Optimizing Clinical Outcomes and Value-Based Management in Multiple Myeloma—The Role of Isatuximab

Introduction

Multiple myeloma (MM), the second most common hematologic malignancy, is an incurable plasma-cell cancer with an estimated 34,470 new diagnoses and 12,640 deaths in the United States in 2022.^1,2 Landmark advances in MM therapeutics, including proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies (mAbs), antibody–drug conjugates, a novel selective inhibitor of nuclear export, and combinations thereof, have resulted in significant improvements in survival outcomes for patients with MM.^1,3-6 Nevertheless, relapse and disease progression are inevitable, and poorer response rates and shorter durations of response occur with each subsequent line of therapy (LOT).^7,8 As these novel therapies for MM are not curative, the current therapeutic paradigms seek to optimize treatment choice and sequencing to extend progression-free and overall survival (PFS and OS, respectively) in patients with relapsed/refractory MM (RRMM), converting this incurable disease into a chronic one.⁹

In addition to the clinical challenges associated with managing MM, the financial toxicity associated with MM care has been recognized as a significant barrier to care and to optimizing clinical and pharmacoeconomic outcomes for patients with MM.^10-17 Given the rapid and continued expansion of available treatments and the complexity of optimizing treatments, maintaining clinical benefits while addressing the high costs of the MM therapy are increasingly important.¹⁸

Here, we review the latest clinical evidence from the phase 3 ICARIA-MM and IKEMA studies of isatuximab, an anti-CD38 mAb, in patients with RRMM. In addition, the cost implications of MM management and evolving approaches for mitigating the cost burden without compromising clinical outcomes for patients with MM are discussed.

Isatuximab: An Update on the Latest Clinical Evidence
Brief Overview of Isatuximab

Isatuximab is an IgG1κ mAb that binds selectively to a unique epitope on CD38, inhibits CD38 ectoenzyme activity, and targets tumor cells through various mechanisms, including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and immune-cell depletion/inhibition of immunosuppressive cells.^19,20

To date, 2 indications for the use of isatuximab in the treatment of adults with MM have gained approval in the United States, European Union, and Japan—isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd), for the treatment of adult patients with MM who have received ≥2 prior therapies including lenalidomide and a PI; and isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd) for those with RRMM who have received 1 to 3 prior LOTs.^21-25

Isa-Kd Extends Median PFS to Nearly 3.5 Years in IKEMA

Addition of isatuximab to the Kd backbone in the IKEMA study was previously shown to significantly improve PFS over Kd alone in patients with RRMM, reducing the risk of disease progression or all-cause death by 47% (hazard ratio [HR], 0.531; 95% confidence interval [CI], 0.318-0.889; P = .0013).²⁴

An updated final analysis of IKEMA data, conducted following 159 PFS events and at a median follow-up of 44 months, showed the longest median PFS (mPFS) to date with a regimen based on a PI backbone in patients who relapsed after a prior therapy, including lenalidomide.^26,27 The mPFS with Isa-Kd was 41.7 months (HR, 0.59; 95% CI, 27.1-not reached; n = 179), compared with 20.8 months in patients treated with Kd alone (95% CI, 16.2-28.2; n = 123), as evaluated by an Independent Review Committee (Figure 1).²⁷

Addition of isatuximab to Kd also delayed the time to next treatment and prolonged PFS2 (the length of time from treatment allocation to the date of first documentation of progressive disease after initiation of further treatment or death from any cause).²⁶ The median time to next treatment was 44.9 months with Isa-Kd compared with 25.0 months with Kd (HR, 0.55; 95% CI, 0.40-0.76). The median PFS2 was 47.2 and 35.6 months (HR, 0.68; 95% CI, 0.50-0.94) with Isa-Kd and Kd, respectively.

The safety profile in both arms at the longer follow-up remained consistent with the IKEMA interim analysis, with the most frequent adverse reactions being infusion-related reactions (IRRs; 45.8%), diarrhea (39.5%), hypertension (37.9%), and upper respiratory tract infections (37.3%).²⁶

Subgroup analyses confirm superior PFS benefit of Isa-Kd compared with Kd

Subgroup analyses of data from the IKEMA study demonstrated superior clinical benefit of Isa-Kd over Kd alone across subgroups, including patients of various age groups (≥65 years vs <65 years), with renal impairment (RI), with gain/amplification of 1q21 (referred to hereafter as 1q21+), with high-risk cytogenetics, with ≥1 previous LOTs, and with refractory status (lenalidomide- or bortezomib-refractory) (summarized in Table 1).^24,28-31

A key subgroup that has recently been gaining attention is the subset of patients with 1q21+, a potential prognostic marker that has been proposed for inclusion in risk stratification models for MM.^30,33 1q21+ is detected in 40% of patients with MM, making it one of the most common high-risk chromosomal abnormalities (HRCAs).^30,33 In patients with MM, 1q21 amplification, defined as >1 additional copy (amp[1q21], total of ≥3 copies), is associated with worse outcomes than those with 1q21 gain, defined as 1 additional copy of 1q21.³⁴ In this context, it is notable that the PFS benefit with Isa-Kd was seen across all 1q21+ subgroups, including patients with 1q21+ (≥3 copies with or without HRCA), isolated 1q21+ (≥3 copies without HRCA), gain(1q21) (3 copies with or without HRCA), and amp(1q21) (≥4 copies with or without HRCA).³⁰

