Dexamethasone-Sparing Approach Helps Frail Older Adults

Treated with a dexamethasone-sparing regimen, frail older adult patients with newly diagnosed multiple myeloma (MM) show significant reductions in disease progression and improvements in quality of life, new research shows.

The study “is the first randomized phase 3 study dedicated to frail patients,” said first author Salomon Manier, MD, PhD, an associate professor of hematology at Lille University Hospital, Lille, France. He presented the findings this week at the American Society of Hematology (ASH) 2024 Annual Meeting in San Diego.

“It shows that daratumumab-lenalidomide [with limited dexamethasone] led to a significant reduced risk of progression or death by 49% in frail patients, with a favorable safety profile and an improved health-related quality of life,” Manier said.

Older adult patients who are newly diagnosed with MM have varying levels of fitness or frailty and have been shown to have shorter survival, with higher rates of nonhematologic adverse events and treatment discontinuation.

While the regimen of daratumumab, lenalidomide, and dexamethasone has become a standard of care, with efficacy and tolerance, including for patients with frailty, the infection and pneumonia rates with the approach can be high, particularly for patients with frailty.

To evaluate if an alternative, dexamethasone-sparing approach could improve outcomes while limiting toxicity for older adults, Manier and his colleagues conducted the prospective, open-label phase 3 IFM2017-03 trial, involving 295 patients (age, 65 years) with newly diagnosed MM at 90 centers in France.

The patients had a median age of 81, with 84% older than 75 years and 61% older than 80 years. All had an Eastern Cooperative Oncology Group proxy frailty score ≥ 2.

The patients were randomized 1:2 to treatment either with the Rd regimen of 28-day cycles of lenalidomide (25 mg/d, 21/28) and dexamethasone (20 mg once weekly) or with the dexamethasone-sparing regimen (DR) of daratumumab (1800 mg subcutaneous once weekly for 8 weeks, once every 2 weeks for 16 weeks, and once every 4 weeks thereafter), lenalidomide (25 mg/d, 21/28), and two cycles of dexamethasone (20 mg once weekly for 8 weeks then stopping).

The randomization included stratification based on age and cancer stage. Baseline characteristics were well balanced in the two groups.

Both regimens were administered until disease progression or unacceptable toxicity.

As of the data cut-off in November 2024, with a median follow-up of 46.3 months, 81 of the original 200 patients in the DR arm remained on treatment, and 11 of 95 continued in the Rd arm.

The overall median treatment duration among the 200 original patients in the DR arm was 31.6 months and 14.3 months in the Rd arm.

The study met its primary endpoint of progression-free survival (PFS), with a median rate of 53.4 months in the DR arm vs 22.5 months in the Rd arm (hazard ratio, 0.51; P

The improved PFS in the DR arm was observed across all subgroups based on age, Charlson, cancer stage, cytogenetics, and creatinine clearance; however, those with lower frailty scores had better outcomes in both groups.

A median overall survival was not reached in the DR arm vs 47.2.0 months in the Rd arm (HR, 0.52; P = .0001).

The DR arm also showed a higher overall best response rate of 94% vs 86% (P =.005), respectively, with deeper responses in the DR arm at all time points, including the earliest points at 4 months.

In terms of adverse events (AEs), at least one AE of grade 3 or higher occurred in 89% in the DR arm and 79% in the Rd arm.

Those in the DR arm had significantly more grade 3 or higher hematologic AEs with neutropenia (62% vs 34%); however, grade ≥ 3 infections were similar, with 19% in the DR arm and 21% in the Rd arm. Infections involving pneumonia occurred in 6% and 8%, respectively.

There were no significant differences between the two arms in discontinuations due to AEs (30% in the DR arm and 34% in the Rd arm).

While health-related quality of life measures at baseline were well balanced between the two groups, those in the DR arm reported significantly shorter times to clinically meaningful improvement in all domains of the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30).

“The safety profile was significantly improved and was favorable, without increased infection or pneumonia rates, with similar rates of treatment discontinuation,” Manier said.

Based on the findings, “we believe that the dexamethasone-sparing strategy is effective and safe for treating these frail patients with multiple myeloma,” he added.

Commenting on the study, Manni Mohyuddin, MD, an assistant professor in the multiple myeloma program at the Huntsman Cancer Institute, University of Utah, Salt Lake City, noted that, with the popularity of triplet regimens such as daratumumab, lenalidomide, and dexamethasone, the Rd regimen in the study is not as commonly used.

“But what this trial tells us is that efficacy outcomes in such a group of patients are encouraging despite getting rid of dexamethasone so quickly,” he said in an interview.

However, “while the tide is changing, dexamethasone is still given long-term, week after week after week in most myeloma protocols and in the community,” he noted. “Hopefully, this trial, and some of the other work, will lead to a change in this space.” 

Mohyuddin suggests one approach can involve starting off with just daratumumab and a low dose of dexamethasone, then adding lenalidomide at a lower dose later in a sequential/graded approach.

“Other approaches that should be studied should be bispecific antibodies used sparingly, with less frequent dosing, or finite period,” he added. “There is lot to refine.”

Mohyuddin added a critique that the study’s endpoint of PFS may not have been ideal for the population of elderly and frail patients.

“Older people generally prioritize functional independence and quality of life, and perhaps a more patient-centered endpoint could have led to an even more informative study,” he said.

Manier’s disclosures included consultancy with Takeda Pharmaceuticals, Sanofi, Novartis, Janssen, GlaxoSmithKline,Celgene/BMS, Amgen, Adaptive Biotechnologies, Roche, Regeneron, and AbbVie. Mohyuddin had no disclosures.