The Evolving Clinical and Pharmacoeconomic Impact of Isatuximab in Multiple Myeloma Management

Faculty Perspectives: The Evolving Clinical and Pharmacoeconomic Impact of Isatuximab in Multiple Myeloma Management

Overview of multiple myeloma (MM) and the current state of MM management

MM is a clonal malignancy of terminally differentiated plasma cells, characterized by the accumulation of malignant cells in the bone marrow.1 MM can result in low blood counts, bone marrow failure, organ damage, and susceptibility to infections.1,2 Although considered rare, MM is the second most common hematologic malignancy; 32,920 new diagnoses and 12,410 myeloma deaths are projected in the United States in 2021.2,3 The median age of patients at MM diagnosis is 69 years, with MM most commonly diagnosed in patients aged 65 to 74 years, making it a malignancy of predominantly older adults.3

The introduction of novel therapies, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and combinations thereof, has transformed the MM treatment paradigm, facilitating dramatic improvements in patient outcomes, significantly extending median disease-free survival and overall survival (OS).3,4 The survival gains are underscored by the dramatic increase in median survival, from 29 months in the early 1990s to more than 8 years in 2018; indeed, just over the most recent 2 decades, the 5-year survival rate has increased from 34.9% in 2000 to 54% in 2021.3,5-9

Despite these advances, relapse and disease progression occurs in nearly all patients, with diminishing response rates and progressively shorter durations of response with each subsequent line of therapy (LOT).10,11 There is, therefore, a continued need for therapies that can extend progression-free survival (PFS) and OS via improvements in the depth and duration of response in patients with relapsed/refractory MM (RRMM). In this context, mAb-based therapies targeting surface antigens overexpressed in myeloma cells, such as CD38, are one of the newer classes of agents introduced into the MM treatment schema.12 To date, 2 anti-CD38 mAbs–daratumumab and isatuximab–have gained approval for MM indications (Table 1).1,13-15 Daratumumab- and isatuximab-containing combination regimens are included as category 1 recommended treatments in the National Comprehensive Cancer Network clinical practice guidelines for MM management (Table 1).1 The role of isatuximab and the evolving clinical evidence for the use of isatuximab across the disease continuum in various patient populations in MM are discussed in the subsequent section.

Table 1

Isatuximab: Overview of the Clinical Profile and Place in the MM Treatment Paradigm
Isatuximab mechanism of action and rationale for use in MM

Isatuximab is an IgG1κ mAb that binds selectively to a unique epitope on CD38 and targets tumor cells through various mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity, and immune cell depletion/inhibition of immunosuppressive cells (Figure 1).16 CD38, a type II transmembrane glycoprotein that functions both as a signal-transducing receptor and a multifunctional ectoenzyme, is expressed on the surface of most (>90%) malignant plasma cells from patients with MM, but is expressed at low-to-moderate levels on normal cells.17 The overall mechanism of action of isatuximab operates via both tumor cell–targeted and immunomodulatory effects.16 Isatuximab binding to CD38 on MM cells promotes natural killer cell– and CD8+ T-cell–mediated MM cell lysis.16,18 Activation of natural killer cell–mediated ADCC has been shown to be the most significant mechanism underlying the clinical efficacy of isatuximab in MM.19 Isatuximab also induces macrophage-driven ADCP.16 Isatuximab also modulates the immune microenvironment by activating natural killer cells and macrophages, as well as by inducing apoptosis and inhibiting the proliferation of immunosuppressive regulatory T-cells.18

Figure 1

In addition to inhibiting the CD38 ADP-ribosyl cyclase ectoenzyme activity, isatuximab is thought to be unique among currently available anti-CD38 mAbs in its ability to induce apoptosis directly without crosslinking.16,20 Another key mechanistic difference between isatuximab and daratumumab is the dose-dependent inhibition of CD38 enzymatic activity by isatuximab, with a more limited and dose-unresponsive inhibition mediated by daratumumab under the same experimental conditions.20 Preclinical studies demonstrated the anti-MM activity of isatuximab, as a single agent and synergistically with lenalidomide, or pomalidomide, and dexamethasone.16,21 In a murine xenograft model utilizing myeloma cell lines, for instance, the combination of isatuximab and carfilzomib promoted tumor regression, while each agent by itself attenuated tumor growth.22 Based on the mechanism of action of isatuximab and the evidence from preclinical studies, clinical studies have and continue to assess the efficacy and safety of isatuximab, as monotherapy or in combination regimens, in MM and other hematologic malignancies.17,23

