Abstract
We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥ 1× 10−5; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in two years from start of therapy (median: 7 months). Overall MRD negative rate was 64% (n=28). MRD-negative rate after one-line of therapy was 71% (20/28). MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs. chemotherapy alone as first-line treatment (29%, 2/7), p=0.005. MRD negative rate amongst patients in complete response were 75% (15/20); in very good partial response: 50% (11/22) and there were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs. MRD positive patients, except younger age among MRD-negative patients. MRD negative patients were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs. 22% (2/7), p=0.04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs. MRD positive patients was 100% (26 patients, 0 events) vs. 64% (16 patients, 5 events), p=0.006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.
Keywords: minimal residual disease, flow cytometry, next generation flow cytometry, AL amyloidosis
INTRODUCTION:
Achievement of minimal residual disease (MRD) negativity has been associated with improved survival outcomes in multiple myeloma across different therapeutic regimens and lines of therapy.1 Light chain (AL) amyloidosis is typically associated with a low clonal plasma cell burden.2 However, even low levels of unstable light chains secreted by these plasma cells can deposit in organs like heart, kidney, liver and nerves, resulting in organ dysfunction.3–5 A rapid reduction of light chains to very low levels with treatment results in organ improvement and better survival.6,7 We have previously demonstrated that lack of residual bone marrow monotypic plasma cells using flow cytometry (sensitivity ≥ 1 × 10−4) is associated with superior outcomes.8–11 There is limited data on outcomes in AL amyloidosis using next generation MRD assessment methods [next generation flow cytometry (NGF) or next generation sequencing (NGS)], which are currently endorsed for MRD response evaluation for multiple myeloma by the International Myeloma Working Group.12–16 The sensitivity of these methods varies between ≥ 1 × 10−5 to 1 × 10−6.17
We hypothesized that elimination of clonal disease by high-sensitivity MRD methods, like NGF would be associated with improved outcomes in patients with AL amyloidosis.
METHODS
Patients with systemic AL amyloidosis treated at Mayo Clinic in Rochester, MN who underwent bone marrow MRD assessment using NGF from 08/1/2017 to 11/30/2018 were included in the study. MRD testing was done at the discretion of the treating physician. This study was approved by the Institutional Review Board. Bone marrow MRD assessment was carried out using two-tube, eight color next generation flow cytometry (sensitivity ≥ 1 × 10−5) using antibodies to CD138, CD27, CD38, CD56, CD45, CD19, CD117, CD81, kappa and lambda light chains, based on the Euroflow guidelines and IMWG consensus criteria.12 Tube 1 contained antibodies to CD138, CD27, CD38, CD56, CD45, CD19, CD117 and CD81 and tube 2 contained antibodies to CD138, CD27, CD38, CD56, CD45, CD19, kappa and lambda light chains. Per institutional protocol, a minimum of 2 mL bone marrow aspirate was tested with the goal of obtaining 5 million events per tube (total 10 million events). Per protocol, the study was considered successful with at least 2 million events collected. Abnormal plasma cell populations were detected through demonstrating CD38 and CD138 positivity along with immunoglobulin light chain restriction (i.e. the presence of either predominately kappa or lambda light chains) and abnormality of CD56, CD117, CD27, CD81, CD19 and/or CD45 expression.
MRD testing was available in 53 unique patients with AL amyloidosis, of which 44 patients underwent testing in two years of starting last line of treatment. The outcomes of these 44 patients are reported here to minimize the impact of variable MRD assessment time-points. Hematologic and organ response were assessed by consensus criteria.6,18
Analysis was carried out using JMP® 14 (SAS Institute Inc., Cary, NC) statistical software. Chi-Square and Fischer Exact tests were used to carry out univariate analysis for categorical variables and Wilcoxon Rank Sum/Kruskal Wallis for continuous variables. Survival analysis was carried out using Kaplan-Meier method and Log-Rank test was used to compare survival curves. Progression free survival (PFS) was defined as hematologic/organ progression or death from the time of MRD assessment and estimated using the Kaplan-Meier method. Overall survival (OS) was defined as time to death or last follow-up from MRD assessment.
