Abstract
Introduction:
Little is known on continued response following completion of therapy in light chain (AL) amyloidosis.
Methods:
We studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first-line therapy.
Results:
By end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10-year OS 87% vs 71% vs 56%, P < .001).
Conclusions:
This study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.
Keywords: autologous stem cell transplant, immunoparesis, off-therapy, survival
1 |. INTRODUCTION
Response assessment in light chain (AL) amyloidosis is primarily based on the serum-free light chain assay. This test measures the circulating free light chain, which are responsible for amyloid deposition. Since the test cannot differentiate between clonal and polyclonal free light chains, the difference between involved and uninvolved light chains (dFLC) is the widely accepted response measurement.1 When complete response (CR) is suspected, the absence of monoclonal protein on serum and urine protein electrophoresis/immunofixation (PEL/IFE) along with normal serum-free light chain ratio defines amyloid complete response.1 Response in AL amyloidosis should be rapid to allow improvement in survival.2 This is reflected in the consensus hematological response criteria which were validated at 3 and 6 months from treatment initiation.1 However, response is a dynamic process and may improve with time, occasionally off-therapy. Little is known on off-therapy response improvement in AL amyloidosis.
2 |. METHODS
Newly diagnosed AL amyloidosis patients seen within 90 days of diagnosis between September 2001 and August 2015 who achieved very good partial response (VGPR) or CR to first-line therapy and had regular follow-up at our institution were included in this study. The Mayo Foundation Institutional Review Board (IRB) approved the study. All patients gave written informed consent to have their medical records reviewed according to IRB requirements and Minnesota state law.
All patients were assessed for response at end of therapy (EOT). EOT was considered the time after which no further therapy was given. Day + 100 from autologous stem cell transplant (ASCT) was considered the EOT for ASCT. Immunoparesis was assessed qualitatively as number of suppressed uninvolved immunoglobulins and quantitatively as the average difference of the uninvolved immunoglobulins from their respective lower limit of normal, as previously described.3 Organ response was assessed using current consensus criteria for heart,1 kidney,4 and liver5 as well as using proposed graded organ response.6 The chi-square test and Fisher’s exact test were used to compare differences between continuous variables, and the Wilcoxon signed-rank test was used for non--parametric group comparisons. Survival analysis was done using the Kaplan-Meier method. Progression-free survival (PFS) was defined as the time from diagnosis until hematological progression or death, where patients known to be alive and progression-free at the end of follow-up were censored. Hematological progression was defined according to consensus criteria7 or upon initiation of second line therapy, whichever came first.
3 |. RESULTS
The baseline characteristics of the 373 patients included in this analysis are summarized in Table 1. The median age was 59, and 59% of patients were male. The kidneys and the heart were the most prevalent involved organs, seen in 70% and 56% of patients, respectively.
TABLE 1.
Baseline characteristics of the study cohort
| Entire cohort |
CR by EOT |
VGPR by EOT |
Delayed CR |
P for the entire cohort | P for CR at EOT vs delayed CR | |
|---|---|---|---|---|---|---|
| Characteristic | N = 373 | N = 172 | N = 136 | N = 65 | ||
| Age (y), median (IQR) | 59 (53–66) | 59 (53–65) | 61 (54–68) | 58 (51–62) | .01 | .13 |
| Male sex, N (%) | 220 (59%) | 95 (55%) | 87 (64%) | 38 (58%) | .29 | .65 |
| Involved organs, N (%) | ||||||
| Renal | 260 (70%) | 115 (67%) | 102 (75%) | 43 (66%) | .23 | .91 |