The impact of Isa-Kd on renal outcomes is also notable; RI is a common complication of MM, with 61% of patients with MM diagnosed with RI and 50% diagnosed with chronic kidney disease within the first few years of MM diagnosis.^35-37 In addition, existing RI worsens as patients progress through LOTs and the likelihood of recovering kidney function diminishes with progression of RRMM.³⁷ In IKEMA, patients with an estimated glomerular filtration rate (eGFR) as low as 15 mL/min/1.73 m² were eligible for enrollment.²⁴ Moreover, unlike phase 3 studies of daratumumab in RRMM, a prespecified subgroup analysis examined efficacy, renal response, and safety in patients with RI (eGFR <60 mL/min/1.73 m²) in IKEMA.²⁸ Median PFS in patients with RI was longer with Isa-Kd (median PFS not reached for Isa-Kd vs 13.4 months for Kd; HR, 0.27; 95% CI, 0.11-0.66).²⁸ Complete renal responses occurred more frequently (52.0% vs 30.8% with Kd) and were durable with Isa-Kd (32.0% vs 7.7% in Kd).²⁸

Overall, the updated data from IKEMA demonstrate an extension of median PFS beyond 3 years and PFS benefits across different subgroups, including difficult-to-treat patients with RRMM, such as those with ≥1 conventional HRCAs, 1q21+, and RI. These findings support the sustained PFS benefit of Isa-Kd, cementing the role of Isa-Kd as a new standard of care and a best-in-class anti-CD38 mAb therapy for patients with RRMM.^27,38

Updated ICARIA-MM Data: OS Improvement

Analysis of the ICARIA-MM study showed that Isa-Pd improved median PFS, compared with Pd, in the entire cohort and across all prespecified patient subgroups, including those aged ≥75 years, with International Staging System stage III disease, with renal insufficiency, with high-risk cytogenetics, with 2 to 3 or >3 previous LOTs, refractory to lenalidomide, refractory to a PI, and double-refractory to lenalidomide and a PI.^25,38-41 Follow-up analysis, after a median follow-up duration of 35.3 months (interquartile range, 33.5-37.4), confirmed the PFS benefit with Isa-Pd; median PFS per investigator assessment was significantly longer with Isa-Pd (11.1 months; 95% CI, 7.8-13.8) compared with Pd alone (5.9 months [95% CI, 4.5-7.9]; HR, 0.60; 95% CI, 0.46-0.78; P <.0001).⁴² Analysis showed that median PFS on subsequent therapy or death was longer in the isatuximab group (17.5 months [95% CI, 14.9-19.2] compared with 12.9 months [95% CI, 10.1-16.6]; P = .020).⁴²

The median OS had not been reached at the time of primary analysis; the 12-month OS was 72% and 63% in the Isa-Pd and Pd arms, respectively (HR, 0.687; 95% CI, 0.461-1.023; P = .0631).²⁵ In a prespecified updated OS analysis conducted 24 months after the primary analysis (data cutoff for the second interim analysis: October 7, 2020), median OS was 24.6 months (95% CI, 20.3-31.3) with Isa-Pd compared with 17.5 months (95% CI, 1.42-26.2) with Pd alone (HR, 0.76; 95% CI, 0.57-1.01; 1-sided log-rank P = .028, not crossing prespecified stopping boundary) (Figure 2).⁴²

Consistent with data in the previous interim analysis, the overall response rate and the depth of response were also significantly improved with the addition of isatuximab to Pd.⁴² Moreover, 7% of patients treated with Isa-Pd reached minimal residual disease negativity, at a sensitivity level of 10⁻⁵, compared with 0% with Pd alone.

No new safety signals were observed with the longer follow-up with Isa-Pd. The most frequent grade 3 or worse treatment-emergent adverse events with Isa-Pd compared with Pd alone were neutropenia (50% vs 35%), pneumonia (23% vs 21%), and thrombocytopenia (13% vs 12%).⁴² The most frequent serious adverse event (all grades, both groups) was pneumonia, reported in 23% in the Isa-Pd group and 21% in the Pd group. Treatment-related deaths occurred at the same rate in both groups—2 (1%) in the Isa-Pd group (1 due to sepsis and 1 due to cerebellar infarction) and 2 (1%) in the control group (1 due to pneumonia and 1 due to urinary tract infection).

