1. Clinical characteristics of multiple myeloma with or without AL amyloidosis.
We recruited 158 multiple myeloma patients in our study from January 1, 2010 to December 31, 2018. There were 36 smoldering multiple myeloma patients and 122 symptomatic multiple myeloma patients. Among them, forty-nine patients (31%) were diagnosed with AL amyloidosis. There were 21 AL amyloidosis patients in smoldering multiple myeloma and 28 patients AL amyloidosis patients in symptomatic multiple myeloma. Table 1 lists the clinical characteristics of symptomatic multiple myeloma patients with or without AL amyloidosis at the time of diagnosis. The two groups showed similar incidence of serious anemia, severe bone destruction, hypercalcemia, renal dysfunction, severe hypoalbuminemia, higher BMPC, higher LDH, worse D-S stage, treatment regimens and better initial therapeutic effect. Compared with the patients without AL amyloidosis, patients with AL amyloidosis showed higher incidence of BNP ≧ 700 pg/ml (46.4% VS 10.6%, P < 0.001), ALP > 187.5 IU/L (14.2% VS 2.1%, P = 0.035) and ALB < 25 g/L (39.2% VS 10.6%, P < 0.001). Table 2 lists the clinical characteristics of smoldering multiple myeloma patients with or without AL amyloidosis at the time of diagnosis. Similarly, compared with the patients without AL amyloidosis, patients with AL amyloidosis also only showed higher incidence of BNP ≧ 700 pg/ml (28.5% VS 0%, P = 0.030)and ALB < 25 g/L (42.8% VS 6.7%, P = 0.024).
2. Clinical characteristics of multiple myeloma with different light chain types of AL amyloidosis.
We observed more patients with multiple myeloma had λ-type AL amyloidosis (N = 35, 71.5%) than κ-type AL amyloidosis (N = 14, 28.5%).We then further compared the clinical characteristics of multiple myeloma patients with different light chain types of AL amyloidosis (Table 3). There was no significant difference (P > 0.05) in the incidence of serious anemia, severe bone destruction, hypercalcemia, LDH ≧ 240 IU/L or bone marrow plasma cells ≧ 20% between the two groups. There is no difference in the incidence of ALB < 25 g/L between the two groups, but κ-type AL amyloidosis patients had significantly higher incidence of renal insufficiency (57.1% VS 11.4%, P = 0.001).Patients with κ-type AL amyloidosis had a higher incidence of ALP > 187.5 IU/L (42.8% VS 5.7%, P = 0.001). No statistically significant difference was observed for BNP ≧ 700 pg/ml between two groups.
3. Pathological biopsy of AL amyloidosis.
AL amyloidosis was confirmed from pathological biopsies at ≥ one body part. Bone narrow biopsy was performed in all 49 patients with AL amyloidosis, and 17 patients (34.6%) were positive. Six of nine patients (66.6%) were positive for the subcutaneous abdominal fat pad aspirates biopsy. All the 28 patients with renal biopsy were positive, including 21 patients with negative bone narrow biopsies and 2 patients with negative subcutaneous abdominal fat pad aspirates. Histologic confirmation of AL amyloidosis at other sites were obtained for the six patients that were undetermined from the bone marrow, subcutaneous abdominal fat and the renal biopsies, including two tongue biopsies, one liver biopsy, one myocardial biopsy, one nerve biopsy and one gastrointestinal tract biopsy.
4. Organ involvement.
Organs involvement among the 49 patients with multiple myeloma and AL amyloidosis are as follows: kidney (36, 73.4%), heart (27, 55.1%), liver (13, 26.5%), skin (8, 16.3%), gastrointestinal tract (6, 12.2%), soft tissue (4, 8.2%), nerve (4, 8.2%), and pulmonary (1, 2%). Thirty-four patients (69.4%) had one or two organs involved and 15 (30.6%) patients had ≥ 3 organs involved. Eighteen of 36 patients with kidney involvement had heart involvement. Ten of 13 patients with liver involvement also had heart involvement. Five of 6 patients with gastrointestinal tract involvement also had heart involvement. Organs involvement among the 28 patients with symptomatic multiple myeloma and AL amyloidosis are as follows: kidney (20, 71.4%), heart (17, 60.7%), liver (7, 25.0%), skin (4, 14.3%), gastrointestinal tract (5, 17.8%), soft tissue (2, 7.1%), nerve (2, 7.1%), and pulmonary (1, 3.6%). Eighteen patients (64.2%) had one or two organs involved and 10 (35.8%) patients had ≥ 3 organs involved. In addition, organs involvement among the 21 patients with smoldering multiple myeloma and AL amyloidosis are as follows: kidney (16, 76.1%), heart (10, 47.6%), liver (6, 28.5%), skin(4, 19%) gastrointestinal tract (1, 4.7%), soft tissue (2, 9.5%), nerve (2, 9.5%), and pulmonary (0, 0%). Sixteen patients (76.2%) had one or two organs involved and 5 (23.8%) patients had ≥ 3 organs involved.
