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Abstract

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.

Keywords

isatuximab monoclonal antibody anti-CD38 antibody relapsed/refractory multiple myeloma daratumumab

Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells.¹ Over recent decades, the application of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) has extensively changed the natural process and improved the outcomes of the disease. However, the treatment of MM remains complex and challenging given the high incidence rate of disease relapse and patient resistance to treatment regimens.² There is a strong demand for novel treatment approaches, which has led to the development of many immunotherapy-based strategies over recent years.

CD38, a cell-surface protein, functions as a receptor and can interact with CD31. It also has enzymatic activity related to the production of ADP ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), which regulate intracellular calcium stores. Furthermore, the ADPR produced through CD38-mediated catalysis can be further metabolized to yield the immunosuppressive molecule adenosine.³

CD38 is highly expressed on normal plasma cells and malignant MM cells; however, its expression is low on myeloid and lymphoid cells, as well as in some non-hematopoietic tissues, making it an appealing target for novel MM-directed therapy.⁴ Isatuximab, a CD38-targeting monoclonal antibody, has been approved by the United States Food and Drug Administration for the treatment of relapsed MM as a combination therapy with pomalidomide and dexamethasone (Isa-Pd) and carfilzomib and dexamethasone (Isa-Kd).⁵

This review summarizes the mechanisms of action, pharmacokinetics, pharmacogenetics, efficacy, and clinical safety of isatuximab in MM and compares isatuximab with daratumumab, the first anti-CD38 antibody developed, in terms of mechanism and efficacy. The mechanisms underlying resistance to CD38 monoclonal antibodies are also discussed.

Mechanisms of Action, Pharmacokinetics, and Pharmacogenetics

Mechanisms of Action

Isatuximab is an immunoglobulin G (IgG) 1 monoclonal antibody directed against a distinct epitope on CD38. Isatuximab mediates MM cell death through multiple mechanisms, including antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC), effects that are fragment crystallizable (Fc) region-dependent.⁶ In the process of ADCC, which is the predominant mechanism underlying the effects of isatuximab, when Fcγ receptors on immune effector cells bind to the Fc region of the antibody, immune effector cells release toxic proteins, such as perforin and granzyme, leading to tumor cell lysis.⁷

Isatuximab can also directly induce MM cell death through caspase-dependent apoptosis and the lysosomal cell killing pathway without the need for cross-linking agents.^8,9 In addition, isatuximab can modulate the enzymatic activity of CD38 and enhance the natural killer cell- and T-cell-mediated immune response.^3,10

Pharmacokinetics and Pharmacogenetics

At the recommended dose and schedule (10 mg/kg weekly for 4 weeks and every 2 weeks thereafter), it takes an average of approximately 8 weeks for isatuximab to reach steady-state. The predicted maximum plasma concentration (C_max) of isatuximab at steady-state is 351 μg/mL and its area under the plasma concentration-time curve (AUC) is 72 600 μg·h/mL (51.7%). The mean predicted total distribution volume is 8.13 L. The time to near-complete (≥99%) elimination after the last dose is approximately 2 months.¹¹

Pharmacokinetic modeling in the preliminary stage of drug development demonstrated that isatuximab exhibits both linear and nonlinear elimination, with linear clearance accounting for 90% of the total clearance. Isatuximab is cleared through protein catabolic pathways. Patients secreting IgG M-protein demonstrate an almost two-fold higher isatuximab clearance rate compared with those secreting non-IgG M-protein.¹²

Isatuximab has no pharmacokinetic interaction with other anti-MM agents such as pomalidomide, lenalidomide, and dexamethasone.^13,14 Clinical findings, along with exposure-response analyses and a pharmacokinetic/pharmacodynamics modeling framework, have supported the 20 mg/kg dose for isatuximab monotherapy and the 10 mg/kg dose for combination therapy.^13,15,16

Isatuximab in Relapsed/Refractory Multiple Myeloma (RRMM) (Table 1)

Isatuximab Monotherapy

The first single-agent isatuximab study was conducted on 84 patients with RRMM who had received a median of 5 (range: 1-13) lines of therapy with an IMiD and a PI. This phase I trial demonstrated that isatuximab monotherapy was well tolerated at doses of up to 20 mg/kg. At doses of ≥10 mg/kg, Isatuximab displayed notable clinical activity with an overall response rate (ORR) of 23.8% and median progression-free survival (PFS) of 3.7 months. Approximately 51% of the patients experienced infusion-related reactions (IRRs), with most being of grade 1 or 2 severity.¹³

Table 1.

Pivotal Clinical Studies of Isatuximab in RRMM.

