Consolidation with carfilzomib, lenalidomide, and dexamethasone (KRd) following ASCT results in high rates of minimal residual disease negativity and improves bone metabolism, in the absence of bisphosphonates, among newly diagnosed patients with multiple myeloma

Gavriatopoulou, Maria; Terpos, Evangelos; Ntanasis‐Stathopoulos, Ioannis; Malandrakis, Panagiotis; Eleutherakis‐Papaiakovou, Evangelos; Παπαθεοδώρου, Αθανάσιος; Kanellias, Nikolaos; Migkou, Magdalini; Fotiou, Despina; Dialoupi, Ioanna; Ρούσσου, Μαρία; Kokkali, Nikoletta-Aikaterini; Kastritis, Efstathios

doi:10.1038/s41408-020-0297-2

Cited by 15 publications

(11 citation statements)

References 18 publications

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“…In a prospective trial, Gavriatopoulou et al, 2020, 11 evaluated the role of CRd as consolidation among 40 NDMM patients (median age, 56 years) with at least PR and less than MRD negative state after ASCT. These patients were given four cycles of CRd as consolidation followed by lenalidomide maintenance until progression.…”

Section: Resultsmentioning

confidence: 99%

“… NA 12/111 (11) 9/111 (8) 15/111 (13) NA Skin disorders=10/111 (9) Landgren et al, 2019 2 Toxicity profile not included in the interim results. NA NA NA NA NA NA Weisel et al, 2019 33 2/10 (20) 1/10 (10) 6/10 (60) 2/10 (20) NA NA NA Self-limiting ventricular tachycardia=1/10 (10) NA Diarrhea=1/10 (10) Cerebrovascular disorder=2/10 (20) Alsina et al, 2019 10 6/51 (12.1) NA NA NA NA NA NA NA Hyponatremia=6/51 (12.1) Increased ALT=5/51 (9.1) NA Pawlyn et al, 2019 30 NA NA NA NA NA NA NA NA NA NA Gavriapopolou et al, 2020 11 NA NA NA NA NA NA NA NA NA NA …”

Section: Resultsmentioning

confidence: 99%

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Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Imtiaz¹,

Khan²,

Ehsan³

et al. 2021

OTT

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Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a total of 27 studies (n=4538 patients) with overall response rates (ORR) ranging between 80% and 100%. Studies evaluating the combination of CFZ with daratumumab reported an ORR of approximately 100%. Achievement of minimal residual disease (MRD) negativity, measured by multi-parameter flow cytometry (MPFC), ranged between 60% and 95% in 4 (n=251) out of 6 studies that measured MRD-negativity. The interim results of the ENDURANCE trial failed to show superior efficacy and progression-free survival (PFS) of carfilzomib-lenalidomide when compared to bortezomib–lenalidomide combination, albeit with a lower incidence of neuropathy. Hematological toxicity was the most common adverse event observed with these regimens, and the most common non-hematological adverse events were related to cardiovascular and electrolyte disturbances. We need to further evaluate the role of CFZ in NDMM by conducting more Phase III trials with different combinations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Imtiaz¹,

Khan²,

Ehsan³

et al. 2021

OTT

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“…Although treatment of myeloma bone disease is primarily based on bone-targeting agents such as bisphosphonates and denosumab [ 4 ], anti-myeloma regimens including proteasome inhibitors seem to exert a beneficial effect on bone metabolism as well [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. In particular, bortezomib has inhibitory effects on osteoclastogenesis, but it also enhances bone formation [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Carfilzomib with dexamethasone (Kd) is a well-established regimen for patients with relapsed/refractory multiple myeloma (RRMM) in the clinical practice [ 17 , 18 , 19 ]. However, clinical data on the net effects of carfilzomib on indices of bone metabolism are limited [ 5 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study

Terpos

Ntanasis‐Stathopoulos

Katodritou

et al. 2021

Cancers

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Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

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“…Moreover, osteoprotegerin (OPG), a RANKL antagonist, and DKK1 are suppressed by MM cells [ 81 ]. Several anti-myeloma agents exert a beneficial effect on bone remodeling by restoring the homeostasis of the BMM [ 86 , 87 , 88 , 89 ].…”

Section: The Bmm In MMmentioning

confidence: 99%

The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma

Giannakoulas

Ntanasis‐Stathopoulos

Terpos

2021

IJMS

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The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.

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Consolidation with carfilzomib, lenalidomide, and dexamethasone (KRd) following ASCT results in high rates of minimal residual disease negativity and improves bone metabolism, in the absence of bisphosphonates, among newly diagnosed patients with multiple myeloma

Cited by 15 publications

References 18 publications

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study

The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma

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