The management of light chain (AL) amyloidosis in Europe: clinical characteristics, treatment patterns, and efficacy outcomes between 2004 and 2018

Overall, 4480 patients were enrolled; Table S1 lists the participating centers. Patients who participated in clinical trials (N = 177 for first-line treatment and N = 38 for second line) were only included in the analyses for patient characteristics. Table 1 presents the demographic and clinical characteristics at diagnosis for patients who started first-line treatment in 2004–2018 (N = 4480), pre-2010 (N = 1415), and post-2010 (N = 3065).

Table 1 Patient demographic and disease characteristics at diagnosis, overall (2004–2018), and by first-line treatment initiation period (pre- and post-2010).

In 967 (21.6%) patients with available data, the median time from symptoms to diagnosis was 5.1 months (5.4 and 5.0 months pre- and post-2010, respectively) and the median time from diagnosis to initiation of first-line treatment was 0.7 months.

Clonal disease was immunoglobulin light chain only in 41.0% while 4.4% of patients had IgM-related AL amyloidosis (Table S2). Heart (67.9%) and kidneys (66.1%) were the most frequently involved organs. Most patients (74.1%) had ≤2 organs involved and 34.3% had only one organ involved.

Cardiac stage (Mayo 2004 with European modification) [25, 26] at the time of diagnosis was available for 3775 (84.3%) patients, of whom 696 (18.4%) were stage I, 1413 (37.4%) stage II, 1003 (26.6%) stage IIIa, and 663 (17.6%) stage IIIb. Per Mayo 2012 staging [27] (available for 3065 patients), 19.8%, 24.2%, 29.2%, and 26.7% were rated as stage I, II, III, and IV, respectively. Cardiac stage distribution at diagnosis was similar for the two chronological periods (Table 1).

First-line treatment

Table 2 depicts regimen categories and the most common individual regimens that were used as first-line therapies. Bortezomib-based regimens (54.8%, N = 2454) were the most common first-line therapy, followed by chemotherapy (19.4%, N = 869) [mostly melphalan with dexamethasone (MDex)], and immunomodulatory drug (IMiD)-based regimens (N = 488, 10.9%). High-dose melphalan (HDM) with ASCT was used at first line in 6.2% (N = 278); 74.1% (N = 206) received induction prior to HDM-ASCT (bortezomib-based in 68.0% and IMiDs in 18.0%). First-line treatments among participating countries are shown in Table S3.

Table 2 First-line treatment regimens, overall (2004–2018), and by first-line treatment initiation period (pre- and post-2010).

There was a significant change of first-line treatment type in the two chronological periods. Pre-2010, most patients received chemotherapy (in 42.6%, MDex in 32.4%), followed by IMiD-based regimens (30.3%), and bortezomib-based therapy (in 11.5%) while, after 2010, bortezomib-based regimens were used in the majority of patients (74.7%); VCD was the most frequently used bortezomib-based regimen (20.6% of all regimens post-2010), followed by bortezomib and dexamethasone (VD, 10.5%) and bortezomib with MDex (VMD, 5.4%). ASCT was performed in 7.6% of patients pre-2010 and in 5.5% post-2010.

Pre-2010, chemotherapy (mostly MDex) was the most frequently used regimen across all cardiac stages (range: 39.7% for stage I to 50.7% for stage IIIa). Post-2010, bortezomib-based regimens, and VCD in particular, were used in the majority of patients across all cardiac stages (range: 64.8% for stage I to 82.3% for stage IIIb) (Table S4). In patients with kidney involvement bortezomib-based therapy was used in 54.9%, chemotherapy in 19.2%, and IMiDs in 10.4%. Among patients with nerve involvement, 44.0% received bortezomib-based therapy, whereas 31.9% and 7.4% were given chemotherapy and IMiDs, respectively (Table S5). Most patients with IgM-related amyloidosis received rituximab-based regimens at first line, 33.3% (N = 23) and 39.8% (N = 51), pre- and post-2010, respectively (Table S6).

