Impact of bone marrow minimal residual disease status on quality of organ response in systemic <scp>AL</scp> amyloidosis
Authors: Rajshekhar Chakraborty, Madeleine Hopson, Divaya Bhutani, George Vlad, Mathew S. Maurer, Jan M. Griffin, Markus Y. Mapara, Jai Radhakrishnan, Suzanne Lentzsch
Journal: American Journal of Hematology (2022)

The current hematologic response criteria in AL amyloidosis are based on the degree of free light chain (FLC) reduction and disappearance of serum/urine monoclonal protein. Patients achieving a complete response (CR) or very good partial response (VGPR) after treatment have a significantly superior organ response and overall survival than those achieving a partial response (PR) or less. However, not all patients achieving ≥VGPR attain an organ response. In AL amyloidosis, elongation of amyloid fibrils can continue despite a very low concentration of amyloidogenic FLCs. This begs a question whether the presence of minimal residual disease (MRD) in bone marrow after treatment can lead to ongoing production of low-level FLCs promoting end-organ damage. As technologies to perform bone marrow MRD assessment continue to improve, including next-generation MFC and next-generation sequencing (NGS), it has become increasingly important to ascertain the impact of post-treatment MRD status on quality of organ response. The aim of our retrospective cohort study was to investigate the impact of post-treatment MRD status among deep hematologic responders (≥VGPR) on frequency and depth of organ response in heart and kidneys. We included all consecutive patients with AL amyloidosis who were diagnosed or treated at Columbia University until May 2021 and had available data on post-treatment MRD by flow cytometry on bone marrow aspirate within 1.5 years of treatment initiation. All patients were followed until 12/31/2021. The STROBE checklist is provided in Appendix S1. The primary endpoint of the study was incidence of organ response and depth of organ response in heart and kidneys by MRD status. Best hematologic response was adjudicated based on standard criteria, and evaluated any time at or before MRD assessment. Cardiac and renal response was also adjudicated based on standard criteria at the time of MRD assessment and at most recent follow-up. Grading of organ response was performed based on percentage reduction of NT-pro-BNP (for cardiac) or percentage reduction of 24-hour urine protein (for renal). MRD assessment was performed using the EuroFlow™ platform (Cytognos® kit; markers-CD117, CD19, CD38, CD45, CD56, CD81, CD27, CD138, cytoplasmic kappa, and cytoplasmic lambda). A minimum sensitivity of 10−5 was achieved in all patients. A modified version of Major Organ Deterioration-Progression Free Survival (MOD-PFS) was evaluated as an exploratory endpoint, components of which are described in Appendix S2. Two-sided Fisher's exact test was used to test differences between categorical variables. Two-sided Wilcoxon rank sum test was used to compare continuous variables. Survival analysis was done using the Kaplan and Meier method, with differences between survival curves tested for statistical significance by two-sided log-rank test. Statistical analysis was done using JMP Pro 15.0 (SAS Institute Inc., Cary, NC). After screening 136 patients in our database during the study time period, a total of 45 patients in VGPR, low-dFLC-PR, or aCR, who had data on post-treatment MRD status were included (Appendix S3). Among 45 patients, 28 (62%) were MRD-positive and 17 (38%) were MRD-negative. The baseline clinical demographic characteristics of the entire cohort and of MRD-positive and MRD-negative subgroups are shown in Appendix S4. The median age of our study cohort was 66 years (range, 39–78). Daratumumab-based frontline therapy was used in 53% of patients, with the most common regimen being Dara-CyBorD. The median time from treatment initiation to MRD assessment was 7.3 months (range, 1.15–17.98 months). The median number of total nucleated events was 1.26 × 107 (range, 5.42 × 106 to 2.17 × 107). Among MRD-positive patients, the median percentage of clonal plasma cells was 0.0171% (range, 0.0006–0.343), corresponding to a median of 2372 events (range, 130–48 053). The most common hematologic response status at the time of MRD assessment was CR (n = 25; 56%), followed by VGPR (n = 13; 29%), and low-dFLC-PR (n = 7; 16%). At the time of MRD assessment, median dFLC was significantly higher in MRD-positive compared with MRD-negative patients (0.41 [−0.9 to 2.05] vs. −0.05 [−2.47 to 1.59] mg/dl respectively; p = .009). Similarly, there was a trend toward higher median iFLC in MRD-positive compared with MRD-negative patients (1.295 [0.29–5.8] vs. 0.73 [0.21–4.3] mg/dl respectively; p = .16). In patients achieving less than CR, the median duration between assessment of best hematologic response and MRD assessment was 2.04 months (range, 0.07–7.03). Among five MRD-negative patients who were not in CR at the time of MRD assessment, three converted to CR at an interval of 3–10 months thereafter and two remain in VGPR/low-dFLC-PR at 1.5–2 months of follow-up. Among 14 MRD-positive patients who were not in CR at the time of MRD assessment, 10 patients remained in VGPR/low-dFLC-PR at most recent follow-up, 3 converted to CR at an interval of 6–32 months post-MRD assessment, and 1 patient was lost to follow-up. We investigated the association between MRD status and organ response in heart and kidneys both at the