Study group	Isa monotherapy	Isa-Pd versus Pd (ICARIA-MM)	Isa-Rd	Isa-Kd versus Kd (IKEMA)
Median prior lines	5	3	5	2
Median ORR (%)	24.3	60.4 versus 35.3	56	87 versus 83
Median PFS (months)	3.6	11.53 versus 6.47	8.5	NR versus 19.2
Median OS (months)	18.6	At 12 months: 72% versus 63%	NR
Reference	¹⁷	¹⁸	¹⁹	²⁰

Abbreviations: ORR, overall response rate; PFS, progression-free survival; OS, overall survival; RRMM, relapsed/refractory multiple myeloma; Isa, isatuximab; Pd, pomalidomide/dexamethasone; Rd, lenalidomide/dexamethasone; Kd, carfilzomib/dexamethasone; NR, not reached.

In a dose-finding study for isatuximab in RRMM, 97 patients were assigned to 4 different treatment schedules, as follows: 3 mg/kg Q2W, 10 mg/kg Q2W (2 cycles)/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW (1 cycle)/Q2W. The ORR was 24.3% in groups receiving isatuximab at doses of ≥10 mg/kg and was even higher among patients over the age of 70 than in younger patients (46.2% vs 19.7%). There were also notable differences in ORRs (40.9% vs 17.3%) between patients with and those without high-risk cytogenetic markers.¹⁷ In stage 2 of this study, the activity of isatuximab (20 mg/kg QW/Q2W) as a single agent or in combination with dexamethasone (Isa-dex) was assessed. The Isa-dex group achieved a markedly higher ORR (43.6%) than the Isa group (23.9%). The most common adverse events (AEs) of ≥grade 3 were a decrease in the lymphocyte count (Isa 27.5% vs Isa-dex 48.1%) and anemia (Isa 22.9% vs Isa-dex 14.8%). This study showed that dexamethasone, a “backbone treatment” of various regimens,^21,22 could improve clinical activity when combined with isatuximab, with no unexpected safety issues being detected.²³

Combinations With IMiDs

Mikhael et al reported the results of their phase 1b study on Isa-Pd combination therapy. This study included 45 patients who had been heavily pretreated with a median of 3 (range: 1-10) therapy lines; 82% of the patients were refractory to lenalidomide and 84% to PIs. The patients were randomized to isatuximab dosing regimens of 5, 10, or 20 mg/kg QW/Q2W. Pomalidomide and dexamethasone were administered at the standard treatment dosage. After a median follow-up of 9.2 months, the ORR was 62.2%, twice as high as that for pomalidomide/dexamethasone (Pd) alone (28%-31%).^24–26 Attal et al found similar results in a phase 3 study, with improved ORR and median PFS being reported in the Isa-Pd cohort compared with the Pd group (ORR: 60.4% vs 35.3%, PFS: 11.53 months vs 6.47 months). Moreover, responses were achieved faster in the Isa-Pd cohort. The median time to first response better than partial remission was 35 days versus 58 days in the Pd-only group.¹⁸ In addition, for patients experiencing renal impairment, the Isa-Pd regimen also yielded longer PFS than Pd treatment alone (9.5 months vs 3.7 months).²⁷ Extended PFS was also observed in patients above 75 years of age and those with high-risk cytogenetics.^28,29

Martin et al assessed the isatuximab plus lenalidomide and dexamethasone regimen and reported an ORR of 48% among patients who had received more than 3 pretreatment lines and an ORR of 52% among those refractory to lenalidomide. In addition, the isatuximab 10 mg/kg QW/Q2W regimen achieved a longer PFS (9.7 months) than the 10 mg/kg Q2W regimen (5.7 months). Treatment-emergent AEs of grade ≥3 were pneumonia, fatigue, lung infection, febrile neutropenia, anaphylactic reaction, and hypokalemia.¹⁹

Combination With Carfilzomib

Trials of Isa-Kd also showed promising outcomes. The IKEMA study enrolled 302 patients with RRMM who were randomly assigned to the Isa-Kd arm or the carfilzomib/dexamethasone (Kd) arm at a 3:2 ratio. The Isa-Kd arm showed better outcomes, achieving an ORR of 87% and PFS not reached at 20.7 months of follow-up compared with 83% and 19.2 months, respectively, for the Kd arm.²⁰ Notably, 41.4% of the Isa-Kd population reached minimal residual disease (MRD) negativity with very good partial response (VGPR) or better, compared with only 22.9% in the Kd cohort.³⁰ Better PFS and disease response was also demonstrated even among patients with renal impairment. More patients in the Isa-Kd group showed reversal of renal impairment and durable renal responses relative to the Kd group.³¹

