diagnosed Transplant Eligiblesupporting

confidence: 72%

ASH 2018—Highlights in Multiple Myeloma

Jeryczynski

Krauth

2019

memo

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“…2 In particular, increasing the adoption of lenalidomide earlier in the myeloma treatment paradigm as maintenance therapy post high-dose melphalan and autologous stem cell transplantation (ASCT), or as a first-line therapy for elderly patients, has resulted in an increasing need for effective treatments for lenalidomide-refractory RRMM. 3,4 Efficacy results from phase 3 studies of novel combination therapies in lenalidomide-refractory patients remain unsatisfactory, and recent studies of lenalidomide-based combination therapies in RRMM exclude lenalidomide-refractory patients. [5][6][7][8][9][10] Daratumumab is a human immunoglobulin Gk (IgGk) monoclonal antibody targeting CD38 with a direct on-tumor [11][12][13][14] and immunomodulatory mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Chari

Martínez‐López

Mateos

et al. 2019

Blood

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118

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K E Y P O I N T S l Daratumumab plus carfilzomib/ dexamethasone induced deep durable responses, regardless of prior treatment with lenalidomide. l Splitting the first dose of daratumumab was feasible, and the regimen was well tolerated.Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomiderefractory patients were eligible. Carfilzomib-and daratumumab-naïve patients (n 5 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m 2 initial dose, escalated to 70 mg/m 2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide.

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“…Using primary samples, Chaidos et al [77] showed that the malignant counterparts of plasmablasts and pre-plasma cells could reconstruct MM in immunodeficient mice upon transplantation. From these observations, it can be speculated that IMiDs preferentially target MM stem cells, providing a molecular basis for the clinical finding that post-transplantation maintenance with lenalidomide significantly prolonged the survival of MM patients [85][86][87][88][89][90]. However, much less is known about the mechanism underlying the preferential effects of IMiDs on MM stem cells.…”

Section: Clonal Composition Affects Drug Sensitivitymentioning

confidence: 99%

Molecular basis of clonal evolution in multiple myeloma

Furukawa

Kikuchi

2020

Int J Hematol

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The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at the MGUS stage and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes including drug sensitivities. In general, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs but could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ~ 20% of MM evolve neutrally in the context of strong oncogenic drivers, such as high-risk IgH translocations, and are relatively resistant to IMiDs. Further understanding of the genomic landscape and the pattern of clonal evolution may contribute to the development of more effective treatment strategies for MM.

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Maintenance Treatment and Survival in Patients With Myeloma

Abstract: Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.

Cited by 74 publications

References 56 publications

ASH 2018—Highlights in Multiple Myeloma

ASH 2018—Highlights in Multiple Myeloma

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Molecular basis of clonal evolution in multiple myeloma

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