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A progression-free survival (PFS) benefit for an all-oral regimen for relapsed/refractory multiple myeloma (RRMM) failed to translate into improved overall survival (OS), according to long-term follow-up from a randomized trial.

After a median follow-up of 85 months, median OS was 53.6 months for patients treated with ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone -- IRd regimen -- versus 51.6 months with placebo plus Rd. A number of subgroups appeared to benefit more from IRd, which was associated with 13-25% reductions in the survival hazard. A similar proportion of patients in each group received one or more additional lines of therapy, and both groups had similar rates of second malignancies.

The results failed to extend the primary findings of the TOURMALINE-MM1 trial, which showed a statistically significant improvement in progression-free survival (PFS) with IRd, as reported in the .

A number of confounding factors could have influenced the survival analysis, not the least of which is the overall improvement in OS for multiple myeloma in recent years, concluded Paul R. Richardson, MD, PhD, of Dana-Farber Cancer Institute in Boston, and co-authors.

"These results were obtained in the context of the longest median OS reported to date in phase III studies of Rd-based therapy in RRMM," the researchers noted. "Furthermore, greater OS benefit was observed in subgroups of patients with adverse prognostic factors... . The impact of the evolving RRMM treatment landscape on the ability to demonstrate OS benefit in clinical trials warrants further consideration regarding randomized trial design and the utility of OS as an endpoint."

"The availability of multiple active salvage therapies may limit the ability to demonstrate OS benefit in clinical trials in early-relapse setting," the team added.

More Options, Ongoing Needs

Patients with RRMM have a growing number of treatment options, which have led to improved OS. Nonetheless, a need persists for effective and tolerable therapies for patients who continue to relapse, are refractory to treatment, have high disease burden or high-risk cytogenetics, or who have characteristics that complicate treatment, such as advanced age and/or frailty, Richardson and co-authors noted.

The IRd regimen offered the potential to build on the recent therapeutic success in myeloma and address some of the ongoing needs. The international randomized, phase III TOURMALINE-MM1 trial involved 722 patients with RRMM, who were randomized to Rd plus ixazomib. The primary endpoint was PFS, and OS was a key secondary endpoint. As , the IRd regimen led to a median PFS of 20.6 months versus 14.7 months with Rd (HR 0.74, P=0.01).

At the data cutoff for the OS analysis, 239 of the 722 patients remained alive: 113 in the IRd group and 116 in the Rd arm. The 2-month difference in favor of median OS favoring IRd did not achieve statistical significance in the intention-to-treat analysis (HR 0.939, 95% CI 0.74-1.125, P=0.495). A per-protocol analysis and two sensitivity analyses yielded HRs of 0.76, 0.70, and 0.68, none of which achieved statistical significance.

Subgroup analyses produced HRs favoring IRd, but not statistically significant differences. Trends in favor of IRd included 17p deletion (HR 0.916), high-risk cytogenetics (HR 0.870), expanded high-risk cytogenetics (HR 0.862), being refractory to any prior regimen (HR 0.794) or to last regimen (HR 0.742), being refractory to thalidomide (HR 0.781), age 65-75 (HR 0.757), International Staging System stage III disease at entry (HR 0.779), receipt of two or three prior regimens (HR 0.845), or having standard-risk cytogenetics (HR 0.875).

An exploratory analysis of OS by subsequent therapy showed that fewer patients in the IRd arm received a protease inhibitor as next-line therapy and more received daratumumab (Darzalex). Subsequent-line daratumumab was associated with a median OS of 78.9 months for the IRd patients versus 83.4 months for the control arm (HR 1.15), whereas IRd-treated patients who subsequently received daratumumab had a median OS of 49.2 months versus 35.5 months for the control group (HR 0.83).

The IRd regimen also demonstrated a trend toward better survival among patients who received no subsequent therapy (50.4 vs 31.5 months), whereas the reverse was true among patients who did receive additional treatment (54.3 vs 58.1 months).

Interpreting 'Inconceivable' Results

Seeking to interpret the results, the authors of an accompanying editorial found inspiration in the classic 1987 movie, . Having heard the character Vizzini exclaim "It's inconceivable" on three occasions -- only to face an alternate reality each time -- the character Inigo Montoya replies, "I don't think that word means what you think it means."

"Twenty years ago, it was inconceivable that the median OS for a patient with myeloma would be in excess of 10 years; yet, that is where we are in the field using modern myeloma therapy," stated Anita D'Souza, MD, of the Medical College of Wisconsin in Milwaukee, and Sagar Lonial, MD, of Winship Cancer Institute of Emory University in Atlanta.

"Twenty years ago, it was inconceivable to consider alkylator-free induction regimens for fit or frail patients, yet it has become all but routine to use induction therapy regimens that do not use this class of agents. Twenty years ago, it was inconceivable that postrelapse outcomes could be nearly as long as initial responses and that the results of phase III trials could be confounded by postsalvage therapies," the editorialists continued. "Yet, this is what we see in the phase III TOURMALINE-MM1 trial."

When compared with other randomized phase III trials that evaluated a novel agent combined with Rd, ixazomib performed at least as well, with the exception of a trial of daratumumab, which involved patients with fewer lines of therapy, D'Souza and Lonial said. Additionally, more patients in TOURMALINE-MM1 might have received newer drugs in the salvage setting, potentially increasing OS for both treatment arms.

"Good salvage therapy does not eliminate the benefit of effective prolongation of PFS but can diminish the benefits as measured by OS," the editorialists observed. "This does not reduce the value or benefit of PFS prolongation."

Returning to the movie, they pointed out: "Vizzini loses because he overplays his hand and does not recognize that the world is changing around him, whereas Inigo triumphs in the end as he is able to see the new world and different possibilities for what the future may hold."

"We are no different in MM therapy; the world is changing before our eyes, and we need to be sure that we do not stick with outdated measures of efficacy that may stifle the innovation needed to ultimately cure this disease," D'Souza and Lonial wrote. "We should celebrate the fact that a significant majority of our patients are able to receive effective therapies after first and second relapses and a patient can catch up even after a less-effective earlier regimen."

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