CAR-T Therapy in Multiple Myeloma: Beyond Prejudice, Towards Value

1. Introduction

Dedication This work is dedicated to all patients and families living with multiple myeloma, whose resilience continues to inspire. Our goal is not only to advance science, but to restore dignity, equity, and hope in treatment. May these findings serve as a reminder that true progress is measured not solely in survival curves, but in the quality of lives preserved.

Multiple myeloma is a clonal plasma cell malignancy marked by progressive marrow infiltration, end-organ damage, and inevitable relapse. Over the past two decades, therapeutic advances including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies, and multidrug combinations have improved survival, yet the disease remains incurable [1].

Despite these innovations, current practice still relies heavily on mid-20th century strategies such as alkylating agents and high-dose melphalan with autologous stem cell transplantation. These regimens, though foundational, dominate frontline algorithms and accumulate toxicity over time. Successive therapies often drive marrow exhaustion, T-cell dysfunction, and reduced eligibility for advanced immunotherapies [2,3,4].

Consequently, patients encounter novel options like chimeric antigen receptor (CAR) T-cell therapy only after years of exposure to less effective and toxic regimens precisely when risk is highest and benefit attenuated. This entrenched sequencing reflects not only clinical inertia but also economic prejudice, with CAR-T frequently dismissed as prohibitively expensive.

Here, we reframe the role of CAR-T in multiple myeloma. Integrating survival outcomes with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), we demonstrate that the value of CAR-T surpasses conventional approaches when analyzed in terms of both efficacy and cost-utility. By emphasizing timing and measurable benefit, we argue that CAR-T should be reconsidered not as a last-resort experiment, but as a rational and pragmatic therapeutic option.

2. Myeloma Therapies

Cancer has been recognized since antiquity, with treatments ranging from heavy metals and herbal remedies to surgical resection and dietary interventions. Multiple myeloma, however, was first described in the 1840s, and early therapies included rhubarb, opium, corsets, and leeches rudimentary measures that reflect both the limits and persistence of early medical practice [5]. Multiple myeloma (MM) is a plasma-cell malignancy and the second most common haematological cancer, predominantly affecting older adults. It is characterised by clonal plasma-cell expansion, monoclonal protein secretion, and organ damage defined by the CRAB criteria (hypercalcaemia, renal impairment, anaemia, bone disease) [1].

Over the past two decades, treatment has evolved from conventional alkylators and autologous stem cell transplantation to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies, increasingly delivered in triplet or quadruplet regimens. Despite these advances, MM remains incurable: drug-resistant subclones persist, survival plateaus at ~50% at 5 years, and outcomes vary widely across countries depending on healthcare access. The need for transformative therapies is therefore pressing [6].

The 20th century reshaped oncology through global upheavals. Both World Wars accelerated scientific discovery, and in the post-war era, multiple myeloma reached its first true therapeutic milestone with the advent of bone marrow transplantation [7,8,9]. Until the early 2000s, myeloma management reflected a broader pharmacological paradigm drug development was largely driven by geopolitical competition and the pharmaceutical race that followed. As a result, treatment remained anchored in successive pharmacologic regimens, mirroring the trajectory of many solid and hematologic malignancies. Only in recent years has the field shifted toward cellular and immune-based therapies, reopening a vision reminiscent of ancient holistic medicine one that emphasizes individualized, patient-centered, and precision-guided approaches.

The Cold War transformed oncology into a pharmacological race. In the context of geopolitical rivalry, successive drugs were rapidly synthesized and introduced, often without long-term evaluation [10]. Even tragedies such as the thalidomide [11] disaster did not halt this momentum; instead, compounds were reformulated and reintroduced, spawning analogs such as lenalidomide and pomalidomide alongside dexamethasone-based regimens. Melphalan, itself derived from nitrogen mustard used as chemical warfare in the First World War [12], remains embedded in frontline myeloma protocols to this day. Our purpose is not to discard therapies that still provide benefit, but to critically reassess toxic, decades-old regimens and create space for more effective, safer, and innovative approaches. In this context, the entrenched skepticism toward cellular therapies such as CAR-T reflects inertia rather than evidence (Table 1).

