Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy

Danhof, Sophia; Strifler, Susanne; Hose, Dorothea; Kortüm, Martin; Bittrich, Max; Hefner, Jochen; Einsele, Hermann; Knop, Stefan; Schreder, Martin

doi:10.1007/s00432-018-2807-1

Cited by 19 publications

(20 citation statements)

References 35 publications

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“…Neither cytogenetic risk nor the number and type of prior therapy predicted for outcome in our cohort. Patients with low tumor burden as defined by ISS stages I and II at start of treatment appeared to gain increased benefit compared to those with stage III disease, confirming our previous observation (Danhof et al 2019). We could also demonstrate that highly pretreated patients (> 4 prior therapies) showed a similar PFS compared to patients with a lower number of previous therapies, justifying the use of this regimen even in late stage MM.…”

Section: Discussionsupporting

confidence: 87%

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

Hose

Schreder

Hefner

et al. 2020

J Cancer Res Clin Oncol

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Background The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. Purpose To analyze the efficacy and safety of elo/pom/dex in a "real world" cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna. Findings We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. Conclusion Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.

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Section: Discussionsupporting

confidence: 87%

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

Hose

Schreder

Hefner

et al. 2020

J Cancer Res Clin Oncol

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“…However, relapses occur limiting the efficacy of this promising treatment approach. Lower expression of the targeted antigen on cell surface have been suggested as a possible mechanism of resistance to targeted mAb therapy (148,149). Regarding CAR-T therapies, the composition and phenotypic of the administered T cells product, in term of the T-cells subsets, play a critical role for the clinical success of this strategy.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

et al. 2020

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Immunotherapy has recently emerged as a promising treatment option for multiple myeloma (MM) patients. Profound immune dysfunction and evasion of immune surveillance are known to characterize MM evolution and disease progression. Along with genomic changes observed in malignant plasma cells, the bone marrow (BM) milieu creates a protective environment sustained by the complex interaction of BM stromal cells (BMSCs) and malignant cells that using bidirectional connections and cytokines released stimulate disease progression, drug resistance and enable immune escape. Local immune suppression and T-cell exhaustion are important mediating factors of clinical outcomes and responses to immune-based approaches. Thus, further characterization of the defects present in the immune system of MM patients is essential to develop novel therapies and to repurpose the existing ones. This review seeks to provide insights into the mechanisms that promote tumor escape, cause inadequate T-cell stimulation and impaired cytotoxicity in MM. Furthermore, it highlights current immunotherapies being used to restore adaptive T-cell immune responses in MM and describes strategies created to escape these multiple immune evasion mechanisms.

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“…Ongoing studies are exploring the different potential mechanisms of resistance to anti-CD38 mAbs, as well as how to overcome them. Lower basal levels of the target antigen have been proposed as a possible mechanism of intrinsic resistance to mAbs [122,123]. Regarding daratumumab, the downregulation of CD38 on cell surfaces could partially explain the loss of response to mAb therapy [124].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Bonello

Mina

Boccadoro

2019

Cancers

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Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs ® ), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.Cancers 2020, 12, 15 2 of 24 Cancers 2020, 12, 15 3 of 24 (Bregs, which promote tumor growth and immune escape), as well as a subset of regulatory T cells (Tregs) express CD38, and their levels are reduced after daratumumab exposure. Conversely, daratumumab results in significant expansion of CD8+ cytotoxic and CD4+ helper T cells, likely following the depletion of regulatory cells. Remarkably, expanded effector T cells also show increased killing capacity due to augmented levels of granzyme B, which activates caspases and triggers cell apoptosis [23][24][25]. In addition, among the activities promoted by CD38, there is a nicotinamide adenine dinucleotide (NAD)-ase activity, which results in reduced levels of NAD+ in T cells, responsible for the loss of their effector functions (exhausted T cells). In murine models, anti-CD38 mAbs administration induced higher levels of NAD+ in T effector cells, thus enhancing their antitumor activity [23]. The main mechanisms of action of anti-CD38 monoclonal antibodies are summarized in Figure 1.

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Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy

Cited by 19 publications

References 35 publications

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

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