Isatuximab in Newly Diagnosed MM

Based on the results obtained with isatuximab in RRMM, many clinical trials have also been conducted to evaluate the activity of isatuximab in newly diagnosed MM (NDMM). Significant results have been reported in trials incorporating isatuximab in conventional standard triplet therapy of bortezomib/lenalidomide/dexamethasone (VRD) or bortezomib/cyclophosphamide/dexamethasone (VCD) in transplant-ineligible NDMM patients.^13,32 The ORR was 100% and 93.3% for these 2 regimens, respectively. The most frequent toxicities included constipation, IRRs, diarrhea, and peripheral sensory neuropathy.³³

A recent interim analysis of the GMMG-CONCEPT trial reported the best response of the first 50 high-risk MM patients that received induction therapy with isatuximab/carfilzomib/lenalidomide/dexamethasone (Isa-KRd). In total, 45 out of the 50 patients showed a VGPR or better and 20 of 31 evaluable patients reached MRD negativity. The median 24-month PFS was 75.5%.³⁴

Despite these promising results, more clinical studies are required to demonstrate the efficacy of isatuximab in patients with NDMM irrespective of eligibility for transplantation.

Isatuximab in High-Risk Smoldering Multiple Myeloma

High-risk smoldering multiple myeloma (HRSMM) is considered an asymptomatic cancer with a high risk of progression to MM after 5 years of diagnosis.³⁵ A multicenter, phase 2 trial studied isatuximab treatment in 24 HRSMM patients and demonstrated potential clinical activity, with an ORR of 62.5% and a clinical benefit rate of 79% being achieved. Additionally, isatuximab treatment improved the quality of life (QOL) scores of patients and decreased their anxiety regarding progression to MM.³⁶

Toxicity Profiles

Preclinical and clinical studies have shown that isatuximab is safe, with IRRs being the most commonly reported nonhematologic adverse reactions. Most AEs were moderate and occurred during the first infusion.^13,19 IRRs mostly included symptoms such as nasal congestion, dry cough, rhinitis, sore throat, and dyspnea.³⁴ To prevent IRRs, patients received standard prophylactic medications, including diphenhydramine, methylprednisolone, ranitidine, and acetaminophen, 15 to 30 min before infusion.^37,38 Fatigue, upper respiratory tract infections, dyspnea, pneumonia, and urinary tract infections were also frequently observed in isatuximab combination therapy,^20,24 which was in agreement with the toxicity profile of the individual drugs.

In terms of hematological laboratory abnormalities, the most common grade ≥3 AEs of the isatuximab regimen were neutropenia, lymphopenia, leukopenia, thrombocytopenia, and anemia.^17,19,20,24 Most were manageable with dose modifications and the use of granulocyte colony-stimulating factors.²⁴

Comparison with Daratumumab

Daratumumab was the first CD38-targeting monoclonal antibody developed and was approved for MM treatment in 2015. The efficacy of daratumumab monotherapy and the combination with IMiDs or PIs in both RRMM and NDMM have been demonstrated in a series of clinical trials (Table 2).

Table 2.

Pivotal Clinical Studies of Daratumumab in RRMM and NDMM.

Study group	Number of patients	Median ORR (%)	Median PFS (months)	Median OS	Reference
RRMM
Dara monotherapy (SIRIUS)	148	29.2	3.7	1-year OS: 65%	³⁹
Dara-Pd versus Pd (APOLLO)	151 versus 153		12.4 versus 6.9		⁴⁰
Dara-Rd versus Rd (POLLUX)	286 versus 283	92.9 versus 76.4	44.5 versus 17.5	NR (at 42 months: 65% vs 57%)	⁴¹
Dara-Vd versus Vd (CASTOR)	251 versus 247	83.0 versus 63.0	16.7 versus 7.1	NR (at 3 years: 61% vs 51%)	⁴²
Dara-Kd versus Kd (CANDOR)	312 versus 154	84.3 versus 74.7	NR versus 15.8	NR	⁴³
NDMM
Dara-Rd versus Rd (MAIA)	368 versus 369	92.9 versus 81.3	NR versus 33.8	NR	⁴⁴
Dara-VMP versus VMP (ALCYONE)	350 versus 356	90.9 versus 73.9	36.9 versus 19.3	NR	⁴⁵
Dara-VTd versus VTd (CASSIOPOEIA)	543 versus 542	92.6 versus 89.9	NR (at 8 months：93% vs 85%)	NR	⁴⁶
Dara-VRd versus VRd (GRIFFIN)	104 versus 103	99.0 versus 81.8	NR (at 24 months: 95.8% vs 89.8%)	NR (at 24 months: 95.8% vs 93.4%)	⁴⁷

Abbreviations: RRMM, relapsed/refractory multiple myeloma; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; Dara, daratumumab; Pd, pomalidomide/dexamethasone; Rd, lenalidomide/dexamethasone; NR, not reached; Kd, carfilzomib/dexamethasone; Vd, bortezomib/dexamethasone; VMP, bortezomib/melphalan/prednisone; VTd, bortezomib/thalidomide/dexamethasone; VRd, bortezomib/lenalidomide/dexamethasone.