Addition of isatuximab to Pd extends PFS across subgroups

Subgroup analyses have demonstrated the PFS advantage of the addition of isatuximab to Pd across almost all prespecified subgroups, including patients of various age groups (≥65 years vs <65 years, <65 years vs 65-74 years vs ≥75 years), with RI, with 1q21+, with plasmacytomas, with high-risk cytogenetics, with ≥1 previous LOTs, and East Asian patients.^{30,38,39,41,43-45}

Notably, Isa-Pd demonstrated PFS benefit across all 1q21+ subgroups, including gain(1q21) and amp(1q21), regardless of the HRCA status.³⁰

Overall, these data demonstrate sustained and substantial PFS benefit with the addition of isatuximab, with Isa-Pd nearly doubling the median PFS to >3 years, compared with Pd alone. In this regard, these data underscore the unique and striking benefit of the Isa-Pd regimen in patients with RRMM, in providing a 2-fold PFS benefit as well as a significant (7-month) OS benefit, which is not typical for currently available therapies in RRMM.

The role of isatuximab in MM continues to evolve, with other clinical studies addressing the role of this mAb in different disease/treatment settings, such as in a quadruplet regimen along with bortezomib, lenalidomide, and dexamethasone (Isa-VRd; in GMMG HD7/NCT03617731) and in earlier LOTs (for high-risk newly diagnosed MM [NDMM], in combination with carfilzomib, lenalidomide, and dexamethasone in NCT03104842; Isa-VRd in NDMM IMROZ/NCT03319667).^46-49

Therapeutic Approach to Mitigating Costs Associated with MM Management

The management of MM is challenging, not only due to the disease course characterized by relapses but also due to disease-related complications, such as RI, that must be considered when optimizing treatments.^37,50,51 The complexity of MM care, especially RRMM, is further exacerbated by the substantial cost implications for the patient and the healthcare system.^35,52-59 The confluence of numerous factors, including medical expenses and financial losses or burdens due to decreased productivity or job loss, contributes to the “financial toxicity” associated with cancer treatment (Figure 3).^{10,12,14,15,17,60} The impact of financial toxicity extends far beyond the patient’s pockets, with the potential to impact clinical and quality-of-life (QOL) outcomes of treatment in MM, even in clinical trial settings.^{10,12,14,15,61,62} Although financial toxicity is not unique to MM or even to cancer as such, this issue has been gaining attention in MM practice due to the overall substantial costs and the variety of cost drivers associated with patient-, disease-, and treatment-related factors in MM.

Cost Drivers in MM Therapy

MM therapy is characterized by numerous cost drivers that contribute to the overall economic and healthcare resource burden as well as the financial toxicity to patients (Figure 4). Some of the key cost drivers in MM therapy include older age and higher comorbidity burden of patients diagnosed with MM; presence of various high-risk features requiring intensive and/or risk-adapted treatments; disease-related complications, such as RI; use of multidrug regimens including triplet or quadruplet combinations, often involving novel drugs or novel classes of agents; continuation of therapy until disease progression, which prolongs the therapeutic window; a clinical course characterized by relapses requiring multiple LOTs; use of costly oral oncolytics or treatments requiring frequent/prolonged infusions; extensive supportive care measures; and care disparities.^{11,35,52,55,58,59,62,63} A detailed discussion of phase-, treatment-, and patient population–specific cost analyses studies was included in a preceding publication on isatuximab and MM care costs.⁶³ Additional/new data on key cost drivers are discussed briefly below.

Impact of RI on care costs

Optimizing treatment that enables preservation or improvement of renal function can mitigate costs associated with MM care.³⁵ A retrospective analysis found that, compared with patients without RI, those with RI had significantly higher per-patient annual all-cause healthcare resource utilization, as well as inpatient, outpatient, and total costs; the total all-cause costs for patients with RI was $230,631 (standard deviation, $225,246), compared with $172,410 (standard deviation, $152,196; P <.001) for those without RI.³⁵

Risk status

In an analysis of real-world treatment practices and outcomes in RRMM, particularly by cytogenetic risk, patients stratified as having high-risk features were more frequently hospitalized, leading to higher potential cost burden in high-risk RRMM patients.⁵⁹

Therapeutic regimens, disease progression, and LOTs

The rapid succession of novel therapies in MM, including those based on triplet or quadruplet regimens that utilize multiple classes of agents, may also add to the cost burden.^56,64,65 It is important to note that clinical benefits of novel therapies do not always predicate higher costs or a lack of cost-effectiveness.^3,66,67 A recent systematic review of economic assessments of MM treatment regimens concluded that, concurrent with an increased frequency and improvements in the methodological quality of studies in the last decade, novel therapies in MM may be cost-effective.⁶⁷

Given that most treatments for RRMM, including in clinical trials, are continued until disease progression or death, the prolonged treatment duration adds to long-term costs.⁶⁸ Moreover, the disease course of MM is such that relapse occurs in nearly all patients and after each/multiple LOTs; therefore, cumulative care costs over the lifetime of a patient with MM can exacerbate the cost burden.^68-72 The use of multidrug regimens, the current cornerstone of MM practice, can be costly.^52,68 Patients on multidrug regimens are exposed to many classes of drugs and continue to require treatment, which can contribute to chronic financial toxicity.^55,73,74 In a recent study of adult patients with MM who received ≥4 prior LOTs, including those with triple-class exposure, between 2012 and 2021, MM-related healthcare costs ($670,561 per patient) accounted for around 88.5% of the total all-cause healthcare costs; the majority (67.2%) of MM-related costs were attributed to drug and infusion costs.⁷³

