Response Seen With Ixazomib Plus Daratumumab and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed MM

Ixazomib (Ninlaro) plus daratumumab (Darzalex) and low-dose dexamethasone yielded a high response rate and improved quality of life (QOL) in frail patients with newly diagnosed multiple myeloma, according to data from the phase 2 Hovon 143 study (NTR6297) which was published in the Journal of Clinical Oncology.¹

Moreover, the research team emphasized that treatment discontinuations due to toxicity and early mortality remain a concern for this cohort of frail patients.

Investigators reported an overall response rate (ORR) of 78% (95% CI, 0.73-0.82) for patients treated with the ixazomib combination during induction. Among these responders, 5 patients (8%) had a stringent complete responses, 18 achieved a very good partial responses (28%), and 28 (43%) had a partial responses.

“Study results from nontransplant eligible patients cannot be translated to frail patients with multiple myeloma,” wrote the investigators. “This trial provides a platform for the future design of trials for frail patients for more precise treatment guidance by proposing a frailty subclassification and indicates that frail patients have different [adverse] effect profiles and might need lower starting dose, only allowing dose increments in the absence of side effects.”

Investigators set out to assess ixazomib and daratumumab in this subset of frail patients with newly diagnosed disease due to the combination's favorable safety profile.^2-4 Moreover, the dose of dexamethasone utilized in the study was significantly reduced in comparison with other trials in this patient population due to the notable mortality that has been associated with higher doses of the agent.⁵

The phase 2, prospective, multicenter Hovon 143 study enrolled a total of 65 frail patients with newly diagnosed multiple myeloma. The trial was conducted at 39 institutions across the Netherlands and Belgium. Patients received 8 28-day induction cycles of ixazomib (4 mg on days 1, 8, and 15), intravenous daratumumab (16 mg/kg; cycles 1-2 on days 1, 8, 15, and 22; cycles 3-6 on days 1 and 15; cycles 7-9 on day 1). Moreover, patients received dexamethasone on any of the days that daratumumab was given, with a 20 mg dose being administered during cycles 1 through 2 and 10 mg administered in all subsequent cycles. This regimen was followed by 8-week cycles of maintenance ixazomib on days 1, 8, 15, 29, 36, and 43, as well as daratumumab on day 1, up to a maximum of 2 years or disease progression.

In order to be eligible for the trial, patients were required to have previously untreated, symptomatic multiple myeloma and be frail according to the International Myeloma Working Group frailty index. Moreover, sufficient bone marrow capacity was necessary for enrollment. The study had a liberal exclusion criteria, as only those with severe organ dysfunction were excluded from the trial. The primary end point of the study was ORR.

Additional finding from the study indicated that patients achieved a median progression-free survival (PFS) of 13.8 months (95% CI, 7.8-NR). The median PFS for patients who were defined as frail based on age alone observed was 21.6 months (95% CI, 9.2-NR). For patients determined to be frail due to other parameters, the median PFS was 13.8 months (95% CI, 7.8-NR). Frail patients based on both age and other parameters had a median PFS of 10.1 months (95% CI, 3.3-21.4).

Moreover, median overall survival (OS) was not reached in this study. Investigators reported a 12-month OS rate of 78% (95% CI, 66%-87%). For frail patients based on age alone, the 12-month OS rate was 92% (95% CI, 57%-99%). For frail patients based on other parameters, as well as age and other parameters, the 12-month OS rates were 78% (95% CI, 59%-89%) and 70% (95% CI, 44%-85%), respectively.

After a median follow-up of 22.9 months (range, 12.7-31.0), a total of 43 (38%) patients on the study had progressed or died.

“The results of this first prospective study, which was specifically designed for frail non-transplant eligible newly diagnosed multiple myeloma patients, showed that treatment with ixazomib, daratumumab, and low-dose dexamethasone resulted in a rapid and high overall response of 78%,” wrote the investigators.

In terms of discontinuations, 51% of patients discontinued the ixazomib combination prior to initiation of maintenance, the most common reasons being progression (19%), intercurrent death (9%), toxicity (9%), noncompliance to treatment (6%), and other reasons (8%).

Health-related QoL (HRQoL) was measured with a baseline HRQoL questionnaire, which identified a compliance of 96.6% after 3 induction cycles and 92.7% after 9 cycles. The baseline QOL score was 54.1, which increased to 65.8 and 71.5 after 3 and 9 induction cycles, respectively.

“We propose to design studies that are sufficiently powered to determine the outcome in different frailty subcategories based on age-only versus with geriatric impairments and/or comorbidities. This will allow a straight comparison of the outcome of frail patients within and across studies, which will pave the way for more precise treatment guidance,” the authors of the study concluded.

References

1. Stege CAM, Nasserinejad K, van der Spek E, et al. Ixazomib, daratumumab, and low-dose dexamethasone in frail Patients with newly diagnosed multiple myeloma: The Hovon 143 Study. J Clin Oncol. 2021;JCO2003143. doi:10.1200/JCO.20.03143
2. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378:518-528. doi:10.1056/NEJMoa1714678
3. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115. doi:10.1056/NEJMoa1817249
4. Kumar SK, Berdeja JG, Niesvizky R, et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019;33(7):1736-1746. doi:10.1038/s41375-019-0384-1
5. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37. doi:10.1016/S1470-2045(09)70284-0