Multiple myeloma (MM) treatment has evolved significantly since 2000, fueled by the approval of new agents as well as the precision medicine movement that is the mantra of clinical medicine, regardless of disease. Although there is universal recognition of the need for second-line therapeutic regimens, determining the “best” choices as treatment moved from monotherapy to doublets and then to triplets is not straightforward, explained Sarah Goldman-Mazur, MD, PhD.

Analyzing Treatment Choices

An analysis of data from Connect® MM-The Multiple Myeloma Disease Registry that included 855 patients treated from 2010-2016 found that treatment choices “coincided with the approval status of newer agents and clinical study results. Thus, lenalidomide and bortezomib was the go-to doublet early in the decade beginning in 2010 but in later years carfilzomib, pomalidomide, daratumumab, and elotuzumab dominated therapies and triplet combinations were becoming more common.”

Dr. Goldman-Mazur and colleagues designed a retrospective analysis of second-line treatment regimens used at the Mayo Clinic with the goal of characterizing the treatments and looking at post-progression survival. They analyzed records from Mayo Clinic patients with MM who had at least one confirmed relapse after first-line treatment. They focused on second-line treatments initiated from February 2001 through February 2021, identifying a cohort of 1,439 patients, among whom the median age at time of diagnosis was 62.7 and more than one-half were men. The


1l A retrospective analysis suggests that the evolution of second-line MM treatments has significantly improved overall survival and time to new treatment.

2l Be aware that this activity is based on findings reported at a medical meeting and thus should be interpreted with caution until published in a peerreviewed medical journal.

full range of disease stages was well-represented in the cohort: International Staging System stage I: 23.5%, International Staging System stage II: 32.9%, and International Staging System stage III: 28.8%.

Agents & Classes of Choice

“In first-line therapy, novel agents were used in 82.8% of cases, regimens based on proteasome inhibitors (PI) in 26.5%, immunomodulatory drugs (IMID) in 42.0%, and combination of PI+IMID in 21.1%,” the researchers reported. “Upfront autologous stem cell transplantation (ASCT) was performed in 50.1% of patients, and maintenance after first-line was used in 25.2%.”

Dr. Goldman-Mazur and colleagues tracked the evolution of therapy by first looking at the data in 2-year intervals and then, for “descriptive purposes,” they used stacked area charts that illustrated the treatments in three “stacks” divided into 6-year intervals. When they plotted the number of agents used in the second-line regimens, doublets were the predominant choice in 2003, but their use declined through 2005, then steadily increased to 2007, when the use of doublets began a steady decline. There was a slight uptick from 2017 to 2021, but doublets still represented a minority of secondline regimens. Beginning in 2007, the popularity of triplet therapy steadily increased until 2017, when triplet regimens were the dominant second-line choice.

Turning to the agent class, in 2001, roughly 30% of second-line regimens were PI-based, 30% were IMID-based, 10% were monoclonal antibodies, and 20% were alkylating agents or anthracyclines. But by 2021, the distribution shifted significantly, and monoclonal antibody-based regimens represented about 20% of second-line therapy choices.

Evolving Impact on Outcomes

Dr. Goldman-Mazur noted that the evolving regimens had a significant impact on clinical outcomes, beginning with time to move on from second-line treatment to new therapy— in 2003-2006, the median time to new treatment was 10.4 months and by 2015-2021, second-line therapy was holding myeloma at bay for a median of 16.6 months before a new therapy had to be tried (P=0.00007). Likewise, the overall survival time from first relapse was a median of 30.9 months in 2003-2008 versus a median of 65.8 months in 2015-2021 (P<0.0001), she explained. “Over time, the landscape of secondary treatment has become more diverse, which means it can now be reflective of an individualized approach to patients,” she concluded.

When asked if the analysis had identified the most common and second most common second-line regimen used currently, Dr. Goldman-Mazur said that the data could not answer that question, because they “didn’t actually compare survival or effectiveness of the different regimens, thus one can only hypothesize about comparative benefits.”