Daratumumab resistance is frequent in advanced‐stage multiple myeloma patients irrespective of<scp>CD</scp>38 expression and is related to dismal prognosis

Pick, Marjorie; Vainstein, Vladimir; Goldschmidt, Neta; Lavie, David; Libster, Diana; Gural, Alexander; Grisariu, Sigal; Avni, Batia; Yehuda, Dina Ben; Gatt, Moshe E.

doi:10.1111/ejh.13046

Cited by 71 publications

(51 citation statements)

References 35 publications

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“…e presence of high-risk cytogenetics (particularly del(17p) and amp [1q21]) is associated with development of EMD [4]. EMD is associated with an adverse prognosis in newly diagnosed and in relapsed MM patients and tends to be resistant to proteasome inhibitors, immunomodulatory agents, and even novel agents such as daratumumab [5][6][7]. As such, infusional "traditional" chemotherapy agents are used in the treatment of patients with relapsed/refractory MM (RRMM) as a means of rapid tumor debulking or as a bridge to high-dose therapy and stem cell transplant.…”

Section: Introductionmentioning

confidence: 99%

Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Parrondo

Roy

Sher

et al. 2020

Case Reports in Hematology

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Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

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Section: Introductionmentioning

confidence: 99%

Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Parrondo

Roy

Sher

et al. 2020

Case Reports in Hematology

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“…Mechanistically, the anti-MM effects of therapeutic antibodies do not solely rely on intrinsic pathways of cell death but are mediated via external lysis of target cells with complement components and cytotoxic granules from killer T cells and NK cells [95][96][97][98]. Hence, the activity of immunotherapies may not be limited by a complex clonal architecture with spatial genomic heterogeneity, except for the presence of EMDs [99]. This action is an obvious advantage of therapeutic antibodies and is strengthened by IMiD-induced activation of immune cellmediated cytotoxicity and blockade of immune checkpoints [100][101][102][103][104].…”

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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“…Pick et al treated with daratumumab 37 patients with a median number of 5 previous lines of therapy [20]. While patients treated earlier showed a high rate of durable responses, those with more advanced disease had a dismal prognosis (ORR 36%, PFS and OS 2.3 and 6.6 months, respectively).…”

Section: Article Highlightsmentioning

confidence: 99%

“…Fifteen patients after 1-3 prior lines (median 2) have been enrolled so far. After a median of 7 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) cycles, current ORR is 87%. Seven patients achieved VGPR and 6 patients PR.…”

Section: Elotuzumab In Combination With Pismentioning

confidence: 99%

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

Musto

Rocca

2020

Expert Review of Hematology

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Introduction: In the last few years, monoclonal antibodies have rapidly modified the therapeutic strategies for treating patients with multiple myeloma. Areas covered: In this review, the most recent literature data regarding indications for which monoclonal antibodies are currently or will be shortly approved as salvage therapies in relapsed/refractory myeloma are discussed. In particular, updated results until March 22, 2020 of antibodies directed against CD38 (daratumumab and isatuximab), SLAMF7 (elotuzumab), BCMA (GSK2857916/belantamab mafodotin), and PD-1/PD-1 L axis (nivolumab and pembrolizumab) will be analyzed in detail. Expert opinion: Monoclonal antibodies represent a new, very effective approach that will open novel and dynamic treatment scenarios for myeloma patients in the coming years. Optimal positioning and selection of different antibodies that are or will be soon available, appropriate combinations and careful evaluation of possible new toxicities should be considered in the future management of these patients.

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Daratumumab resistance is frequent in advanced‐stage multiple myeloma patients irrespective ofCD38 expression and is related to dismal prognosis

Abstract: Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.

Cited by 71 publications

References 35 publications

Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

Molecular basis of clonal evolution in multiple myeloma

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

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