| Cardiac | 210 (56%) | 100 (58%) | 74 (54%) | 36 (55%) | .79 | .7 |
| Nerve | 56 (15%) | 19 (11%) | 27 (20%) | 10 (15%) | .09 | .37 |
| Hepatic | 55 (15%) | 31 (18%) | 15 (11%) | 9 (14%) | .21 | .43 |
| Gastrointestinal | 49 (13%) | 20 (12%) | 17 (13%) | 12 (18%) | .39 | .18 |
| >1 organ | 219 (59%) | 99 (58%) | 84 (62%) | 36 (55%) | .58 | .76 |
| Lambda restricted, N (%) | 283 (76%) | 132 (77%) | 107 (79%) | 44 (68%) | .23 | .16 |
| Heavy chain isotype | ||||||
| IgG | 114 (30%) | 28 (16%) | 62 (46%) | 24 (37%) | <.001 | .003 |
| IgA | 44 (12%) | 21 (12%) | 21 (15%) | 2 (3%) | ||
| IgM/IgD | 11 (3%) | 2 (1.5%) | 8 (6%) | 1 (2%) | ||
| Light chain only | 204 (55%) | 121 (70.5%) | 45 (33%) | 38 (58%) | ||
| Number of suppressed uninvolved immunoglobulins, % | ||||||
| 0 | 33% | 32% | 31% | 35% | .62 | .43 |
| 1 | 41% | 43% | 35% | 41% | ||
| >1 | 26% | 25% | 34% | 24% | ||
| Deep immunoparesisa , % | 28% | 22% | 32% | 37% | .04 | .02 |
| BMPCs, % median (IQR) | 8 (5–11) | 7 (5–10) | 9 (5–14) | 6 (5–10) | .14 | .41 |
| dFLC, mg/L, median (IQR) | 130 (65–410) | 140 (80–410) | 120 (50–330) | 160 (70–490) | .19 | .73 |
| 2004 Mayo AL amyloidosis stage, % I/II/IIIA/IIIB | 34/43/19/4 | 32/39/24/5 | 34.5/46.5/16/3 | 38/45/15/2 | .46 | .29 |
| 2012 Mayo AL amyloidosis stage, % I/II/III/IV | 40/27/19/14 | 35/26/23/16 | 47/25/16/12 | 41/33/16/10 | .3 | .32 |
| First line treatment | ||||||
| ASCT | 241 (65%) | 101 (59%) | 85 (62%) | 55 (85%) | .002 | .001 |
| MDex | 81 (21.5%) | 40 (23%) | 33 (24%) | 8 (12%) | ||
| Bortezomib-based | 37 (10%) | 25 (14%) | 10 (7%) | 2 (3%) | ||
| IMiD-based | 8 (2%) | 3 (2%) | 5 (4%) | 0 | ||
| MP/dexamethasone alone | 6 (1.5%) | 3 (2%) | 3 (3%) | 0 | ||
Abbreviations: AL, light chain amyloidosis; ASCT, autologous stem cell transplantation; BMPCs, bone marrow plasma cells; CR, complete response; dFLC, difference between involved and uninvolved light chains; EOT, end of therapy; IMiD, immunomodulatory drug; IQR, interquartile range; MDex, melphalan-dexamethasone; MP, melphalan-prednisone; VGPR, very good partial response.
Depth of immunoparesis was calculated based on average relative difference of the uninvolved immunoglobulins from their respective lower limit of normal. Negative average is considered to represent a deep immunoparesis.
Bold entries indicate statistical significance at <.05
By EOT, 46% of the cohort (n = 172) achieved a complete response, while 54% (n = 201) achieved VGPR. The median EOT iFLC and dFLC were 17 and 5 mg/L, respectively. During follow-up and with no further therapy, 65 patients (17.5%) were upstaged from VGPR to CR (delayed CR group), which resulted in best response CR rate of 64% (n = 237). The baseline characteristics of patients in the three response groups (CR by EOT, VGPR by EOT, and delayed CR) were balanced with a several exceptions (Tables 1 and 2). The delayed CR group was enriched with patients who received ASCT (59% vs 62% and 85%, respectively, P < .001), while the CR at EOT group was more likely to have light chain-only disease (70.5% vs 33% and 58%, P < .001). There was no difference in the number of suppressed uninvolved immunoglobulin between groups. However, patients with a delayed CR had a higher likelihood of having deep immunoparesis (defined as negative value of the average deviation from of the uninvolved immunoglobulins from their lower limit of normal; Table 1).
TABLE 2.
FISH findings in the entire study cohort and by hematological response group
| Entire cohort |
CR by EOT |
VGPR by EOT |
Delayed CR |
P for the entire cohort | P for CR at EOT vs delayed CR | |
|---|---|---|---|---|---|---|
| FISH probe | N = 215 | N = 97 | N = 77 | N = 41 | ||
| t(11;14) | 47% | 48% | 38% | 61% | .05 | .16 |
| Del13q/−13 | 36% | 42% | 29% | 37% | .17 | .53 |
| Trisomies | 25% | 26% | 31% | 10% | .02 | .02 |
| High-risk FISH | 12% | 15% | 11% | 10% | .65 | .49 |
Abbreviations: CR, complete response; EOT, end of therapy; FISH, fluorescence in situ hybridization; VGPR, very good partial response.