Response to first-line treatment

After first-line therapy, 63.4% of patients with available information achieved at least hematologic PR (including CR: 23.2% and VGPR: 21.2%, Table S7). The hematologic response rate was 68.4% with bortezomib-based regimens (CR: 26.1%, VGPR: 25.7%); 49.0% (CR: 14.3%, VGPR: 13.4%) with chemotherapy, and 53.7% (CR: 17.5%, VGPR: 9.3%) with IMiD-based regimens (Table S8). Hematologic response rates were similar among bortezomib-based regimens: 63.7% (CR: 19.2%, VGPR: 27.7%) for VCD, 62.1% (CR: 12.7%, VGPR: 27.4%) for VD, and 57.3% (CR: 20.5%, VGPR: 25.1%) for VMD. In ASCT-treated patients, 88.0% achieved ≥PR (CR: 43.4%, VGPR: 27.0%) (Table S9). The proportion of patients who failed to achieve a response or died within 3 months after starting therapy without any response assessment, pre- and post-2010, was 35.6% and 31.3% with bortezomib-based, 50.5% and 52.6% with chemotherapy, 43.9% and 65.4% with IMiD-based regimens, and 24.8% and 3.7% with ASCT (Table S10).

Hematologic response rates significantly improved post-2010 (67.1% vs 55.6% pre-2010, p < 0.001), with deeper responses (25.0% vs 19.5% CRs and 25 4% vs 12.4% VGPRs). As a consequence of the improvement in hematologic responses non-responding patients significantly decreased from 44.4% (SD: 16.7%, PD: 19.6%) pre-2010 to 32.9% (SD: 14.8%, PD: 9.4%) post-2010 (Table S11).

Among patients with available information, hematologic response was achieved in 58.6% of patients at 3 months from the start of first-line therapy (1594/2720) and in 70.1% of patients at 6 months (1633/2329). Three-month ORR was 45.6% (CR + VGPR: 24.8%) pre-2010 and 63.6% (CR + VGPR: 38.9) post-2010, and 6-month ORR was 58.3% (CR + VGPR: 31.0%) and 75.1% (CR + VGPR: 54.5%), respectively (Table S12).

Hematologic response rates at 3 months were 64.1% for bortezomib-based regimens, 42.2% for chemotherapy and 42.8% for IMiD-based regimens. At the 6-month landmark, response rates for patients with available information were 74.5% for bortezomib-based regimens, 54.1% for chemotherapy, and 55.1% for IMiD-based regimens (Table S13).

Median ToT for first-line therapy was 4.7 (range: 4.4–5.0) months; similar in the pre- and post-2010 era (4.7 vs 4.8 months) and was shorter in patients with more advanced disease stages (Table S14).

Second-line therapy

Overall, 1759 patients received second-line treatment. After the second-line therapy, 58.7% of patients with available information achieved at least hematologic PR (including CR: 15.3% and VGPR: 20.1%, Table S7). Median time from start of first line to second-line therapy was 9.5 (0.6–165.7) months and was shorter post-2010 (8.6 vs 11.3 months). Pre-2010, bortezomib-based regimens were the most frequent second-line treatment (N = 349, 45.0%) while post-2010 IMiD-based regimens became the major choice (N = 410, 41.7%) (Table 3). Notably, 15.6% of patients who received bortezomib at first line and required a second-line treatment, received bortezomib-based therapy again (Table S15). Per cardiac stage, 50.8% of patients with stage I, 46.6% with stage II, 33.1% with stage IIIa, and only 18.6% with stage IIIb received second-line treatment. Among patients who received first-line ASCT and required second-line therapy (N = 122), 30.3% received bortezomib-based, and 33.6% IMiD-based regimens. Salvage therapy for patients who failed to respond to primary therapy was based on bortezomib and IMiDs in most cases, with bortezomib used in most patients after primary failure to IMIDs (55.7%), and IMiDs (51.8%) in most patients after primary failure to bortezomib.

Table 3 Second-line treatment regimens, overall (2004–2018), and by first-line treatment initiation period (pre- and post-2010).Survival

The median follow-up for the whole cohort was 54.5 (51.4–57.8) months (Table S16). The median OS was 48.8 (45.2–51.7) months; 51.4 (47.3–57.7) months for the pre-2010 group and 46.7 (41.3–52.2) months for the post-2010 group (Table S17).

