Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma

Dimopoulos, Meletios A.; Dytfeld, Dominik; Grosicki, Sebastian; Moreau, Philippe; Takezako, Naoki; Hori, Mitsuo; Leleu, Xavier; LeBlanc, Richard; Suzuki, Kenshi; Raab, Marc S.; Richardson, Paul G.; McKiver, Mihaela Popa; Jou, Ying Ming; Shelat, Suresh G.; Robbins, Michael; Rafferty, Brian T.; Miguel, Jesús F. San

doi:10.1056/nejmoa1805762

Cited by 432 publications

(388 citation statements)

References 23 publications

Supporting

Mentioning

373

Contrasting

Unclassified

Order By: Relevance

“…Toxicity was as expected. In the randomized phase 2 ELOQUENT‐3 trial, the addition of elotuzumab to pomalidomide plus low‐dose dexamethasone resulted in a 46% reduction in the risk of death or progression versus pomalidomide plus low‐dose dexamethasone alone ( P = 0·008) (Dimopoulos et al , ). Other phase 2 and phase 3 RRMM trials are currently evaluating pomalidomide plus low‐dose dexamethasone with agents such as carfilzomib (NCT01464034) (Shah et al , ), daratumumab (NCT03180736) and isatuximab (NCT02990338) (Richardson et al , ).…”

Section: Discussionmentioning

confidence: 99%

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

et al. 2019

View full text Add to dashboard Cite

Summary Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM‐014 trial, we examined the safety and efficacy of pomalidomide plus low‐dose dexamethasone immediately after lenalidomide‐based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28‐day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28‐day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. The intention‐to‐treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior‐bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior‐bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior‐bortezomib subgroup). The most common grade 3/4 treatment‐emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide‐based therapy in lenalidomide‐pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: http://www.ClinicalTrials.gov identifier NCT01946477.

show abstract

Section: Discussionmentioning

confidence: 99%

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The fact that these outcomes were achieved in a patient population that had largely (87Á5%) just become refractory to lenalidomide is noteworthy, as it confirms that pomalidomide-dexamethasone is capable of not only achieving response in the immediate aftermath of lenalidomide failure, but of maintaining response to a clinically meaningful extent and in a highly tolerable manner. Granted, the ORR and depth of response achieved in this cohort are somewhat less in comparison to those of various triplet regimens which have been recently studied and approved for use in the relapsed/refractory space (Shah et al, 2015;Chari et al, 2017;Dimopolous et al, 2018;Richardson et al, 2019); however, the study retains importance for two main reasons. First, it will help to put to rest the notion that lenalidomide-refractory patients require a "class-switch" away from immunomodulatory drug (IMiD)containing therapy at the time of progression due to IMiD resistance.…”

mentioning

confidence: 85%

“…Regarding the third, we currently have encouraging but still yet to be conclusive data regarding monoclonal antibody activity within high‐risk subgroups. This includes the randomized phase 2 ELOQUENT‐3 study (Dimopolous et al , ), which demonstrated improved PFS with the addition of elotuzumab to pomalidomide‐dexamethasone in patients with RRMM (including a trend towards improved PFS in patients with high‐risk cytogenetics), and the single‐arm phase 2 EQUULEUS study of daratumumab‐pomalidomide‐dexamethasone (Chari et al , ), which demonstrated an impressive response rate of 60% in a heavily pre‐treated and predominantly IMiD/proteasome inhibitor‐refractory population (albeit with an exploratory analysis that was in fact worrisome for inferior PFS in patients with high‐risk cytogenetics). Along these lines, we similarly await the published results of MM‐014 Cohort B, which will hopefully include an analysis of cytogenetic and/or International Myeloma Working Group‐defined risk.…”

mentioning

confidence: 99%

Pomalidomide in lenalidomide‐refractory multiple myeloma: Far from futile

Richardson

2019

Br J Haematol

Self Cite

View full text Add to dashboard Cite

“…In the randomized phase II ELOQUENT-3 trial, the addition of elotuzumab to Pd in RRMM patients significantly increased the ORR (53% vs. 26%) and prolonged median PFS (10.3 vs. 4.7 months, HR 0.54, p = 0.008), as compared to Pd alone. Again, the safety profiles of the two arms of the study were overlapping, meaning that elotuzumab did not add significant toxicity to Pd [69]. On this basis, in 2018 the FDA approved the triplet elotuzumab-Pd for the treatment of RRMM patients who had received at least 2 prior regimens including lenalidomide and a PI.…”

Section: Clinical Developmentmentioning

confidence: 99%

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

Bonello

Mina

Boccadoro

2019

Cancers

View full text Add to dashboard Cite

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.

show abstract

Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma

Cited by 432 publications

References 23 publications

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

Pomalidomide in lenalidomide‐refractory multiple myeloma: Far from futile

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

Contact Info

Product

Resources

About