Daratumumab in RRMM

Daratumumab monotherapy in RRMM yielded an ORR of 29.2% and PFS of 3.7 months.³⁹ Concerning combination regimens, according to the result of the open-label, phase 3 POLLUX trial, the ORR and median PFS were notably enhanced by the addition of daratumumab to lenalidomide and dexamethasone (Dara-Rd) when compared with those of the Rd group (ORR 92.9% vs 76.4% and PFS 44.5 months vs 17.5 months, respectively). Benefits were also observed among patients aged >75 years and among those with a high cytogenetic risk.⁴¹ The APOLLO study investigated the efficacy of Pd with (Dara-Pd) or without daratumumab among a total of 304 patients who had received pretreatment with at least one therapy. After a median duration of 16.9 months, 51% of the Dara-Pd cohort reached VGPR or better, which was comparable to that of the control group (17.2%).⁴⁰

The CASTOR trial recruited 498 patients with RRMM. Prolonged PFS and increased MRD negativity were found in the group receiving triple therapy consisting of daratumumab, bortezomib, and dexamethasone compared with the group receiving bortezomib and dexamethasone alone (median PFS, 16.7 months vs 7.1 months; MRD negativity, 14% vs 2%).⁴² The CANDOR study demonstrated that the risk of disease progression or death was markedly lower in patients receiving daratumumab plus Kd than in those receiving Kd only (median PFS: not reached and 15.8 months, respectively).⁴³

Daratumumab in NDMM

Daratumumab has also been studied in patients with NDMM who are ineligible for stem cell transplantation. The phase 3 MAIA study reported that the Dara-Rd regimen significantly prolonged overall survival and PFS.⁴⁴ Similar conclusions were reached in the ALCYONE trial, which enrolled 706 transplantation-ineligible patients with NDMM to compare the activity of daratumumab, bortezomib, melphalan, and prednisone (Dara-VMP) with that of VMP alone. The ORR was 90.9% versus 73.9% and the median PFS was 36.9 months versus 19.3 months, respectively.⁴⁵

Daratumumab has also demonstrated high clinical efficacy among patients eligible for transplantation. In the phase 3, open-label, randomized CASSIOPOEIA trial, 1085 patients were assigned to 2 groups, namely, a bortezomib, thalidomide, and dexamethasone (VTd) group or a daratumumab combined with VTd (Dara-VTd) group. All the patients received 4 pre-transplant induction cycles and 2 post-transplant consolidation cycles. One hundred days after transplantation, daratumumab had improved the MRD negativity rate by 20% (64% for Dara-VTd vs 44% for VTd).⁴⁶

The GRIFFIN trial, another phase 3 trial for transplant-eligible patients, assessed the activity of a combination of daratumumab with the conventional triple regimen bortezomib, lenalidomide, and dexamethasone (Dara-VRd). After a median follow-up of 22.1 months, an increase in MRD negativity was found in the Dara-VRd arm (51%, compared with 20.4% in the VRd arm).⁴⁷

Furthermore, incorporating daratumumab into MM therapy is considered to prolong PFS even among high-risk patients with chromosome abnormalities, including del(17p), t(4;14), and t(14;16).^48,49

Although daratumumab also kills tumor cells both via ADCC, ADCP, and CDC and by reducing the immunosuppressive activity of regulatory T and B cells, the underlying mechanisms differ slightly from those of isatuximab in several aspects. First, the 2 agents target distinct CD38 epitopes.⁵⁰ Secondly, isatuximab can directly induce apoptosis in myeloma cells,^8,9 whereas daratumumab cannot induce cell death without being combined with cross-linking agents.⁵¹ Furthermore, isatuximab modulates CD38 enzymatic activity more effectively than daratumumab.⁹

The results of studies assessing isatuximab therapy were comparable to those for daratumumab. The ORRs for the Isa-Pd and Dara-Pd regimens were 60.4% to 62.6% and 60.66%, respectively,^18,24,52 while those for the Isa-Kd and Dara-Kd regimens were 87% and 84%, respectively.^20,43 However, the 2 drugs have not been studied in the same setting. Moreover, the infusion time for isatuximab at the 10 mg/kg dose was approximately 3 h,²⁴ which was shorter than the 3.9 h or longer reported for daratumumab.⁴³ On the other hand, while daratumumab can be administered subcutaneously, isatuximab-based regimens rely on intravenous formulations, which limits their application. A phase 1b study is currently ongoing to evaluate a subcutaneous formulation of Isa-Pd (ClinicalTrials.gov ID: NCT04045795).