RESULTS
Of the 44 AL amyloid patients who underwent MRD testing in two years from start of therapy, 64% (n=28) patients were MRD negative. The median number of events analyzed per patient was 8.7 million, with a range of 4.8 to 9.7 million, therefore assuring a sensitivity of 10-5 or better.19 Table 1 depicts the baseline characteristics of the entire cohort and compares MRD negative vs. MRD positive patients The median age at MRD assessment was 63 years and 59% (n=26) of patients were male. Involved light chain was lambda in 71% (n=31) of patients. Organ involvement was as follows, kidney: 71%, heart: 48%, peripheral nervous system (NS): 16%, autonomic NS: 11% and liver: 5%. At diagnosis, the median bone marrow plasma cell percentage was 10% (inter-quartile range, IQR: 5–29%) and difference in involved and uninvolved light chains (dFLC) was 14.6 mg/dL (IQR: 7.5–47.8). The median lines of therapy received was one (range 1–5), with 64% (n=28) of patients being evaluated after one line of therapy. Patients who achieved MRD negativity were younger than those who remained MRD positive (62 vs. 68 years, p=0.03). (Table 1) There were no differences in other baseline characteristics of patients who were MRD negative vs. MRD positive, including bone marrow plasma cells (median: 10% vs. 9%, p=0.8); dFLC (14.4 vs. 15.9 mg/dL, p=0.9); organ involvement, specifically cardiac involvement (43 vs. 56%, p=0.4) and cardiac biomarkers (median NTProBNP: 971 vs. 880 pg/mL, p=0.5). (Table 1)
Table 1:
Baseline and treatment characteristics
| All Patients, N=44 % (n) or median (IQR) | MRD negative, N= 28 % (n) or median (IQR) | MRD positive, N= 16 % (n) or median (IQR) | p-value | |
|---|---|---|---|---|
| Age, years | 63 (58–69) | 62 (56–67) | 68 (62–71) | 0.03 |
| Sex, male | 59 (26) | 57 (16) | 63 (10) | 0.7 |
| Lambda involved light chain | 71 (31) | 64 (18) | 81 (13) | 0.2 |
| Baseline dFLC, mg/dL | 14.6 (7.6–47.8) | 14.4 (9.7–67.7) | 15.9 (4.5–43.9) | 0.9 |
| Baseline BMPCs % | 10 (5–29) | 10 (5–30) | 9 (5–25) | 0.8 |
| NTProBNP, pg/mL | 926 (163–2273) | 971 (152–1814) | 880 (151–5912) | 0.5 |
| Troponin-T, ng/mL | 0.01 (0.003–0.035) | 0.01 (0.005–0.02) | 0.02 (0.001–0.04) | 0.6 |
| 24-hour urine protein, mg | 3488 (853–9391) | 3539 (660–10775) | 3271 (1396–8997) | 0.9 |
| Organ involvement | ||||
| Heart | 48 (21) | 43 (12) | 56 (9) | 0.4 |
| Kidney | 71 (31) | 71 (20) | 67 (11) | 0.9 |
| Liver | 5 (2) | 7 (2) | 0 (0) | 0.2 |
| Peripheral Nerves | 16 (7) | 18 (5) | 13 (2) | 0.6 |
| Autonomic Nerves | 11 (5) | 11 (3) | 13 (2) | 0.9 |
| Treatment History/Response | ||||
| One line of therapy | 65 (28) | 71 (20) | 50 (8) | 0.2 |
| ASCT as last line of therapy | 57 (25) | 64 (18) | 44 (7) | 0.2 |
| Time from start of treatment to MRD testing, months | 7 (4–13) | 7 (3–13) | 7 (5–14) | 0.9 |
| Complete response at MRD assessment | 46 (20) | 54 (15) | 31 (5) | 0.2 |
| Median iLC level at MRD assessment, mg/dL | 1.3 (0.7–2.1) | 1.3 (0.7–2.1) | 1.3 (0.7–2.2) | 0.99 |
Table abbreviations: ASCT: autologous stem cell transplant; BMPCs: bone marrow plasma cells; dFLC: difference in involved and univolved free light chains; iLC: involved light chains
Median time from start of immediate prior line of therapy to MRD assessment was 7 months in both MRD negative (IQR: 3–13 months) and MRD positive (IQR: 5–14) patients, p=0.9. Autologous stem cell transplant (ASCT) was part of last line of therapy before MRD assessment in 64% of MRD negative patients and 44% of MRD positive patients, p=0.2. Interestingly, in patients undergoing MRD evaluation after one line of therapy (n=28), MRD negative rates were higher in those who underwent ASCT vs. not [86% (18/21) vs. 29% (2/7), p=0.005]. Patients undergoing ASCT were younger (median: 62 vs 68 years, p=0.007), which might explain the younger age seen in MRD negative patients.