Today the therapeutic landscape of multiple myeloma shifted toward more targeted drug classes. Proteasome inhibitors, HDAC6 inhibitors, and XPO1 inhibitors represented a new generation of pharmacology still drug-based, but increasingly mechanism-specific. In parallel, monoclonal antibody development brought therapies such as daratumumab into clinical practice, marking a departure from purely cytotoxic regimens toward immune-based approaches [1,6]. This period bridged the traditional chemotherapeutic era and today’s paradigm of cellular and precision-guided therapies (summarized in Table A1 (Appendix A).)

Importantly, in this modern era, treatment success is no longer defined solely by survival gains; quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) have emerged as essential metrics, reflecting that efficacy must be weighed against toxicity, cost, and patient quality of life.

Although multiple myeloma originates from clonal plasma cells, it is no longer regarded as a purely cell-autonomous disease. The bone marrow microenvironment (BMME) provides the niche that sustains hematopoiesis and immune surveillance, but in MM this architecture is hijacked tumor cells evade immune detection, suppress hematopoiesis, and promote osteolysis and infection risk. Resistance often stems not only from the tumor cell itself but also from stromal, immune, and endothelial interactions [24,25,26]. This paradigm has redirected therapeutic strategies toward targeting both the tumor and its niche. Approaches include adhesion inhibitors (e.g., VLA-4 antagonists), cytokine/chemokine blockade (IL-6, CXCR4), anti-angiogenic and osteoclast-inhibiting therapies, and immunotherapies such as CAR-T cells, bispecific antibodies, and checkpoint blockade. Exosome-disrupting agents are also under investigation for interrupting intercellular communication [27,28,29].

Among immune-based strategies, antibody-drug conjugates (ADCs) provide proof of principle. Belantamab mafodotin, an anti-BCMA ADC, showed activity in triple-class refractory disease in the DREAMM-2 [30] trial but was limited by ocular toxicity, leading to its withdrawal from the US market. Nevertheless, it remains under study in combination regimens and in settings where CAR-T or bispecifics are not available, illustrating the expanding but heterogeneous nature of the BCMA-targeting arsenal [31].

3. From Immunotherapy Origins to Car-T

Immunotherapy has long been intertwined with oncology, tracing back to William Coley’s late 19th-century bacterial vaccines, which for the first time suggested that immune activation could drive tumor regression. Though primitive, Coley’s toxins reframed cancer as more than a cell-autonomous disease [32]. This idea re-emerged in the cytokine era of the 1970s and 1980s, when interferon-α and interleukin-2 were introduced into clinical oncology. These agents revealed the capacity of exogenous immune stimulation to induce tumor responses, yet their efficacy was modest and toxicity profound, underscoring the need for more precise immune manipulation.

The 1990s marked the true molecular revolution. Advances in genetic engineering enabled the creation of T-cell receptors with redirected specificity, and in 1993 the first chimeric antigen receptor (CAR) was described. By fusing an antibody-derived binding domain with intracellular signaling motifs, CARs could bypass MHC restriction and target tumor antigens directly. The incorporation of co-stimulatory domains such as CD28 and 4-1BB further enhanced T-cell persistence, expansion, and metabolic fitness, transforming early prototypes into clinically viable platforms [33,34].

Proof of principle came with CD19-directed CAR-T cells. Preclinical experiments demonstrated regression of aggressive B-cell lymphomas in murine models, followed by remarkable clinical responses in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma. Deep and durable remissions, accompanied by the persistence of functional memory T cells, established CAR-T therapy as one of the most disruptive innovations in hematology [35,36,37,38] (see Figure 1).

