Real-World Treatment Sequencing, Attrition Rates, and Survival Outcomes in Multiple Myeloma: A Retrospective Study over Four Decades

Introduction:

Despite the increase in the number and efficacy of available therapies for multiple myeloma (MM), it remains an incurable disease for most patients. However, real-world data on treatment sequences are still scarce. This study aims to describe this progression by estimating the attrition rate (AR), which measures the loss of patients in subsequent lines of therapy (LoT), time to next treatment or death (TNTD), progression-free survival (PFS), overall survival (OS) and the rate of complete responses (CR).

Methods:

We conducted a retrospective analysis of 1,297 MM patients (1980-2020) at our center, with a median follow-up of 134 months (IQR 72–208). Patients were categorized into 4 periods: 1980-89 (n=180), 1990-99 (n=291), 2000-09 (n=306), and 2010-20 (n=520), and 4 age groups: ≤60 years (n=558), 61-70 years (n=316), 71-80 years (n=310), and >80 years (n=113). AR was defined as the proportion of patients who died without proceeding to the next LoT despite failing the previous one. TNTD was defined as the time between the date of treatment initiation and the date of the subsequent line of therapy, or the date of death from any cause, whichever occurred first. PFS was defined as time from diagnosis of symptomatic MM to death or progression. OS was defined as time from diagnosis to death.

Results:

All patients received first-line treatment, whereas only 65%, 42%, and 25% received a second, third, and fourth LoT, respectively. AR was 22%, 26%, and 32% for these LoTs, respectively, with a progressive decrease over the study period and an increase with age in all LoTs. The proportion of patients receiving three or more LoTs increased during the study period, being 25%, 41%, 56%, and 39% for the four periods considered (p-value <0.001).

TNTD decreased across successive LoTs: from 20 months (95% CI, 18-22) for the second to 11 months (95% CI, 9-12), for the third and 8 months (95% CI, 7-9) for the fourth LoT. Significant improvement in TNTD from first LoT to second was observed: from 15 months (95% CI, 12-19) in 1980-89 to 24 months (95% CI, 20-27) in 2010-20.

PFS for first-line therapy improved significantly over time: 16 months (95% CI, 13-21) in 1980-89, 17 months (95% CI, 15-20) in 1990-99, 25 months (95% CI, 23-26) in 2000-2009, and 24 months (95% CI, 21-28) in 2010-20. Nevertheless, the median PFS was significantly lower after the first LoT. Thus, the median PFS after the second, third and fourth LoT was 9 (95% CI, 8-10), 7 (95% CI, 6-8) and 5 months (95% CI, 4-6), respectively, with no improvement overtime and regardless of patient’s age.

OS also improved over time; median survival increased progressively from 27 months (95% CI, 22-35) in 1980-89 to 71 months (95% CI, 62-83) in 2010-20 for first-line therapy from 11 months (95% CI, 7-16) to 43 months (95% CI, 33-52) for second-line therapy, from 10 months (95% CI, 7-23) to 25 months (95% CI, 21-33) for third-line therapy, and from 14 months (95% CI, 6-54) to 18 months (95% CI, 15-26) for fourth-line therapy.

CR rate significantly increased in the last periods studied. No patient achieved CR between 1980-89 after the first line, whereas 5.8%, 10.2%, 16.4% of patients obtained CR between 1990-99, 2000-09 and 2010-20, respectively. However, after every LoT the CR rate decreased: in second line 0%, 2.6%, 8.2% and 10.4% of patients achieved a CR for each period, and the response was even lower on successive lines. Finally, achieving a CR after the first line significantly prolonged survival, even after adjusting for the significant predictive factors obtained in the multivariate analysis: age, gender, Durie-Salmon stage, renal insufficiency, the performance status and the period when the patient was treated.

Conclusions:

In our series, 20-30% of patients were lost after each LoT. However, a greater proportion of patients received more than two LoTs in the most recent periods studied. OS has improved in recent years due to the achievement of deeper responses in a higher percentage of patients with a significant prolongation of PFS in the first line and greater availability of therapeutic alternatives. Nonetheless, PFS in patients receiving subsequent therapy lines has not improved over the years, regardless of age. Finally, achieving CR after the first line prolongs survival even after adjusting for the predictive factors of response, which highlights the importance of receiving the best available therapy early on.