It remains uncertain whether isatuximab can be an alternative to daratumumab in MM therapy. A phase 1b study of Isa-Pd administered by fixed-volume infusion enrolled 7 daratumumab-refractory patients with RRMM. Of the 6 participants for whom the response could be evaluated, 3 experienced a minimal response (MR) or better.⁵³ Another small case series consisting of 9 patients also demonstrated encouraging results for Isa-Pd after daratumumab therapy, with 7 patients showing a MR or better.⁵⁴ Mikhael et al reported the effect of single-agent isatuximab in patients who developed daratumumab resistance. One of 32 patients achieved a MR and 17 had stable disease as best overall response.⁵⁵ A descriptive analysis reported the outcomes of the Isa-Pd regimen in 5 relapsed patients who had previously received daratumumab therapies. One achieved a partial response (PR), 2 achieved a minor response-stable disease, and 2 achieved progressive disease as best response.⁵⁶ Isatuximab-based regimens have shown poor activity in patients refractory to daratumumab, which may be due to their partly overlapping mode of action. The results of several trials assessing isatuximab in patients exposed or refractory to daratumumab have been reported; however, their conclusions are limited owing to the small sample sizes and the possibility of patient selection bias.

Conclusions and Future Directions

Isatuximab-based therapies have demonstrated effectiveness and a manageable safety profile in the treatment of MM. The enhancement of anti-MM activity resulting from the addition of IMiDs to CD38 monoclonal antibodies may be due to the increased effect exerted by ADCP and ADCC, as well as CD38 upregulation, on regulatory T cells.⁶ Pomalidomide has been shown to enhance isatuximab-mediated ADCP and ADCC in vitro.⁵⁰ Meanwhile, PIs show substantial efficacy in combination with isatuximab, likely due to their multiple effects on MM cells and the tumor microenvironment.⁵⁰

However, different from Dara-VMP and Dara-Rd, which have been recommended by the National Comprehensive Cancer Network (NCCN) for patients with NDMM who are not eligible for transplantation, there is currently a lack of results on the application of isatuximab in NDMM. Several trials evaluating isatuximab combination therapies in NDMM are currently underway.⁵⁷ Additionally, the IONA-MM trial (ClinicalTrials.gov ID: NCT04458831) is ongoing to confirm the efficacy and safety of isatuximab-based therapies in a real-world setting.

Although therapeutic strategies that incorporate CD38 antibodies have demonstrated efficacy in MM and have been tolerated by patients, primary resistance and acquired resistance have both been reported. Several studies have investigated the mechanisms of resistance and potential strategies to overcome it, as shown in Table 3. One of the associated mechanisms may be related to reduced CD38 expression, resulting in an impairment of classic Fc-mediated cytotoxic activities.¹⁰ Thus, the addition of other drugs, such as all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor ricolinostat, which increase the expression of CD38, may be a potential approach for reversing resistance.^58,59 In patients on daratumumab monotherapy who achieve PR or better before progression, the addition of ATRA and the reintensification of daratumumab resulted in significantly prolonged disease control (median PFS 9.9 months vs 17.7months).⁶⁰ Isatuximab-mediated ADCC was also enhanced through the use of ATRA in MM cell lines.⁹ However, in the most recent study, Frerichs et al found that the increased efficacy associated with the addition of ATRA was limited and temporary due to the transient nature of the upregulation of CD38 expression.⁶¹

Table 3.

Potential Strategies to Overcome Resistance.

Potential strategies to overcome resistance	Mechanisms	References
IMiDs	Enhanced ADCC, ADCP, direct effects, and immunomodulatory activity of CD38 antibodies	⁶
ATRA	Enhanced ADCC and CDC and downregulation of CD55 and CD59 expression levels	⁵⁸
Administration of ex vivo-expanded NK cells	Enhanced ADCC	⁶²
YM-155	Downregulation of survivin expression	⁶³
PD-1/PD-L1 inhibitors	Enhanced immunomodulatory activity	⁶⁴
Anti-CD47 monoclonal antibodies	Downregulation of CD47 expression	⁶⁵

Abbreviations: IMiDs, immunomodulatory drugs; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CDC, complement-dependent cytotoxicity; NK, natural killer.