For multiple myeloma, these breakthroughs were especially consequential. Myeloma had long been treated with successive pharmacological regimens that yielded incremental benefits but failed to overcome relapse biology. The ability to engineer autologous T cells against plasma cell antigens most notably B-cell maturation antigen (BCMA) opened a new therapeutic horizon. CAR-T was no longer an experimental curiosity confined to lymphoid malignancies, but a rational extension into plasma cell disorders, with the promise of converting transient responses into durable remissions [35,38].

4. First in Class Approvals: Ide-Cel and Cilta-Cel

The therapeutic milestone for multiple myeloma arrived with B-cell maturation antigen (BCMA) as a target. Two autologous CAR-T products are now approved. Idecabtagene vicleucel (ide-cel, Abecma) received FDA approval in April 2021 (KarMMa trials) and, in heavily pretreated patients (≥3 prior lines including PI, IMiD, and anti-CD38), achieved an overall response rate (ORR) of 76% versus 32% with standard care, ≥VGPR of 58% versus 14%, one-year progression-free survival (PFS) of 55% versus 30%, and minimal residual disease (MRD) negativity of ~20%. Common toxicities include neutropenia, leukopenia, and cytokine release syndrome (CRS), with grade ≥3 CRS in ~14% [39,40].

Ciltacabtagene autoleucel (cilta-cel, Carvykti) received FDA approval in February 2022 as a second-generation BCMA CAR-T with dual epitope binding, demonstrating median overall survival (OS) of ~56 months, median PFS of ~18 months, and MRD negativity of ~68% by 2025 analyses. Toxicities include CRS (mostly low-grade), ICANS, cytopenias, and infections [39,41]. Despite transformative efficacy, accessibility remains limited: ide-cel is available in only a handful of countries (United States, France, Switzerland, Japan, Germany), while cilta-cel is approved only in the United States and Germany, with manufacturing delays and patient selection criteria further restricting broader use [42].

Beyond BCMA, relapse after CAR-T underscores the need for alternative strategies, including novel targets such as CS1/SLAMF7, CD138, GPRC5D, and FcRH5 to circumvent BCMA-negative relapse; enhanced designs such as dual-target CARs (e.g., BCMA + CS1), armored CAR-Ts secreting cytokines (IL-15), and allogeneic “off-the-shelf” constructs to reduce antigen escape and overcome manufacturing bottlenecks; and combination approaches integrating CAR-T with IMiDs, checkpoint inhibitors, or γ-secretase inhibitors to deepen and prolong responses [39].

5. Why Bcma Is an Ideal Target in Multiple Myeloma

B-cell maturation antigen (BCMA, also known as TNFRSF17) has emerged as the leading target for cellular and antibody-based immunotherapies in multiple myeloma. Several biological features make BCMA uniquely suitable: it is highly and consistently expressed on malignant plasma cells with limited distribution in normal tissues, thereby reducing off-tumor toxicity; it plays a central role in plasma cell survival through interactions with ligands such as BAFF and APRIL, meaning that its blockade not only identifies but also biologically disrupts myeloma cell fitness; its high antigen density enhances CAR-T recognition and killing efficiency; and, unlike CD19 or CD20 in other B-cell malignancies, its expression persists even in late-stage and refractory disease, allowing targeting across multiple treatment lines. These properties explain why BCMA-directed CAR-T therapies (ide-cel, cilta-cel) have achieved deep and durable responses and why BCMA has become the benchmark target for bispecific antibodies and antibody–drug conjugates. At the same time, however, antigen escape and downregulation underscore the need for next-generation approaches such as dual-target CARs, armored constructs, and alternative antigens (CS1, GPRC5D, FcRH5) to sustain efficacy [43].

6. Challenges and Future Directions

CAR-T cell therapy introduces unique risks-CRS, ICANS, prolonged cytopenias that demand specialized management. Furthermore, relapse mechanisms include antigen loss, T-cell exhaustion, and microenvironmental resistance. Integration with biomarker-guided monitoring, earlier-line application, and rational combinations will be crucial to sustain durable benefit [44]. Most importantly, success is not defined by survival curves alone. In an era of rising healthcare costs, QALY and ICER analyses contextualize CAR-T within a framework of value, not just efficacy. These metrics suggest that CAR-T, though logistically demanding, offers pragmatic and measurable benefit compared with entrenched, toxic regimens.

