Elotuzumab 300mg powder for solution for infusion vials

To the Editor: In China, multiple myeloma (MM) has a crude prevalence of 7 per 100,000 population and an incidence of 1.6 per 100,000 population.[1] The term “1q21 abnormality” refers to genetic alterations including deletions, duplications, and amplifications in the 1q21 region of chromosome 1. Gain or amplification 1q21 (1q21+), which refers to an additional copy or multiple copies of genetic material in the long arm of chromosome 1 at position 21, is a well-documented abnormality that correlates with adverse clinical outcomes in patients with MM and has been demonstrated to be associated with poor prognosis, drug resistance, and disease progression in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM).[2] However, treatment options specifically for 1q21+ patients have seldom been recommended in guidelines due to the lack of clinical data, except for the 2018 Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) 3.0, which makes recommendations for transplant-eligible NDMM patients. This study aimed to evaluate the effectiveness of treatment regimens for RRMM with 1q21+ and to review relevant studies. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) extension statement and was registered in the PROSPERO database (No. CRD42023401904). PubMed, EMBASE, and the Cochrane CENTRAL Database were searched on September 8, 2022 (details are provided in Supplementary Materials, https://links.lww.com/CM9/C264). Randomized controlled trials (RCTs) of patients aged 18 years or older with a diagnosis of RRMM and 1q21+ were considered. We included patients who were treated with either single or combined pharmacological therapy using the following drugs regardless of dose and frequency. (1) Anti-CD38 monoclonal antibodies (mAbs): Daratumumab (dara) and isatuximab (Isa), (2) exportin-1 (XPO1) inhibitor: Selinexor, (3) antibody–drug conjugate (ADC): Belantamab, (4) anti-signaling lymphocytes activating molecule factor 7 (SLAMF7) mAbs: Elotuzumab (E), (5) protease inhibitors (PIs): Ixazomib (I) and carfilzomib (K), (6) immunomodulatory imide drug (IMiD): Pomalidomide (P). In addition, we included intervention with bortezomib (V) plus lenalidomide (R) plus dexamethasone (d). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), overall response rate (ORR), which was calculated as rate of complete response (CR) plus rate of very good partial response (VGPR), duration of response (DOR), and time to progression (TTP). Two reviewers extracted the following data from each study: Trial characteristics, participant characteristics, intervention information, and outcome information. Comparative data were synthesized using RevMan 5.3 (https://test-training.cochrane.org/online-learning/core-software-cochrane-reviews/review-manager-revman/download-revman-5). We calculated the hazard ratio (HR) and its 95% confidence interval (CI) for dichotomous outcomes, and the mean difference (MD) and its 95% CI for continuous outcomes. We synthesized single-group data and performed a proportional meta-analysis in R version 4.1.0 (https://www.r-project.org) with a meta-analysis package using the restricted maximum likelihood (REML) method. A fixed-effects model was used to synthesize data. Where significant heterogeneity was identified, namely I2 >50%, we explored the sources of heterogeneity through subgroup analysis of clinical, methodological, and statistical variations, and employed a random-effects model to pool data. We described the results of individual studies’ when a meta-analysis was inappropriate due to clinical or methodological heterogeneity. The quality of the included RCTs was assessed independently by two reviewers using the Cochrane Collaboration Risk of Bias 2.0 tool for randomized studies. Any disagreements were resolved by discussion. More details of methods are given in Supplementary Materials, https://links.lww.com/CM9/C264. Finally, five studies with nine references[3–11] were included [Supplementary Figure 1, https://links.lww.com/CM9/C264]. The five included RCTs (2094 patients) all enrolled 1q21+ patients (n = 926, 44.2%) as a subgroup. Two studies (n = 619) reported that the HRs (95% CI) for OS of elotuzumab plus lenalidomide plus dexamethasone (ERd) and ixazomib plus lenalidomide plus dexamethasone (IRd) exhibited no significant differences from those with Rd, with values of 0.81 (0.61–1.06)[8] and 0.86 (0.66–1.12).[9] Two studies (n = 255) reported no significant difference in the HR (95% CI) for OS of IsaPd or IsaKd compared with that of Pd or Kd (HR 0.76, 95% CI 0.56–1.04) [Supplementary Figure 2A, https://links.lww.com/CM9/C264].