The median involved LC levels at the time of MRD assessment were 1.3 mg/dL in both groups (IQR, MRD negative: 0.7–2.1; MRD positive: 0.7–2.2), p=0.99. MRD negative rates were 71% (20/28) in patients tested after one line of therapy and 50% (8/16) in patients tested after ≥2 prior lines of therapy. At MRD assessment, 96% (42/44) of patients were in complete response (CR; n=20) or very good partial response (VGPR; n=22). below. MRD negative rates amongst patients in CR were 75% (15/20) and amongst patients in VGPR were 50% (11/22). A detailed description of dFLC (difference in involved and uninvolved light chains), serum and urine immunofixation status of the 11 VGPR patients and two patients who were in VGPR are provided in Table 2. In the VGPR MRD negative patients, the median dFLC was very low at 0.16 mg/dL (range: −1.3 to 4), FLC ratio was abnormal in 4/11 (36%) of patients, serum immunofixation was positive in 3/11 (27%) patients and urine immunofixation was positive in 3/11 (27%) patients. As described in Table 2, there were patients who were classified as VGPR due to equivocal immunofixation (serum N=3, urine N=1) or because immunofixation was not done (serum N=2, urine N=3). Of the remaining two patients who were not in CR/VGPR, the first patient was in partial hematologic response with elevated levels of both involved and uninvolved FLCs in presence of renal dysfunction and no evidence of monoclonal protein on serum immunofixation. The second patient had concern for hematologic progression with gradually rising FLCs in presence of renal dysfunction, with negative serum immunofixation. In these two patients, MRD assessment was done to clarify bone marrow disease status. Both patients were found to be bone marrow MRD negative and no change in therapy was instituted as a result. Both remain progression free at last follow-up. It is possible that variable marrow involvement and sampling heterogeneity contributed to MRD negativity in these two patients, as has been observed in multiple myeloma. Both these patients have been excluded from survival analysis.
