Invited discussant of the ­DETERMINATION trial, Joseph Mikhael, MD, MEd, Professor of Applied Cancer Research and Drug Discovery at the Translational Genomics Research Institute, City of Hope Cancer Center, described the many implications of the important findings for DETERMINATION and offered some take-home messages for clinicians. To begin, Dr. Mikhael commended the investigators for studying a population in which 19% of participants were Black, who historically suffer worse outcomes from myeloma and have been greatly underrepresented in clinical trials.

Joseph Mikhael, MD, MEd

“This was a very positive study demonstrating that upfront transplant prolongs progression-free survival by 21 months, so melphalan still has a role and transplant remains a valuable component of therapy…. However, the similar overall survival seen now in multiple trials means the timing of transplantation—whether early or delayed—can be individualized based on factors such as age, risk status, patient preference, and feasibility,” he said.

Dr. Mikhael continued: “Now we have a more flexible ‘menu,’ where perhaps we don’t always have to include transplant upfront, despite its benefits…. We’ve now created greater choices in myeloma.” In choosing from this “menu,” it is important to “listen to our patients and to understand what is valuable to them.”

Additional Considerations

“We don’t ‘save the best for last’ anymore in myeloma, and early treatment has a downstream effect,” Dr. Mikhael commented. However, he said he may be “less enthusiastic” for upfront transplant in patients who are older than the study’s upper limit of 65, have specific toxicity concerns and other malignancies, or simply prefer to defer or avoid transplantation. “The toxicity of transplant is real; it costs patients at least 3 months of quality of life,” he pointed out. “Clinicians may become callous to these toxicities.”

The study also confirmed that maintenance therapy until disease progression is an important part of therapy, but its benefit is still greater after transplantation; maintenance was longer in the nontransplant arm, but this did not result in a “matched improvement” in progression-free survival. With lenalidomide optimally prescribed until disease progression, Dr. Mikhael said it is important to select a dose that a patient can tolerate long term and to be “flexible” in dosing, to prevent treatment discontinuation.

The field is rapidly evolving, and Dr. Mikhael made this prediction: With the use of quadruplets, the greater achievement of deeper responses and MRD negativity, and the application of immunotherapy upfront, “I can see a day with more limited use of transplantation.” 

DISCLOSURE: Dr. Mikhael has served as a consultant for Amgen, Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Sanofi, and Takeda.