Route of delivery

The route of delivery of MM therapies can also impact the cost of treatments.^75-78 All-oral regimens have been associated with lower treatment burden and indirect costs, compared with therapies requiring frequent and/or lengthy subcutaneous or intravenous infusions.⁷⁵ Indirect costs, such as those associated with disability use and productivity loss, can also differ based on route of drug delivery and, thereby, contribute to the cost burden for patients with MM.⁷⁷ While oral regimens offer advantages, including convenience and cost benefits, they also present challenges, including ensuring medication adherence and the economic burden associated with nonadherence.⁷⁷

Although conclusions drawn from cost-effectiveness studies of MM therapies may vary depending on the underlying assumptions and the quality of the studies,⁴ overall, these data highlight the substantial costs associated with the care and treatment of patients with MM and the unmet need for strategies to account for cost implications in MM clinical pathways.

Principles Underlying Cost Mitigation in MM Practice

Cost implications of cancer therapy are now beginning to prompt clinical studies that evaluate strategies for mitigating costs, such as by reducing a drug dose, without compromising the clinical efficacy.⁷⁹ Strategies for mitigating these costs without compromising clinical effectiveness and outcomes—generation of cost-effective care/clinical pathways; increasing market competition; value-based pricing; improvements in national guidelines; authorizing Medicare to negotiate prescription drug prices; and copay assistance programs—are an increasingly important aspect of MM care.^3,52 Some of the principles underlying cost mitigation to provide value-based MM care proposed during the First International Summit on Interventional Pharmacoeconomics held in 2020 are summarized in Figure 5.⁸⁰

Changing treatment-related parameters, such as shortening the infusion duration or reserving costlier options for later LOTs, may help optimize treatments based both on efficacy and costs.^81,82 New formulations that allow for subcutaneous rather than intravenous delivery may increase convenience for patients, mitigate IRRs, and reduce treatment costs by obviating “in-chair” infusion times. A subcutaneous formulation of daratumumab was recently approved for treatment of patients with RRMM.⁸³ A subcutaneous formulation of isatuximab, used in combination with Pd, demonstrated comparable clinical efficacy with intravenous isatuximab, without new safety signals and with fewer IRRs.^84,85 A collaboration spearheaded by the manufacturer of isatuximab focused on accelerating global pivotal studies and clinical development of the subcutaneous formulation of isatuximab was recently announced; the clinical studies are expected to begin in the second half of 2022.⁸⁶

The development and implementation of copay assistance programs for MM patients with commercial insurance, such as the CareASSIST program for SARCLISA^® (isatuximab-irfc), can also help defray the copay burden.³

Interventions that address financial toxicity for patients with hematologic malignancies are being explored; a recent pilot study identified patients at risk of financial toxicity and implemented a comprehensive intervention driven by nurse navigators, clinical pharmacists, and community pro bono financial planners.⁸⁷ The data showed that financial toxicity was associated with increased noncompliance, including to prescription (16.8%) and over-the-counter medications (15.9%). The comprehensive intervention not only improved patients’ QOL and mental health but also reduced the risk of death.⁸⁷

Continued analysis of the cost impact of therapies, especially financial toxicity to patients, and programs that screen for risk of cost-associated toxicity and provide support are needed for patients with MM.

CD38-Targeted mAb Therapies in MM and the Impact of Isatuximab on Costs

Cost implications of CD38-targeted mAb-based MM treatments have been addressed in a few studies^81,82,88-96; these studies were summarized in a preceding publication on isatuximab and MM care costs.⁶³ Given the more recent introduction of isatuximab to MM practice, limited data on the cost implications for isatuximab are available.^91,92,97,98 A recent cost-effectiveness analysis, facilitated by an indirect treatment comparison of PFS with Isa-Kd with daratumumab-carfilzomib-dexamethasone (Dkd), showed slight incremental gains in life years of 0.12 months and 0.48 months over 6 months and 1 year of treatment of patients with RRMM with Isa-Kd compared with Dkd, respectively.⁹² The clinical gains were estimated to generate cost savings of approximately $24,000 or about 15% of Isa-Kd therapy. Similar incremental survival gains and the resultant cost benefits were noted for Isa-Pd over daratumumab-pomalidomide-dexamethasone, with the isatuximab regimen generating favorable incremental cost-effectiveness ratios at 1 and 3 years, but not at the 5-year horizon.⁹¹ The costs associated with isatuximab over a 12-month course were estimated to be lower than that for daratumumab in an analysis predating the approval of subcutaneous daratumumab; treatment of an 80-kg patient for a 12-month (52-week) treatment course with isatuximab would cost an estimated $145,600, compared with $163,300 with daratumumab.⁹⁷

As data for isatuximab-containing regimens—including the significant and sustained PFS benefit over the long-term in IKEMA, the OS benefit in ICARIA-MM, and efficacy in difficult-to-treat subgroups in IKEMA and ICARIA-MM—continue to evolve, isatuximab may become the value-based standard of care in the management of RRMM.