Clinical evidence for isatuximab in MM

Isatuximab has been investigated as monotherapy and in combination with other agents for the treatment of patients with RRMM.20,25-29 While studies of isatuximab monotherapy indicate that it is active and generally well tolerated in patients with RRMM, the synergistic activity of isatuximab in combination therapies has propelled interest in studies of isatuximab-containing combination regimens in RRMM.20 To date, 2 indications for the use of isatuximab in the treatment of adults with MM have gained approval—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.14,30 The approvals of the regimens were based on data from the ICARIA-MM and the IKEMA studies, respectively.27,28

The ICARIA-MM study

The randomized, multicenter, open-label, phase 3 ICARIA-MM study compared the PFS benefit of Isa-Pd to Pd in patients with RRMM who had received ≥2 previous LOTs, including lenalidomide and a PI.27 A total of 307 patients were randomized 1:1 to the 2 treatment arms; 154 received isatuximab (10 mg/kg) with pomalidomide (4 mg) and dexamethasone 40 mg (20 mg for patients aged ≥75 years), while 153 received pomalidomide (4 mg) plus dexamethasone (40 mg).27 At a median follow-up of 11.6 months (interquartile range, 10.1-13.9), median PFS was 11.5 months (95% confidence interval [CI], 8.9-13.9) with Isa-Pd, compared with 6.5 months (4.5-8.3) with Pd (hazard ratio [HR], 0.596; 95% CI, 0.44-0.81; P = .001 by stratified log-rank test) (Figure 2). The addition of isatuximab to Pd also resulted in a reduction in the risk of disease progression or all-cause death by 40% (HR, 0.596; 95% CI, 0.436-0.814; P = .001) at the time of the primary analysis (Figure 2).14 The PFS benefit with Isa-Pd was seen in all prespecified patient subgroups, including those aged ≥75 years, International Staging System stage III, those 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.30-33 At the time of the primary analysis, the median OS had not been reached; 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).27 Overall response rate (ORR) was superior with Isa-Pd compared with Pd (60.4% [95% CI, 52.2-68.2] vs 35.3% [27.8-43.4]; P <.0001; Table 2).14 Subsequent post-hoc analyses also showed that the response, long-term treatment benefit, and safety profile of frail patients treated with Isa-Pd was consistent with that seen in the elderly (≥75 years) and the overall population.14,33 The ORR with Isa-Pd in patients with and without renal impairment (56% and 68%, respectively) was higher than that with Pd (25% and 43%, respectively).34

Figure 2

Table 2

The IKEMA study

The randomized, open-label, parallel-group, phase 3 IKEMA study compared the efficacy of Isa-Kd with Kd in patients with RRMM who had received 1 to 3 previous LOTs and had measurable serum or urine M-protein.28 Of the 302 enrolled patients (median LOTs, 2), 179 were randomly assigned to receive isatuximab (10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks), along with the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone, while 123 received Pd alone. Primary analysis showed that median PFS had not been reached in the Isa-Kd group, compared with 19.15 months (95% CI, 15.77-not reached) in the Kd group (HR, 0.53 [99% CI, 0.32-0.89]; one-sided P = .0007). Isa-Kd significantly improved PFS over Kd in patients with RRMM, reducing the risk of disease progression or all-cause death by 47% (HR, 0.531; 95% CI, 0.318-0.889; P = .0013; Figure 3).28 The addition of isatuximab yielded a PFS advantage across almost all prespecified subgroups, including patients aged ≥70 years, those with renal impairment, with high-risk cytogenetics, with 1q21 gain (with and without high-risk cytogenetics), with ≥1 previous LOTs, with prior IMiD or PI treatment, and refractory to lenalidomide.28,35 The comparison of response end points with Isa-Kd and Kd is shown in Table 3.