Fluorescence in-situ hybridization (FISH) data were available for 58% of patients (n = 215). The distribution of the major FISH aberrations is provided in Table 2. Patients with a delayed CR were more likely to harbor t(11;14) compared to those with CR or VGPR at EOT (61% vs 48% vs 38%; P = .05). Conversely, they were less likely to have trisomies compared with their counterparts (10% vs 26% vs 31%; P = .02).
When adjusted to ASCT status, no difference in duration of therapy was noted between the three response groups. Improvement in response occurred due to normalization of sFLCR in 54% of patients (n = 35), immunofixation negativity conversion in 34% of patients (n = 22) and both sFLCR normalization and immunofixation conversion in 12% patients (n = 8). Of note, of the 43 patients with abnormal sFLC ratio at EOT who later had sFLCR normalization, the sFLCR was abnormally skewed toward the involved light chain in 79% of these patients. The median time from EOT response assessment to CR conversion was 9 months (IQR 6–17), similar for those with immunofixation negative conversion and those with serum FLC ratio normalization (median 10 vs 9 months, respectively, P = .1). IgG isotype was more prevalent in those with conversion to immunofixation negativity (43% vs 29%), but statistical significance was not reached (P = .17). Patients with sFLCR normalization, on the other hand, were more likely to have light chain-only isotype (65% vs 53%, P = .06). In the delayed CR group, the change in quantitative free light chains between EOT and CR conversion was minimal; the best responseCR conversion iFLC and dFLC values were 15 and 5 mg/L, respectively, corresponding to a median change in iFLC from EOT to best response of −2 (IQR −8 to +3) mg/L and a median change in dFLC of +2 (IQR −3 to +8) mg/L.
A flow cytometry-based assay for minimal residual disease (MRD) assessment from a marrow sample at EOT was available for 250 patients (98%), of which 76% of patients had low sensitivity MRD assay (sensitivity 10−3 to 3 × 10−4) and 24% of patients had high-sensitivity MRD assay (sensitivity 1 × 10−4 to 2 × 10−5). Of the patients who attained CR at EOT, 78% were MRD-negative and a similar proportion of MRD negativity was noted for those who attained a delayed CR (81%). In contrast, patients with VGPR at EOT had the lowest MRD negativity rate (41%, P < .001).
Organ response was evaluable for heart, kidney, and liver in 344 patients (92% of study cohort; cardiac evaluable n = 191; renal evaluable n = 235; hepatic evaluable n = 49). Of these patients, 81% achieved organ response in at least one organ. The overall organ response rate was similar between patients with a delayed CR and patients who achieved CR at EOT, with lower organ response rates in patients who achieved VGPR by EOT (92% vs 85% vs 70%, respectively; P < .001; P = .18 for the comparison between delayed CR and CR at EOT). For organ response by organ, a comparable organ response rate was seen between the delayed CR and CR at EOT groups (Figure 1).
FIGURE 1.
Overall organ response stratified by the hematological response groups and assessed organs
As for depth of organ response based on previously proposed graded organ response criteria, deeper cardiac response was noted in both CR groups than VGPR at EOT (P = .004; Figure 2A), with no difference in depth of response between the two CR groups (P = .35). Renal CR rate was significantly higher in the delayed CR and CR at EOT groups than VGPR at EOT (P = .007; Figure 2B), with similar depth of renal response between the former groups (P = .79). Hepatic responses were deeper among the delayed CR group compared with CR at EOT and VGPR at EOT groups (P = .001/P = .02 for the comparison between delayed CR and CR at EOT; Figure 2C).
FIGURE 2.
