麻豆传媒

CHICAGO -- The progression-free survival (PFS) benefit with autologous stem-cell transplantation (ASCT) in newly diagnosed multiple myeloma was confirmed in the DETERMINATION study, yet the lack of overall survival difference suggests that the timing of transplant, whether early or delayed, can be individualized.

All patients in the phase III study received the triplet regimen of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd), along with lenalidomide maintenance. Median PFS improved from 46.2 months with RVd alone to 67.5 months with the addition of transplant (HR 1.53, 95% CI 1.23-1.91, P<0.001), reported Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.

Despite this 21-month improvement in PFS, overall survival turned out no different between groups, with 5-year rates of 79.2% and 80.7%, respectively (HR 1.10, 95% CI 0.73-1.65), according to findings presented at the American Society of Clinical Oncology annual meeting and published simultaneously in the .

The data confirm that ASCT improves PFS and remains standard of care in the setting of triplet therapy, Richardson said during a press briefing.

"Our results clearly, however, provide support for personalized treatment approaches," he added. "If we do not see benefit in overall survival, and you can reasonably delay transplant in a tailored fashion, you can have a pretty efficacious outcome."

The trial, which was launched back in 2009, aimed to answer two key questions: to what degree does ASCT enhance the effect of treatment in newly diagnosed disease, and can ASCT be kept in reserve?

In the RVd-alone arm, only 28% of patients ultimately went on to receive ASCT at relapse, with others receiving various newer anti-myeloma agents instead.

"We have a more flexible menu where we don't always have to include transplant frontline, despite its benefit," said study discussant Joseph Mikhael, MD, of the City of Hope Cancer Center in Duarte, California, during the meeting's Plenary Session of top abstracts. "In relapsed myeloma, I've often joked of it as the Cheesecake Factory menu, for which you almost need an outline or a table of contents -- we have more choices than ever."

"The similar overall survival of multiple trials now -- not just the DETERMINATION study -- means that timing of transplant, whether it's early or delayed, can be individualized," he said.

Reasons a clinician would be "more enthusiastic" for transplant, Mikhael noted, might include when it's preferred by the patient ("obviously"), if the ability to store cells isn't an option, if alternatives are limited, and if the patient might not be eligible in the near future.

Reasons to be "less enthusiastic" might involve patient concerns over toxicities or older age. Risk factors may play a role as well, said Mikhael, but whether ASCT should be automatic for high-risk patients is not necessarily a settled question.

During his presentation, Richardson highlighted that the trial had the highest proportion of African-American patients in a phase III myeloma study to date -- approximately 20% -- but this group appeared to experience no additional benefit from ASCT. Other subgroups in whom transplant's benefit was less clear included those with stage III disease on the Revised-International Staging System (ISS) and patients with del(17p).

Mikhael pointed out that in updated data from the MAIA trial -- in which patients were given daratumumab (Darzalex), lenalidomide, and dexamethasone indefinitely -- two-thirds of patients were alive without disease progression at 5 years without upfront transplant. And with quadruplet regimens entering into the conversation and CAR T-cell therapy moving into earlier lines, he suggested that transplant may play a different role in the future, perhaps guided by patients' minimal residual disease (MRD) status plus other factors.

"We may not have this simplistic way of thinking, 'Are you transplant-eligible or non-eligible?'" he said. "I want to be careful how I say this, but I do potentially see a day in the future with an even more limited role for autologous stem-cell transplant in multiple myeloma."

Another important finding from DETERMINATION, said Richardson, was that it demonstrated a clear benefit of giving lenalidomide maintenance until disease progression. A -- the Intergroupe Francophone du Myélome 2009 study conducted in France -- had an identical design but only used 1 year of lenalidomide maintenance. In that trial, the median PFS was 47.3 months with transplant and 35 months with RVd alone.

"We improved outcomes in both arms highly significantly," said Richardson. "Thus, we are able to say that the use of lenalidomide maintenance therapy until progression is now the standard of care."

Study Details

DETERMINATION randomized 722 newly diagnosed adults with symptomatic multiple myeloma (ages 18 to 65 years) in a 1:1 ratio across 56 sites in the U.S.

All patients received one cycle of RVd prior to randomization, then two additional cycles followed by stem-cell mobilization. The RVd-alone group (n=357) went on to receive five more cycles of RVd followed by lenalidomide maintenance (10 mg daily for the first 1-3 months; then 15 mg starting at 4 months) until progression. The ASCT group (n=365) received high-dose melphalan plus ASCT followed by two more cycles of RVd, and then lenalidomide maintenance. The study's primary endpoint was PFS.

Patients were stratified by ISS stage and cytogenetic risk. Median age of the trial population was 55-57, more than half were men, three-fourths were white, 19% were Black, and 3% were Asian.

Rates of partial response or better were similar between the RVd-alone group and transplant group (95.0% vs 97.5%, P=0.55), with complete responses or better in 42.0% and 46.8%, respectively (P=0.99).

Duration of response was longer in the transplant group, however (56.4 vs 38.9 months), and among patients tested, a higher proportion of patients in the ASCT group achieved MRD negativity (54.4% vs 39.8%).

Not surprisingly, transplant was accompanied by more toxicity, with 94.2% reporting at least one grade ≥3 adverse event versus 78.2% for the group treated with RVd alone.

While secondary primary cancers were similar between groups (10.7% in the transplant group and 10.4% in the RVd-alone group), more cases of acute myeloid leukemia/myelodysplastic syndromes were observed with transplant -- 10 cases (2.7%) versus none in the RVd-alone group (P=0.002).