Elotuzumab in multiple myeloma

KEYWORDS:

• Elotuzumab
• multiple myeloma
• therapy

1. Introduction

Multiple myeloma (MM) treatment has changed over the years, doubling the patients’ life expectancy. This result is predominantly related to the extensive use of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), representing myeloma therapy milestones.

However, the outcome of patient refractory to PI and IMiDs remains poor [1]. In this scenario, several monoclonal antibodies (mAbs) have been developed. Elotuzumab (formerly HuLuc63) is a humanized IgG1 antibody targeting signaling lymphocytic-activation molecule F7 (SLAMF7), a homotypic adhesion molecule highly expressed on MM plasma cells [2].

2. SLAMF7 role and inhibition

The SLAMF7, a member of the SLAM superfamily, acts as self-ligands, which exert activating or inhibitory influences on the immune system. It contains a cytoplasmic region including two immunoreceptor tyrosine-based switch motifs, which, once phosphorylated, induce downstream pathways regulating the activation and differentiation of several immune cells [2].

The promoter region of SLAMF7/CS1 can bind Blimp-1 (B-lymphocyte-induced maturation protein-1), which is highly expressed in MM that enhances SLAMF7/CS1 transcription, determining a high surface expression of SLAMF7 on MM plasma cells [2].

Elotuzumab selectively recognizes SLAMF7, acting through a dual effect: a) NK cell-mediated antibody-dependent cellular cytotoxicity on SLAMF7-expressing MM cells and b) direct activation of NK cells. In vitro studies have shown that it fails to induce direct or complement-mediated lysis of MM cells and has no clinical activity when used as a single agent [2]. Conversely, elotuzumab inhibits cell viability of human MM cells co-cultured with bone marrow stromal cells in a dose-dependent manner, overcoming the stimulatory and protective effects of the microenvironment on the MM cells’ growth and survival [2]. Moreover, elotuzumab can induce SLAMF7 expression in NK cells and, acting as a self-ligand, amplify its molecular effect [2]. Moreover, elotuzumab facilitates the macrophage-mediated killing of MM cells [2].

Several strategies have been explored to increase the cytotoxic effect of elotuzumab. Mouse models showed that pre-treating MM plasma cells with bortezomib or lenalidomide could increase the anti-elotuzumab anti-neoplastic activity [2].

3. Clinical studies

3.1. Elotuzumab as single agent

A multicenter, first in humans, phase 1 study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of elotuzumab in RRMM. Patients were enrolled into six dosing cohorts (0.5-mg/kg, 1.0-mg/kg, 2.5-mg/kg, 5.0-mg/kg, 10-mg/kg, and 20-mg/kg). The most frequent treatment-emergent adverse events (AEs, mostly grade 1–2) included chills, fatigue, pyrexia, cough, headache, anemia, nausea, and back pain. No elotuzumab-related death [3] and no objective response were accounted for; only nine patients (26.5%) achieved stable disease, while the remaining cases had progressive disease (PD).

3.2. Elotuzumab, in combination with IMiDs

3.2.1. EloRd

IMiDs appear to be the ideal elotuzumab companions for their direct and indirect effects on T- and NK-cells function [2].

In a randomized, multicenter, open-label, dose-escalation phase 2 study, RRMM patients received elotuzumab (10 or 20 mg/kg) lenalidomide and dexamethasone (EloRd) until disease progression or unacceptable toxicity. Sixty-one (84%) patients achieved an objective response (33 [92%] with 10 mg/kg, 28 [76%] with 20 mg/kg). The most common any grade AEs were diarrhea, muscle spasms, and fatigue. The most common grade 3–4 AEs were lymphopenia and neutropenia [4].

Considering these promising results, the phase-3-study ELOQUENT-2 compared the efficacy of EloRd vs. Rd in patients with RRMM (Table 1).

Table 1. Selected elotuzumab-based trials in multiple myeloma.