5. Death rate and causes of death in patients with and without AL amyloidosis.
Regarding the death rate, 54 of the 109 (49.5%) patients without AL amyloidosis died during study period. All these patients died of multiple myeloma. Thirty one of the 49 (63.3%) patients with AL amyloidosis died during study period, including 19/34 patients (55.8%) with one or two organs involvement and 12/15 patients (80%) with ≥ 3 organs involvement died. Specifically, 19/26 (73.0%) patients with heart involvement died. All 13 patients with liver involvement died, six of which died of cardiac amyloidosis. Twenty four of the 36 patients (66.7%) with kidney involvement died, 12 of which died of cardiac amyloidosis. Five of six patients (83.3%) with gastrointestinal tract involvement died, three of which died of cardiac amyloidosis. Causes of death are showed in Table 4. Twelve patients did not have clear causes of death, among the remaining 19 patients, 13 died of cardiac amyloidosis, making it the leading cause of death. Other causes include renal failure caused by renal amyloidosis(2), digestive tract hemorrhage caused by digestive tract involvement(2), and other MM-related deaths such as infection and hypercalacemia (2).
6. Survival of all patients with symptomatic multiple myeloma and patients complicated by AL amyloidosis.
The Median follow-up time was 56months (49.0-63.1 months). Fifty four of the 122 patients (44.2%) died during the follow-up. The overall median survival time for patients was 51.0 months (43.0–59.0 months).We divided the patients by the clinical characteristics to study the factors affecting symptomatic multiple myeloma patients’ survival. Survival time was significantly shorter in patients with ALP > 187.5 IU/L, ALB < 25 g/L, LDH ≧ 240 IU/L, BNP ≧ 700 pg/ml, treatment regimen with Bortezomib, initial therapeutic effect better than MR, and the presence of AL amyloidosis (Table 5). Cox regression adjusting for covariates was performed to evaluate the hazard ratio of each clinical character in symptomatic multiple myeloma having prognostic significance: BNP ≧ 700 pg/ml (HR = 2.455, P = 0.004)and initial therapeutic effect better than MR (HR = 0.106, p < 0.001).Given that patients with amyloidosis had significantly shorter survival time than patients without amyloidosis (36.9 vs. 55.5 months, P = 0.023, Fig. 1A), we further analyzed the impact of the type and number of organ involvement on the survival of all the patients with multiple myeloma. The results showed that survival time was significantly shorter with heart involvement (Fig. 1B; median survival time of 33.4 vs. 53.8 months, P = 0.024), liver involvement (Fig. 1C; 25.2 vs. 53.2 months, P = 0.013).
7. Survival of all patients with smoldering multiple myeloma and patients complicated by AL amyloidosis.
The Median follow-up time was 54.1months (41.8–66.5 months). Nineteen of the 36 patients (52.7%) died during the follow-up. The overall median survival time for patients was 48.1 months (35.2–61.0 months).Then, we divided the patients by the clinical characteristics to study the factors affecting smoldering multiple myeloma patients’ survival. Survival time was significantly shorter in patients with ALP > 187.5 IU/L, BNP ≧ 700 pg/ml, treatment regimen with Bortezomib, initial therapeutic effect better than MR, and the presence of AL amyloidosis (Table 6). Cox regression adjusting for covariates was performed to evaluate the hazard ratio of each clinical character in smoldering multiple myeloma having prognostic significance: the presence of AL amyloidosis (HR = 8.741, P = 0.002), treatment regimen with Bortezomib (HR = 0.249, p = 0.024) and initial therapeutic effect better than MR (HR = 0.196, p = 0.009).Given that patients with amyloidosis had significantly shorter survival time than patients without amyloidosis (24.0 vs. 69.8 months, P < 0.001, Fig. 2A),we further analyzed the impact of the type and number of organ involvement on the survival of all the patients with smoldering multiple myeloma. The results showed that survival time was significantly shorter with heart involvement (Fig. 2B; median survival time of 12.8 vs. 61.7 months, P < 0.001), kidney involvement (Fig. 2C; 23.1 vs. 63.5 months, P = 0.001), liver involvement (Fig. 2D; 10.1 vs. 56.3 months, P < 0.001), gastrointestinal tract involvement (Fig. 2E; 1.0 vs. 49.5 months, P = 0.013) and ≥ 3 organs involvement (Fig. 2F; median survival time of 11.4 vs. 54.6 months, P = 0.001).
8. Correlation analysis between BNP and cardiac amyloidosis in symptomatic multiple myeloma.
Kolmogorov-Smirnow test showed that BNP was not normally distributed. To investigate the relationship between BNP and cardiac amyloidosis, we performed the Spearman’s correlation test. We observed that BNP at diagnosis was significantly correlated with cardiac amyloidosis (r = 0.496, P < 0.001).
9. Treatment regimens, initial therapeutic effect in symptomatic or smoldering multiple myeloma with AL amyloidosis.
The previous results suggested that treatment regimen and initial therapeutic effect were significantly associated with the prognosis of symptomatic and smoldering multiple myeloma. We further found that in patients with symptomatic multiple myeloma complicated by AL amyloidosis, the survival time of Bortezomib group (42.9 vs.9.2 months, p = 0.013, Fig. 3A) and better ITE group (53.7 vs.8.8 months, p < 0.001, Fig. 3B) were longer. In addition, similarly, in patients with smoldering multiple myeloma complicated by AL amyloidosis, the survival time of Bortezomib group (36.7 vs. 4.2 months, p < 0.001, Fig. 3C) and better ITE group (not reach vs.15.4 months, p = 0.006, Fig. 3D) were also longer.