[5,10] The HR for PFS was reported in five studies (n = 789) [Supplementary Figure 2B, https://links.lww.com/CM9/C264].[3–7] The results revealed that the addition of isatuximab to Pd or Kd lowered the risk of progression or death by 54% compared with that for Pd or Kd alone (two studies, n = 255, HR 0.46, 95% CI 0.33–0.66).[3,5] The addition of elotuzumab lowered the risk by 29% compared with that of Pd or Rd alone (two studies, n = 362, HR 0.71, 95% CI 0.55–0.93).[4,6] The addition of ixazomib lowered the risk by 22% compared with that of Rd alone (one study, n = 172, HR 0.78, 95% CI 0.49–1.24).[7] A higher ORR was observed for IsaPd than for Pd in one study (n = 48, 51.9% vs. 9.5%, P = 0.0011).[5] VGPR was higher for IsaPd than for Pd, as reported in one study (n = 48, 33.3% vs. 0, P = 0.0018).[5] Additionally, one study[7] that compared IRd and Rd reported the CR rate, DOR, and TTP [Supplementary Figure 3, https://links.lww.com/CM9/C264]. The overall quality assessment result for each study is given in Supplementary Figure 4, https://links.lww.com/CM9/C264. One study[7,9] was rated as having some concerns of bias due to a lack of information on randomization methods and allocation concealment, but the other four studies were rated as having low risk. Our findings indicated that the addition of isatuximab to Pd or Kd was associated with a significant benefit in PFS compared with Pd or Kd alone. Benefits of isatuximab were also observed in ORR and VGPR. Moreover, the addition of isatuximab, ixazomib, and elotuzumab to Kd, Pd, or Rd significantly reduced the risk of disease progression compared with Kd, Pd, or Rd alone. However, the benefits of isatuximab, ixazomib, and elotuzumab were not significant for OS. In the present study, the lowest proportion of disease progression or death was observed for IsaKd (35%), followed by IRd (45%); Kd (50%); IsaPd (54%); EPd, ERd, and Rd (60%); and Pd (75%), suggesting that isatuximab-based combinations are more beneficial for RRMM patients with 1q21+ than ixazomib- and elotuzumab-based combinations. Notably, we did not identify eligible RCTs of daratumumab, another anti-CD38 mAb, which was approved by the Food and Drug Administration in 2015 for MM patients and for RRMM patients with 1q21+. A previous study reported a median PFS of 6.0 months for RRMM patients with 1q21+ (vs. 25.2 months for patients without 1q21+) who were treated with daratumumab as a monotherapy or a combination with PIs and IMiDs,[12] indicating that chromosome 1q status might be a prognostic factor for relapse/refractory patients. Another study reported a longer median PFS (24.5 months) for RRMM patients with 1q21+ who received a daratumumab-based regimen (compared with 23.5 months in RRMM patients without 1q21+) than that reported by Parrondo et al[13]. The similar PFS outcomes indicate that daratumumab-based therapy may abrogate the poor outcomes associated with the presence of 1q21+. Improved ORR and VGPR were generally observed for IsaKd compared with IsaPd and IRd. However, the results should be interpreted carefully due to the variation in baseline characteristics. First, the age range varied among the studies involving IsaKd,[3] IRd,[7] and IsaPd.[5] Although the studies had similar median ages of patients (65–68 years old), Loiseau et al[7] and Moreau et al[3] enrolled patients with wider age ranges (38–91 years old and 55–70 years old, respectively) than Harrison et al[5] (60–74 years old). Considering the possible impact of age, the inclusion of younger patients may have contributed to the better responses in the studies of Moreau et al[3] and Loiseau et al[7]. In addition, different prior treatments may have influenced the results.[14] The results may also have been affected by the efficacy of lenalidomide and pomalidomide on their own or in combination with other drugs. The different ORR (17% vs. 68% vs. 83%) and VGPR (2% vs. 40% vs. 52%) of Pd, Rd, and Kd observed in this review provide indirect support to this argument. Overall, we reviewed RCT data from 1q21+ subgroup analysis, provided clinical suggestions, and filled the gap in the treatment options for the difficult-to-treat subgroup of patients with 1q21+ RRMM. The addition of isatuximab may significantly improve survival for RRMM patients with 1q21+. More studies are needed to validate the present results. Acknowledgments We acknowledge all authors who are solely responsible for content and editorial decisions. Conflicts of interest Zhanzhi Xie is a Sanofi employee and may hold shares and/or stock options in the company. This work was supported by Sanofi.

