Patient characteristics

We analyzed data from 1297 patients treated between 1980 and 2020, with a median follow-up of 134 months (IQR 72–208). Patient’s characteristics are summarized in Table 1. The median age at diagnosis increased over time, from 64 years (IQR 56–72) between 1980–89 to 66 years (IQR 57–76) (p < 0.002) in the most recent period, mostly due to a significant rise in the percentage of patients older than 80 years (up to 13%) in the last period studied. Six hundred and seventy-one (51.7%) were males and 626 (48.3%), females. Although patients were diagnosed at various disease stages, a significantly higher proportion were diagnosed at an earlier stage in the most recent decade (2010–2020). Compared to the first period with ISS staging (1990–1999), more patients were classified as ISS Stage I (31.1% vs. 26.2%, p < 0.001). Additionally, compared to the earliest period studied (1980–1989), fewer patients were diagnosed with a Durie–Salmon Stage III score (40.7% vs. 61.5%, p < 0.001) or with renal insufficiency (Durie–Salmon Stage B) (13.6% vs. 27.4%, p < 0.001). The functional status of patients at diagnosis, measured by the Eastern Cooperative Oncology Group Performance Status (ECOG-PS), showed a notable improvement over time, with the percentage of patients having an ECOG-PS higher than 1 dropping from 73% in the 1980–89 period to 28% in the 2010–2020 period (p < 0.001). There was an increase in the proportion of patients who received an ASCT from 29.9% in the second, 49% in the third, and 46.7% in the fourth period.

Table 1 Baseline Characteristics of Patients at Diagnosis.Number of lines of treatment

The number of LOT received per patient increased in later periods. The proportion of patients that received at least 3 LOT increased from 26% between 1980–1989, to 56.2% between 2000–2009 (p < 0.001), while the patients who received at least 4 lines increased from 10.5% to 40.5% in this period (p < 0.001). The proportion of patients receiving more LOT in later periods is probably underestimated due to a shorter follow-up. These data are summarized in Table 2.

Table 2 Lines of treatment received per period.Treatment patterns

Treatment regimens evolved significantly over time with the introduction of novel agents. Until 1999, nearly all patients received chemotherapy across all treatment lines.

Between 2000 and 2009, chemotherapy remained the predominant first-line therapy (75.2%), though the use of bortezomib (Bor) (10%) and thalidomide/lenalidomide (T/R) (11.1%) increased. In second-line therapy, Bor-based regimens (40%) were most common, followed by chemotherapy (36.9%) and T/R-based regimens (30%). The distribution in third-line therapy was more balanced, with chemotherapy (30%), Bor (24%), and T/R (24%), while in fourth-line therapy, chemotherapy remained dominant, though T/R and Bor continued to be used in a subset of patients.

By 2010–2020, treatment patterns shifted significantly, with Bor-T/R-based regimens becoming the most frequent first-line therapy (35.2%), followed by Bor-based regimens (31.3%). Chemotherapy use declined to 15.4%, while T/R-based regimens alone were used in 8.3% of patients. Anti-CD38 therapy was introduced in this period but remained uncommon in first-line therapy (2.3%). In second-line therapy, treatment distribution was more diverse, with chemotherapy, T/R-based regimens, and carfilzomib (K) each used in about 20% of patients, followed by Bor-based (18%) and CD38-based therapies (14%). Chemotherapy remained the most frequent third-line therapy (18%), while T/R-based regimens were used in 10% of patients, similar to Bor, K, pomalidomide, and CD38-based therapies. In fourth-line therapy, CD38-based regimens were the second most common (17%), while T/R-based regimens were used less frequently (Fig. 1).

Fig. 1: Treatment patterns by line of treatment and period.

LoT line of treatment, Chemo chemotherapy, Bor bortezomib, T thalidomide, R lenalidomide, B bortezomib, K carfilzomib, Pom pomalidomide.

Attrition rate

In our cohort, all patients received first-line treatment. The AR increased progressively with each LOT across all time periods. Moreover, the AR for every LOT decreased over the successive time periods. In the first time period (1980–1989), the AR was 37.8% after the first LOT, 55% after the second, and 59.6% and 63.2% after the third and fourth, respectively. In the 1990–1999 period, the ARs were 31.6%, 35.4%, 54.5%, and 43.4% after the first, second, third and fourth LOTs, respectively. During 2000–2009, the ARs were 17.9%, 20.6%, 23.8%, and 36.3% for the corresponding lines. Finally, in the most recent period studied (2010–2020), the ARs were lower; 15% for both the first and second LOT, 20.5% for the third, and 17.7% for the fourth LOT (Fig. 2A and Supplementary Table 1).

Fig. 2: Attrition rate across successive lines of therapy.

A Attrition rate by line of treatment and period. B Attrition rate by line of treatment and age.

Regarding the patient’s age at diagnosis and regardless of the time period, the ARs were higher in older patients. For those under 60 years of age, the AR was 19% after the first LOT, 17% after the second, and 26.2% after both the third and fourth. In contrast, for patients over 80, the ARs were 46.9%, 50%, 69.2%, and 66.7% for the first, second, third and fourth LOT, respectively (Fig. 2B and Supplementary Table 1).