CAR-T therapies such as ide-cel and cilta-cel have shown remarkable efficacy, yet access remains limited. Ide-cel is available only in a handful of countries including the United States, France, Switzerland, Japan, and Germany while cilta-cel is currently approved in just the United States and Germany. Even where approvals exist, practical barriers slow down implementation: manufacturing slots are scarce, certified centers are few, and referral often comes very late in the disease course. By the time patients reach CAR-T, they have already received multiple lines of toxic therapy, their T cells are exhausted, and the window for maximum benefit has narrowed [42]. (see Figure 2 for therapy path).

This delay feeds into the common prejudice that CAR-T is “too expensive for too little gain.” In reality, cost should be seen in context. Traditional myeloma care relies on years of continuous drug combinations, hospital visits, toxicity management, and supportive treatments each with its own burden and expense. A one-time CAR-T infusion is often labeled as “too expensive,” largely because the entire cost is charged upfront. Yet when placed in context, the picture changes. Patients with multiple myeloma routinely cycle through years of triplet or quadruplet drug regimens, autologous stem cell transplantation (ASCT), and supportive care. The cumulative cost of these conventional strategies many of which extend life by only a few years can approach or even exceed 3 million USD per patient [45,46,47,48]. By contrast, CAR-T consolidates this expense into a single treatment, with the potential for deeper and longer-lasting remissions. In countries where CAR-T is approved, much of the cost is already covered by national health systems; the “sticker shock” comes not from actual excess, but from the visibility of a lump-sum charge. In reality, it is the so-called “cheaper” therapies that often prove more expensive in the long run, while CAR-T offers a concentrated investment with measurable value. Indeed, when the cost of ASCT is combined with years of ongoing pharmacological regimens, the total expense often surpasses that of CAR-T, underscoring the need to reassess what we call “expensive” or “affordable [42].

More importantly, treatment success today is not measured only in how long patients live, but also in how well they live. Analyses of quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) suggest that CAR-T can deliver measurable value, especially if used earlier in the treatment course.

Instead of asking whether CAR-T is “too expensive,” the more relevant question is whether we are using it at the right time and in the right patients. Earlier referral, streamlined manufacturing, and safer outpatient management of toxicities could improve both patient outcomes and cost-effectiveness. Seen through this lens, CAR-T is not a last-resort luxury, but a rational, pragmatic therapy that deserves a central place in modern myeloma care.

7. Materials and Methods

This study analyzed historical and current treatment strategies for multiple myeloma (MM) in terms of cost, treatment duration, and mean overall survival (OS). When available, Kaplan-Meier survival curves were digitized using WebPlotDigitizer. The area under the curve (AUC) was estimated via the trapezoidal rule to calculate mean OS. Accuracy was cross-validated through geometric approximation and visual estimation. The graphs of the obtained data were analyzed using Graphpad Prism 8 (see method abstract below Figure 3).

In cases where Kaplan-Meier plots were unavailable and mean OS was not explicitly reported, median OS values were extracted and multiplied by a correction factor of 1.3, as recommended by prior modeling studies [49,50] , to approximate mean OS. All OS values were converted into total days using the standard monthly average (30.44 days).

We developed a novel ECOG-based QALY framework tailored for multiple myeloma. Each therapy was assigned quality-of-life weights according to ECOG performance status, and QALYs were derived by combining these coefficients with survival data from phase II/III trials. Drug costs were retrieved from publicly available pricing sources (e.g., Drugs.com), and incremental cost-effectiveness ratios (ICERs) were calculated by comparing total cost per QALY gained across regimens.

To anchor the analysis historically, we used Samuel Solly’s first reported myeloma case in 1844 as a baseline comparator: one year of survival, assumed at ECOG 3, treated with rhubarb and opium at negligible cost. This provided a reference point against which modern therapies could be contextualized. All therapies from early alkylating agents to contemporary CAR-T products were evaluated using the same assumptions and optimization model, enabling direct comparison across eras.