Table 2:
Free light chain and immunofixation status in MRD negative patients who were not in complete response
| Involved FLC (mg/dL) | Uninvolved FLC (mg/dL) | dFLC (mg/dL) | FLC ratio | Serum IFE | Urine IFE | |
|---|---|---|---|---|---|---|
| MRD Negative Patients in VGPR | ||||||
| 1 | 0.64 | 0.97 | −0.33 | Normal | Equivocal | Not done, UPEP negative |
| 2 | 1.35 | 0.4 | 0.95 | Abnormal | Negative | Negative |
| 3 | 1.85 | 1.73 | 0.12 | Normal | Negative | Positive |
| 4 | 0.02 | 0.3 | −0.28 | Abnormal | Equivocal | Negative |
| 5 | 0.7 | 0.17 | 0.53 | Normal | Not done | Not done, UPEP negative |
| 6 | 19.4 | 15.4 | 4 | Normal | Positive | Not done |
| 7 | 2.23 | 1.33 | 0.9 | Normal | Equivocal | Positive |
| 8 | 1.03 | 0.931 | 0.099 | Normal | Not done | Equivocal |
| 9 | 1.34 | 0.66 | 0.68 | Normal | Positive | Positive |
| 10 | 1.42 | 2.76 | −1.34 | Abnormal | Negative | Negative |
| 11 | 0.19 | 0.029 | 0.161 | Abnormal | Positive | Negative |
| MRD negative patients in < VGPR | ||||||
| 12 | 30.7 | 13.3 | 17.4 | Normal | Negative (polyclonal) | Not done |
| 13 | 45.3 | 3.8 | 41.5 | Abnormal | Negative | Not done, UPEP negative |
Table abbreviations: dFLC: difference in involved and univolved free light chains; FLC: free light chain; IFE: immunofixation
Organ response:
MRD negativity was associated with higher likelihood of cardiac response at the time of MRD assessment, 67% (8/12) vs. 22% (2/7), p=0.04. Cardiac response rates at 1 year from MRD assessment in MRD negative vs. MRD positive patients were 64% (7/11) vs. 50% (5/10), p=0.6. For renal response assessment, patients on dialysis prior to start of therapy were excluded. Renal response rates at the time of MRD assessment were similar in MRD negative vs. MRD positive patients, 69% (11/16) vs. 89% (8/9), p=0.2. Renal response rates within one year of MRD assessment were also similar [81% (13/16) vs. 86% (6/7), p=0.8].
Survival:
The median follow-up after MRD testing was 14 months (95% confidence interval: 12–17). Survival analysis was restricted to the 42 (of 44) patients in CR/VGPR. PFS from the time of MRD assessment was significantly longer in MRD negative vs. MRD positive patients. While the median PFS was not reached in either group, the estimated 1-year PFS from MRD assessment in MRD negative patients was 100% (26 patients, 0 events) vs. 64% in MRD positive (16 patients, 5 events), p=0.006, respectively. Of the five progression events in the MRD positive group, two were renal organ progression, two were hematologic progression, and there was one death due to complications of renal amyloid requiring dialysis. Amongst MRD negative patients, there was no difference in PFS from the time of MRD assessment in patients with CR or VGPR. There were no events either group, with 1 year PFS being 100% in both. On the other hand, amongst patients who were MRD positive, patients with CR appeared to have better outcomes with 1 year PFS of 100% in CR patients vs. 49% in patients with VGPR, p=0.1. There was no difference in overall survival in the two groups, with median OS not reached (p=0.8).
DISCUSSION
Two-thirds of patients with AL amyloidosis in our study achieved MRD negativity by next generation flow cytometry. MRD negativity rates were higher in those undergoing testing after one-line of therapy and highest amongst those undergoing ASCT as part of first-line therapy. MRD negativity was associated with better cardiac response rates and progression free survival.
Previous studies of small series of amyloid patients have shown that about 40–50% of patients in CR are MRD negative by Euroflow based MRD assessment.13,14,16 In our series, 75% of patients in CR and 50% of patients in VGPR were MRD negative. Prior studies included both newly diagnosed and relapsed patients with AL amyloidosis and MRD testing was conducted 20 to 36 months after response was achieved.13,16 Our series also includes both newly diagnosed (65%) and relapsed (35%) patients. However, the median time from start of treatment to MRD assessment was significantly shorter (7 months) in the current study, highlighting that MRD assessment has prognostic value even early in treatment course. This opens up the possibility of MRD risk-adapted clinical trials in AL amyloidosis with interventions to optimize outcomes early in treatment course. Such studies are already underway in multiple myeloma.20 Similar to our report, studies assessing MRD in multiple myeloma clinical trials have also included patients in less than complete hematologic response.21–24 There were two MRD negative patients in our cohort who were not in CR or VGPR. MRD assessment in these patients was done to clarify the status of their disease as they had elevated light chains in presence of renal dysfunction, with no evidence of monoclonal protein on serum immunofixation. While they may have been truly MRD negative, it is also possible that these patients were false negative as bone marrow plasma cell involvement can be variable and sampling heterogeneity may result in false negative results. Similar findings have been seen in multiple myeloma.21,23 These patients were excluded from survival analysis to ensure uniformity.