Graded organ response stratified by the hematological response groups. A, Cardiac response. B, Renal response. C, Hepatic response
Time to maximal cardiac response was longer among the delayed CR group compared with the CR and VGPR at EOT groups (36 vs 29 vs 24 months, P = .12). Time to maximal renal response was significantly longer among the delayed CR group compared with CR and VGPR at EOT (61 vs 34 vs 27 months; P < .001). Time to maximal hepatic response was longer among the delayed CR group but statistical significance was not reached (59 vs 38 vs 23 months, P = .52). Cardiac progression rate was similar between groups (23% for delayed CR, 39% for CR at EOT and 40% for VGPR at EOT; P = .24), while renal progression was far less common among the delayed CR group (21% vs 41% vs 48%; P = .01). One hepatic progression was documented in a patient with a VGPR at EOT.
The median follow-up among survivors was longer for patients with a delayed CR compared with CR at EOT and VGPR at EOT (145 vs 115 vs 101 months, respectively; P = .01). Patients who had a delayed CR had a longer PFS compared with those who achieved CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; Figure 3A). As groups were unbalanced with respect to ASCT, we assessed PFS based on response category in the subset of patients receiving ASCT, which showed a similar pattern (median PFS 159 vs 130 vs 54 months, P < .001; Figure 3B), but with a less pronounced difference in PFS between the delayed CR to CR by EOT (P = .21). Similarly, OS was longer among those who had delayed CR compared with their respective counterparts (10-year OS 87% vs 71% vs 56%, P < .001; Figure 3C). This advantage was significant among ASCT-only patients as a whole (10-year OS 91% vs 85% vs 63%, P < .001; Figure 1D), but not statistically different between delayed CR to CR by EOT (P = .17). Among the subset of delayed CR group, no difference in PFS or OS was seen when considering improved response due to sFLC normalization or immunofixation negative conversion (P = .65 and P = .94 for PFS and OS, respectively).
FIGURE 3.
Kaplan-Meier curves of survival based on level of response. A, Progression-free survival (PFS) in the whole cohort. B, PFS in the ASCT sub-group. C, Overall survival (OS) in the whole cohort. D, OS in the ASCT sub-group
4 |. DISCUSSION
In this study, the first to assess delayed CR response in AL amyloidosis, 17.5% of the study population enjoyed improvement in response from VGPR to CR in a median of 9 months from EOT. This is a similar lag time reported in a study among multiple myeloma patients undergoing ASCT and were then observed off-therapy.8 In that study, continued off-therapy response after ASCT translated into longer time to next therapy, PFS and OS compared to those with no continued response. This improvement in response category may be seen due to slow clearance of the associated heavy chain and/or gradual immune recovery resulting in normalization of the serum-free light chain ratio. Indeed, in our patient population, IgG isotype was more common among those patients with immunofixation negativity conversion, correlating with a longer half-life of this isotype. Moreover, the percentage of MRD negativity at EOT was similar between the CR at EOT and the delayed CR groups, supporting that both groups have reached a similar level of hematological response, despite discrepancies in serological response at EOT. Therapy-related immunoparesis may result in skewed sFLCR for a long period of time and will impact serological response evaluation. It is probably one of the reasons why off-therapy response improvement was mostly seen in ASCT population and was driven by normalization of sFLCR in two third of the patients in whom response improved. We would anticipate similar kinetics with the use of daratumumab,9–11 which results in substantial immunoparesis and impacts response evaluation using sFLCR, as already been recognized, despite normal iFLC.10,11
The delayed CR group exhibits unique clonal characteristics compared with the CR and VGPR at EOT groups, with higher t(11;14) frequency, lower trisomies frequency, and higher proportion of deep baseline immunoparesis. This may indicate that it is not only the monoclonal protein kinetics that impact the achievement of CR but rather a slow and not yet well-defined process of immune reconstitution favoring long-term disease control in the delayed CR group, as was demonstrated in multiple myeloma.12,13 This immune reconstitution was mainly observed among patients who undergo ASCT, a therapy which is more likely to produce “immune reset” and may explain the dominance of ASCT on the delayed CR group. Albeit overall similar outcomes between the two CR groups, it may well be that analysis was underpowered to demonstrate differences in outcomes between the delayed CR and CR at EOT groups.