When considering transplant status, the ARs were higher in patients who did not undergo an ASCT, being 29.2%, 36%, 42.8%, and 43.8% after the first, second, third and fourth LOT, respectively. In comparison, patients who received an ASCT had ARs of 11%, 10.7%, 18.8%, and 19.5%. These data are summarized in Supplementary Table 1.

Time to next treatment or death

The TTNTD was shorter after each LOT. We also observed that TTNTD was more prolonged in the last two periods studied (2000–2020), but only after the first and second LOT (p = 0.0003), while no differences were observed after subsequent lines, where TTNTD remained relatively stable across decades. After the first line, TTNTD increased from 15.4 months in the 1980s to 23.9 months in 2010–2020. In the second line, TTNTD was shorter in 2010–2020 (8.1 months) compared to 2000–2009 (12.1 months), possibly due to the earlier use of highly active agents in first-line therapy during the last decade, leading to more resistant disease at the time of second-line initiation. These results are summarized in Table 3.

Table 3 Time to next line of treatment or death (months).

Regarding patient age, TTNTD was significantly longer in younger patients after the first LOT (p < 0.0001), likely due to the use of more intensive treatment regimens. However, no significant differences were observed regarding age in subsequent lines. This may be explained by selection bias, as only patients who are fit enough to continue treatment reach later lines, potentially minimizing age-related differences. Among patients under 60 years, TTNTD progressively decreased from 26.8 months after the first line to 5.6 months after the fourth. In those aged 61–70 years, TTNTD ranged from 20.0 months in the first line to 5.8 months in the fourth. In older age groups, TTNTD was generally shorter, particularly in patients over 80, where it remained around 9 months across all lines. Detailed age-related data are presented in Table 3.

Responses

Treatment responses improved significantly across all LOT over the decades. For first-line therapy, ORR increased from 46.7% in 1980–89 to 75.5% in 2011–20 (p < 0.001), while second-line therapy resulted in an ORR rise from 19.3% to 53.1% over the same periods (p < 0.001). Similar improvements were observed after third- and fourth-line therapies, with ORRs increasing from 15.6% and 5.9% in 1980–89 to 41.2% and 37.8% in 2011–20, respectively. CR rates also improved significantly in recent decades. Among patients diagnosed between 1980 and 1989, only one achieved CR, and it occurred in third-line therapy. In contrast, in the last period studied (2011–20), CR rates reached 16.4% in the first line, 10.4% in the second, 8.8% in the third, and 5.5% in the fourth (Fig. 3A).

Fig. 3: Response rate across successive lines of therapy.

A Overall response rate by line of treatment and period. B Overall response rate by line of treatment and age. NR not reached.

Regarding age, the responses declined with increasing patient’s age and successive LOT. However, the differences regarding the age of the patient in the ORR are only statistically significant in the first LOT (p < 0.001), probably due to the small number of older patients treated in later lines. Younger patients ( ≤ 60 years) demonstrated the most favorable outcomes, with an ORR of 67.9% in the first line, including a 13% CR rate (p = 0.001), and an ORR of 32% in the fourth line, with a CR rate of only 5.8%. Among patients aged 61–70 years, the ORR dropped from 64.9% (CR 12%) in the first line to 25.5% (CR 4.1%) in the fourth. For those aged 71–80 years, the decline was more pronounced, with ORRs falling from 53.9% (CR 6.1%) to 24.6% (CR 1.8%). The oldest group ( > 80 years) achieved only a 43.4% ORR and 3.5% CR in the first line, and an ORR of 16.7% with no CR by the fourth line (Fig. 3B).

Progression-free survival and overall survival

In the earlier periods, PFS was more limited, consistent with the use of conventional chemotherapy and the absence of novel agents. PFS improved significantly for first-line therapy across the studied periods, increasing from a median of 15.8 months (95% CI, 13.3–20.5) in 1980–89 to 24.1 months (95% CI, 20.9–28.1) in 2010–20 (p = 0.001). In contrast, over the different time periods, no significant improvement in PFS was observed after second-line or subsequent treatments (Fig. 4A and Supplementary Table 2).

Fig. 4: Survival analysis across successive lines of therapy.

A Progression-free survival by line of treatment and period. B Overall survival by line of treatment and period. NR not reached.

Age at diagnosis only showed a significant effect in the first LOT. Patients aged ≤60 years exhibited the longest PFS in the first line, with a median of 27.6 months (95% CI, 24.3–32.4), compared to 20.9 months (95% CI, 17.3–24.3) for patients aged 61–70 years, 16.4 months (95% CI, 14.7–18.5) for those aged 71–80 years, and 10.3 months (95% CI 8.1–17.5) for patients aged >80 years (p < 0.0001). However, in subsequent lines, no differences in PFS were found across age groups, with median PFS of approximately 8, 6, and 4 months in the second, third, and fourth lines, respectively (Supplementary Table 3 and Supplementary Fig. 1).

