Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study

Rajkumar, S. Vincent; Attal, Michel; Richardson, Paul G.; Rajkumar, Vincent; Miguel, Jesús F. San; Beksaç, Meral; Špıčka, Ivan; Leleu, Xavier; Schjesvold, Fredrik; Moreau, Philippe; Dimopoulos, Meletios A.; Huang, Jeffrey Shang-Yi; Minařík, Jiří; Cavo, Michèle; Prince, H. Miles; Macé, Sandrine; Corzo, Kathryn P.; Campana, Frank; Le-Guennec, Solenn; Dubin, Franck; Anderson, Kenneth C.; Harrison, Simon; Janowski, Wojt; Kerridge, Ian; Spencer, Andrew; Delforge, Michel; Fostier, Karel; Vlummens, Philip; Wu, Ka Lung; LeBlanc, Richard; Pavic, Michel; Sébag, Michaël; Hájek, Roman; Maisnar, Vladimír; Pour, Luděk; Gregersen, Henrik; Benbouker, Lotfi; Caillot, Denis; Escoffre‐Barbe, Martine; Façon, Thierry; Frenzel, Laurent; Hulin, Cyrille; Karlin, Lionel; Kolb, Brigitte; Pégourie, Brigitte; Perrot, Aurore; Tiab, Mourad; Vincent, Laure; Niederwieser, Dietger; Anagnostopoulos, Αchilles; Delimpasi, Sosana; Kyrtsonis, Marie‐Christine; Symeonidis, Argiris; Illés, Árpád; Mikala, Gábor; Nagy, Zsolt; Bringen, Sara; Corradini, Paolo; Ciceri, Fabio; Lemoli, Roberto M.; Liberati, Anna Marina; Nozzoli, Chiara; Zambello, Renato; Iida, Shinsuke; Ikeda, Takashi; Iyama, Satoshi; Matsumoto, Morio; Shimazaki, Chihiro; Sunami, Kazutaka; Suzuki, Kenshi; Uchiyama, Michihiro; Koh, Youngil; Kım, Kihyun; Lee, Jae Hoon; Min, Chang‐Ki; Blacklock, Hillary; Goodman, Hugh J. B.; Neylon, Annette; Simpson, David; Grosicki, Sebastian; Jurczyszyn, Artur; Walter‐Croneck, Adam; Warzocha, Krzysztof; Araujo, Luiz Felipe Lopez; Moreira, Cláudia; Doronin, Vadim; Mendeleeva, Larisa; Vorobyev, Vladimir I.; Vranovský, Andrej; Alegre, Adrián; Gironella, Mercedes; Pérez, Marta Sonia González; Montes, Carmen; Ocio, Enrique M.; Rodríguez, Paula; Hardling, Mats; Lauri, Birgitta; Wang, Ming-Chung; Yeh, Su‐Peng; Arat, Mutlu; Demırkan, Fatih; Gülbaş, Zafer; Beşışık, Sevgi Kalayoğlu; Karadoğan, İhsan; Tuğlular, Tülin; Ünal, Ali; Vural, Fılız; Sive, Jonathan; Streetly, Matthew; Yong, Kwee; Tache, Jason

doi:10.1016/s0140-6736(19)32556-5

Cited by 457 publications

(502 citation statements)

References 27 publications

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“…In the last decade, carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, daratumumab, isatuximab, and selinexor have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, and promise to improve outcomes further. Numerous combinations have been developed using drugs that have shown activity in multiple myeloma, and the most commonly used regimens are listed in Table 6 54‐76 . These drugs work through a variety of mechanisms, some of which are not fully understood.…”

Section: Treatment Of Newly Diagnosed Myelomamentioning

confidence: 99%

“…Recent advances in the treatment of relapsed multiple myeloma, including new active agents and results of major randomized trials are discussed below (Table 8). 66,68,69,71‐73,75 137‐140 One important consideration is that the lenalidomide‐containing regimens listed in Table 8 were tested mainly in patient populations who were not previously exposed to lenalidomide. In contrast, current clinical practice typically consists of patients who have been treated with lenalidomide and are often relapsing while on a lenalidomide‐containing regimen.…”

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

“…Istatuximab is a monoclonal antibody targeting CD38 that has shown promise in relapsed, refractory multiple myeloma. In a randomized trial, isatuximab, pomalidomide, dexamethasone (Isa‐Pd) was associated with better PFS compared to Pd in patients with relapsed and refractory multiple myeloma; median PFS 11.5 months vs 6.5 months, P = .001 75 . Based on these data, isatuximab has been approved by the FDA for the treatment of relapsed refractory myeloma in patients who have received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor.…”

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

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Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

2020

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Disease overview: Multiple myeloma accounts for approximately 10% of hematologic malignancies.Diagnosis: The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). Risk stratification:The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma.Risk-adapted initial therapy: In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd).Maintenance therapy: After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma.Management of refractory disease: Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.

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Section: Treatment Of Newly Diagnosed Myelomamentioning

confidence: 99%

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

Section: Treatment Of Relapsed Multiple Myelomamentioning

confidence: 99%

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Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

2020

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“…Subgroup analysis revealed that PFS benefit was also maintained in high-risk patients (median PFS 7.5 vs. 3.7 months, HR 0.66, 95% CI 0.30-1.28). The median OS was NR in either group, although a trend to improved OS was observed in the triplet arm (HR 0.687, 95% CI 0.461-1.023; p = 0.06) [37]. Regarding the safety profile, Isa-Pd induced a slightly higher rate of grade 3-4 infections (42.8% vs. 30.2%) and neutropenia (84.9% vs. 70.1%) [50].…”

Section: Isatuximabmentioning

confidence: 91%

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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“…These encouraging clinical data supported the initiation of a large-scale, phase 3 study (ICARIA, NCT02990338), comparing Isa-Pd vs Pd [64]. Three-hundred and seven patients with pomalidomide-naïve RRMM, who had received a median of 3 prior lines (range 2-11, including lenalidomide and a PI) and refractory to the last line of therapy were randomized.…”

Section: Isatuximabmentioning

confidence: 91%

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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Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study

Cited by 457 publications

References 27 publications

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

Multiple myeloma: 2020 update on diagnosis, risk‐stratification and management

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

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

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