Patients who achieved MRD negativity had a higher likelihood of achieving cardiac response, though no difference was observed in renal response rates in our cohort. This suggests that even low level of light chains produced by residual plasma cells can be cardiotoxic, a finding supported by pre-clinical studies showing that cardiotropic light chains induce oxidative stress and protein remodeling, even in the absence of fibril deposits.25,26 Along the same lines as our findings, Palladini et al. demonstrated that patients who achieved MRD negativity have a higher likelihood of developing future organ response.16 In an update, Milani et al. reported higher organ response rates (90%) in MRD negative patients than historically observed with less deep hematologic responses.27
Although the sample size is small, patients in our study who underwent ASCT as part of first-line therapy had higher MRD negative rates vs. those receiving non-transplant therapy (86% vs. 29%, p=0.005). In the randomized clinical trial of early vs. delayed ASCT in multiple myeloma, patients undergoing ASCT had higher MRD negative rates compared to those receiving chemotherapy alone.28 There were no difference in baseline characteristics of patients who ultimately achieved MRD negativity vs. those who remained MRD positive, except younger age in the MRD negative group a finding likely explained by higher probability of ASCT in younger patients. Even with short follow-up, we observed that MRD negativity is associated with improved PFS in AL amyloidosis. This is concordant with the report from Jimenez-Zepada et al demonstrating a trend towards improved PFS in MRD negative patients with NGF.13
Our study has limitations given the heterogeneity of patients tested and lack of pre-defined time-points for MRD assessment, though the majority were evaluated after first-line therapy. Further, we limited our assessment to patients tested in two years of starting therapy to minimize variation. It is to be noted that this is a highly select patient cohort, with lower cardiac involvement than expected, as patients with advanced cardiac involvement may not have lived long enough to get to a deep response. ASCT is over-represented, likely because it is routine to obtain a bone marrow biopsy post-transplant. This is one of the largest MRD assessment studies with NGF reported to date in AL amyloidosis. Our results can inform future evaluation of MRD assessment in clinical practice and incorporation of MRD endpoints in clinical trials. MRD should be explored as a surrogate endpoint in clinical trials and MRD based risk-adapted trials may help optimize treatment for AL amyloidosis.
In conclusion, MRD negativity measured by NGF in patients with AL amyloidosis is associated with better cardiac response rates and improved PFS, even within a short follow-up. Future studies that evaluate MRD at more uniform time points and in a homogenous cohort are needed to validate these results.
FIGURE 1:
Progression free survival from the time of minimal residual disease (MRD) assessment in patients who were MRD negative vs. MRD positive
ACKNOWLEGMENT (FUNDING SOURCES):
Amyloidosis Foundation
CONFLICT OF INTEREST DISCLOSURE: SS: Honoraria/consultancy: Janssen; AD: Research Funding from Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK; PK: Research Funding from Celgene, Takeda. MQL: Research Funding from Celgene; MAG: Honoraria/consultancy from Ionis, Alnylam, Prothena, Celgene, Janssen, Specytrum, Annexon, Apellis, Amgen, Medscape, Abbvie, Research to Practice, Physcians Education Resource and Teva; SKK: Research Funding and membership on an entity’s Board of Directors or advisory committees: AbbVie, Celgene, Janssen, KITE, Merck. Membership on an entity’s Board of Directors or advisory committees: Oncopeptides, Takeda. Research funding from Novartis and Roche.
Footnotes
Conflicts of interest: All potential conflicts of interest have been disclosed.
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