ASCT Early in Multiple Myeloma Treatment Improves PFS, but OS Same as RVd

When is the right time for transplant in multiple myeloma (MM) treatment?
Given the advances over the past decade—including the arrival of the first chimeric antigen receptor (CAR) T-cell therapies—the question can be difficult to answer. The use of autologous stem cell transplant (ASCT) is not without risk, and it guides the course of future treatment.

It’s a question investigators explored with the DETERMINATION trial (NCT01208662), which compared long-term outcomes of different initial treatments in MM. Two groups of patients were randomly assigned to receive either an early course of a standard triplet therapy or a treatment centered on ASCT.

Curiously, whereas the ASCT group showed a significant 21.4-month advantage in progression-free survival (PFS), there was no advantage in overall survival (OS).

Results were presented on June 5 during the plenary session at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago and published in the New England Journal of Medicine (NEJM).
It would seem that the OS result would catch the eye of payers, given the cost and toxicity of ASCT, but the issue is more complex. The group that did not receive upfront transplant ultimately needed more treatment; one-fourth of those who deferred transplant later needed one.

MM is a highly heterogenous disease; 34,470 cases will be diagnosed in 2022 in the United States with an estimated 12,640 deaths, according to information from ASCO. Of note, 18% of patients in the DETERMINATION trial were Black, one of the higher enrollment percentages of this important subgroup in MM.

Study design. The trial involved 722 patients aged 18 to 65 years whose MM had been newly diagnosed. One group was assigned to received 3 cycles of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, known as RVd, followed by stem cell collection—to be used later if needed—and 5 more RVd cycles (Arm A). The other group was treated with melphalan to aid in stem cell collection, followed by ASCT, followed by 2 cycles of RVd (Arm B). Both groups received lenalidomide maintenance until their disease progressed or until they could no longer tolerate the drug.

Lead investigator Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts, explained that it’s important to understand how far the field has come since DETERMINATION was designed more than a decade ago. As well as the new treatments, there are also new evaluation methods such as testing for minimum residual disease (MRD).

“We started in 2010; we have mature data in 2022. The good news is that our triplet therapies have now been added to by what we call quadruplets—with the integration of monoclonal antibodies and next-generation novel therapies. And the results from these studies are extremely exciting and promising,” he said.

New developments in MM “inform our decision-making even more, with the value of certain research tools such as MRD, providing us with additional guidance as to what makes the best choices there may be for patients.”
After a median follow-up of 76 months, results showed
the following:

• Median PFS was 46.2 months among patients who did not receive ASCT, and 67.6 months among those in the ASCT arm, (HR 1.53; 95% CI, 1.23-1.91; P < .0001).
• No OS advantage was seen in either group.
• Among patients who did not receive transplant, 63% needed additional treatment compared with 53% of those in the ASCT group; 28% of those who did not receive the initial transplant later received one.
• 90 deaths occurred in the nontransplant arm vs 88 deaths in the ASCT arm, which translated to 4-year OS rates of 84% vs 85% (HR 1.10; 95% CI, 0.81-1.47; P = .274). The 5-year OS estimates did not differ.
• Adverse events (AEs) were less likely in patients who did not receive transplant than in ASCT patients (78% vs 94%, respectively). Quality-of-life scores with ASCT were initially lower than those in the nontransplant arm but later recovered.
• Both groups had roughly the same likelihood of secondary malignancies, with 10% for nontransplant vs 11% for ASCT patients, but the latter group was far more likely to have secondary acute myeloid leukemia or myelodysplastic syndromes. The ASCT group also reported more blood-borne AEs than the nontransplant group, at 90% vs 61%.

Richardson predicted that the results of DETERMINATION would be important in real-world practice, especially for clinicians treating younger patients with a new MM diagnosis. The need for customized approaches was emphasized by both Richardson and plenary commenter Joseph Mikhael, MD, a professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute, an affiliate of City of Hope Cancer Center, in Phoenix, Arizona.

According to the NEJM paper, the most important findings of the study may be the subgroup analyses still to come: investigators plan to drill down into outcomes among Black patients and among those with higher body mass index. Work is underway to examine outcomes “according to cytogenetic risk and specific genetic abnormalities, given preliminary whole genome–sequencing analyses suggesting lower response rates associated with the presence of 17p deletion and TP53 mutations and the known association of 17p deletion with impairment of the tumor suppressor p53, an impairment that confers resistance to chemotherapy.”

Mikhael said that although he envisioned a time when ASCT would be less common, it remains very much the standard of care for younger patients. But the role of transplant will evolve, as a patient’s age, risk status, and treatment preferences are considered. The ability to store a patient’s stem cells may be a factor in decision-making, along with short-term and long-term toxicities. In addition, the move to quadruple therapy will shift decision-making.

“We may not have this simplistic way of saying that [a patient] is eligible or not eligible” for transplant, Mikhael said.

Reference
Richardson PG, Jacobus SJ, Weller E, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2204925