Elotuzumab (Empliciti)

Number: 0899

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses elotuzumab (Empliciti) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of elotuzumab (Empliciti) is required of all Aetna participating providers and members in applicable plan designs. For precertification of elotuzumab (Empliciti), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Multiple Myeloma

   Aetna considers elotuzumab (Empliciti) medically necessary for the treatment of previously treated multiple myeloma when any of the following criteria are met:

   1. The requested medication will be used in In combination with lenalidomide and dexamethasone in members who have received at least one prior therapy; or
   2. The requested medication will be used in combination with bortezomib and dexamethasone in members who have received at least one prior therapy; or
   3. The requested medication will be used in In combination with pomalidomide and dexamethasone in members who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of elotuzumab (Empliciti) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Elotuzumab is available as Empliciti in 300 mg and 400 mg vials. Recommended dosing is as follows:

Multiple Myeloma

Elotuzumab with lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first 2 cycles and every 2 weeks thereafter until disease progression or unacceptable toxicity. Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.

Elotuzumab with pomalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and 20 mg/kg every 4 weeks thereafter until disease progression or unacceptable toxicity. Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.

Source: Bristol-Myers Squibb Company, 2019

Experimental and Investigational

Aetna considers elotuzumab (Empliciti) experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• B-cell lymphoma (including lymphoplasmacytic lymphoma)
• Extra-medullary myeloma
• Light chain amyloidosis
• Newly diagnosed (not previously treated) multiple myeloma
• Non-Hodgkin lymphoma (including diffuse large B-cell lymphoma, follicular lymphoma, indolent B-cell lymphoma, mantle-cell lymphoma, and primary mediastinal lymphoma)
• Primary amyloidosis
• Smoldering multiple myeloma
• Systemic lupus erythematosus.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
HCPCS codes covered if selection criteria are met :
Elotuzumab (Empliciti) :
HCPCS codes covered if selection criteria are met:
J9176	Injection, elotuzumab, 1 mg
Other HCPCS codes related to the CPB:
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J8540	Dexamethasone, oral, 0.25 mg
J9041	Injection, bortezomib, 0.1 mg
J9046	Injection, bortezomib, (dr. reddy's), not therapeutically equivalent to J9041, 0.1 mg
J9047	Injection, carfilzomib, 1 mg
J9048	Injection, bortezomib (fresenius kabi), not therapeutically equivalent to J9041, 0.1 mg
J9049	Injection, bortezomib (hospira), not therapeutically equivalent to J9041, 0.1 mg
J9051	Injection, bortezomib (maia), not therapeutically equivalent to j9041, 0.1 mg
ICD-10 codes covered if selection criteria are met:
C90.02	Multiple myeloma in relapse
ICD-10 codes not covered for indications listed in the CPB:
C82.00 - C82.09	Follicular lymphoma
C83.00 - C83.09	Small cell B-cell lymphoma
C83.10 - C83.19	Mantle-cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.50 - C83.59	Lymphoplasmacytic diffuse lymphoma
C85.10 - C85.99	Other and unspecified types of non-Hodgkin lymphoma
C90.00 - C90.01	Multiple myeloma not having achieved remission and in remission [not covered for newly diagnosed multiple myeloma and smoldering multiple myeloma]
C90.20 - C90.22	Extramedullary plasmacytoma
E85.0 - E85.9	Amyloidosis
M32.0 - M32.9	Systemic lupus erythematosus (SLE)

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Empliciti is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies.
• Empliciti is indicated in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Compendial Uses

• Therapy for previously treated multiple myeloma for relapsed or progressive disease in combination with bortezomib and dexamethasone

Multiple myeloma (MM) is characterized by the neoplastic proliferation of clonal plasma cells in the bone marrow resulting in skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Additional disease-related complications include hypercalcemia, renal insufficiency, anemia, and infections.