Treatment duration was modeled in cycles by dividing survival time by average cycle length, with drug dosages calculated assuming full administration across standardized body parameters (BSA 1.73 m², weight 70 kg). Costs were derived from dosing requirements and public pricing data.

Health-related quality of life (HRQoL) was estimated using a novel ECOG-based utility model, developed to compensate for the lack of validated mappings between ECOG status and utility values in multiple myeloma. While frameworks such as EQ-5D and EORTC exist in other malignancies, no standard approach was available for MM; thus, we constructed a consensus utility scale that reflects the disease’s chronic yet progressive course.

• ECOG 0 → 0.9
• ECOG 1 → 0.7
• ECOG 2 → 0.5
• ECOG 3 → 0.3
• ECOG 4 → 0.1
• ECOG 5 → 0

Research manuscripts reporting large datasets that are deposited in a publicly available database should specify where the data have been deposited and provide the relevant accession numbers. If the accession numbers have not yet been obtained at the time of submission, please state that they will be provided during review. They must be provided prior to publication.

These estimates are not empirically derived but provide a transparent and reproducible framework for scenario-based cost-utility modeling. The scale balances optimistic full-health assumptions against conservative underestimation and enables comparative evaluation across treatment strategies within a consistent methodological structure. Quality-adjusted life years (QALYs) were calculated as the product of estimated mean overall survival and the corresponding utility score derived from ECOG performance status:

QALY= Life years x Utility

Cost-effectiveness was evaluated using the standard incremental cost-effectiveness ratio (ICER) formula:

Historical anchor: The earliest reported myeloma case, described by Dr. Samuel Solly in 1844, survived approximately 12 months after diagnosis and was treated with rhubarb, opium, and orange peel supportive rather than disease-modifying therapy. Based on functional decline, we estimated a Karnofsky score <50 (ECOG 3), corresponding to a utility value of 0.3. This case was used as a baseline reference (ΔQALY = 0.3) against which subsequent therapeutic developments were contextualized (see details Supplementary Tables S2–S5, Appendix A).

Introducing the See-Saw Framework to illustrate the cumulative therapeutic burden: Across stratified patient populations in multiple myeloma (MM), we introduce the See-Saw Model) a conceptual and visual framework designed to complement traditional cost-effectiveness approaches. Unlike conventional models that evaluate isolated treatment regimens, the model integrates:

• Total ICER values
• QALY outputs
• Across transplant-eligible, ineligible, and frail patient groups

This framework visually demonstrates the disproportionate economic and clinical load borne by different subgroups, highlighting how high-cost, low-benefit regimens can destabilize overall health system equity especially in vulnerable populations. Designed for accessibility and adaptability, the model serves as a practical decision-support tool for:

• Policymakers
• Clinicians
• Health economists

It can be applied to both disease-specific evaluations and broader healthcare resource allocation analyses.

8. Results

8.1. Therapy Costs

The cumulative costs of myeloma therapies varied widely across both monotherapy and combination regimens. As shown in Appendix B; Figure B1 [51,52,53,54,55,56,57,58,59,60,61] and Figure B2 [61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91] (Supplementary Figure S1,S2) traditional agents such as melphalan remain relatively inexpensive, while prolonged regimens based on immunomodulatory drugs, proteasome inhibitors, or monoclonal antibodies accumulate costs exceeding one million USD. Combination therapies such as VRd, D-VRd, and Isa-VRd often surpass 2-3 million USD per patient, reflecting not only drug prices but also prolonged treatment duration. By contrast, the upfront costs of CAR-T therapies (ide-cel, cilta-cel) appear high but remain comparable or in some cases lower than the cumulative expense of multi-year pharmacological strategies (Supplementary Material Table S1,S2).