Figure 3

Table 3

Moreover, updated PFS and depth-of-response data from the IKEMA trial were presented at the 8th COMy Congress, May 12-14, 2022, in Paris, France.36 At a median follow-up of 44 months, there was a significant PFS benefit with Isa-Kd compared with Kd (35.7 vs 19.2 months; HR, 0.58; 95% CI, 0.42-0.79) in patients with RRMM. PFS2 (defined as the time from randomization to disease progression on the next line of treatment or death), complete response (CR) rate, and the percentage of patients reaching minimal residual disease (MRD) also significantly favored Isa-Kd over Kd; these data support Isa-Kd as a standard-of-care treatment for patients with RRMM. Further details of these updated data will be presented in a future issue of Faculty Perspectives on The Evolving Clinical Impact of Isatuximab in Multiple Myeloma Management.

Additional clinical studies of isatuximab in MM

In addition to the ICARIA-MM and IKEMA studies, the quadruplet regimen of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) is being investigated in 2 ongoing phase 3 studies. The randomized, open-label, phase 3 IMROZ study (NCT03319667) is evaluating the clinical benefit of Isa-VRd, compared with VRd, in patients with transplant-ineligible newly diagnosed MM (NDMM).37 The ongoing phase 3 GMMG HD7 study (NCT03617731) is evaluating the efficacy of induction therapy with Isa-VRd followed by isatuximab plus lenalidomide maintenance, compared with induction with VRd and lenalidomide-only maintenance, in transplant-eligible patients with NDMM.38 Data presented at the 2021 American Society of Hematology Annual Meeting & Exposition showed that the study met its primary end point, MRD negativity, as assessed by next-generation flow (NGF), after induction therapy; MRD negativity rates after induction were 35.6% and 50.1% (odds ratio [OR], 1.83; 95% CI, 1.34-2.51; P <.001) for VRd and Isa-VRd, respectively (Table 4).38 Multivariate analyses including treatment arm, Revised International Staging System (R-ISS), performance status, renal impairment, and age and sex indicated that treatment with Isa-VRd, compared with VRd, was the only significant predictor for increased MRD negativity after induction (OR, 1.82; 95% CI, 1.33-2.49; P <.001). The MRD negativity benefit at the end of induction was observed across all subgroups, including patients with renal impairment, high-risk cytogenetics, World Health Organization performance status, and R-ISS stage.38 Based on these data, Isa-VRd is the first regimen to demonstrate a rapid and statistically significant benefit from treatment by reaching a MRD negativity of 50.1% at the end of induction and to show superiority over VRd in a phase 3 trial.38

Table 4

MRD is defined as the absence of myeloma cells in the bone marrow after treatment, as assessed by NGF, next-generation sequencing, or a validated equivalent method, with a minimum sensitivity of 1 in 100,000 nucleated cells or higher.1,39 In addition to its role of MRD negativity as a robust prognostic indicator in MM, even in patients with conventional CR, MRD is also being explored as a potential surrogate end point in clinical trials to accelerate regulatory drug approval.40,41 Given the evolving role of MRD as a sensitive indicator of disease control and the depth of response to treatment, MRD status may play a role in guiding treatment decisions in the future.41 In this context, the demonstration of the superiority of the Isa-VRd regimen over VRd in terms of MRD negativity is significant and notable.38

Isatuximab monotherapy was evaluated in patients with daratumumab-refractory MM in a recent phase 2 study.29 In the heavily pretreated cohort of daratumumab-refractory RRMM patients treated with isatuximab monotherapy, 1 (3.1%) patient achieved minimal response and 17 (53.1%) patients had stable disease (SD) as best overall response, with the longest duration of SD being 18.5 months, although no objective responses were noted. The disease control rate was 37.5%, with better disease control rate in patients with longer intervals (in particular, ≥6 months) from the last daratumumab dose to the first isatuximab dose (26.4% [last dose <6 months] vs 58.3% [last dose ≥6 months] vs 60.0% [last dose ≥12 months]). As additional data from the IMROZ, GMMG HD7, and other ongoing clinical trials of isatuximab in MM emerge, the patient populations and indications where this mAb therapy could provide clinical benefit are likely to expand.