Increased expression levels of complement inhibitors (CD55 and CD59) also contribute to the resistance to anti-CD38 antibodies.^9,66 The CDC-resistant MOLP-8 cell line expresses high levels of CD59, and inhibition of CD59 lead to cell lysis by isatuximab-mediated CDC.⁹

Bone marrow stromal cells also protect myeloma cells against CD38 antibody-mediated ADCC through the upregulation of antiapoptotic molecules such as survivin.¹⁰ This effect could be partially reversed by the downregulation of survivin expression using the small-molecule inhibitor YM-155.⁶³

Other mechanisms of resistance include the upregulation of CD47 and several alternative immune checkpoints as well as the reduction of NK cell numbers.^65,67,68 Studies have shown that using ex vivo-expanded CD38-knockout NK cells can enhance daratumumab-mediated ADCC activity.⁶² The combined targeting of the CD38 and programmed cell death-1 (PD-1) or programmed death ligand-1 (PD-L1) pathways also contributes to improving the efficacy of anti-CD38 antibodies. PD-1 blockade markedly enhanced daratumumab-mediated cytotoxicity in vivo in murine CD38+ tumor models.⁶⁴

In conclusion, isatuximab monotherapy and combination regimens provide additional treatment options in MM; however, more studies are needed to assess their potential for application in this disease.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fei Shen

Abbreviations

References

Kazandjian

. Multiple myeloma epidemiology and survival: a unique malignancy. Semin Oncol. 2016;43(6):676-681. doi: 10.1053/j.seminoncol.2016.11.004.

Kumar

Dimopoulos

Kastritis

, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443-2448. doi: 10.1038/leu.2017.138.

Saltarella

Desantis

Melaccio

, et al. Mechanisms of resistance to anti-CD38 daratumumab in multiple myeloma. Cells. 2020;9(1):167. doi: 10.3390/cells9010167.

Moreno

Perez

Zabaleta

, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin Cancer Res. 2019;25(10):3176-3187. doi: 10.1158/1078-0432.CCR-18-1597.

Podar

Leleu

. Relapsed/refractory multiple myeloma in 2020/2021 and beyond. Cancers. 2021;13(20):5154. doi: 10.3390/cancers13205154.

Feng

Zhang

Acharya

, et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma. Clin Cancer Res. 2017;23(15):4290-4300. doi: 10.1158/1078-0432.CCR-16-3192.

Wang

Erbe

Hank

, et al. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol. 2015;6:368. doi: 10.3389/fimmu.2015.00368.

Jiang

Acharya

, et al. SAR650984 Directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016;30(2):399-408. doi: 10.1038/leu.2015.240.

Zhu

Song

Wang

, et al. Isatuximab acts through Fc-dependent, independent, and direct pathways to kill multiple myeloma cells. Front Immunol. 2020;11:1771. doi: 10.3389/fimmu.2020.01771.

10.

Van de Donk

Usmani

. CD38 Antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;9:2134. doi: 10.3389/fimmu.2018.02134.

11.

Dhillon

. Isatuximab: first approval. Drugs. 2020;80(9):905-912. doi: 10.1007/s40265-020-01311-1.

12.

Fau

El-Cheikh

Brillac

, et al. Drug-disease interaction and time-dependent population pharmacokinetics of isatuximab in relapsed/refractory multiple myeloma patients. CPT Pharmacometrics Syst Pharmacol. 2020;9(11):649-658. doi: 10.1002/psp4.12561.

13.

Martin

Strickland

Glenn

, et al. Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma. Blood Cancer J. 2019;9(4):41. doi: 10.1038/s41408-019-0198-4.

14.

Ocio

Otero

Bringhen

, et al. Preliminary results from a phase I study of isatuximab (ISA) in combination with bortezomib, lenalidomide, dexamethasone (VRd), and in patients with newly diagnosed multiple myeloma (NDMM) non-eligible for transplant. Blood. 2018;132(suppl 1):3160. doi: 10.1182/blood-2018-99-111244.

15.

Rachedi

Koiwai

Gaudel-Dedieu

, et al. Exposure-response analyses and disease modeling for selection and confirmation of optimal dosing regimen of isatuximab in combination in patients with multiple myeloma. Blood. 2019;134(suppl 1):1897. doi: 10.1182/blood-2019-128875.

16.

Koiwai

El-Cheikh

Thai

H-T

, et al. PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma. CPT Pharmacometrics Syst Pharmacol. 2021;10(8):928-940. doi: 10.1002/psp4.12666.

17.

Mikhael

Richter

Vij

, et al. A dose-finding phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma. Leukemia. 2020;34(12):3298-3309. doi: 10.1038/s41375-020-0857-2.

18.

Attal

Richardson

Rajkumar

, et al. 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. Lancet. 2019;394(10214):2096-2107. doi: 10.1016/S0140-6736(19)32556-5.

19.

Martin

Baz

Benson

, et al. A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;129(25):3294-3303. doi: 10.1182/blood-2016-09-740787.

20.

Moreau

Dimopoulos

Mikhael

, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4.

21.

