Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

Mateos, María‐Victoria; Blacklock, Hilary; Schjesvold, Fredrik; Oriol, Albert; Simpson, David; George, Anupkumar; Goldschmidt, Hartmut; Larocca, Alessandra; Chanan‐Khan, Asher; Sherbenou, Daniel W.; Avivi, Irit; Benyamini, Noam; Iida, Shinsuke; Matsumoto, Morio; Suzuki, Kenshi; Ribrag, Vincent; Jagannath, Sundar; Ocio, Enrique M.; Rodríguez‐Otero, Paula; Miguel, Jesús F. San; Kher, Uma; Farooqui, Mohammed Z.H.; Liao, Jason J. Z.; Marinello, Patricia; Lonial, Sagar; Nicol, Andrew; Grigoriadis, George; Catalano, John; LeBlanc, Richard; Elemary, Mohamed; Bahlis, Nizar J.; Façon, Thierry; Karlin, Lionel; Attal, Michel; Engelhardt, Monika; Weisel, Katja; Mackensen, Andréas; Nagler, Arnon; Yehuda, Dina Ben; Magen-Nativ, Hila; Palumbo, Antônio; Cavo, Michèle; Tobinai, Kensei; Chou, Takaai; Kosugi, Hiroshi; Taniwaki, Masafumi; Sunami, Kazutaka; Ando, Kiyoshi; Ganly, Peter; Gjertsen, Bjørn T.; Lahuerta, Juan José; Bladé, Joan; Rocafiguera, Albert Oriol; Mateos, María Victoria; Larson, Sarah; Atanackovic, Djordje; Devarakonda, Srinivas; Bitran, Jacob D.; Zonder, Jeffrey A.; Morganstein, Neil; Hay, Mohammad Maher Abdul; Saylors, Gene; Kio, Ebenezer A.; Oliff, Ira; Kirkel, Dean; Shtivelband, Mikhail; Yuen, Carrie; Yee, Andrew J.; Shah, Jatin J.; Htut, Myo; Raza, Shahzad; Chhabra, Saurabh; Stiff, Patrick J.; Hari, Parameswaran; Bank, Bruce; Malek, Ehsan; Gasparetto, Cristina; Faroun, Ycaoub; Kreisle, William; Singhal, Seema; Rosenblatt, Jacalyn; Usmani, Saad Z.; Lee, Wes; Safah, Hana; Lutzky, Jose; Suh, Jason; Pan, Dorothy; Baron, Ari David; Manges, Robert; Steis, Ronald G.; Oliveira, Moacyr Ribeiro de; Moreb, Jan S.; Callander, Natalie S.; Anz, Bertrand; Raptis, Anastasios; Stampleman, Laura; Melear, Jason M.; Boyd, Thomas E.; Garbo, Lawrence; Klein, Leonard M.; Shao, Spencer H.; Lyons, Roger M.; McIntyre, Kristi; Tarantolo, Stefano; Yasenchak, Christopher A.; Yimer, Habte

doi:10.1016/s2352-3026(19)30110-3

Cited by 187 publications

(155 citation statements)

References 30 publications

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“…2 previous lines of therapy showed an unfavorable benefit/risk profile for the triple combination. 48 The median PFS was 5.6 months in the pembrolizumab plus pomalidomide and dexamethasone group and 8.4 months in the pomalidomide and dexamethasone-only group. 48 Serious AEs (SAEs) occurred in 56 of 121 patients (46%) in the pomalidomide and dexamethasone group compared with 75 of 120 patients (63%) in the pembrolizumab plus pomalidomide and dexamethasone group.…”

Section: Joseph Mikhaelmentioning

confidence: 90%

“…48 The median PFS was 5.6 months in the pembrolizumab plus pomalidomide and dexamethasone group and 8.4 months in the pomalidomide and dexamethasone-only group. 48 Serious AEs (SAEs) occurred in 56 of 121 patients (46%) in the pomalidomide and dexamethasone group compared with 75 of 120 patients (63%) in the pembrolizumab plus pomalidomide and dexamethasone group. 48 Four treatment-related deaths (3%) occurred with pembrolizumab plus pomalidomide and dexamethasone.…”

Section: Joseph Mikhaelmentioning

confidence: 90%

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Treatment Options for Triple-class Refractory Multiple Myeloma

Mıkhael

2020

Clinical Lymphoma Myeloma and Leukemia

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The advent of new, more effective, and less toxic therapies has revolutionized the management of multiple myeloma in the past decade. Despite the availability of new treatments, most patients with multiple myeloma will become refractory to the therapies that currently comprise the hematologic standard of care for the malignancy, including proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Moreover, in recent years, a new subset of patients with multiple myeloma refractory to all 3 of these agents has emerged. This population, for whom a clear treatment paradigm has remained undefined, has been characterized by poor survival outcomes. The current approaches to the treatment of triple-class refractory disease are limited and include conventional chemotherapy, salvage autologous stem cell transplantation, and recycling previous regimens, each of which have generally had short-lived efficacy. It is anticipated that additional agents will be available for triple-refractory disease in the near future, including selinexor, chimeric antigen receptor T-cell therapy, and next-generation monoclonal antibodies. The development and further refinement of novel treatments for this subset of patients should be considered a key clinical and research priority.

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Section: Joseph Mikhaelmentioning

confidence: 90%

Section: Joseph Mikhaelmentioning

confidence: 90%

Treatment Options for Triple-class Refractory Multiple Myeloma

Mıkhael

2020

Clinical Lymphoma Myeloma and Leukemia

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“…Lenalidomide downregulates PD-1 expression of myeloma patient-derived T cells, allowing the restoration of their cytotoxicity. However, combination anti-PD-1 and IMiD therapy has been discontinued due to increased risk of patient death in addition to an absence of significant difference in the phase III clinical trial (KEYNOTE183/NCT02576977, KEYNOTE185/NCT02579863) [64,65] (Table S1). Lenalidomide has been shown to disrupt the cross-talk between myeloma and stromal cells in the tumor microenvironment.…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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“…In phase II trials, ORR was 50% in RRMM patients receiving pembrolizumab plus Rd and 60% in patients receiving pembrolizumab plus Pd [86]. However, in 2017, following the preliminary results of the two randomized phase III trials KEYNOTE 185 (pembrolizumab-Rd vs. Rd) and KEYNOTE 183 (pembrolizumab-Pd vs. Pd), the FDA prompted the discontinuation of any further investigations of these combinations, in light of the increased risk of death for patients in the pembrolizumab group versus the control group (HR for OS in pembrolizumab-Pd vs. Pd 1.61; HR for OS in pembrolizumab-Rd vs. Rd 2.06) [87,88]. The main concern with this combination is indeed the increased risk of enhancing immune-mediated toxicity, resulting in various AEs, such as dermatologic, pulmonary, cardiac, gastrointestinal and hepatic toxicities.…”

Section: Clinical Developmentmentioning

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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Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

Cited by 187 publications

References 30 publications

Treatment Options for Triple-class Refractory Multiple Myeloma

Treatment Options for Triple-class Refractory Multiple Myeloma

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

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

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