Conclusions

Clinical evidence from the IKEMA and ICARIA-MM studies demonstrates the sustained and striking PFS benefit of isatuximab in patients with RRMM. Updated data from the IKEMA study support the efficacy and safety of Isa-Kd in patients with RRMM, with a median PFS longer than 3 years and nearly double that over the Kd backbone, as well as PFS benefit in patients with high-risk cytogenetics, 1q21+, RI, and of older age. The latest ICARIA-MM data demonstrate the superior PFS benefit with Isa-Pd in patients with RRMM, as well as a 7-month increase in the median OS, compared with Pd alone—a finding that is striking in the RRMM space.

A detailed understanding of the optimal therapeutic options for patients with RRMM can help refine the MM treatment schema for patients with this challenging malignancy and provide avenues for differentiated therapies. In parallel with clinical advances and introduction of novel therapies, the cost implications and financial toxicity associated with MM care costs are gaining increasing attention. Clinicians are increasingly tasked with optimizing the therapeutic outcomes for each patient with MM, while also considering cost implications of therapy, and integrating approaches to address the impact of financial toxicity.

References

1. SEER Program. Myeloma. Cancer Stat Facts. SEER. Published 2022. https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed January 19, 2022.
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7-33.
3. Fonseca R, Hinkel J. Value and cost of myeloma therapy-we can afford it. Am Soc Clin Oncol Educ Book. 2018;38:647-655.
4. Fonseca R, Abouzaid S, Bonafede M, et al. Trends in overall survival and costs of multiple myeloma, 2000-2014. Leukemia. 2017;31:1915-1921.
5. Braunlin M, Belani R, Buchanan J, et al. Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011-2019 oncology clinic electronic health record data. Leuk Lymphoma. 2021;62:377-386.
6. Binder M, Nandakumar B, Rajkumar SV, et al. Mortality trends in multiple myeloma after the introduction of novel therapies in the United States. Leukemia. 2022;36:801-808.
7. Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252-262.
8. Mikhael J. Treatment options for triple-class refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2020;20:1-7.
9. Kumar S, Baizer L, Callander NS, et al. Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: consensus recommendations of the NCI Multiple Myeloma Steering Committee. Blood Cancer J. 2022;12:98.
10. ASH Clinical News. Multiple myeloma patients experience heavy financial burden, high financial toxicity. Published February 1, 2016. www.ashclinicalnews.org/on-location/multiple-myeloma-patients-experience-heavy-financial-burden-high-financial-toxicity. Accessed July 29, 2022.
11. Rajkumar SV. Value and cost of myeloma therapy. Am Soc Clin Oncol Educ Book. 2018;38:662-666.
12. Fortune EE, Miller MF, Kranzler EC, et al. Financial burden is associated with postponing care and decreasing physical and emotional quality of life among patients with multiple myeloma and chronic lymphocytic leukemia. Blood. 2020;136:45.
13. Seitzler S, Finley-Oliver E, Simonelli C, Baz R. Quality of life in multiple myeloma: considerations and recommendations. Expert Rev Hematol. 2019;12:419-424.
14. King-Kallimanis B, Chen TY, Kanapuru B, et al. Financial toxicity in patients with multiple myeloma participating in clinical trials: a U.S. Food and Drug Administration pooled analysis. J Clin Oncol. 2020;38(suppl 15):e19370-e19370.
15. Warsame RM, Dispenzieri A, Dueck AC. Financial toxicity and impact on health-related quality of life in patients with plasma cell disorders. Blood. 2020;136(suppl 1):20-21.
16. Parker C, Berkovic D, Ayton D, et al. Patient perceived financial burden in haematological malignancies: a systematic review. Curr Oncol. 2022;29:3807-3824.
17. Sidana S, Allmer C, Larson MC, et al. Patient experience in clinical trials: quality of life, financial burden, and perception of care in patients with multiple myeloma or lymphoma enrolled on clinical trials compared with standard care. JCO Oncol Pract. 2022;18:e1320-e1333.
18. Chen CC, Parikh K, Abouzaid S, et al. Real-world treatment patterns, time to next treatment, and economic outcomes in relapsed or refractory multiple myeloma patients treated with pomalidomide or carfilzomib. J Manag Care Spec Pharm. 2017;23:236-246.
19. Richardson PG, Attal M, Campana F, et al. Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA phase III study design. Future Oncol. 2018;14:1035-1047.
20. Richardson PG, Beksaç M, Špička I, Mikhael J. Isatuximab for the treatment of relapsed/refractory multiple myeloma. Expert Opin Biol Ther. 2020;20:1395-1404.
21. Sanofi Press Release. European Commission approves second indication of Sarclisa® (isatuximab) for relapsed multiple myeloma - Sanofi. Published 2021. www.sanofi.com/en/media-room/press-releases/2021/2021-04-19-05-00-00-2212005. Accessed July 28, 2022.
