ULTRA FRAIL-MM Clinical Trial: Go-Slow Approach Incorporating Isatuximab, Lenalidomide and Dexamethasone for Ultra-Frail Newly Diagnosed Myeloma

Introduction: Isatuximab, an anti CD38 monoclonal antibody, has been shown to be effective in multiple randomized controlled trials for patients with multiple myeloma (MM). The anti CD38 class of drugs is generally fairly tolerated with a low rate of infusion reactions after the initial dose, and these drugs are safe in patients with impaired renal function, impaired liver function and other comorbidities. Conversely, other classes of drugs such as immunomodulatory drugs and proteasome inhibitors are associated with high discontinuation rates and toxicity in patients that are frail. A trial of ixazomib, daratumumab and dexamethasone exclusively for frail patients was conducted by the HOVON group. Unfortunately, in over half of the patients, the treatment still had to be discontinued prematurely. Patients currently defined as frail are a heterogenous cohort, as an International Myeloma Working Group (IMWG) frailty score of 2 can be obtained on the virtue of age alone, and patients frailty score higher than 2 are even more susceptible to the toxicity of therapy. Current frailty assessments are limited in that patients over the age of 80 may be considered frail, even if they have no other comorbidities or limitations in performing tasks of living. A new frailty class, ultra-frail (those with IMWG frailty score of three or more) has been proposed (Zweegman- COMY 2022, Cook- ASH 2023), and these patients had a discontinuation rate of 57.9% within first 9 cycles of therapy, highlighting the need for safer and effective treatments for this group of patients. The standard of care for older and frail patients with newly diagnosed myeloma is currently daratumumab/lenalidomide/dexamethasone (DRd) based on the MAIA trial. In the MAIA trial, deaths occurring within 90 days of receipt of the first dose of study treatment were reported in 6.0% of frail patients (a total of 7 patients), with adverse events being the primary cause of death in six of these patients (85.7%), highlighting the unmet need for increased tolerability of treatment when these drugs are first started. Methods: We intend to enroll 40 newly diagnosed ultra-frail MM patients on this single arm trial (NCT06517017). All patients are considered transplant ineligible. Ultra-frail will be defined as score ≥ 3 on the IMWG criteria (Zweegman-COMY 2022). There will be no limitations or exclusions based on functional status, co-morbidities, risk status, or organ function. One prior cycle of therapy will be allowed prior to enrollment. The primary endpoint of this trial will be the completion rate of 9 cycles of treatment. A key exploratory endpoint is longitudinal assessment of various frailty scores, including IMWG frailty score, simplified frailty score and 4-meter walk test. These will be ascertained at the start of therapy, after two cycles of therapy, after six cycles of therapy, and at the end of formal treatment according to the study (nine cycles of therapy). Isatuximab will be administered subcutaneously at 1400 mg weekly on D1, D8, D15 and D22 of a 28-day cycle for first two cycles, and every two weeks on Day 1 and Day 15 of a 28-day cycle subsequently. Dexamethasone 20mg will be administered on the days of isatuximab injection and may be discontinued after two cycles of therapy at the investigator's discretion. Low dose lenalidomide (2.5mg to 10mg depending on renal function) will be added after two cycles of therapy have been completed, at three weeks on/one week off dosing. Treatment will be continued until either progression, drug intolerance, completion of the trial procedures. For the primary analysis of rate of completion of 9 cycles of therapy, a one-sided exact binomial test will be performed at the 0.05 significance level. The null hypothesis is that 42% of patients will complete 9 cycles of therapy. The alternative hypothesis is that the rate of completion will be higher. The trial will enroll starting October 2024 at its first site, with plans to expand to additional sites soon. Conclusion: ULTRA FRAIL-MM is the first trial to exclusively enroll patients with ultra-frail MM and evaluate a gentle go-slow approach incorporating anti-CD38 therapy, with early discontinuation of steroids, and a delayed start of lenalidomide. We hypothesize that this will lead to low rates of treatment discontinuation due to toxicity and allow for improved outcomes in this patient population.

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