Authors	Disease status	No. of patients	Schedule	ORR	Median PFS
Phase II
Dimopoulos et al [11,12]	Refractory or relapsed and refractory to Lena and a proteasome inhibitor	117	Elo 10 mg/kg on days 1, 8, 15, 22 cycles 1–2, 20 mg/kg on day 1 from cycle 3; Poma 4 mg 21/28; Dexa 40 mg (patients ≤75 years) 20 mg (patients >75 years) on days 1, 8, 15, 22; versus Poma 4 mg 21/28; Dexa 40 mg (patients ≤75 years) 20 mg (patients >75 years) on days 1, 8, 15, 22;	53% 26%	10.3 mo 4.7 mo
Jakubowiak et al [14]	Relapsed/refractory	155	Elo 10 mg/kg on days 1, 8, 15 cycles 1–2; on days 1, 11 cycles 3–8, on days 1, 15 thereafter. Bz 1.3 mg/m^2 on days 1, 4, 8, 11 cycles 1–8 and on days 1, 8, 15 thereafter; Dexa 20 mg on non-Elo dosing days, and 16 mg (8 mg orally plus 8 mg IV) on Elo dosing days; versus Bz 1.3 mg/m^2 on days 1, 4, 8, 11 cycles 1–8 and on days 1, 8, 15 thereafter; Dexa 20 mg on non-Elo dosing days, and 16 mg (8 mg orally plus 8 mg IV) on Elo dosing days;	66% 63%	9.7 mo 6.9 mo
Phase III
Lonial et al [5]	Relapsed/refractory	321	Elo 10 mg/kg on days 1, 8, 15, 22 cycles 1–2, on days 1, 15 from cycle 3; Lena 25 mg 21/28; Dexa 40 mg on days 1, 8, 15, 22; versus Lena 25 mg 21/28; Dexa 40 mg on days 1, 8, 15, 22;	79% 66%	19.4 mo 14.9 mo
Dimopoulos et al [10]	Newly diagnosed and unfit	748	Elo 10 mg/kg on days 1, 8, 15, 22 cycles 1–2, on days 1, 15 cycle 3–18, 20 mg/kg on day 1 from cycle 19; Lena 25 mg 21/28; Dexa 40 mg on days 1, 8, 15, 22; versus Lena 25 mg 21/28; Dexa 40 mg on days 1, 8, 15, 22;	83% 79%	31.4 mo 29.5 mo
Retrospective
Gentile et al [8]	Relapsed/refractory	300	Elo 10 mg/kg on days 1, 8, 15, 22 cycles 1–2, on days 1, 15 from cycle 3; Lena 25 mg 21/28; Dexa 40 mg on days 1, 8, 15, 22;	77%	17.6 mo

Abbreviations: Bz = bortezomib; Dexa = dexamethasone; Elo = elotuzumab; Lena = lenalidomide; No = number; ORR = overall response rate; PFS = progression free survival.

Overall, 646 patients have been randomized. The median age was 66 years (range 37–91), and the median number of prior lines of therapy was 2 (range 1–4); 35% of the cases were resistant to the most recent line of therapy (bortezomib 22%, and thalidomide 10%).

The 1-year progression-free survival (PFS) was 68% and 57% in EloRd and Rd groups; the 2-year PFS was 41% and 27%, respectively. The benefit of PFS in the elotuzumab group was consistent across predefined high-risk subgroups [5].

Similar results have been observed in the 4-year follow-up analysis. In a post hoc analysis, the most significant PFS benefit was observed in patients at the median time or further from diagnosis (≥3.5 years) and with one prior line of therapy [6].

In the final 5-year analysis, the median OS was 48.3% and 39.6%, respectively (P = 0.0408). Early and sustained separation of OS and PFS curves was seen over time. The safety profile of EloRd remained consistent with the primary analysis [7].

The results of the ELOQUENT-2 were also confirmed outside the clinical trial. Recently, we reported data from an Italian real-life experience on EloRd in 300 RRMM patients ensuring the ELOQUENT-2 results (Table 1) [8]. An extended follow-up analysis of our cohort showed that this triplet maintains its efficacy, with a 3-year PFS similar to that reported in ELOQUENT-2 [6]. The 3-year OS probability of our cohort was inferior to that reported in the ELOQUENT-2 trial (48 vs. 60%, respectively), likely related to a higher rate of patients previously exposed to lenalidomide in our cohort (27% vs. 5%); this population showed a significantly lower ORR compared to lenalidomide-naive patients [9]. In contrast with ELOQUENT-2 results, a longer time from diagnosis failed to affect PFS in our analysis. Conversely, ≥2 lines of previous therapy were associated with a significantly shorter PFS in univariate but not multivariate analysis, likely due to the efficacy of subsequent new treatments [9].

Unfortunately, the ELOQUENT-1 trial, which evaluated EloRd in newly diagnosed, transplantation-ineligible MM patients, failed to demonstrate the additive clinical activity of elotuzumab to Rd (Table 1) [10]. In fact, after a median follow-up of 65.3 months, the median PFS was not significantly different between the two arms of the trial (31.4 months in the EloRd cohort versus 29.5 months in the Rd cohort; P = 0.44) [10].

3.2.2. EloPd

Considering elotuzumab’s efficacy and safety profile in combination with lenalidomide, the drug was tested in a phase-2-study with dexamethasone and pomalidomide. RRMM, previously exposed to lenalidomide and PI, were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (EloPd) or pomalidomide and dexamethasone (Pd) (Table 1).

The administration of elotuzumab in this schedule was different from EloRd: while in cycles 1 and 2, patients received 10 mg per kilogram of body weight on days 1, 8, 15, and 22 during, as well as EloRd schedule, in cycle 3 the dosage was increased to 20 mg per kilogram on day 1, instead of 10 mg on days 1 and 15.

