Первый рецидив у пожилых людей с множественной миеломой: создание новых путей на неизведанных территориях.

In their paper, Touzeau et al. present the results of a phase 2 study of a novel all orally administered regimen of iberdomide, ixazomib and dexamethasone (I2D) for individuals with myeloma aged 70 years and older in the second line of therapy. 1 The study design beautifully illustrates approaches to expanding the evidence base for treating older adults, pioneering a regimen that meets many of the treatment preferences expressed by older adults with its broad eligibility, ensuring generalizability to the heterogenous group of older adults and capturing data to categorize frailty and examine outcomes in this vulnerable subgroup. 2

The MAIA trial establishing the triplet combination of daratumumab, lenalidomide and dexamethasone (Dara‐Rd) as standard of care for front‐line treatment of transplant‐ineligible individuals with myeloma was published in 2019. 3 With median progression‐free survival (PFS) beyond 5 years, myeloma providers are beginning to treat individuals experiencing their first progression after having experienced a long interval of well‐tolerated, lower burden therapy on the triplet regimen. 4 While available treatment options are numerous, several factors create challenges in selecting treatment in the population initially treated with Dara‐Rd. These individuals were already considered ineligible for stem cell transplant at the time of diagnosis, whether due to age, impaired functional status or comorbidities. Now 5 years older, these individuals may have accumulated additional ageing‐associated vulnerabilities, impacting treatment selection. While this group has not received a proteasome inhibitor, both bortzomib and carfilzomib present potential problems. Bortezomib is associated with peripheral neuropathy and an increased risk of falls, raising concerns in individuals with pre‐existing peripheral neuropathy or gait abnormalities. 5 The risk of cardiac toxicity gives clinicians pause in individuals with pre‐existing cardiac disease or frailty. 6

Touzeau et al. introduce the novel regimen which balances on the narrow tightrope between efficacy and toxicity that can be difficult to navigate in potentially vulnerable older adults with multiple myeloma. The regimen incorporates the cereblon E3 ligase modulator iberdomide and the orally administered proteasome inhibitor ixazomib, while limiting dexamethasone to the first six cycles. Key eligibility criteria enrolled patients aged ≥70 at first relapse who had received one prior line of therapy. The primary outcome was the rate of patients achieving at least very good partial response (≥VGPR). Dosing of each medication was tailored to reduce the risk of toxicity in older adults, including a lower starting dose of ixazomib and shorter duration, dose‐reduced dexamethasone. The investigators successfully enrolled a cohort of 70 older adults with a median age of 76, half of whom were categorized as frail by the International Myeloma Working Group Frailty score. The overall response rate was 64%, with a 12‐month duration of response of 76%. The median PFS was 13 months, and was similar in frail and nonfrail patients. Toxicities, particularly non‐haematological toxicities, were proportionate to those expected and generally mild. Rates of toxicity were similar in the frail and nonfrail subgroups as well. Only 6% of participants discontinued therapy due to toxicity, supporting the tolerability of the regimen.

The proportion of participants achieving ≥VGPR was 36%, which did not meet the a priori hypothesis that the regimen would provide a ≥VGPR rate of 45%. Does the failure to meet the primary objective mean that this is a failed regimen? I would argue no, that the regimen still merits substantial interest, despite not meeting this primary objective. The investigators designed the trial in an area that has been uncharted territory. While front‐line trials have long divided patients with myeloma into those considered transplant‐eligible or transplant‐ineligible, studies in the relapsed setting have generally enrolled participants broadly, not restricted by age or health status (aside from those excluded due to comorbidities). The investigators derived their hypothesized primary outcome point estimate from the OPTIMISMM trial of pomalidomide, bortezomib and dexamethasone, wherein the ≥VGPR rate was 53%. 7 Only recently have secondary analyses presented subgroup analyses stratified by frailty. 8 Indeed, among the frail patients in the OPTIMISMM trial, the median PFS was only 9.7 months, and the treatment discontinuation rate was 30%. Examining outcomes in the subset of frail patients in other studies in the relapsed setting (Table 1 ), we see that the I2D regimen provides a PFS estimate of great interest, combined with a lower treatment discontinuation rate than other comparable trials. Thus, the investigators have succeeded in designing a regimen that provided a PFS similar or superior to that seen in comparable studies, while better tolerated, as evidenced by a lower rate of treatment discontinuation. Given that many older adults prioritize quality of life and maintenance of function balanced with effectiveness of treatment, this regimen merits further study, regardless of not meeting the primary objective in this study. 9

In summary, the phase II study of iberdomide, ixazomib and dexamethasone has taken the field into uncharted territory, enrolling a cohort of older adults with relapsed multiple myeloma, half of whom were categorized as frail. The I2D regimen was well‐tolerated and effective, with a median PFS exceeding 1 year. While the study did not meet its primary objective of demonstrating a ≥ VGPR rate of 45%, the regimen remains of significant interest when taking into account the significant unmet need for treating vulnerable older adults with relapsed myeloma.

Wildes TM. First relapse in older adults with multiple myeloma: Creating new pathways in uncharted territory. Br J Haematol. 2025;206(5):1523–1525. 10.1111/bjh.20000

REFERENCES

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3. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–2115.

4. Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, et al. Health‐related quality of life in transplant‐ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021;39(3):227–237.

5. Schoenbeck KL, Fiala MA, Wildes TM. Bortezomib in first‐line therapy is associated with falls in older adults with multiple myeloma. J Geriatr Oncol. 2021;12(7):1005–1009.

6. Dong S, Mehra N, McCaughan G, Wang B, Sperling A, Cowan A, et al. Carfilzomib dosing in multiple myeloma: an international survey of oncologist practices. Clin Lymphoma Myeloma Leuk. 2024;24(S2):P380.

7. Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open‐label, phase 3 trial. Lancet Oncol. 2019;20(6):781–794.

8. Mian H, McCurdy A, Giri S, Grant S, Rochwerg B, Winks E, et al. The prevalence and outcomes of frail older adults in clinical trials in multiple myeloma: a systematic review. Blood Cancer J. 2023;13(1):6.

9. Maheshwari S, Arias M, Ubersax C, Tucker A, Bal S, Ravi G, et al. Understanding health outcome preferences of older adults diagnosed with multiple myeloma. J Geriatr Oncol. 2024;15(5):101781.