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Balancing Care and the Cost of Treating Multiple Myeloma

Faculty Perspectives: Optimizing Clinical Outcomes and Value-Based Management in Multiple Myeloma—The Role of Isatuximab
Sundar Jagannath, MBBS
Director, Center of Excellence for Multiple Myeloma
Mount Sinai Medical Center
New York, NY

The goal of cancer treatment is to cure the disease and allow the patient to have a productive life. Although a cure has been elusive for patients afflicted with multiple myeloma, there has been a steady improvement in life expectancy with the approval of several new drugs for the treatment of myeloma. Five-year relative survival was 34.2% in 2000, which has improved to 58.3% as of 2014, during which time 2 immunomodulatory drugs and 2 proteasome inhibitors were approved. Since then, several new classes of drugs have been approved, bringing the optimism that cure is a distinct possibility for a majority of patients.

The molecular pathogenesis of myeloma indicates the founder clones (hyperdiploid or translocation of IgH, IgL, or IgK) grow and multiply over time with new subclones emerging along the way.1 To address this, the treatment has also evolved to incorporate more classes of drugs (quadruple therapy) upfront and a prolonged maintenance strategy.2 The tumor microenvironment also plays an important role in the control or progression of myeloma cells. Immunotherapy offers the possibility to eradicate tumor cells independent of chemotherapy resistance, restore immune balance to control the tumor, and evoke immune memory to ultimately prevent the tumor from emerging.3

In this regard, anti-CD38 monoclonal antibody therapy fits very well into this paradigm for the management of multiple myeloma. A monoclonal antibody can be combined with chemotherapy agents to augment tumor cytoreduction and modulate the immune microenvironment to prolong duration of remission. Addition of isatuximab (Isa) to a carfilzomib-and-dexamethasone (Kd) backbone in relapsed or refractory myeloma with 1 to 3 lines of prior therapy (IKEMA) was shown to almost double the median progression-free survival (PFS) from 20.8 months to 41.7 months (hazard ratio [HR], 0.59; confidence interval [CI], 16.2-28.2; n = 123). The treatment was equally efficacious in elderly (>65 years), lenalidomide-refractory, and high-risk genetics subgroups of patients. This has translated to improvement in the overall survival (OS) from a median of 17.5 months for Kd and 24.6 months for Isa-Kd. Similar results have been obtained when daratumumab (Dara) has been added to Kd. Likewise, addition of Isa to a pomalidomide and low-dose dexamethasone (Pd) backbone in relapsed and refractory myeloma failing 2 lines of therapy (ICARIA-MM) was shown to improve median PFS from 5.9 months to 11.1 months. After a median follow-up of 35 months, the OS was better for Isa-Pd (median, 24.6 months) compared with 17.5 months for Pd (HR, 0.76; CI, 0.57-1.01).4 Similar results are also seen with Dara, confirming the findings as a class effect of anti-CD38 antibody therapy.

At a first glance, the cost of caring for patients with myeloma appears to increase with the approval of every new drug as the patients tend to live longer but are not cured. Although there are several novel agent combinations that have been approved for the treatment of relapsed myeloma, the clinical decision made at the bedside considers treatment history, frailty, comorbidities, disease burden and risk category, and patient preference. The cost of caring for these patients is also becoming an increasingly important consideration. The value of 1 treatment option against another is indirectly compared through matrix-like gain in quality-adjusted life year (QALY) and the incremental cost-effectiveness ratio (ICER). It becomes more cost prohibitive to use less effective therapy earlier, as patients would like to exhaust all treatment options available to them to control their cancer. Also, with each recurrence, fewer patients can receive salvage therapy, especially elderly patients.

Almost doubling of PFS with the addition of an anti-CD38 monoclonal antibody to Kd is unprecedented and is very meaningful to patients in terms of the improved quality and quantity of life. An indirect healthcare economic analysis showed a gain in life years of 0.48 months following a year of treatment with slight cost advantage for Isa-Kd over Dara-Kd.5 Combining an anti-CD38 antibody with carfilzomib is still cost-ineffective compared with some alternatives, such as combining with bortezomib. Subcutaneous formulations may have some cost-saving advantage over intravenous formulations.

Likewise, addition of an anti-CD38 monoclonal antibody to Pd improves PFS and OS. Cost-effectiveness analysis comparing Isa-Pd and Dara-Pd for 1 year of treatment showed a gain of 0.5 months in QALY and cost savings by ICER with Isa-Pd.

Multiple myeloma is twice as common in the black population than in Caucasians in the United States. Financial toxicity prevents underserved populations from accessing expensive medications. The authors have discussed the cost drivers in myeloma therapy and have offered mitigating solutions, including pharmacy assistance programs and copay assistance, to help defray the financial burden on the patients. These are especially important if we are to make these lifesaving drugs available to underserved populations in the United States. Special attention should be paid to patient education, accessibility of drug, and transportation needs for this population.

References

  1. Diamond B, Ziccheddu B, Boyle E, et al. Chemotherapy-related mutational signatures reveal the origins of therapy-related myeloid neoplasms. Blood. 2021;138(suppl 1):3271.
  2. Laubach JP. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 24 months of maintenance. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; Dec 11, 2021; Atlanta, GA. Abstract 79.
  3. Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020;130:1565-1575.
  4. Moreau P, Dimopoulos MA, Mikhael J, et al; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361-2371.
  5. 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.