Schmidt-Wolf and colleagues (2014) stated that MM, with an incidence of 4 to 6/100,000 inhabitants, is a fairly frequent malignancy of B cells.  The incidence increases markedly with age. While standard treatments are associated with high response rates in patients with newly diagnosed multiple myeloma (MM), effective therapy for relapsed and refractory patients remains a challenge. The present standard of care in the progressive or refractory MM was elaborated by the working group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013.  Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant co-morbidities.  Ongoing studies address the question about the least toxic and the most effective treatment.  Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended including the use of 3rd generation immunomodulatory drugs (IMIDs; e.g., pomalidomide), new proteasome inhibitors (e.g., carfilzomib, ixazomib or oprozomib), antibodies (e.g., daratumumab, denosumab, elotuzumab, romosozumab, siltuximab, tabalumab), Bruton's tyrosine kinase (BTK)-, heat shock protein (HSP)-inhibitors and other innovative phase I/II agents.

Ashjian and Redic (2016) noted that there have been a number of recent advances in the treatment of patients with relapsed and refractory MM.  However, despite additional Food and Drug Administration (FDA)-approved therapies including carfilzomib and pomalidomide as well as clinical trials investigating new combinations of existing treatments, MM remains an incurable disease.  New therapies currently in the drug development pipeline for relapsed and refractory MM include additional proteasome inhibitors (ixazomib, marizomib, oprozomib), histone deacetylase inhibitors (panobinostat, quisinostat, ricolinostat), mAbs (daratumumab, elotuzumab), BTK inhibitors (ibrutinib) and others.

On November 30, 2015, the FDA approved elotuzumab (Empliciti) in combination with lenalidomide and dexamethasone to treat people with MM who have received 1 to 3 prior medications.  The FDA approval was based on the findings of the phase III clinical trial by Lonial et al (2015).  The most common side effects of Empliciti are constipation, cough, diarrhea, fatigue, nasopharyngitis, pneumonia, pyrexia, decreased appetite, peripheral neuropathy, and upper respiratory tract infection.

Lonial and associates (2013) reviewed the scientific literature regarding the development and clinical investigation of a CS1-targeted monoclonal antibody (mAb), elotuzumab, for the potential treatment of MM.  Elotuzumab is an immunostimulatory mAb targeting signaling lymphocytic activation molecule F7 (SLAMF7). This binding triggers the interactions of natural killer T cells to mediate the destruction of myeloma cells via the antibody dependent cellular cytotoxicity process. The authors summarized the pre-clinical pharmacological data, along with safety, tolerability and effectiveness of elotuzumab alone and in combination. They stated that elotuzumab, in combination with lenalidomide, showed high overall response rate (ORR) in phase I and II clinical trials.  Furthermore, the improvements observed in progression-free survival (PFS) suggested superiority over lenalidomide/dexamethasone alone, with a similar tolerability profile.  These researchers noted that while elotuzumab is associated with a higher incidence of infusion reactions, these can be managed with appropriate pre-medication.  The authors noted that the high activity of the elotuzumab/lenalidomide combination is being further investigated in phase III clinical trials.  They stated that elotuzumab represents an exciting potential therapeutic option for patients with MM, including those with relapsed and refractory disease, as well as in the induction and post-transplant maintenance settings, and possibly even for early therapy in patients with high-risk smoldering myeloma.

In a phase III, multi-center, randomized controlled trial (RCT), Lonial and colleagues (2015) randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group).  Co-primary end-points were PFS and the ORR.  Final results for the co-primary end-points were reported on the basis of a planned interim analysis of PFS.  Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group.  After a median follow-up of 24.5 months, the rate of PFS at 1 year in the elotuzumab group was 68 %, as compared with 57 % in the control group; at 2 years, the rates were 41 % and 27 %, respectively.  Median PFS in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio [HR] for progression or death in the elotuzumab group, 0.70; 95 % confidence interval [CI]: 0.57 to 0.85; p < 0.001).  The ORR in the elotuzumab group was 79 %, versus 66 % in the control group (p < 0.001).  Common grade 3 or 4 adverse events in the 2 groups were fatigue, lymphocytopenia, neutropenia, and pneumonia.  Infusion reactions occurred in 33 patients (10 %) in the elotuzumab group and were grade 1 or 2 in 29 patients.  The authors concluded that patients with relapsed or refractory MM who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30 % in the risk of disease progression or death.