22. Sanofi-Aventis. SARCLISA® (isatuximab-irfc) injection, for intravenous use [package insert]. Revised March 2021. Published March 2021. https://products.sanofi.us/Sarclisa/sarclisa.pdf. Accessed February 4, 2022.
23. Frampton JE. Isatuximab: a review of its use in multiple myeloma. Target Oncol. 2021;16:675-686.
24. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361-2371.
25. Attal M, Richardson PG, Rajkumar SV, 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;394:2096-2107.
26. Moreau P, Dimopoulos MAC, Mikhael J, et al. VP5-2022: updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Ann Oncol. 2022;33:664-665.
27. Moreau P, Dimopoulos M, Mikhael J; IKEMA Study Group. Updated progression-free survival and depth of response in IKEMA, a randomized phase 3 trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma. Presented at: The 8th World Congress on Controversies in Multiple Myeloma (COMy); May 12, 2022; Paris, France. https://comylive.cme-congresses.com. Accessed August 23, 2022.
28. Capra M, Martin T, Moreau P, et al. Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis. Haematologica. 2022;107:1397-1409.
29. Facon T, Moreau P, Martin TG, et al. Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis. Hematol Oncol. Published online June 2, 2022.
30. Martin T, Richardson PG, Facon T, et al. Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA. Haematologica. 2022;107:2485-2491.
31. Dimopoulos MA, Moreau P, Augustson B, et al. Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma based on prior lines of treatment and refractory status: IKEMA subgroup analysis. Am J Hematol. Published online May 23, 2022.
32. Leleu X, Martin T, Weisel K, et al. Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes. Ann Hematol. 2022;101:2123-2137.
33. Hanamura I. Multiple myeloma with high-risk cytogenetics and its treatment approach. Int J Hematol. 2022;115:762-777.
34. Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019;133:660-675.
35. Medhekar R, Gilligan AM, Kent ST, et al. Healthcare resource utilization (HRU) and costs associated with renal impairment (RI) among treated multiple myeloma (MM) patients. J Clin Oncol. 2018;36(15 suppl):e18922-e18922.
36. Bhowmik D, Song X, Intorcia M, Kent ST, Shi N. Healthcare resource use and costs associated with chronic kidney disease in US private insurance patients with multiple myeloma. J Oncol Pharm Pract. 2019;25:855-864.
37. Dimopoulos MA, Mikhael J, Terpos E, et al. An overview of treatment options for patients with relapsed/refractory multiple myeloma and renal impairment. Ther Adv Hematol. 2022;13:20406207221088458.
38. Bringhen S, Pour L, Vorobyev V, et al. Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis. Leuk Res. 2021;104:106576.
39. Schjesvold F, Bringhen S, Richardson PG, et al. Isatuximab plus pomalidomide and dexamethasone in frail patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Am J Hematol. 2021;96:E423-E427.
40. Schjesvold F, Richardson PG, Facon T, et al. Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Haematologica. 2022;107:774-775.
41. Dimopoulos MA, Leleu X, Moreau P, et al. Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis. Leukemia. 2021;35:562-572.
42. Richardson PG, Perrot A, San-Miguel J, 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): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23:416-427.
43. Schjesvold FH, Richardson PG, Facon T, et al. Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Haematologica. 2021;106:1182-1187.
44. Harrison SJ, Perrot A, Alegre A, et al. Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics. Br J Haematol. 2021;194:120-131.
45. Sunami K, Ikeda T, Huang SY, et al. Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in east Asian patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Clin Lymphoma Myeloma Leuk. 2022;22:e751-e761.
46. Orlowski RZ, Goldschmidt H, Cavo M, et al. Phase III (IMROZ) study design: isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2018;36(15 suppl):TPS8055-TPS8055.
47. Musto P, La Rocca F. Monoclonal antibodies in newly diagnosed and smoldering multiple myeloma: an updated review of current clinical evidence. Expert Rev Hematol. 2020;13:501-517.
48. Goldschmidt H. Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma patients: the phase III GMMG-HD7 Trial. In: ASH; 2021. https://ash.confex.com/ash/2021/webprogram/Paper145097.html. Accessed January 28, 2022.
49. Leypoldt LB, Besemer B, Asemissen AM, 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;36:885-888.
50. Hernández-Rivas JÁ, Ríos-Tamayo R, Encinas C, et al. The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies. Biomark Res. 2022;10:1.
51. Bozic B, Rutner J, Zheng C, et al. Advances in the treatment of relapsed and refractory multiple myeloma in patients with renal insufficiency: novel agents, immunotherapies and beyond. Cancers (Basel). 2021;13:5036.