Cost Implications of MM Therapy
Balancing the use of novel therapies against the implications for the cost of therapy in MM

Management of MM is associated with significant costs in terms of the economic impact of treatments and supportive care, hospitalization, and healthcare resource utilization.42-46 The cost implications for the care and treatment of patients with MM and the drivers of cost vary, depending on the treatment phase (initial/continuing/terminal care), disease progression, requirement for managing MM-associated complications such as skeletal-related events, route of administration of therapies (all-oral regimens or regimens requiring frequent and/or lengthy subcutaneous or intravenous infusions), and LOT (initial/post-transplant/subsequent LOTs for RRMM).44-52 In the current era of an expanding arsenal of antimyeloma therapies, many of which include agents with novel mechanisms of action and are covered by patent exclusivity, it is all the more important to balance the clinical benefit with the implications for the costs of the MM therapy.53 Cost-effectiveness analyses are inherent to understanding the affordability and access to the expanding range of options in MM and for complementing available clinical data for novel agents and combinations thereof and optimal treatment sequencing.6,43,54 In the subsequent sections, we discuss the cost implications of MM therapy, with a focus on recent evidence on CD38-targeted mAb therapies in MM.

Factors that impact the cost of MM management

Although MM is not unique among cancers in terms of the concerns around cost of care, especially around introduction of novel potentially lifesaving therapies, these issues are of heightened interest in MM due to manifold reasons.43 MM therapy has been shifting away from monotherapy and doublets to triplets and quadruplet regimens in recent decades, predicating the use of multidrug combinations, which can amplify treatment costs.43,55-57 An example of the temporal trends in MM care costs from 2000 to 2014, a period that saw the approval of bortezomib, carfilzomib, lenalidomide, panobinostat, pomalidomide, and thalidomide for MM indications (Figure 4A). Notably, multiple novel therapies and multidrug agents have since gained approval (Figure 4B). A 2018 study estimated the average all-cause per-patient per-month costs for first-, second-, and third-line MM treatments to be 1.5 to 3 times the costs in 2014 ($22,527 in first-line, $35,266 in second-line, and $47,417 in third-line estimated in 2018, compared with approximately $15,000 in 2014).52 Treatment continuation until progression of MM can also add to the costs of care, extending the duration that a patient may be on treatment.43 Moreover, as relapse is an inevitable outcome in most patients diagnosed with MM, often requiring multiple LOTs, the cumulative costs of treatment over the lifetime of a patient diagnosed with MM can exacerbate the concern of cost at each individual LOT.7,10,43,44,49

Figure 4

MM is a malignancy that occurs primarily in older adults, with a median age at diagnosis of 69 years.3 With an increasing proportion of the aging population and the extension of survival of patients with MM, the population of individuals diagnosed and living with this malignancy is expected to continue increasing in coming years.58 Indeed, a study that projected the incidence, prevalence, and the number of MM patients treated with systemic therapy by LOT between 2020 and 2025, using a combination of data from the Surveillance, Epidemiology, and End Results (SEER) program and physician surveys estimated an increase in MM prevalence in the United States from 144,922 in 2020 to 162,339 in 2025.58 An understanding of the cost implications across the continuum of MM care, including at different disease phases and LOTs and in various patient populations, is critical to ensure that potentially lifesaving/life-prolonging therapies are accessible to the widest swath of patients, while mitigating the financial toxicity to the individual patient and the healthcare system.

Studies have evaluated the cost implications of MM therapy in Medicare beneficiaries.44,46,50,53 For instance, a retrospective population-based study of data linked data from the SEER program and the Medicare claims database showed that among older adults with MM (mean [SD], 75.8 [6.8] years), the mean adjusted incremental MM lifetime costs were $184,495 (95% CI, $183,099-$185,968), with costs increasing along the continuum of MM care at a mean per-patient per-month phase-specific incremental value of $1244 (95% CI, $1216-$1272) from the prediagnosis phase to terminal care.44 Moreover, prescription drugs were the largest cost drivers, accounting for 44.9% of costs, in the continuing care phase.44 In another analysis of SEER-Medicare linked data, novel agents were only cost-effective compared with chemotherapy at high willingness-to-pay thresholds, in the range of $230,000, despite their significant impact on survival rates.53 Similarly, novel therapies, including daratumumab-, elotuzumab-, and ixazomib-based triplets introduced in second- and third-line RRMM, yielded significant clinical benefits in terms of prolonging OS, PFS, and quality of life; however, not all regimens were considered cost-effective, at the commonly cited threshold of $150,000 per quality-adjusted life-year (QALY).59 Studies have also evaluated the clinical effectiveness of novel therapies and treatment sequences in concert with their costs, cost-effectiveness, and the impact on QALYs.48,60 In a study of patients with transplant-ineligible MM patients from a Dutch registry, newer regimens had the largest expected gains in OS; however, their cost-effectiveness ratios were above currently accepted willingness-to-pay thresholds.48 An earlier study from 2016 found that increased utilization of novel agents improved survival, while increasing costs, with combinations containing thalidomide, lenalidomide, and bortezomib, in that particular order, yielding the most favorable incremental cost-effectiveness ratio.61

