Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients

Oostvogels, Rimke; Jak, Margot; Raymakers, Reinier; Mous, Rogier; Minnema, Monique C.

doi:10.1111/bjh.15504

Cited by 21 publications

(22 citation statements)

References 29 publications

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“…The overall response rate was 41% in this study; in others, the ORR was 21% 13 and 25% 12 in the selinexor studies, 33% 15 and 55% 16 in the nelfinavir studies 28.6%, 52%, and 67% in three studies investigating retreatment after daratumumab. 45 , 46 In contrast, the ORR was higher with 60%, 47 81%, 3 and 85% 9 in three CAR-T cell studies.…”

Section: Discussionmentioning

confidence: 77%

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Real-World Outcome in the Pre-Car-T Era of Myeloma Patients Qualifying for Car-T Cell Therapy

Brechbühl¹,

Bacher

Jeker

et al. 2020

Mediterr J Hematol Infect Dis

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Introduction: CAR-T cell therapy is likely to be introduced starting from 2021 in patients with relapsed/refractory myeloma (r/r MM) in Europe. In order to qualify for commercial CAR-T treatment, it is assumed that r/r MM patients will have to be exposed to at least three lines of previous treatments including lenalidomide, bortezomib and anti-CD38 treatment. However, the outcome of this particular subgroup of r/r MM patients is largely unknown whereas this knowledge is crucial to estimate the possible benefit of eventual CAR-T treatment. Methods: In this non-interventional, retrospective single-center study, we analyzed all subsequent r/r MM patients treated between 01/2016 (when anti-CD38 treatment was commercially introduced in Switzerland) and 04/2020 at the University Hospital of Bern. Patients were eligible for the study if they had received at least three lines of treatment including one proteasome inhibitor (PI), one immunomodulatory drug (IMID) and one anti-CD38 antibody, and if they were in need of subsequent treatment and effectively received further lines of treatment. Results: Among 56 patients fulfilling the criteria of at least three lines of treatment including PI, IMID and anti-CD38 treatment, only 34 (60%) effectively received subsequent further therapy. This suggests that 40% of r/r MM patients never receive additional treatment after at least three lines of treatment including PI, IMID and anti-CD38 treatment. For patients receiving further treatment, the median number of previous lines of treatment was 4.5 (range 2-12), including autologous stem cell transplantation in 31 (91%) patients. 13 (37%) patients were penta-refractory. The most frequently used treatment options were IMID/dexamethasone treatment in 11 (32%) patients, followed by PI/dexamethasone in 10 (29%) patients. 21 (62%) patients received two or more additional lines of therapy. The median PFS was 6.6 months (range 0–36.6 months), the median TTNT was 7.5 months (range 1.4-24.5 months) and the median OS was 13.5 months, (range 0.1-38 months) for the first subsequent treatment. The overall response rate (ORR) to the first subsequent treatment was 41%, with a median duration of the response of 5 months (range 1-37 months). 12% of the patients achieved VGPR or better, with a median duration of response of 8 months (range 3-37 months). Conclusion: Myeloma patients refractory after at least three lines of anti-CD38/PI/IMID treatment have a poor prognosis with a PFS of 6.6 months and OS of 13.5 months. These data may serve as reference to compare the potential benefit of CAR-T treatment in this group of myeloma patients when available in the near future.

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Section: Discussionmentioning

confidence: 77%

“…Related studies on retreatment with IMiD’s and PI’s after anti-CD38 treatment reported even shorter survival rates, with a median PFS of 4 months for patients receiving PI’s, and three months for IMID’s. 46 In similar patient cohorts, the median PFS was 3.7 months for selinexor and 3.4 months for nelfinavir. 12 , 16 …”

Section: Discussionmentioning

confidence: 90%

Real-World Outcome in the Pre-Car-T Era of Myeloma Patients Qualifying for Car-T Cell Therapy

Brechbühl¹,

Bacher

Jeker

et al. 2020

Mediterr J Hematol Infect Dis

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“…The main treatment options for R/R MM patients include ASCT, PIs (bortezomib, carfilzomib, ixazomib), IMiDs (e.g., lenalidomide, pomalidomide, MoAb (e.g. daratumumab [DARA], elotuzumab), alkylating chemotherapy drugs, anthracyclines, panobinostat, and corticosteroids, administered alone, or more commonly as part of two- or three-drug combinations [19,[26], [27], [28], [29], [30], [31], [32], [33], [34], [35]]. The combination of daratumumab DARA, lenalidomide, and dexamethasone (Dex) has been proposed as the most effective regimen in the population of R/R MM patients.…”