52. Rajkumar SV, Harousseau JL. Next-generation multiple myeloma treatment: a pharmacoeconomic perspective. Blood. 2016;128:2757-2764.
53. MacEwan JP, Batt K, Yin W, et al. Economic burden of multiple myeloma among patients in successive lines of therapy in the United States. Leuk Lymphoma. 2018;59:941-949.
54. Gordan LN, Marks SM, Xue M, et al. Daratumumab utilization and cost analysis among patients with multiple myeloma in a US community oncology setting. Future Oncol. 2022;18:301-309.
55. Madduri D, Hagiwara M, Parikh K, et al. Real-world treatment patterns, healthcare use and costs in triple-class exposed relapsed and refractory multiple myeloma patients in the USA. Future Oncol. 2021;17:503-515.
56. Seefat MR, Cucchi DGJ, Dirven S, et al. A systematic review of cost-effectiveness analyses of novel agents in the treatment of multiple myeloma. Cancers (Basel). 2021;13:5606.
57. Kocaata Z, Wilke T, Fischer F, et al. Healthcare resource utilization and cost of patients with multiple myeloma in Germany: a retrospective claims data analysis. Pharmacoecon Open. 2022;6:619-628.
58. Richter J, Anupindi VR, Yeaw J, et al. Real-world treatment patterns in relapsed/refractory multiple myeloma: clinical and economic outcomes in patients treated with pomalidomide or daratumumab. J Oncol Pharm Pract. 2022;28:395-409.
59. Lin HM, Davis KL, Kaye JA, et al. Real-world treatment patterns, outcomes, and healthcare resource utilization in relapsed or refractory multiple myeloma: evidence from a medical record review in France. Adv Hematol. 2019;2019:4625787.
60. Evguenia O, Banerjee R, Desai A, et al. Financial toxicity in hematological malignancies: a systematic review. Blood Cancer J. 2022;12:74.
61. Klein J, Bodner W, Garg M, et al. Pretreatment financial toxicity predicts progression-free survival following concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer. Future Oncology. 2019;15:1697-1705.
62. Longo CJ. Linking intermediate to final “real-world” outcomes: is financial toxicity a reliable predictor of poorer outcomes in cancer? Curr Oncol. 2022;29:2483-2489.
63. Faculty Perspectives. The evolving clinical and pharmacoeconomic impact of isatuximab in multiple myeloma management. Value-Based Cancer Care. Published June 24, 2022. www.valuebasedcancer.com/special-issues/isatuximab-in-multiple-myeloma-management/3180-the-evolving-clinical-and-pharmacoeconomic-impact-of-isatuximab-in-multiple-myeloma-management. Accessed August 31, 2022.
64. Carlson JJ, Guzauskas GF, Chapman RH, et al. Cost-effectiveness of drugs to treat relapsed/refractory multiple myeloma in the United States. J Manag Care Spec Pharm. 2018;24:29-38.
65. Blommestein HM, Franken MG, van Beurden-Tan CHY, et al. Cost-effectiveness of novel treatment sequences for transplant-ineligible patients with multiple myeloma. JAMA Netw Open. 2021;4:e213497.
66. Aguiar PM, Lima TM, Storpirtis S. Systematic review of the economic evaluations of novel therapeutic agents in multiple myeloma: what is the reporting quality? J Clin Pharm Ther. 2016;41:189-197.
67. Asrar MM, Lad DP, Prinja S, Bansal D. A systematic review of economic evaluations of treatment regimens in multiple myeloma. Expert Rev Pharmacoecon Outcomes Res. 2021;21:799-809.
68. Rajkumar SV. Value and cost of myeloma therapy. Am Soc Clin Oncol Educ Book. 2018;38:662-666.
69. Richter J, Jagannath S. Are 4-drug regimens here to stay? Role in induction and salvage therapies. Cancer J. 2019;25:32-37.
70. AJMC Staff. UCSF’s Dr Thomas Martin discusses quadruplets vs triplets in multiple myeloma. AJMC. Published October 25, 2021. www.ajmc.com/view/ucsf-s-dr-thomas-martin-discusses-quadruplets-vs-triplets-in-multiple-myleoma. Accessed January 26, 2022.
71. AJMC Staff. Boston Medical Center’s Shah: nonclinical factors can drive value equation in multiple myeloma. AJMC. Published November 1, 2021. www.ajmc.com/view/boston-medical-center-s-shah-non-clinical-factors-can-drive-value-equation-in-multiple-myeloma. Accessed January 26, 2022.
72. Scheid C, Blau IW, Sellner L, et al. Changes in treatment landscape of relapsed or refractory multiple myeloma and their association with mortality: insights from German claims database. Eur J Haematol. 2021;106:148-157.
73. Jagannath S, Joseph N, He J, et al. Healthcare costs of multiple myeloma patients with four or more prior lines of therapy, including triple-class exposure in the United States. Oncol Ther. Published online May 17, 2022.
74. Jagannath S, Joseph N, He J, et al. Healthcare costs incurred by patients with multiple myeloma following triple class exposure (TCE) in the US. Oncol Ther. 2021;9:659-669.
75. Ailawadhi S, DerSarkissian M, Duh MS, et al. Cost offsets in the treatment journeys of patients with relapsed/refractory multiple myeloma. Clin Ther. 2019;41:477-493.e7.
76. Mankinen P, Vihervaara V, Torvinen S, et al. Costs of administration, travelling, and productivity losses associated with hospital administration of multiple myeloma drugs in Finland. J Med Econ. 2019;22:328-335.