After a minimum follow-up of 9.1 months, the median PFS was 10.3 months in the EloPd group and 4.7 months in the Pd group. The overall response rate (ORR) was 53% and 26%, respectively. The most common grade 3–4 AEs were neutropenia, anemia, and hyperglycemia, equally distributed in both arms [11].

Recently, this trial showed that the EloPd schedule achieved a statistically significant OS improvement compared to Pd (median OS 29.8 months versus Pd 17.4 months; hazard ratio of 0.59; P = 0.0217) [12].

This EloPd combination’s benefit was also confirmed in a real-world cohort of patients with advanced MM, who received a median number of five prior lines of therapy. Median PFS was 6.4 months, with 12-month and 18-month PFS rates of 35% and 28%, respectively [13].

3.3. Elotuzumab in combination with proteasome inhibitors

3.3.1. Elotuzumab, bortezomib, and dexamethasone (EloBd)

The EloBd combination was tested in an open-label phase 2 study in which this association was compared to dexamethasone and bortezomib (Bd) (Table 1). Median PFS was longer in the EloBd (9.7 months) vs. Bd (6.9 months) arms but not statistically significant (P = 0.09). No additional clinically significant adverse events occurred in EloBd vs. Bd groups [14]. Based on these modest results in terms of efficacy, EloBd never became a reference therapy in RRMM.

Recently, the SWOG-1211 study showed no advantage to adding elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) as maintenance therapy [15].

3.3.2. Elotuzumab and carfilzomib-based regimens

Elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (EloKRd) without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses in untreated MM patients without transplant intent [16]. Recently, data from a phase 2 trial showing the efficacy and safety of elotuzumab in combination with pomalidomide, carfilzomib, and dexamethasone (EloKPd) in high-risk RRMM have been reported. The results indicate that this quadruplet exhibits promising results associated with manageable adverse events [17].

4. New combinations

Nowadays, several clinical trials are testing the elotuzumab efficacy in RRMM in combination with (a) pomalidomide, dexamethasone, and bortezomib (ClinicalTrials.gov Identifier: NCT02718833), (b) belantamab mafodotin in patients already exposed at least to 1 IMiD and 1 PI (ClinicalTrials.gov Identifier: NCT05002816), (c) pomalidomide, dexamethasone, isatuximab (ClinicalTrials.gov Identifier: NCT04835129), (d) in combination with umbilical cord blood NK cell lenalidomide and high-dose melphalan followed by autologous stem cell transplantation (ClinicalTrials.gov Identifier: NCT01729091). Moreover, elotuzumab will be explored with lenalidomide and dexamethasone in naive high-risk smoldering MM (ClinicalTrials.gov Identifier: NCT02279394).

5. Expert opinion

Elotuzumab combinations are safe and effective strategies for RRMM. Nevertheless, their real potential and optimal use timing should be further explored.

The MM algorithm is changing daily. Induction regimens based on quadruplets rather than triplets and anticipation of daratumumab are at the forefront. Nevertheless, the availability of therapeutic regimens that may be effective in RRMM patients after the induction failure of daratumumab-based combinations, i.e. with dexamethasone and IMiDs with or without a PI. In this context, elotuzumab represents an excellent therapeutic weapon with a good efficacy profile, even in patients pretreated with PI or lenalidomide and, without any limitation of use after the failure of daratumumab. Moreover, it showed a good safety profile, with different toxicity than other drugs active on myeloma (i.e. no neuropathies or severe anemia and thrombocytopenia). Furthermore, elotuzumab is characterized by a low rate of infusion-related reactions than anti-CD38 antibodies, often used to treat RRMM patients. Finally, when combined with other anti-MM drugs, elotuzumab adds minor toxicity than anti-CD38 antibodies. This makes it a manageable drug even in those patients who have discontinued a previous treatment due to toxicity. Most of the efficacy data for elotuzumab (from both controlled and real-life studies) come from the EloRd association, approved by the FDA as a therapy for RRMM in November 2015. The EloRd schedule has shown the greatest effectiveness as the first salvage regimen in lenalidomide-naive patients and in patients with relatively longer disease duration. However, more and more patients not eligible for the autologous stem cell transplant receive as first-line therapy regimens containing lenalidomide, most often in combination with daratumumab and dexamethasone. Consequently, the elotuzumab combination regimen on which to turn the spotlight is EloPd (approved by the FDA in November 2018), which has demonstrated the ability to bypass both lenalidomide and daratumumab resistance. EloPd is currently the only schedule showing a significant survival benefit in a randomized trial for RRMM patients who received at least two prior therapies, including lenalidomide and PI. New combination regimens are currently being studied to investigate the combination strategy further and the correct timing to insert therapy with elotuzumab.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.