Early mortality (i.e., within 3 months from start of therapy) was 13.4%, did not improve (11.4% in the pre-2010 and 14.4% in the post-2010 era, Table S18) and was higher in patients with severe cardiac disease in both pre-2010 and post-2010 periods: 1.1% and 2.1% for stage I patients, 7.8% and 7.7% for stage II, 22.7% and 15.6% for stage IIIa, and 39.3% and 39.8% for stage IIIb, respectively (Table 4). The median OS for stage I patients was 116.5 months for the pre-2010 group and was not reached for post-2010 patients (log-rank p = 0.670); for stage II patients, median OS was 47.3 months pre-2010 and 67.0 months post-2010 (log-rank p = 0.0539); for stage IIIa patients was 14.2 and 30.7 months, respectively (log-rank p = 0.0170) and for stage IIIb patients, 5.0 and 4.5 months (log-rank p = 0.530), respectively (Fig. 1). The OS per revised Mayo 2012 was not reached in stage I patients, was 69.7 in stage II patients, 24.7 in stage III patients, and 10.6 months for stage IV patients (Fig. S1).

Table 4 Early mortality rates by cardiac stage and first-line treatment initiation period.Fig. 1: Kaplan–Meier graph of overall survival by first-line treatment initiation period (pre- and post-2010) and Mayo2004/European stage at diagnosis.figure 1

Stage I, Stage II, Stage IIIa and Stage IIIb represent the comparison of survival curves in the pre- and post-2010, separately for the respective patient subgroups defined by Mayo 2004/European stage at diagnosis.

The OS was similar between regimen groups (45.3 vs 48.6 vs 41.1 months for bortezomib-, IMiD-, and chemotherapy-based therapy, respectively), while the 3-month OS rate of patients undergoing ASCT was 97.8%. Median OS for patients with stage I disease was not reached for bortezomib-based regimens and was 81.1 and 88.5 months for IMiD-based and chemotherapy regimens, respectively. For stage II, the median OS was 67.0 vs 39.4 vs 44.8 and for stage IIIa 32.8 vs 7.3 vs 14.3 for bortezomib-based, IMiD-based, and chemotherapy regimens, respectively. However, in patients with stage IIIb disease median OS was poor across all regimen groups (4.6 vs 5.3 vs 4.6 respectively) (Table S19). The median OS in patients with IgM-related AL amyloidosis was 39.7 months (51.7 months pre-2010 and 29.8 months post 2010 era, p = 0.2772; Table S20).

To evaluate the effect of early hematologic responses on OS we performed a landmark analysis at 3 and at 6 months after treatment initiation. In 2711 evaluable patients the median OS for patients achieving CR at 3 months was 109.4 (range: 97.3–149.7) months, 82.8 (range: 66.0–103.7) months with VGPR, 61.7 months with PR (range: 52.7–69.8), and 21.0 (range: 16.8–25.9) months for those who did not achieve a response (p < 0.0001 by log-rank; Fig. 2). At 6 months, the median OS for patients (N = 2322) with CR was 142.6 (range: 104.2−NR) months vs 78.2 months for VGPR (range: 64.5–100.8), 59.9 (range: 51.8–69.8) months for PR and 20.2 (range: 14.8–24.3) months for those who did not achieve a response (p < 0.0001 by log-rank; Fig. S2).

Fig. 2: Kaplan–Meier graph of OS by hematologic response at 3 months after first-line treatment initiation, 2004–2018.figure 2

CR complete response, PD progressive disease, PFS progression-free survival, PR partial response, SD stable disease, VGPR very good partial response.

Analysis by hematologic response at 3 months per Mayo2004/European stage showed that patients with stage I or II disease achieving CR did not reach a median OS, while for patients with stages IIIa and IIIb, median OS was 56.2 and 47.0 months, respectively. The respective median OS for patients with stage I, II, IIIa, and IIIb disease achieving VGPR was 81.1, 111.6, 60.5 and 35.7 months, and 83.5, 70.2, 44.6, and 18.5 months for those with PR. Finally, patients failing to achieve a hematologic response by 3 months had a median OS of 96.4, 23.3, 8.9, and 3.3 months. The between-response difference in OS was statistically significant for all stages (p < 0.001 by log-rank; Fig. S3).

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