77. Merola D, Yong C, Noga SJ, Shermock KM. Costs associated with productivity loss among U.S. patients newly diagnosed with multiple myeloma receiving oral versus injectable chemotherapy. J Manag Care Spec Pharm. 2018;24:1019-1026.
78. Basic E, Kappel M, Misra A, et al. Budget impact analysis of the use of oral and intravenous therapy regimens for the treatment of relapsed or refractory multiple myeloma in Germany. Eur J Health Econ. 2020;21:1351-1361.
79. Szmulewitz RZ, Ibraheem AF, Peer CJ, et al. A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC). J Clin Oncol. 2017;35(6 suppl):176-176.
80. Cavallo J. How to treat patients with multiple myeloma cost-effectively without compromising outcome. The ASCO Post. Published August 25, 2020. https://ascopost.com/issues/august-25-2020/how-to-treat-patients-with-multiple-myeloma-cost-effectively-without-compromising-outcome. Accessed July 26, 2022.
81. Hamadeh IS, Reese ES, Arnall JR, et al. Safety and cost benefits of the rapid daratumumab infusion protocol. Clin Lymphoma Myeloma Leuk. 2020;20:526-532.e1.
82. Patel KK, Giri S, Parker TL, et al. Cost-effectiveness of first-line versus second-line use of daratumumab in older, transplant-ineligible patients with multiple myeloma. J Clin Oncol. 2021;39:1119-1128.
83. Broderick J. FDA approves subcutaneous daratumumab in multiple myeloma. OncLive. Published May 1, 2020. www.onclive.com/view/fda-approves-subcutaneous-daratumumab-in-multiple-myeloma. Accessed July 31, 2022.
84. Quach H, Parmar G, Ocio E, et al. Subcutaneous (SC) isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM): interim phase 1b study results. J Clin Oncol. 2022;40(16 suppl):8025-8025.
85. Moreau P, Parmar G, Prince M, et al. A multi-center, phase 1b study to assess the safety, pharmacokinetics and efficacy of subcutaneous isatuximab plus pomalidomide and dexamethasone, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(1 suppl):2744.
86. Sanofi Press Release. Sanofi announces €300 million collaboration with Blackstone Life Sciences to advance an innovative treatment for multiple myeloma. Published March 15, 2022. www.sanofi.com/en/media-room/press-releases/2022/2022-03-15-06-00-00-2403030. Accessed July 27, 2022.
87. Knight TG, Aguiar M, Robinson M, et al. Financial toxicity intervention improves outcomes in patients with hematologic malignancy. JCO Oncol Practice. 2022;18:e1494-e1504.
88. Pelligra CG, Parikh K, Guo S, et al. Cost-effectiveness of pomalidomide, carfilzomib, and daratumumab for the treatment of patients with heavily pretreated relapsed–refractory multiple myeloma in the United States. Clin Ther. 2017;39:1986-2005.e5.
89. Cushing MM, DeSimone RA, Goel R, et al. The impact of daratumumab on transfusion service costs. Transfusion. 2019;59:1252-1258.
90. Gong CL, Studdert AL, Liedtke M. Daratumumab vs pomalidomide for the treatment of relapsed/refractory multiple myeloma: a cost-effectiveness analysis. Am J Hematol. 2019;94:e68-e70.
91. Alrawashdh N. Economic evaluation of daratumumab and pomalidomide and dexamethasone versus isatuximab and pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. In: ASH; 2020. https://ash.confex.com/ash/2020/webprogram/Paper136348.html. Accessed January 19, 2022.
92. AlRawashdh N, Choi B, Obeng-Kusi M, et al. Economic evaluation of six and 12 month (m) treatment with isatuximab and carfilzomib and dexamethasone (IKd) versus daratumumab and carfilzomib and dexamethasone (DKd) in patients with relapsed or refractory multiple myeloma (RRMM). J Clin Oncol. 2021;39(15 suppl):e20010-e20010.
93. Zeng X, Peng L, Peng Y, et al. Economic evaluation of adding daratumumab to a regimen of bortezomib + dexamethasone in relapsed or refractory multiple myeloma: based on the latest updated analysis of CASTOR. Clin Ther. 2020;42:251-262.e5.
94. Cao Y, Zhao L, Zhang T, Cao W. Cost-effectiveness analysis of adding daratumumab to bortezomib, melphalan, and prednisone for untreated multiple myeloma. Front Pharmacol. 2021;12:608685.
95. Narsipur N, Bulla S, Yoo C, et al. Cost-effectiveness of adding daratumumab or bortezomib to lenalidomide plus dexamethasone for newly diagnosed multiple myeloma. J Manag Care Spec Pharm. 2021;27:1691-1702.
96. Li S, Li J, Peng L, et al. First-line daratumumab in addition to chemotherapy for newly diagnosed multiple myeloma patients who are transplant ineligible: a cost-effectiveness analysis. Clin Ther. 2021;43:1253-1264.e5.
97. Hughes D, Blevins F. A new monoclonal antibody for R/R MM: isatuximab-irfc. Published online July 30, 2020. www.pharmacytimes.com/view/a-new-monoclonal-antibody-for-rr-mm-isatuximab-irfc. Accessed January 27, 2022.
98. Kumar SK. Addition of CD38-directed antibody isatuximab to multiple myeloma armamentarium. The ASCO Post. Published June 10, 2020. https://ascopost.com/issues/june-10-2020/addition-of-cd38-directed-antibody-isatuximab-to-multiple-myeloma-armamentarium. Accessed January 28, 2022.