Baseline patient characteristics and first line therapy
A total of 1439 patients were included in the study and the baseline characteristics are presented in Supplementary Table 1. Patients were diagnosed between 2001 and 2018, the initiation of 2nd line treatment occurred between June 2003 and February 2021. The median age at diagnosis was 62.7 years, 60.1% were male. No significant differences between subgroups divided by the year of relapse (2003–2008, 2009–2014 and 2015–2021) were observed, except the higher prevalence of extramedullary plasmacytomas at diagnosis and higher serum beta-2-microglobulin levels in patients identified with relapse in the most recent period between 2015–2021.
In the 1st line therapy, novel agents were used in 1319 of cases (91.7%, Supplementary Fig. 1); regimens based on PIs in 26.5%, IMIDs in 42.0% and combination of PI + IMID in 21.2% of patients. Upfront single ASCT was performed in 689 patients (47.9%), tandem ASCT in 29 patients (2.0%) and allo-SCT in 3 patients (0.2%). Maintenance after 1st line therapy was used in 362 patients (25.2%), including 194 cases (13.5%) of lenalidomide-based maintenance and 125 cases (8.7%) of bortezomib-based maintenance.
Second line therapy and changes over time
Years 2003–2008 include 298 patients. For 2nd line treatment, during 2003–2008, 233 patients (78.2%) received novel agents. The majority were treated with doublets (n = 210, 70.5%), followed by triplets (n = 44, 14.8%) and salvage ASCT (n = 23, 7.7%) (Fig. 1). The most frequently used regimens were lenalidomide-dexamethasone (RD, n = 96, 32.2%), bortezomib-dexamethasone (VD, n = 55, 18.5%), followed by thalidomide-dexamethasone (n = 25, 8.4%) and salvage ASCT (n = 24, 8.1%) (Fig. 2). The rest of the implemented regimens is listed in Supplementary Table 2. In addition to salvage ASCT, 31 patients (10.4%) underwent single consolidative ASCT (after achieving second remission), 1 (0.3%) tandem ASCT and 3 patients (1.0%) underwent allo-SCT. Sixteen patients (5.4%) were treated with maintenance/consolidation, including 6 patients with lenalidomide- and 2 with bortezomib-based treatments.
Between 2009–2014 seven hundred patients were treated for relapse, and 648 (92.6%) received novel agents. The use of triplets in 2nd line increased (n = 301, 43.0%), although doublets were still more common (n = 356, 50.9%). Most frequently used regimens included: RD (n = 206, 29.4%), bortezomib-cyclophosphamide-dexamethasone (CYBORD, n = 122, 17.4%), bortezomib-lenalidomide-dexamethasone (n = 94, VRD, 13.4%) and VD (n = 93, 13.3%). After achieving response to 2nd line treatment 110 patients (15.7%) underwent consolidative ASCT and 7 allo-SCT (1.0%); 93 (13.3%) received maintenance/consolidation including 31 lenalidomide- and 43 bortezomib-based treatments.
Finally, during 2015–2021, 441 were included, and 425 (96.4%) received novel agents. Triplets were most common (n = 304, 68.9%), followed by doublets (n = 102, 23.0%). Most frequently used regimens include RD (n = 61, 13.8%), carfilzomib-RD (n = 52, 11.8%), daratumumab-RD (n = 45, 10.2%), CYBORD (n = 41, 9.3%), VRD (n = 40, 9.1%), daratumumab-pomalidomide-dexamethasone (n = 26, 5.9%) and daratumumab-VD (n = 23, 5.2%). Fifty-eight patients (13.2%) underwent single consolidative ASCT after 2nd line treatment, 1 (0.2%) underwent tandem ASCT; maintenance/consolidation was applied in 92 patients (20.9%), including 41 lenalidomide- and 16 bortezomib-based treatments.