8.2. QALY Outcomes

While conventional and combination regimens often achieve measurable improvements in survival, their QALY profiles reveal important nuances. Low-intensity regimens such as elotuzumab-based combinations (Elo-Pd, Elo-Rd, Elo-VRd) provide only modest gains (2–3 QALYs) despite prolonged administration. Patients remain under continuous drug exposure, with accumulating toxicity and diminished quality of life. In contrast, cilta-cel consistently outperforms expectations, delivering more than 3.5 QALYs as a one-time therapy exceeding the cumulative benefit of multi-drug regimens such as Elo-based protocols. This paradox highlights a key message: treatments that appear “lighter” or less toxic can, over time, yield less value than an intensive but finite cellular intervention. Similarly, isatuximab and daratumumab improve QALY relative to historical standards but still require ongoing cycles. CAR-T, by eliminating the need for continuous therapy, reframes cost-effectiveness in terms of both financial and human burden. QALY gains with cilta-cel are not only higher, but cleaner: patients spend more time off treatment and in better health (see Figure 4) [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. Importantly, elotuzumab-based regimens are typically administered before referral to CAR-T therapy. Despite being delivered later in the disease course, when patients are more fragile and their T-cell fitness diminished, cilta-cel still surpasses Elo-based combinations in QALY gain. This finding strongly argues against the perception of CAR-T as a “last-resort” option and supports its evaluation in earlier treatment lines, where preserved immune function could further enhance its cost-effectiveness (Supplementary Table S3,S4).

8.3. ICER Comparisions.

Incremental cost-effectiveness ratios (ICERs) revealed striking discrepancies between perceived and actual therapeutic value (see Appendix B, Figure 3 and Figure 4) [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. Traditional agents such as melphalan appeared inexpensive with low ICERs, but their clinical benefit was minimal, rarely exceeding 1 QALY. By contrast, widely used immunomodulators and proteasome inhibitors (e.g., lenalidomide, pomalidomide, bortezomib) displayed elevated ICERs due to high cumulative drug costs and only modest quality-adjusted survival gains. Monoclonal antibodies (daratumumab, isatuximab) improved QALY relative to older regimens but incurred ICER values in the mid-to-high range, reflecting ongoing costs of continuous therapy. Elotuzumab-based combinations were particularly notable: despite being perceived as relatively “light” and tolerable, they generated some of the highest ICERs across combination regimens, underscoring poor value when cost is normalized to QALY gain. In contrast, BCMA-directed CAR-T therapies demonstrated a paradoxical profile. While upfront costs were high, their ICER values were lower than many multi-drug regimens. For example, cilta-cel exhibited one of the most favorable ICERs among modern therapies, outperforming continuous regimens that accumulate costs over years. Even when administered late in the disease course, CAR-T provided superior cost-effectiveness relative to several pharmacological strategies, challenging the notion that it is prohibitively expensive. Taken together, these ICER comparisons highlight the importance of evaluating therapies not by sticker price alone, but by their cost per quality-adjusted year of life. By this standard, CAR-T stands not as an outlier of excess, but as a rational and value-driven therapy in multiple myeloma (Supplementary Figure S5,S6).

8.4. Aggregated Cost–Effectiveness Outcomes and the See-Saw Model

To capture the cumulative burden of sequential therapies, we introduced the concept of cumulative QALY and cumulative ICER. These measures were derived by summing quality-adjusted survival and incremental cost-effectiveness across all therapeutic lines, thereby reflecting the true longitudinal impact of treatment sequencing.

As shown in Table 2, transplant-eligible low/intermediate-risk patients achieved the most favorable balance, with cumulative ICER values around 3.4 million USD/QALY and cumulative QALY gains approaching 18.5. In contrast, high-risk transplant-ineligible patients fared poorly, with cumulative ICERs exceeding 5 million USD/QALY despite achieving only 13.5 QALYs.

This indicates that repeated pharmacological layering in high-risk patients leads to diminishing value returns [61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. To visualize this dynamic, we applied the See-Saw Model (Figure 5).