The achievement of CR is the desired hematological treatment goal as it is associated with better outcomes compared with lower level of response.1 The hematological response should also be as rapid as possible to allow higher chances of organ recovery and a longer survival. However, as shown in this study, CR may still not be achieved at EOT by the conventional definition, but outcome remains favorable if CR is eventually achieved in a delayed fashion. We and others recently re-assessed the definition of the conventional hematological CR definition.14–16 In these studies, both the immunofixation component of the CR definition as well as its light chain component (whether quantitative measure or the light chain ratio) were found to be important from survival standpoint.14–16 However, the quantitative light chain component (expressed as iFLC < 20 mg/L or dFLC < 10 mg/L) directly impacts the organ dysfunction and arguably needs to be achieved early to positively affect survival. This is particularly important in patients with advanced cardiac involvement, an under-represented patient population in this study. On the other hand, immunofixation negativity component of the CR definition represents more the clonal control and can be delayed, due to technical limitations of the response assessment tools or due to gradual response improvement. Indeed, in patients with a delayed CR, the change in the quantitative light chains between EOT and the eventual achievement of CR was minimal, suggesting that survival advantage in the delayed CR group was not due further reduction in the quantitative light chains. Therefore, we suggest that the pursuit of hematological CR should initially focus on light chain response, acknowledging that delayed CR may follow, especially if marrow MRD negativity has been achieved. The decision on using consolidation and/or maintenance after successful therapy remains an answered question. However, physicians caring for AL amyloidosis patients should acknowledge the limitations inherent to the conventional response assessment in AL amyloidosis when choosing to pursue further therapy.
This study highlights another challenge in response assessment in AL amyloidosis, as a result of disease heterogeneity, typical low tumor burden, and limitations of the current response assessment tools. Future research should focus better ways to assess hematological response, such as immunoglobulin-free light chain assay capable of measuring the clonal free light chain component, MASS-FIX-based techniques,17 and marrow MRD assessment.8,18–22 Alternatively, better ways to predict delayed CR among deep responders, using baseline immunologic, or genetic profiling and at EOT should also be explored. This may provide better ways to optimize therapy in a patient population that largely has a poor treatment tolerance.
We acknowledge that this study limitations including its retrospective nature, the disproportional ASCT population, and the selection bias toward patients who achieved deep response to therapy. Despite these limitations, achievement of delayed CR without additional therapy is a novel and important observation in AL amyloidosis. Delayed CR is characterized by distinct immunogenic and genomic profile. Patients with a delayed CR have at least as favorable outcomes as those who achieved CR at EOT. We suggest that off-therapy response improvement should be further explored in order to improve our response assessment tools and tailored therapy approaches.
Novelty statements:
We have demonstrated that nearly a fifth of our patient population who achieved a deep response to initial therapy were upstaged from a very good partial response to a complete response (CR) while being monitored off-therapy. The median time from completion of therapy (EOT) to a delayed CR was 9 months. Patients with a delayed CR exhibited at least similar or better outcomes compared with those who achieved CR at EOT and were better than those achieving VGPR at EOT with no change in their response level.
ACKNOWLEDGEMENTS
The study was supported in part by the Jabbs Foundation (Birmingham, United Kingdom), the Henry J. Predolin Foundation (USA), and National Institutes of Health National Cancer Institute grant P50 CA186781.
Funding information
Jabbs Foundation; Henry J. Predolin Foundation; National Institutes of Health National Cancer Institute, Grant/Award
Footnotes
DATA AVAILABILITY STATEMENT
Data available from the corresponding author on reasonable request.
CONFLICT OF INTEREST
Morie A. Gertz received consultancy from Millennium and honoraria from Celgene, Millennium, Onyx, Novartis, Smith Kline, Prothena, and Ionis. Shaji Kumar received consultancy from Celgene, Millennium, Onyx, Janssen, and BMS; and research funding from Celgene, Millennium, Novartis, Onyx AbbVie, Janssen, and BMS. Martha Q. Lacy received research funding from Celgene; David Dingli received research funding from Karyopharm Therapeutics, Amgen, and Millennium Pharmaceuticals; Prashant Kapoor received research funding from Takeda, Celgene, and Amgen; Angela Dispenzieri received research funding from Celgene, Millennium, Pfizer, and Alnylam, travel grant from Pfizer, and advisory board from Janssen. Eli Muchtar, Nelson Leung, Francis Buadi, Suzanne R. Hayman, Ronald S. Go, Wilson Gonsalves, Taxiarchis v. Kourelis, Rahma Warsame, Yi Lisa Hwa, Amie Fonder, Miriam Hobbs, Stephen Russel, John A. Lust, Mustaqueem Siddiqui, Vincent Rajkumar, and Robert A. Kyle have no conflict of interest.