Progression on treatment/maintenance- impact on 2nd line treatment choices
Progression on treatment (either active or maintenance) occurred in 601 of patients (41.8%) and influenced the choice of 2nd line therapy in comparison to patients relapsing while off treatment (n = 838, 58.2%). This includes more frequent use of quadruplets in comparison to patients who relapsed being off treatment (n = 42, 6.9% vs n = 15, 1.8%; p < 0.001), the use of salvage ASCT (n = 32, 5.3% vs n = 19, 2.3%; p = 0.002), treatment based on PIs (n = 352, 58.6% vs n = 365, 43.6%; p < 0.001) or PI + IMID (n = 145, 24.1% vs n = 128, 15.3%; p < 0.001) and the use of mAb (n = 80, 13.3% vs n = 45, 5.4%; p < 0.001). Patients who relapsed on active treatment/maintenance were treated less often with IMID-based regimen (n = 290, 48.3% vs n = 546, 65.2%; p < 0.001).
One hundred twenty-three patients relapsed on lenalidomide maintenance. The most commonly used 2nd line strategies in those patients were CYBORD (n = 20, 16.3%), VD (n = 14, 11.4%), Dara-VD (n = 12, 9.8%) followed by Dara-PD (n = 9, 7.3%).
Survival over two decades
Median time to next treatment (TTNT) from 2nd line therapy has improved over the time of study (p < 0.01; Fig. 3). Similarly, the median overall survival from 1st relapse has increased over the three time intervals.
Impact of 2nd line regimens on survival
Among the most frequently used doublet regimens (RD vs VD vs PD vs TD) the longest survivals were observed in patients who received RD and PD, including both TTNT from 2nd line therapy and OS from 1st relapse (Fig. 4). For the PD and RD group the median TTNT from 2nd line therapy was 18.2 months (95% CI 15.6–21.1) and 19.0 months (95% CI 12.0-31.6), respectively. Median OS from 1st relapse was 60.7 months (95% CI 54.1–71.3) in the PD group and 75.7 months (95% CI 50.0-101.8) in the RD group.
Among the most common triplet regimens (CYBORD vs VRD vs KRD vs Dara-RD) the longest survivals were observed in patients who received Dara-RD (Fig. 5), although the difference was not statistically significant. In the Dara-RD group the median TTNT from 2nd line therapy was 26.0 months (95% CI 15.7–30.3) and median OS from 1st relapse was not reached.
Third line therapy and its changes over time
From 1439 patients, 1173 had a 2nd relapse, 163 had not progressed at the time of follow up. For 103 the status of progression was unknown. Third line therapy was known for 1133 patients, 29 received hospice/supportive care, and in 1104 3rd line therapy was implemented, the treatment started between August 2004 and April 2021. Like 2nd line therapy, the number of agents used and the variety of regimens in 3rd line started to increase.
Between 2004–2009, 210 patients were treated for 2nd relapse, and 161 patients (76.7%) received novel agents. The majority (n = 147, 70.0%) was treated with doublets, followed by triplets (n = 45, 21.4%; Fig. 6). The most frequently used regimens were VD (n = 59, 28.1%), RD (n = 44, 20.1%), MP (n = 13, 6.2%) and PD (n = 12, 5.7%; Fig. 7). ASCT was used in 6 patients (2.9%), including 2 salvage ASCT (1.0%). Four patients received allo-SCT (1.9%). Two patients (1.0%) received bortezomib-based maintenance.
Next, 522 patients received 3rd line therapy between 2010 and 2015. Almost 89% (n = 464) received novel agents. Most patients received triplet regimens (n = 233, 44.6%), followed by doublets in 227 patients (43.5%) and quadruplets+ (n = 37, 7.1%). The most frequently used regimens included: CYBORD (n = 102, 19.5%), RD (n = 64, 12.3%), PD (n = 63, 12.1%) and VD (n = 45, 8.6%).ASCT was implemented in 29 patients (5.6%), including 11 patients who received salvage ASCT (2.1%). Two patients (0.4%) received pomalidomide-based maintenance, two bortezomib-based maintenance.
Finally, between 2016–2021 372 patients were treated due to 2nd relapse. Over 95% of patients received novel agents (n = 359). The majority received triplet regimens (n = 263, 70.7%), only 63 patient (16.9%) received doublet regimens. Dara-PD was the most frequently used regimen (n = 41, 11.0%), followed by Dara-RD (n = 38, 10.2%), Dara-VD (n = 36, 9.7%) and KPD (n = 31, 8.3%). Eight patients (2.2%) received ASCT, including 1 patient (0.3%) with salvage ASCT. One patient (0.3%) received allo-SCT. Three patients (0.8%) received maintenance (2 daratumumab, 1 bortezomib-based).