OS has also significantly improved over time. Median survival increased progressively from 26.5 months (95% CI, 22.4–34.5) in 1980–89 to 70.7 months (95% CI, 61.5–82.7) in 2010–20 for first-line therapy (p < 0.001), from 11.0 months (95% CI, 7.2–15.7) to 42.6 months (95% CI, 32.8–51.5) for second-line (p < 0.001), from 10.2 months (95% CI, 7.4–22.6) to 24.7 months (95% CI, 21.2–33.2) for third-line (p = 0.002), and from 14.2 months (95% CI, 5.52–53.5) to 18.0 months (95% CI, 14.6–26.4) for fourth-line therapy (p = 0.76; Fig. 4B and Supplementary Table 2). OS decreased progressively with age across all therapy lines. For first-line therapy, younger patients (under 60 years) had the highest OS (70.5 months), while those over 80 had the lowest (24.4 months) (p < 0.001). In second-line therapy, OS ranged from 36.4 months for patients under 60 to 19.3 months for those over 80 (p = 0.012). For third- and fourth-line therapies, OS differences by age were less pronounced and not statistically significant (p = 0.48 and p = 0.83, respectively). (Supplementary Table 3 and Supplementary Fig. 1).

Progression-free survival and overall survival according to treatment regimen

While the global analysis of PFS showed significant improvement only in first-line therapy, specific novel regimens introduced during 2000–2009 and 2010–2020 contributed to meaningful PFS and OS gains in later lines.

Between 2000 and 2009, Bor-T/R-based regimens in first-line therapy achieved a PFS of 51.1 months, compared to 27.4 months for Bor-based therapies (p = 0.086), translating into OS gains of 96.3 and 79.0 months, respectively (p = 0.04). In second-line therapy, no significant PFS differences were observed, but OS was notably prolonged with K-based (68.6 months), Bor-based (38.1 months), and T/R-based therapies (41.9 months), compared to chemotherapy (17.3 months, p < 0.0001). However, sample sizes were small, with only 2 patients receiving CD38-based and Bor-T/R-based regimens, both of whom had not reached PFS and OS. In third-line therapy, K-based regimens showed the highest PFS (35.2 months, p = 0.0011), followed by CD38-based regimens (32.1 months), though patient numbers were low (4 and 5, respectively). OS varied significantly by treatment, with OS not reached in CD38-based and K-treated patients (p < 0.0001). In fourth-line therapy, no significant PFS differences were found, and the use of K-based, CD38-based, and triplet regimens was minimal (Supplementary Fig. 2).

Between 2010 and 2020, first-line therapy further improved, with Bor-T/R-based regimens achieving a PFS of 44.5 months, CD38-based combinations reaching 35.5 months, and K-based therapies achieving 30.3 months (p < 0.0001). OS was not reached in the CD38 group, whereas it reached 106.0 months in Bor-T/R-treated patients, compared to 31.7 months with chemotherapy (p < 0.0001). In second-line therapy, K-based regimens had a PFS of 19.8 months, and CD38-based therapies reached 11.9 months, both surpassing chemotherapy (6.2 months, p = 0.0022). OS in this setting was significantly prolonged, with survival not reached in pomalidomide-based, CD38-based, and K-based regimens, compared to 21.6 months with chemotherapy (p < 0.0001). The use of Bor-T/R regimens in this line was minimal (Fig. 5). In third-line therapy, PFS differences were not statistically significant, and OS was at the limit of significance (p = 0.19 and p = 0.05, respectively). In fourth-line therapy, PFS was longer in the Bor-T/R and T/R-based groups (8.3 months each) than in the chemotherapy group (2.7 months), though OS differences between treatment groups were not significant (Supplementary Fig. 3).

Fig. 5: Survival analysis according to treatment regimen.

A Progression-free survival after first and second line of treatment by treatment regimen between 2010–20. B Overall survival after first and second line of treatment by treatment regimen between 2010–20. QMT Chemotherapy, Bor bortezomib, T thalidomide, R lenalidomide, B bortezomib, K carfilzomib, Pom pomalidomide.

Survival impact of CR achieved after 1st line of therapy

Achieving a CR after the first LOT has emerged as an important factor in improving long-term outcomes in MM. Therefore, we evaluated the impact on survival of attaining CR in first-line therapy. Survival was measured from the date CR was achieved to avoid immortal time bias to ensure that survival outcomes accurately reflected the effect of CR, independent of time already survived before response.

Our results indicate that patients who achieved CR had a median OS of 4.5 years (95% CI 3.9–4.9), compared to 1.6 years (95% CI 1.35–2.11) for those who did not achieve CR (p < 0.001) (Supplementary Fig. 3). This association remained statistically significant after adjusting for age, sex, Durie–Salmon stage, renal function, performance status, and the treatment period, as assessed through multivariate analysis (Supplementary Table 4). These adjustments confirm that achieving CR is independently associated with longer OS across various patient subgroups.