The route of administration of therapies in MM, whether oral, intravenous, or subcutaneous, also has cost implications.47,62-64 A cost modeling analysis of patients with RRMM compared overall, direct, and indirect costs across therapies over a 12-month period from initiation of second-line therapy.47 The data showed that all-oral regimens were associated with lower treatment burden and indirect costs, compared with regimens requiring frequent and/or lengthy subcutaneous or intravenous infusions.47 A retrospective real-world cohort study compared the extent of disability benefit use and consequent loss in workplace productivity for American adults with NDMM receiving oral versus injectable MM therapy.62 Patients who received injectable therapy missed more workdays in the first year after diagnosis, compared with those on only oral therapy (difference of 23 days, 95% CI, 19-26; P <.001). Moreover, use of disability benefits and loss of productivity costs were significantly higher for patients on injectable therapy, compared with those receiving oral therapy ($18,315 in productivity loss with injectables vs $14,429 with oral; $3886, 95% CI, $3540-$4231; P <.001).62 The use of intravenous or subcutaneous PIs for MM therapy is associated with significant healthcare, traveling, and indirect costs in a Finnish study.63 Oral drug–based regimens were determined to provide cost advantages over intravenous drug–based therapies for MM, primarily due to higher drug acquisition costs for intravenous agents, according to a recent German study.64 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.65,66

As mentioned before, cost increases along the MM care continuum have been noted, due to disease progression, the need for multidrug regimens, or multiple LOTs.44,46,49,51,52 For instance, patients with MM in commercial or Medicare databases exposed to 3 classes of drugs—a PI, an IMiD, and an anti-CD38 mAb—who received ≥1 LOTs after the triple-class exposure (TCE), the mean total all-cause healthcare cost per patient was $722,992 (equivalent to $34,578 per-patient per-month), with >90% of all costs related to MM and 66% related to MM drugs/infusion.46 A retrospective cost-of-illness cohort study that assessed the costs of MM treatments from the US payer perspective found that anti-MM pharmacy costs increased from 22% in first-line to 29% in second- and third-line.52 Moreover, average total all-cause per-patient per-month costs also increased with each subsequent LOT, from $22,527 in first-line, $35,266 in second-line, and $47,417 in third-line, indicating the higher costs associated with management of relapsed/refractory disease.52 Similarly, treatment of patients with RRMM with TCE, using US claims data, was associated with high costs, with an estimated monthly expenditure of $35,657.51 The high costs associated with third-to-fifth LOTs for patients with RRMM have been described as “unsustainable and unaffordable” for patients and payers alike.50

It is important to note that not all studies have yielded the conclusion that novel therapies improve clinical outcomes in the absence of cost-effectiveness. For instance, 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 past decade, novel therapies in MM may be considerably cost-effective.67 Similar conclusions are included in other reports.6,68 A systematic review of economic evaluations of the use of novel agents in MM and the reporting quality of these assessments found that while most studies included in the analyses showed that novel therapies were cost-effective at a threshold of up to $100,000/QALY, the reporting quality of the studies needed improvement.68 Specific issues with economic evaluations of MM therapies that warrant improvement include reporting of precision measures for all parameters in the cost modeling, evaluation of the heterogeneity of the results by subgroup analyses, and clear descriptions of the role of the funding source for various aspects of the analyses.68

While crucial, it is important to note that the quality and conclusions of cost-effectiveness modeling studies can vary, based on assumptions and input variables, as well as the output variable(s) that are queried.6 A study that assessed quality-adjusted cost of care, instead of the QALYs metric, for example, concluded that the increased cost of novel MM therapies could be offset by the improvement in health benefits.69 Overall, the evidence discussed here points to substantial costs associated with the care and treatment of patients with MM and a continuing need for increased efforts to describe and integrate cost implications into MM clinical pathways, along with frameworks for mitigating these costs.