On November 06, 2018, the FDA approved elotuzumab (Empliciti) in combination pomalidomide and dexamethasone (EPd) for the treatment of adult patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. This approval was based on results from ELOQUENT-3, a randomized, open-label, Phase 2 trial where EPd demonstrated benefit in patients with relapsed or refractory multiple myeloma, doubling both median progression-free survival (PFS) and overall response rate (ORR) versus pomalidomide and dexamethasone (Pd) (NCT02654132; Dimopoulos et al 2018).

Dimopoulos et al (2018) stated the  immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival. A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. The authors concluded that among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132).

Dimopoulos and colleagues (2020) stated that prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM).  In the ELOQUENT-2 trial, elotuzumab plus lenalidomide / dexamethasone (ERd) significantly improved PFS versus lenalidomide / dexamethasone (Rd) in patients with RRMM and 1 to 3 prior lines of therapy (LoTs).  These investigators reported findings from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM.  A total of 646 patients with RRMM and 1 to 3 prior LoTs were randomized 1:1 to ERd or Rd; PFS ORR were co-primary end-points.  OS was a key secondary end-point, with the final analysis planned after 427 deaths.  ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median of 48.3 versus 39.6 months; HR, 0.82 [95.4 % Cl: 0.68 to 1.00]; p = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key pre-defined subgroups.  No additional safety signals with ERd at extended follow-up were reported.  The authors concluded that ERd was the 1st antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1 to 3 prior LoTs.  The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, International Staging System (ISS) stage III, International Myeloma Working Group (IMWG) high-risk disease, and 2 to 3 prior LoTs.

Hose and colleagues (2021) noted that elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) was approved for relapsed/refractory MM in the U.S. and Europe.  Recently, a small phase-II clinical trial reported an advantage in PFS for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited.  These researchers analyzed the safety and efficacy of elo/pom/dex in a "real world" cohort of patients with advanced MM.  They queried the data-bases of the university hospitals of Würzburg and Vienna.  These investigators identified 22 patients with a median number of 5 LoTs who received elo/pom/dex before licensing within an early access program.  Patients received a median number of 5 4-week treatment cycles.  Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35 % and 28 %, respectively.  The ORR was 50 % and 64 % of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy.  Objective responses were also observed in 5 patients who had been pre-treated with pomalidomide.  Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry versus 6.4 months for ISS III), although this difference did not reach statistical significance.  No infusion-related reactions were reported; the most frequent grade-3/4 adverse events (AEs) were neutropenia and pneumonia.  The authors concluded that Elo/pom/dex was an active and well-tolerated regimen in highly advanced MM even after pre-treatment with pomalidomide.

Warnings and Precautions

• Infusion related reactions: Empliciti (elotuzumab) can cause infusion related reactions. Majority of the infusion related reactions occur with the first administration. Empliciti (elotuzumab) should be administered with pre‐infusion medications including intravenous corticosteroids, oral antipyretics, and an oral or intravenous anthistamine.
• Infections: Infections were reported in majority of patients. Patients should be monitored for infections accordingly and treated immediately.
• Second primary tumors: Second primiary tumors have been reported in the clinical trials. Patients should be monitored for the development of second primary tumors.
• Hepatotoxicity: Elevations in transaminases have been reported in clinical trials. Patients should have liver enzymes monitored routinely. Interrupt Empliciti (elotuzumab) therapy if liver enzymes are Grade 3 or higher.
• Safety and efficacy in pregnancy has not been evaluated.
• There is no information concerning presence of Empliciti (elotuzumab) in human milk, the outcomes on breastfed infant, or the outcomes on production of milk.
• Safety and efficacy in pediatric patients has not been evaluated.

Experimental Indications

There are 2 clinical trials on elotuzumab for the treatment of other malignancies --

1. a phase-I trial: “Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL” (This study is not yet open for participant recruitment; last verified January 2017); and
2. a phase-II trial: “Lenalidomide, Dexamethasone, and Elotuzumab With or Without Cyclophosphamide in Treating Patients With Relapsed Primary Amyloidosis” (This study is currently recruiting participants; last verified September 2017).

