Elotuzumab monotherapy in patients with smouldering multiple myeloma: a phase 2 study

Jagannath, Sundar; Laubach, Jacob P.; Wong, Ellice; Stockerl‐Goldstein, Keith; Rosenbaum, Cara A.; Dhodapkar, Madhav V.; Jou, Ying‐Ming; Lynch, Mark; Robbins, Michael; Shelat, Suresh G.; Anderson, Kenneth C.; Richardson, Paul G.

doi:10.1111/bjh.15384

Cited by 31 publications

(15 citation statements)

References 29 publications

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“…10 Strategies using other immunotherapeutics, such as vaccines (PVX-410), elotuzumab, and daratumumab, have reported ORR of 0%, 10%, and 56% and CR rate of 0%, 0% and 5%, respectively. [28][29][30] Emerging data from the use of myeloma-like regimens, such as carfilzomib, lenalidomide, and dexamethasone with or without autologous stem cell transplantation, have reported high ORR of 98% and 100%, and MRD-negative CR of 55% and 63%, respectively. 31,32 However, it is unclear at this time whether the morbidity associated with such intensive therapies is justified for SMM.…”

Section: Discussionmentioning

confidence: 99%

A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis

Manasanch¹,

Han

Mathur³

et al. 2019

Blood Advances

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Multiple myeloma is, in most patients, an incurable cancer. Its precursors can be identified with routine tests setting the stage for early intervention to prevent active myeloma. We investigated the efficacy and safety of pembrolizumab, an antiprogrammed cell death 1 antibody, in smoldering myeloma patients with intermediate/high risk of progression to symptomatic myeloma. Thirteen patients were treated with a median number of 8 cycles. One patient achieved a stringent complete response with bone marrow next-generation sequencing negativity at 10−4 that is ongoing at 27 months (8%); 11 had stable disease (85%), and 1 progressed (8%). Three patients discontinued therapy due to immune-related adverse events: 2 with transaminitis and 1 due to tubulointerstitial nephritis. Immune profiling of bone marrow samples at baseline showed markers associated with a preexisting immune response in the responder compared with nonresponders and features of increased T-cell exhaustion in nonresponders. Consistent with this, transcriptome sequencing of bone marrow samples at baseline revealed an increased interferon-γ signature in the responder compared with the nonresponders. In summary, our results suggest that smoldering myeloma may be immunogenic in a subset of patients, and therapies that enhance antitumor T-cell responses may be effective in preventing its progression. This trial was registered at www.clinicaltrials.gov as #NCT02603887.

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Section: Discussionmentioning

confidence: 99%

A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis

Manasanch¹,

Han

Mathur³

et al. 2019

Blood Advances

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“…Grade 3-4 toxicities included neutropenia (16%) and infections (12%), mainly related to lenalidomide. Again, single-agent elotuzumab did not show any clinical activity when in the setting of SMM [79].…”

Section: Clinical Developmentmentioning

confidence: 84%

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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“…69 Elotuzumab was first approved for MM on November 30, 2015. 70 Although no studies have found benefit for elotuzumab monotherapy, either in the advanced 71 or smoldering 72 settings, it has demonstrated significant activity in combination with IMiDs and other agents in the relapsed and refractory setting. 73 At the time of publication, elotuzumab has received FDA approval as combination therapy with lenalidomide and dexamethasone (E-Rd) for the treatment of adult patients with RRMM who have received one to three prior therapies or in combination with pomalidomide and dexamethasone (E-Pd) for adult patients who have received at least two prior therapies including lenalidomide and a PI.…”

Section: Special Considerationsmentioning

confidence: 99%

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

Shah

Aiello

Avigan

et al. 2020

J Immunother Cancer

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Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

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Elotuzumab monotherapy in patients with smouldering multiple myeloma: a phase 2 study

Cited by 31 publications

References 29 publications

A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis

A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis

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

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

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