Section: Therapeutic Landscape Of High Risk and Relapsed/refractory Mmentioning

confidence: 99%

“…In the ongoing Phase 2 and Phase 3 clinical studies, DARA is being evaluated in novel combinations with other treatment modalities, including PI's, IMiDs and Dex (Table 1). Notably, a recent observational study indicated that the immunomodulatory effects of DARA may contribute to a high objective response rate of previously IMiD-refractory or PI-refractory MM patients who are treated with DARA monotherapy to retreatment with IMiD/PI-based salvage regimens [29]. Likewise, other anti-CD38 MoAb, including Isatuximab (ISA) [41] and MOR202 [42], have shown promising activity in clinical trials of R/R MM patients.…”

Section: Therapeutic Landscape Of High Risk and Relapsed/refractory Mmentioning

confidence: 99%

Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma

et al. 2019

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Recurrence of disease due to chemotherapy drug resistance remains a major obstacle to a more successful survival outcome of multiple myeloma (MM). Overcoming drug resistance and salvaging patients with relapsed and/or refractory (R/R) MM is an urgent and unmet medical need. Several new personalized treatment strategies have been developed against molecular targets to overcome this drug resistance. There are several targeted therapeutics with anti-MM activity in clinical pipeline, including inhibitors of anti-apoptotic proteins, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, fusion proteins, and various cell therapy platforms. For example, B-cell maturation antigen (BCMA)-specific CAR-T cell platforms showed promising activity in heavily pretreated R/R MM patients. Therefore, there is renewed hope for high-risk as well as R/R MM patients in the era of personalized medicine.

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“…Other anti-CD38 mAb were also clinically developed as isatuximab and MOR202 [4]. The combination of anti-CD38 mAbs with main anti-MM drugs as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) demonstrated a high clinical efficacy in randomized phase III trials [5] leading to new therapeutic paradigms in relapsed/refractory MM patients. However, a considerable amount of MM patients does not respond or are refractory to the treatment with anti-CD38 mAbs either as single agents or in combination with PIs or IMiDs [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents

Costa

Palma

Giuliani

2019

Cells

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In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs.MM is a hematological cancer characterized by the accumulation and proliferation of malignant plasma cells (PCs) in the BM [9]. The close interaction between PCs and BM microenvironment cells creates a permissive niche for tumor survival and disease progression, characterized by osteolytic bone disease and immune-suppression [10]. Both soluble factors and cell-to-cell contact mechanisms are involved in this cross-talk. Among the surface molecules, which allow the adhesion to the microenvironment, MM cells highly express CD38 [11], which made it an attractive therapeutic target for mAbs [12,13]. Several studies demonstrated that only PCs strongly express CD38 antigens in BM, and that no PCs are detectable in either CD38 neg cell fraction or fraction of cells weakly expressing CD38 antigens (CD38 low ) [14,15]. However, activated B cell, T cells and NK cells up-regulate CD38 surface expression to levels similar to that found on PCs [16].CD38 is a 45-kDa type II transmembrane glycoprotein, which plays a dual role as a receptor and ectoenzyme [17]. It is expressed on normal cell subsets, such as T cells, NK cells, B cells, and dendritic cells [18]. It is involved in T cell activation and proliferation, B cell differentiation, and neutrophils and monocytes chemotaxis, [17,19,20]. In addition, CD38 interacts with the non-substrate ligand CD31, which is constitutively expressed by endothelial cells [21]. Interestingly, a co-expression of CD38 and CD31 was also demonstrated in MM cells but not on PC leukemia [22]. Accordingly, we have recently reported that extra-medullary MM cells can also lose the expression of CD38 [23].As ectoenzyme, CD38 acts like a metabolic sensor which catalyzes the extracellular conversion of NAD...

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Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients

Cited by 21 publications

References 29 publications

Real-World Outcome in the Pre-Car-T Era of Myeloma Patients Qualifying for Car-T Cell Therapy

Real-World Outcome in the Pre-Car-T Era of Myeloma Patients Qualifying for Car-T Cell Therapy

Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma

CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents

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