Laubach

Garderet

Mahindra

, et al. Management of relapsed multiple myeloma: recommendations of the international myeloma working group. Leukemia. 2016;30(5):1005-1017. doi: 10.1038/leu.2015.356.

22.

Moreau

San Miguel

Sonneveld

, et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv52-iv61. doi: 10.1093/annonc/mdx096.

23.

Dimopoulos

Bringhen

Anttila

, et al. Results from a phase II study of isatuximab as a single agent and in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2018;132(suppl 1):155. doi: 10.1182/blood-2018-155.

24.

Mikhael

Richardson

Usmani

, et al. A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Blood. 2019;134(2):123-133. doi: 10.1182/blood-2019-02-895193.

25.

Miguel

Weisel

Moreau

, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055-1066. doi: 10.1016/S1470-2045(13)70380-2.

26.

Richardson

Siegel

Vij

, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826-1832. doi: 10.1182/blood-2013-11-538835.

27.

Dimopoulos

Leleu

Moreau

, et al. Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis. Leukemia. 2021;35(2):562-572. doi: 10.1038/s41375-020-0868-z.

28.

Schjesvold

Richardson

Facon

, et al. Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Haematologica. 2021;106(4):1182-1187. doi: 10.3324/haematol.2020.253450.

29.

Harrison

Perrot

Alegre

, et al. Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics. Br J Haematol. 2021;194(1):120-131. doi: 10.1111/bjh.17499.

30.

Martin

Mikhael

Hajek

, et al. Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma: Ikema interim analysis. Blood. 2020;136(suppl 1):7-8. doi: 10.1182/blood-2020-137681.

31.

Capra

Martin T

III

Moreau

, et al. Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis. Blood. 2020;136(suppl 1):46-47. doi: 10.3324/haematol.2021.279229.

32.

Ocio

Bringhen

Oliva

, et al. A phase Ib study of isatuximab in combination with bortezomib, cyclophosphamide, and dexamethasone (VCDI) in patients with newly diagnosed multiple myeloma non-eligible for transplantation. Blood. 2017;130(suppl 1):3160. doi: 10.1182/blood.V130.Suppl_1.3160.3160.

33.

Ocio

Rodríguez Otero

Bringhen

, et al. Updates from a phase Ib study of isatuximab (Isa), bortezomib (V) and dexamethasone (D) plus cyclophosphamide (C) or lenalidomide (R) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2020;38(suppl 15):8529. doi: 10.1200/JCO.2020.38.15_suppl.8529.

34.

Leypoldt

Besemer

Asemissen

, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. Leukemia. 2022;36(3):885-888. doi: 10.1038/s41375-021-01431-x.

35.

Rajkumar

Landgren

Mateos

. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075. doi: 10.1182/blood-2014-09-568899.

36.

Manasanch

Jagannath

Lee

, et al. A multicenter phase II single arm trial of isatuximab in patients with high risk smoldering multiple myeloma (HRSMM). Blood. 2019;134(suppl 1):3116. doi: 10.1182/blood-2019-123205.

37.

Dimopoulos

Bringhen

Anttila

, et al. Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2021;137(9):1154-1165. doi: 10.1182/blood.2020008209.

38.

Martin

Shah

Richter

, et al. Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma. Cancer. 2021;127(11):1816-1826. doi: 10.1002/cncr.33448.

39.

Lonial

Weiss

Usmani

, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-1560. doi: 10.1016/S0140-6736(15)01120-4.

40.

Dimopoulos

Terpos

Boccadoro

, et al. Apollo: phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(suppl 1):5-6. doi: 10.1182/blood-2020-135874.

41.

Bahlis

Dimopoulos

White

, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34(7):1875-1884. doi: 10.1038/s41375-020-0711-6.

42.

Weisel

Spencer

Lentzsch

, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol. 2020;13(1):1-11. doi: 10.1186/s13045-020-00948-5.

43.

Dimopoulos

Quach

Mateos

, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0.

44.

Kumar

Facon

Usmani

, et al. Updated analysis of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM): the phase 3 Maia Study. Blood. 2020;136(suppl 1):24-26. doi: 10.1182/blood-2019-123426.

45.

Mateos

Cavo

Blade

, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi: 10.1016/S0140-6736(19)32956-3.

46.

Moreau

Attal

Hulin

, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.

47.

Voorhees

Kaufman

Laubach

, et al. Daratumumab, lenalidomide, bortezomib and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi: 10.1182/blood.2020005288.

48.

Giri

Grimshaw

Bal

, et al. Evaluation of daratumumab for the treatment of multiple myeloma in patients with high-risk cytogenetic factors: a systematic review and meta-analysis. JAMA Oncol. 2020;6(11):1-8. doi: 10.1001/jamaoncol.2020.4338.

49.