The ICER panel demonstrates that the cumulative economic burden tilts toward high-risk, transplant-ineligible patients, reflecting greater cost-effectiveness challenges in this group. By contrast, the QALY panel shows the balance favoring transplant-eligible patients (both low- and high-risk), who accumulate the largest quality-adjusted survival gains. This divergence highlights the complexity of modern myeloma care: the populations deriving the greatest clinical benefit are not necessarily those for whom therapies are most cost-effective. This model should be interpreted as a pilot conceptual framework, based on the most recent phase II/III clinical trial data rather than a meta-analysis, acknowledging the limited availability of long-term outcomes for novel therapies.

In this framework, transplant eligibility and risk status act as opposing forces:

This see-saw representation underscores the inequity embedded within current sequencing paradigms: the patients most in need of innovation (high-risk, ineligible populations) derive the least value from conventional pharmacological escalation.

9. Discussion

Multiple myeloma has transitioned from a disease once managed with purely palliative strategies to one treated with targeted, immunologic, and gene-modified approaches. Our analysis demonstrates that evaluating therapies only by survival endpoints or upfront cost is incomplete; instead, quality-adjusted survival and long-term value must guide decision-making.

Historically, therapies perceived as “cheap” such as melphalan or corticosteroid-based regimens achieved minimal QALY gains (≤1.0). In contrast, modern triplet and quadruplet regimens frequently exceed USD 3-4 million per patient over the course of treatment, while delivering only moderate improvements in QALY and survival. This creates a paradox: what appears affordable is often the most expensive when cumulative costs are considered, and what appears prohibitively expensive CAR-T therapy may in fact deliver the best value. Our ICER results confirm that cilta-cel, despite upfront pricing of USD 700,000–1,000,000 in 2025, outperforms many continuous regimens in terms of cost per QALY gained.

CAR-T is currently approved as a late-line therapy, typically offered after years of treatment, immune exhaustion, and marrow toxicity. Even under these compromised conditions, CAR-T outperforms several regimens, including elotuzumab-based combinations. This strongly suggests that earlier deployment, in fitter patients, would amplify both QALY gains and cost-effectiveness. Delaying access does not merely reduce efficacy; it represents an ethical failure, withholding the most effective therapy until its benefit is blunted.

The restricted availability of CAR-T (ide-cel and cilta-cel approved in only a few countries) creates profound inequities. Patients in high-income settings may receive one-time cellular therapy with durable remission, while patients in lower-resource regions remain trapped in cycles of outdated or toxic pharmacological regimens. From a health policy perspective, reimbursement structures must recognize that upfront CAR-T costs replace years of cumulative drug expenditure, hospitalizations, and toxicity management. Governments already absorb the majority of these expenses; redirecting investment toward CAR-T would reduce long-term costs and improve outcomes.

Value in oncology cannot be reduced to survival curves alone. Reports of depression and even suicide among trial participants remind us that biological success without dignity is human failure. Quality of life must be central to therapeutic evaluation. Our QALY framework provides one such tool, quantifying not only time lived but how that time is experienced.

The current sequencing paradigm compounds inequity: those at highest risk and least transplant-eligible derive the least cumulative value, as illustrated by our See-Saw model. Meanwhile, access to CAR-T is dictated by geography and wealth rather than biology or need. The right to live longer and better should not depend on financial privilege. True progress in multiple myeloma requires aligning science with justice, compassion, and reform ensuring that the benefits of innovation are shared equitably across populations.

10. Conclusions

Multiple myeloma has evolved from a fatal, palliatively managed disease into one where cellular immunotherapies redefine the horizon of survival. Yet cost and access remain at the center of debate. Our QALY and ICER based framework demonstrates that long-term pharmacological sequencing is not only toxic but cumulatively more expensive than CAR-T therapy, despite the latter’s high upfront price. Importantly, delaying CAR-T until late relapse diminishes its value; earlier integration could maximize both clinical benefit and cost-effectiveness. Beyond numbers, this is an ethical imperative: patients deserve not only longer lives, but better ones. Ensuring equitable access to CAR-T and other advanced therapies requires policy reform that aligns innovation with justice, sustainability, and human dignity.