Extra-Medullary Myeloma

Danhof and colleagues (2021) stated that extra-medullary disease (EMD) represents a high-risk state of MM associated with poor prognosis.  While most anti-myeloma therapeutics demonstrate limited effectiveness in this setting, some studies examining the use of chimeric antigen receptor (CAR)-modified T cells reported promising results.  These researchers have recently designed SLAMF7-directed CAR T cells for the treatment of MM.  SLAMF7 is a trans-membrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow.  Currently, the only approved anti-SLAMF7 therapeutic is elotuzumab; however, its effectiveness in EMD has not been thoroughly examined.  In a retrospective study, these researchers examined the effectiveness of elotuzumab-based combination therapy in a cohort of 15 patients with EMD.  Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, these investigators examined the SLAMF7 expression on extra-medullary located tumor cells before and after treatment.  They observed limited effectiveness of elotuzumab-based combination therapies, with an ORR of 40 % and a PFS and OS of 3.8 and 12.9 months, respectively.  Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry.  Furthermore, to examine a potential antigen reduction under therapeutic selection pressure, these investigators analyzed samples of de-novo EMD (n = 3) outgrown during elotuzumab treatment.  Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples.  The authors concluded that the findings of this study indicated a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.

The authors noted that they are aware of the drawbacks of this study that were, in particular, related to its retrospective nature and the small sample size (n = 15); however, they felt that such real-life data could provide valuable insights, especially for rare disease manifestations, and potentially guide the setup of prospective studies.

Light Chain Amyloidosis

Rodriguez et al (2022) noted that light chain (AL) amyloidosis is challenging to diagnose, and it should be considered a cardiac emergency.  There have been significant advances in the treatment of AL amyloidosis from initial descriptions of melphalan therapy until the recent approval of the 1st AL amyloidosis specific drug (daratumumab).  Comprehension of the pathophysiology and biology of AL amyloidosis is important to understanding the major therapeutic targets in which light chain stability remains as a major key target of therapy.  Organ dysfunction is a result not only from disruption of organ architecture but also direct cellular toxicity.  Novel anti-plasma cell agents for AL like isatuximab (anti CD-38 monoclonal antibody), belantamab (anti-BCMA monoclonal antibody), and elotuzumab (anti-SLAMF7 monoclonal antibody) are currently under investigation.  The authors stated that both diagnostic and therapeutic advances make the future of AL management bright while acknowledging the complexity of this patient population and focusing on a multi-disciplinary approach.

Furthermore, an UpToDate review on “Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases” (Dispenzieri, 2022) does not mention elotuzumab as a management/therapeutic option.

Newly Diagnosed Multiple Myeloma

Radhakrishnan and associates (2017) stated that treatment of MM has undergone significant change in the past 10 years with the introduction of new immunomodulatory agents, proteasome inhibitors, and immunotherapeutic approaches.  Elotuzumab is a humanized monoclonal antibody targeting CS1, which is a member of the SLAM (Signaling Lymphocyte Activation Molecule) family of proteins, expressed on the surface of myeloma plasma cells.  These investigators reviewed the pre-clinical investigations that led to the development of elotuzumab and the clinical studies that resulted in its approval for the treatment of relapsed/refractory MM.  Although pre-clinical data looked very promising, elotuzumab monotherapy did not result in objective clinical responses in patients with relapsed/refractory multiple myeloma.  However, combination treatment with immunomodulators and proteasome inhibitors resulted in substantial clinical activity in relapsed/refractory MM.  The authors concluded that ongoing clinical trials are examining the role of elotuzumab in newly diagnosed MM in combination with standard treatment as well as in the maintenance setting after autologous stem cell transplant.