Analyses of cost-effectiveness of CD38-targeted mAb therapies in MM

Anti–CD38-directed immunotherapies have demonstrated remarkable efficacy, along with a tolerable safety profile, making CD38-targeted mAb-based regimens integral components of the current standard of care for subsets of patients with MM.70,71 Data pertaining to the cost implications of CD38-targeted mAb-based MM treatments continue to emerge, concurrent with the uptake of daratumumab and isatuximab in MM clinical practice, with mixed results.72-82 A 3-state Markov modeling assessment developed from the perspective of US payers concluded that the addition of daratumumab to the bortezomib, melphalan, and prednisone (VMP) regimen was not cost-effective over VMP, with an upper limit of willingness-to-pay threshold that was $150,000/QALY.79 However, a similar modeling analysis concluded that daratumumab with VMP was cost-effective compared with VMP in patients with NDMM, assuming the same threshold of $150,000/QALY.80 In other contexts, including in transplant-ineligible NDMM and RRMM, daratumumab regimens were found to lack cost-effectiveness, compared with the backbone treatments without daratumumab.77,81-83 A recent study compared the cost-effectiveness of 3 separate regimens—daratumumab, lenalidomide, and dexamethasone (Dara-Rd), VRd, and lenalidomide plus dexamethasone (Rd)—in patients with MM who are ineligible for autologous stem-cell transplant.81 The modeling analysis, based on the MAIA and SWOG S0777 studies, showed that Dara-Rd was associated with the highest overall total cost at $626,900, followed by VRd at $385,434, and Rd standard therapy at $329,867. Although VRd appeared cost-effective for 40% of iterations at a willingness-to-pay threshold of $550,000, Dara-Rd failed to be cost-effective over VRd at any reasonable threshold, up to $800,000. As with other analyses, mature OS data for the Dara-Rd regimen is needed for further detailed costs analysis and to determine the incremental cost-effectiveness ratio in QALYs. In an analysis comparing the cost-effectiveness of Dara-Vd to Vd, based on the CASTOR study in patients with RRMM who received ≥1 prior LOTs, adding daratumumab to Vd provided an additional 1.256 QALYs or 1.645 life-years (LYs), with incremental $213,164 or $163,184 per QALY or LY gained, respectively.77 For Dara-Vd to be cost-effective over Vd, daratumumab would have to be priced at 70% of the current price at a willingness-to-pay threshold of $200,000. The authors concluded that addition of daratumumab to Vd in RRMM was likely to exceed the common accepted values of cost-effectiveness from a US payer’s perspective.77

Isatuximab is a more recent entrant into the MM therapeutic space and to date, the cost implications for isatuximab utilization have been discussed in a limited number of studies and expert perspectives.75,78,84,85 A recent cost-effectiveness analysis facilitated by an indirect treatment comparison of PFS with Isa-Kd with daratumumab-carfilzomib-dexamethasone (Dara-Kd) showed that clinically, Isa-Kd was associated with slight incremental gains in LYs of 0.12 months over 6 months of treatment and 0.48 months over 1 year of treatment of patients with RRMM, compared with Dara-Kd.78 The 6-month clinical gain includes cost-savings of approximately $24,000 or about 15% of Isa-Kd therapy, while the 12-month gain is predicated on a minimal cost commitment of approximately $2000 or 0.6% of Dara-Kd treatment. In another cost-effectiveness and cost-utility comparison between Isa-Pd and daratumumab-pomalidomide-dexamethasone (Dara-Pd) from a US payer’s perspective, Isa-Pd was associated with incremental survival gains of 1 month and quality-adjusted survival gains of 0.5 months (or 0.035 years) over Dara-Pd, assuming a treatment duration of 1 year (Figure 5).75 The cost benefits of Isa-Pd over Dara-Pd increase with treatment duration, reaching approximately 7 months in LY gains and 4 months in QALY gains over 5 years of treatment. Due to its lower total costs, the isatuximab regimen yielded savings incremental cost-effectiveness ratios at 1 and 3 years, with the cost of Isa-Pd exceeding that of Dara-Pd at the 5-year time horizon (Figure 5).75