time of MRD assessment and at most recent follow-up. The median follow-up in survivors from MRD assessment was 22.5 months (IQR, 4.8–38.0). The organ response rate stratified by MRD status is summarized in Figure 1 and Appendix S5. Among 45 patients with data on MRD assessment, 26 were evaluable for cardiac organ response. At MRD assessment time-point, the incidence of cardiac organ response in MRD-positive and MRD-negative patients was 64% (9/14) and 92% (11/12), respectively (p = .086). The respective proportion of patients achieving a cardiac VGPR or better was 36% (5/14) and 58% (7/12) (p = .25). At most recent follow-up after MRD assessment, the incidence of cardiac organ response in MRD-positive patients was 71% (10/14) and that in MRD-negative patients was 92% (11/12) (p = .18). The incidence of cardiac VGPR or better in MRD-positive and MRD-negative patients at most recent follow-up was 57% (8/14) and 75% (9/12), respectively (p = .34). The median time from treatment initiation to best cardiac response was 13.7 months (IQR, 8.2–40.8 mo.), with the duration being 13.5 mo. (IQR, 7.8–32.1) in MRD-positive and 13.2 mo. (IQR, 6.9–33.1) in MRD-negative patients. A total of 24 patients were evaluable for renal response. The renal organ response rate at the time of MRD assessment in MRD-positive and MRD-negative patients was 50% (7/14) and 60% (6/10), respectively (p = .63), with the respective renal ≥VGPR rates being 43% (6/14) and 40% 4/10) (p = .89). At most recent follow-up, the renal organ response rate in MRD-positive and MRD-negative patients was 79% (11/14) and 60% (6/10), respectively (p = .33), with the respective renal ≥VGPR rates being 71% (10/14) and 44% (4/9) (p = .196). The median time to best renal response was 18.3 mo. (IQR, 6.6–34.1), with the median duration being 23.0 mo. (IQR, 5.7–42.2) in MRD-positive and 19.9 mo. (IQR, 12.6–31.1) in MRD-negative patients. A total of 9 mMOD-PFS events were observed among 44 evaluable patients. The most common mMOD-PFS event was initiation of a subsequent line of therapy (n = 6), followed by one event each for kidney transplant, IABP placement, and death. The median time to mMOD-PFS for MRD-negative and MRD-positive patients was Not Reached (NR) (95% CI, NR-NR) versus 55 months (95% CI, 18.5-NR), respectively (p = .28). The Kaplan–Meier curve for mMOD-PFS by MRD status is shown in Appendix S4. Two patients have died after MRD assessment thus far, one in each group. To put our results in perspective, Appendix S7 highlights the findings from key publications on bone marrow MRD in AL amyloidosis and impact on clinical outcomes.1-6 We showed that there was a trend toward increased frequency and depth of cardiac organ response in MRD-negative patients, both at the time of MRD assessment and latest follow-up. Notably, in MRD-positive patients, cardiac response rate increased from 64% to 71% and cardiac ≥VGPR rate increased from 36% to 57% between MRD assessment time-point and latest follow-up. The study from Mayo group by Sidana et al. had also demonstrated that the difference in cardiac response rate between MRD-positive and MRD-negative patients at the time of MRD assessment dissipated at 1-year follow-up2. Another study on NGS-based MRD at a median of 15 months from treatment initiation has shown 60% of MRD-positive patients to have a cardiac response.4 There are conflicting data on the impact of MRD status on renal organ response. Using high sensitivity MRD (≥10−5), only one study has shown significantly higher renal response rate in MRD-negative compared with MRD-positive patients.6 On the other hand, the study by the Greek group5 and Mayo group2 did not show any difference in renal response rate by MRD status, which is in line with our findings. We showed that renal response rate in MRD-positive patients increased from 50% to 79% and renal ≥VGPR rate increased from 43% to 71% between MRD assessment and latest follow-up. Our study has several limitations, including a small sample size, retrospective design, short follow-up, and only 53% receiving daratumumab-based therapy. In summary, cumulative data on cardiac and renal response in our study imply that lack of organ response in MRD-positive patients at end-of-treatment should not routinely indicate treatment switch or intensification, especially if hematologic CR is achieved. Spontaneous response upgrade can be seen in a substantial proportion of patients at follow-up. RCTs are needed to determine whether treatment directed toward the goal of MRD eradication will improve clinical outcomes in this population. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Appendix S1 Definition of modified Major Organ Deterioration-Progression Free Survival (mMOD-PFS) used in this study: Appendix S2 Definition of modified Major Organ Deterioration-Progression Free Survival (mMOD-PFS) used in this study: Appendix S3 Baseline Clinical and Demographic Characteristics of the Study Cohort Appendix S4 Kaplan–Meier curve showing modified Major Organ Deterioration-Progression Free Survival (mMOD-PFS) stratified by MRD status. Appendix S5 Organ Response by Minimal Residual Disease Status Appendix S6 Summary of Findings from Key Studies on Bone Marrow Minimal Residual Disease Assessment in AL Amyloidosis Appendix S7 Summary of Findings from Key Studies on Bone Marrow Minimal Residual Disease Assessment in AL Amyloidosis Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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