Kubo and colleagues (2020) stated that novel therapies are needed for patients with newly diagnosed MM (NDMM).  Elotuzumab plus lenalidomide and dexamethasone (ELd) is FDA-approved for the treatment of RRMM.  In a Japanese phase-II clinical trial, these researchers evaluated ELd versus lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation (SCT).  Elotuzumab infusion was accelerated to 5 ml/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 hour.  The primary end-point was ORR in the ELd arm; secondary end-points were the difference in ORR between treatments, and PFS.  Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld).  In the ELd arm, ORR was 88 % [70 % CI: 80 to 93].  The estimated difference in ORR between treatments was 13 % (95 % CI: - 4 to 30) in favor of ELd; PFS data were immature.  Safety was consistent with previous findings of ELd in Japanese patients with RRMM.  No infusion reactions occurred at the maximum rate of 5 ml/min, which was used in 89 % of elotuzumab infusions.  The authors concluded that ELd may be an effective, well-tolerated front-line treatment for patients with NDMM ineligible for SCT.

Smoldering Multiple Myeloma

Smoldering multiple myeloma is an asymptomatic clonal plasma cell disorder (Rajkumar, et al., 2015). Smoldering multiple myeloma is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma.

Jagannath and colleagues (2018) noted that smoldering MM (SMM) is associated with increased risk of progression to MM within 2 years, with no approved treatments.  Elotuzumab has been shown to promote natural killer (NK) cell stimulation and antibody-dependent cellular cytotoxicity (ADCC) in-vitro.  CD56dim (CD56dim /CD16+ /CD3- /CD45+ ) NK cells represent the primary subset responsible for elotuzumab-induced ADCC.  In a phase-II, non-randomized clinical trial, patients with SMM received elotuzumab 20 mg/kg intravenously (cycle 1: days 1, 8; monthly thereafter) or 10 mg/kg (cycles 1, 2: weekly; every 2 weeks thereafter).  The primary end-point was the relationship between baseline proportion of bone marrow-derived CD56dim NK cells and maximal M protein reduction; secondary end-points included ORR and PFS.  A total of 15 patients received 20 mg/kg and 16 received 10 mg/kg; combined data were presented.  At database lock (DBL, September 2014), no association was found between baseline CD56dim NK cell proportion and maximal M protein reduction.  With minimum 28 months' follow-up (DBL: January 2016), ORR (90 % CI) was 10 % (2.7 to 23.2) and 2-year PFS rate was 69 % (52 to 81 %).  Upper respiratory tract infections occurred in 18/31 (58 %) patients; 4 (13 %) patients experienced infusion reactions, all grade 1 to 2.  The authors stated that elotuzumab plus lenalidomide/dexamethasone is under investigation for SMM.

Systemic Lupus Erythematosus

Humbel and colleagues (2021) noted that systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity.  Cytotoxic function of NK cells is compromised in patients with SLE.  These researchers characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identified novel potential therapeutic targets. They examined peripheral blood mononuclear cells (PBMC) from SLE patients and matched healthy controls by single-cell mass cytometry to evaluate the phenotype of NK cells.  Furthermore, these researchers examined the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in-vitro co-culture model.  They found that SLE NK cells expressed higher levels of CD38 and were unable to adequately up-regulate SLAMF1 and SLAMF7 following activation.  Additionally, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in-vitro co-culture system.  The authors concluded that these findings indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells was associated with an altered interplay between SLE NK cells and plasma cells, suggesting that their contribution to the accumulation of (auto)antibody producing cells.  Thus, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell.  Moreover, these researchers stated that because both elotuzumab and daratumumab are safe when used to treat MM and appeared to be well-tolerated when administrated to SLE patients, their use should be examined in controlled studies to evaluate their effectiveness in the treatment of patients with SLE.

The authors stated that this study had several drawbacks.  First, the use of single-cell mass cytometry limited the identification of cell surface receptors to the antibodies included in the panels.  Compared to RNA seq, this method monitored fewer targets but directly identified cell surface proteins that could be targeted by therapeutic mAb.  Second, further investigations are needed to identify the individual implications of the 3 cell surface markers examined in this study in the interaction between NK cells and circulating plasma cells.  So far, this aspect remains unexplored due to the limited number of circulating plasma cells available from the peripheral blood of patients and controls.  These investigators are working on plasma cell line culture system that will allow to individually silence each receptor.  Finally, examination of secondary lymphoid organ and bone marrow aspirations would allow examination of B cells during their maturation process and long-lived plasma cells; however, these tissues are difficult to obtain.

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References