REFERENCES
- 1.Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;30(36):4541–4549. [DOI] [PubMed] [Google Scholar]
- 2.Merlini G, Dispenzieri A, Sanchorawala V, et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers. 2018;4(1):38. [DOI] [PubMed] [Google Scholar]
- 3.Muchtar E, Dispenzieri A, Kumar SK, et al. Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival. Leukemia. 2017;31(1):92–99. [DOI] [PubMed] [Google Scholar]
- 4.Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325–2332. [DOI] [PubMed] [Google Scholar]
- 5.Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol. 2005;79(4):319–328. [DOI] [PubMed] [Google Scholar]
- 6.Muchtar E, Dispenzieri A, Leung N, et al. Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria. Leukemia. 2018;32(10):2240–2249. [DOI] [PubMed] [Google Scholar]
- 7.Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317–2325. [DOI] [PubMed] [Google Scholar]
- 8.Gonsalves WI, Gertz MA, Dispenzieri A, et al. Implications of continued response after autologous stem cell transplantation for multiple myeloma. Blood. 2013;122(10):1746–1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Abeykoon JP, Zanwar S, Dispenzieri A, et al. Daratumumabbased therapy in patients with heavily-pretreated AL amyloidosis. Leukemia. 2019;33(2):531–536. [DOI] [PubMed] [Google Scholar]
- 10.Roussel M, Merlini G, Chevret S, et al. A prospective phase II of daratumumab in previously treated systemic light chain amyloidosis (AL) patients. Blood. 2020;135(18):1531–1540. [DOI] [PubMed] [Google Scholar]
- 11.Sanchorawala V, Sarosiek S, Schulman A, et al. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase II study. Blood. 2020;135(18):1541–1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Arteche-Lopez A, Kreutzman A, Alegre A, et al. Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication. Bone Marrow Transplant. 2017;52(6):832–838. [DOI] [PubMed] [Google Scholar]
- 13.Gonzalez-Calle V, Cerda S, Labrador J, et al. Recovery of polyclonal immunoglobulins one year after autologous stem cell transplantation as a long-term predictor marker of progression and survival in multiple myeloma. Haematologica. 2017;102(5):922–931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Milani P, Basset M, Nuvolone M, et al. Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy. Blood Cancer J. 2020;10(8):90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Muchtar E, Gertz MA, Lacy MQ, et al. Refining amyloid complete hematological response: quantitative serum free light chains superior to ratio. Am J Hematol. 2020;95(11):1280–1287. [DOI] [PubMed] [Google Scholar]
- 16.Sarosiek S, Zheng L, Sloan JM, Quillen K, Brauneis D, Sanchorawala V. Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis. Blood Cancer J. 2020;10(8):88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Mills JR, Kohlhagen MC, Dasari S, et al. Comprehensive assessment of M-proteins using nanobody enrichment coupled to MALDI-TOF mass spectrometry. Clin Chem. 2016;62(10):1334–1344. [DOI] [PubMed] [Google Scholar]
- 18.Kastritis E, Kostopoulos IV, Theodorakakou F, et al. Next generation flow cytometry for MRD detection in patients with AL amyloidosis. Amyloid. 2020;1–5. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
- 19.Muchtar E, Dispenzieri A, Leung N, et al. Optimizing deep response assessment for AL amyloidosis using involved free light chain level at end of therapy: failure of the serum free light chain ratio. Leukemia. 2019;33(2):527–531. [DOI] [PubMed] [Google Scholar]
- 20.Muchtar E, Jevremovic D, Dispenzieri A, et al. The prognostic value of multiparametric flow cytometry in AL amyloidosis at diagnosis and at the end of first-line treatment. Blood. 2017;129(1):82–87. [DOI] [PubMed] [Google Scholar]
- 21.Sidana S, Muchtar E, Sidiqi MH, et al. Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis. Am J Hematol. 2020;95(5):497–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sidiqi MH, Aljama MA, Jevremovic D, et al. Prognostic significance of stringent complete response after stem cell transplantation in immunoglobulin light chain amyloidosis. Biol Blood Marrow Transplant. 2018;24(11):2360–2364. [DOI] [PMC free article] [PubMed] [Google Scholar]