Figure 5

In a recent report published online in The ASCO Post, Shaji J. Kumar, MD, noted that in the absence of randomized trials comparing isatuximab and daratumumab regimens directly, data from the ICARIA-MM and EQUULEUS studies indicate no significant differences between these 2 mAb therapies.85 The different scheduling of the 2 mAbs favors isatuximab, only in instances involving a short duration of treatment. However, Kumar noted that the adoption of isatuximab may ultimately be driven by cost considerations.85 Indeed, isatuximab costs over a 12-month course were estimated to be lower than that for daratumumab, according to a report published prior to the approval of the subcutaneous formulation of daratumumab.84 The costs associated with treatment of an 80-kg patient for a 12-month (52-week) treatment course with isatuximab was estimated at approximately $145,600, compared with $163,300 with daratumumab. These estimates used a wholesale acquisition cost of isatuximab-ifrc in the United States of $3250 for a 25-mL vial (20 mg/mL) and $650 for a 5-mL vial (approximately $130 per 20 mg of drug).

Proposed solutions for mitigating costs of care in MM

Given the high cost burden associated with MM treatment, strategies for mitigating these costs without compromising clinical effectiveness and outcomes have been discussed.42,43,50 These strategies include generation of cost-effective care/clinical pathways, increasing market competition, value-based pricing, improvements in national guidelines, and authorizing Medicare to negotiate prescription drug prices.42,43,50

One key strategy that addressed the significant issue of drug copays is the creation of copay assistance programs by drug manufacturers for MM patients with commercial insurance.6 In addition to providing financial assistance, the patient support programs established by manufacturers provide support with insurance access and reimbursement, as well as resource support, such as with nurse navigators or care coordinators. The CareASSIST program for SARCLISA® (isatuximab-irfc) provides copay assistance for patients with commercial insurance receiving treatment with isatuximab, with the possibility of reducing out-of-pocket payments to $0. The program also offers clinical support services, food and nutrition programs, transportation assistance, health supply/cosmetic aids, patient advocacy support, and home care services support. In addition, insurance-related services offered through the CareASSIST program include insurance verification, help with prior authorization, and support with claims management and appeals.

Studies have also examined cost impacts of changing treatment-related parameters, such as a shorter infusion duration or delaying first-line treatment with daratumumab.76,82 An assessment of the safety profile and cost associated with rapid daratumumab infusion protocol found that the rapid infusion was safe and tolerable, with significant cost-savings—total estimated drug administration costs were $137,200 with regular infusions, compared with $122,200 with rapid infusion (P <.001).76 These savings resulted from cost improvements associated with drugs and their administration, staffing productivity, and patient productivity, providing a cost-based rationale for alternate infusion protocols that do not compromise efficacy or increase risk of infusion-related reactions, while providing treatment attributes that may be preferable to patients, caregivers, and clinicians alike.76 Indefinite administration of novel therapies, including daratumumab-based regimens, until disease progression can have significant cost impacts. In a recent study, Markov cost-modeling analysis was used to compare the healthcare costs and clinical outcomes of transplant-ineligible patients treated with daratumumab in the first-line setting, compared with an approach based on reserving daratumumab use until the second line.82 The cost data showed that while first-line daratumumab in this setting may not be cost-effective under current pricing structures, reserving daratumumab until the second LOT may help mitigate costs, without compromising clinical outcomes.82 This analysis needs to be conducted with mature OS data, which are not yet available, to confirm these findings; the current cost modeling is based on the PFS improvement with daratumumab seen in the MAIA study.82,86,87

In concert with cost-effectiveness studies, analysis of practice patterns can also yield important information on whether improving how novel therapies are used can help mitigate costs of treatment. In an analysis of real-world evidence of daratumumab utilization and costs in US community oncology practice, patients with MM received 14% more daratumumab doses than indicated in the US Food and Drug Administration–approved label, increasing the 1-year daratumumab costs by an estimated $31,353.88


The introduction of novel therapies, including CD38-directed mAbs, has dramatically altered the MM treatment paradigm, providing opportunities for improving outcomes and extending the survival of patients with MM. With the expansion of the MM arsenal, the cost implications of therapies on not only access and affordability of care but also optimal treatment sequences and clinical pathways are likely to continue to be a focus of discussion, investigation, and refinement. While the ultimate responsibility of the clinician is optimizing the clinical outcomes for their individual patient with MM, awareness of the cost implications and strategies for addressing financial concerns can help patients remain on individualized treatments for optimal durations, thereby providing maximum clinical benefit from MM therapy.


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