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BackgroundThe aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.MethodsGMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18–70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0–3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1–2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, and on days 1 and 11 for cycles 3–4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1–14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1–28 for cycles 1–3; thereafter, up to 15 mg orally on days 1–28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1–6, and on day 1 for cycles 7–26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed.FindingsBetween June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7–55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61–77), 69% (61–76), 66% (58–74), and 67% (59–75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both.InterpretationAddition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma.FundingBristol Myers Squibb/Celgene and Chugai.

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In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

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<h3>Background</h3> Daratumumab-refractory multiple myeloma (Dara-R MM) presents a significant treatment challenge. This study aimed to evaluate the efficacy and survival outcomes of elotuzumab, pomalidomide, and dexamethasone (EloPd) in a large, real-world cohort of patients with Dara-R MM, with particular focus on progression-free survival (PFS) and overall survival (OS). <h3>Materials and methods</h3> This retrospective analysis included 247 Dara-R MM patients treated with EloPd. All patients were also refractory to lenalidomide, with 51.4% to a proteasome inhibitor, thus classified as triple-class refractory (TCR). Survival risk-scoring systems for PFS (progression-free risk score-PRS_DaraR) and OS (survival risk score-SRS_DaraR) were developed to stratify patients based on their risk profiles. <h3>Results</h3> The overall response rate was 52.6%, with a median PFS and OS of 6.6 and 17.0 months, respectively. The International Staging System (ISS) stages II and III, low hemoglobin (Hb) levels, the last therapy being daratumumab, and symptomatic relapse were identified as significant independent predictors of shorter PFS in multivariable analysis. In addition to advanced ISS stages, low Hb levels (<10.6 g/dl), symptomatic relapse, and refractory disease exhibited an independent negative impact on OS. Importantly, no significant differences in both PFS and OS were observed between TCR and non-TCR patients. Based on these multivariable analyses, we developed PRS_DaraR and SRS_DaraR according to the magnitude of the hazard ratio. In PRS_DaraR, 10.1% were low-risk, 41.3% intermediate, 43.3% high, and 5.3% very high-risk. The 12-month PFS probabilities were 86.3% (low), 67.6% (intermediate), 52.9% (high), and 31.8% (very high). For SRS_DaraR, 6.1% were low-risk, 47.8% intermediate, 19.4% high, and 26.7% very high. The 12-month OS probabilities were 90.9% (low), 75.7% (intermediate), 55.9% (high), and 32.6% (very high). <h3>Conclusions</h3> This study supports EloPd as an effective treatment option in Dara-R MM patients, providing valuable disease control and acting as a potential bridge to newer therapies, such as CAR-T and bispecific antibodies.

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ABSTRACT: Elotuzumab is a monoclonal antibody targeting signaling lymphocyte activation molecule F7 on plasma and natural killer cells, which enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. Therefore, we studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28-day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide on days 1 to 21; bortezomib on days 1, 8, and 15; and dexamethasone weekly. The trial enrolled 48 patients with a median 3 prior lines (range, 1-9). Prior therapies included pomalidomide (33%), daratumumab (25%), and isatuximab (4%). The ORR was 56.3%, and the median progression-free survival (PFS) was 10 months. In patients with 1 prior line of therapy, ORR was 73.7%; median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is, to our knowledge, one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple-class exposed patients with prior anti-CD38 monoclonal antibody. This trial was registered at ClinicalTrials.gov as #NCT02718833.

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Multiple myeloma (MM) is an intractable hematological malignancy caused by abnormalities in plasma cells. Combination therapy using antibodies and natural killer (NK) effectors, which are innate immune cells with safe and potent antitumor activity, is a promising approach for cancer immunotherapy and can enhance antitumor effects. Elotuzumab (Elo) is an immune‐stimulatory antibody that targets the signaling lymphocytic activation molecule family 7 (SLAMF7) expressed on the surface of MM and NK cells. We confirmed that Elo strongly promoted NK cell‐mediated antibody‐dependent cellular cytotoxicity (ADCC) against SLAMF7‐positive MM cells in a CD16‐dependent NK cell line, and also activated expanded NK cells derived from peripheral blood mononuclear cells of healthy donors and patients with MM in the present study. However, the antitumor effects and genes involved in the direct promotion of NK cell‐mediated activation using Elo in CD16‐independent NK cells are not clearly known. In this study, we demonstrated that Elo pretreatment significantly enhanced CD16‐independent NK cell‐mediated cytotoxicity in both SLAMF7‐positive MM.1S and SLAMF7‐negative K562, U266, and RPMI 8226 tumor cells. Upon direct simulation of CD16‐independent NK cells with Elo, increased levels of CD107a degranulation and IFN‐ γ secretion were observed along with the upregulation of granzyme B, TNF‐ α , and IL‐1 α gene expression. The enhanced NK cell function could also be attributed to the increased expression of the transcription factors T‐BET and EOMES. Furthermore, the augmentation of the antitumor effects of CD16‐independent NK cells upon pretreatment with Elo enhanced the expression of CRTAM, TNFRSF9, EAT‐2, and FOXP3 genes and reduced the expression of HSPA6. Our results suggest that Elo directly promotes the cytotoxic function of CD16‐independent NK cells against target cells, which is associated with the upregulation of the expression of several NK cell‐enhancing genes.

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