Premkumar

Pan

Lentzsch

, et al. Use of daratumumab in high risk multiple myeloma: a meta-analysis. eJHaem. 2020;1(1):267-271. doi: 10.1002/jha2.47.

50.

Martin

Corzo

Chiron

, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with Isatuximab. Cells. 2019;8(12):1522. doi: 10.3390/cells8121522.

51.

Overdijk

Jansen

Nederend

, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via FCγ receptor-mediated cross-linking. J Immunol. 2016;197(3):807-813. doi: 10.4049/jimmunol.1501351.

52.

Chari

Suvannasankha

Fay

, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981. doi: 10.1182/blood-2017-05-785246.

53.

Usmani

Karanes

Bensinger

, et al. Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma. Leukemia. 2021;35(12):3526-3533. doi: 10.1038/s41375-021-01262-w.

54.

Becnel

Horowitz

Thomas

, et al. Descriptive analysis of isatuximab use following prior daratumumab in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(suppl 1):20-21. doi: 10.1182/blood-2020-140526.

55.

Mikhael

Belhadj-Merzoug

Hulin

, et al. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab. Blood Cancer J. 2021;11(5):89. doi: 10.1038/s41408-021-00478-4.

56.

Djebbari

Poynton

Sangha

, et al. Outcomes of anti-CD38 isatuximab plus pomalidomide and dexamethasone in five relapsed myeloma patients with prior exposure to anti-C38 daratumumab: case series. Hematology. 2022;27(1):204-207. doi: 10.1080/16078454.2022.2028978.

57.

Hashmi

Husnain

Khan

Usmani

. CD38-directed Therapies for management of multiple myeloma. Immunotargets Ther. 2021;10:201-211. doi: 10.2147/ITT.S259122.

58.

Nijhof

Groen

Lokhorst

, et al. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015;29(10):2039-2049. doi: 10.1038/leu.2015.123.

59.

García-Guerrero

Götz

Doose

, et al. Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab. Leukemia. 2021;35(1):201-214. doi: 10.1038/s41375-020-0840-y.

60.

Frerichs

Minnema

Levin

, et al. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood. 2019;134(suppl 1):1826. doi: 10.1182/blood-2019-123383.

61.

Frerichs

Minnema

Levin

M-D

, et al. Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood Adv. 2021;5(23):5128-5139. doi: 10.1182/bloodadvances.2021005220.

62.

Naeimi Kararoudi

Nagai

Elmas

, et al. CD38 Deletion of human primary NK cells eliminates daratumumab-induced fratricide and boosts their effector activity. Blood. 2020;136(21):2416-2427. doi: 10.1182/blood.2020006200.

63.

de Haart

Holthof

Noort

, et al. Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance. Haematologica. 2016;101(8):e339-e342. doi: 10.3324/haematol.2015.139667.

64.

Verkleij

CPM

Jhatakia

Broekmans

MEC

, et al. Preclinical rationale for targeting the PD-1/PD-L1 axis in combination with a CD38 antibody in multiple myeloma and other CD38-positive malignancies. Cancers (Basel). 2020;12(12):3713. doi: 10.3390/cancers12123713.

65.

van Bommel

Schepel

, et al. CD20-selective Inhibition of CD47-SIRPα “don’t eat me” signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab. OncoImmunology. 2017;7(2):e1386361. doi: 10.1080/2162402X.2017.1386361.

66.

Nijhof

Casneuf

Van Velzen

, et al. CD38 Expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016;128(7):959-970. doi: 10.1182/blood-2016-03-703439.

67.

Casneuf

Adams

III , et al. Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma. Blood Adv. 2017;1(23):2105-2114. doi: 10.1182/bloodadvances.2017006866

68.

Neri

Maity

Tagoug

, et al. Single cell resolution profiling defines the innate and adaptive immune repertoires modulated by daratumumab and IMiDs treatment in multiple myeloma (MM). Blood. 2017;130(suppl 1):123. doi:10.1182/blood.V130.Suppl_1.123.123.

Isatuximab in the Treatment of Multiple Myeloma: A Review and Comparison With Daratumumab

Abstract

Keywords

Introduction

Mechanisms of Action, Pharmacokinetics, and Pharmacogenetics

Mechanisms of Action

Pharmacokinetics and Pharmacogenetics

Isatuximab in Relapsed/Refractory Multiple Myeloma (RRMM) (Table 1)

Isatuximab Monotherapy

Combinations With IMiDs

Combination With Carfilzomib

Isatuximab in Newly Diagnosed MM

Isatuximab in High-Risk Smoldering Multiple Myeloma

Toxicity Profiles

Comparison with Daratumumab

Daratumumab in RRMM

Daratumumab in NDMM

Conclusions and Future Directions

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

Abbreviations

References