Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Predict Treatment Outcomes.

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses following HDM/SCT and other forms of treatment. The standard definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of a persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic responses according to reductions in free light chain (FLC) measurements. Treatment responses as defined by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a prospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which early FLC responses within weeks of treatment predict hematologic CR, as defined by our standard criteria. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 31 patients with AL amyloidosis, between 2003–2005, 1–3 weeks after treatment with HDM/SCT. Hematologic responses, as defined by standard criteria, as well as FLC responses were subsequently determined at 3, 6 and 12 months. Serum FLC levels or κ/λ FLC ratios were abnormal and informative in 28 patients (90%) prior to HDM/SCT, and these patients were included in subsequent analyses. Twenty patients (71%) achieved normalization of abnormal serum FLC levels or ratios within 1–3 weeks of undergoing HDM/SCT. Of these 20 patients, 13 patients (65%) subsequently achieved a hematologic CR as defined by standard criteria, while 7 (35%) did not, within 3 months following HDM/SCT. In contrast, none of the 8 patients with no demonstrable FLC response within 1–3 weeks of HDM/SCT, were found to have achieved a hematologic CR subsequently. In conclusion, meaningful quantitative FLC responses (or lack of response) can be detected within weeks following HDM/SCT treatment that predict hematologic responses, as defined subsequently by standard criteria based on IFE and marrow studies (p=0.0018 by chi square analysis). Moreover, a lack of an early FLC response predicts for hematologic non-CR. We anticipate that prospective studies of FLC responses in HDM/SCT and other clinical trials for AL amyloidosis will eventually lead to more rapid assessment of treatment responses that will guide therapeutic decisions.

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Early serum free light chain response after high-dose melphalan and stem cell transplantation predicts hematologic response in AL amyloidosis

Bone Marrow Transplantation ◽

10.1038/s41409-021-01535-z ◽

2021 ◽

Author(s):

Vanessa Fiorini Furtado ◽

Dina Brauneis ◽

Janice Weinberg ◽

Noon Elhassan ◽

J. Mark Sloan ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Light Chain ◽

Free Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free ◽

Serum Free Light Chain ◽

High Dose Melphalan

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Serum Free Light Chain Responses after High-Dose Intravenous Melphalan and Autologous Stem Cell Transplantation for AL (Primary) Amyloidosis.

Blood ◽

10.1182/blood.v104.11.942.942 ◽

2004 ◽

Vol 104 (11) ◽

pp. 942-942

Author(s):

Vaishali Sanchorawala ◽

Daniel G. Wright ◽

Barbarajean Magnani ◽

Martha Skinner ◽

David C. Seldin

Keyword(s):

Stem Cell ◽

Plasma Cell ◽

Light Chain ◽

Free Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Serum Free ◽

Hematologic Response ◽

Serum Free Light Chain

Abstract AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. Several approaches have been used to define hematologic responses of plasma cell dyscrasias underlying AL amyloidosis following HDM/SCT and other forms of treatment. The definition of a hematologic complete response (CR) that we have used requires that there be no evidence of a persistent monoclonal gammopathy by immunofixation electrophoresis (IFE) of serum and urine proteins, or of persistent plasmacytosis or plasma cell clonality in a bone marrow biopsy by immunohistochemistry. Others have defined hematologic response as a ≥ 50% reduction in free light chain (FLC) measurements. Hematologic responses by both criteria correlate with survival and clinical improvement following HDM/SCT. We have carried out a retrospective analysis of HDM/SCT treatment outcomes for patients with AL amyloidosis to determine the extent to which hematologic CR, by our standard criteria, correlates with FLC response. Serum free light chain concentrations (FLC) were measured by a sensitive nephelometric immunoassay in 67 patients with AL amyloidosis before and after treatment with HDM/SCT. After treatment with HDM/SCT, 27 patients (40%) achieved a CR by standard criteria. Of these 27 patients, 63% (n=17) demonstrated normalization of FLC levels and an improvement of ≥50% in FLC occurred in 100%. Of the 40 patients who did not achieve a CR, 25% (n=10) experienced normalization of FLC levels, and an improvement of ≥50% occurred in 78% (n=31), while only 5 patients (13%) experienced no significant change in FLC. The average improvement in FLC was 94% for patients who achieved a CR by standard criteria and 72% for those who did not (p=0.0001, t-test). Thus, HDM/SCT was found to induce improvements in FLC levels of ≥50% in the vast majority of AL amyloidosis patients treated with HDM/SCT (87%, or 58/67). These data indicate that a decrease in FLC of ≥50% is a substantially less stringent indicator of hematologic response than is CR, as defined by standard criteria. Nonetheless, these measures of hematologic response are complementary, since decreases in FLC can be detected earlier following treatment than changes in IFE and marrow studies required to determine CR.

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Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis.

Blood ◽

10.1182/blood.v114.22.4352.4352 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4352-4352

Author(s):

Saulius Girnius ◽

Frank Tsai ◽

David C. Seldin ◽

Karen Quillen ◽

Lisa Yanarella ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Light Chain ◽

Predictive Value ◽

Complete Response ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free ◽

Serum Free Light Chain ◽

High Dose Melphalan

Abstract Abstract 4352 AL amyloidosis is a clonal plasma cell dyscrasia which produces insoluble amyloid fibrils from Ig light chains, leading to multiorgan failure. High dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce remission and extend survival, but response is assessed at 6 and 12 months. Serum free light chain (FLC) assays can improve detection of AL amyloidosis, have prognostic significance, and are routinely used to assess response to treatment. Serum half life of FLCs is only 2-6 hours, even with diminished glomerular filtration rates. In a small prospective series, we previously reported that FLC levels 1-3 weeks after HDM/SCT correlate with hematologic response at 1 year. This study was performed to confirm these results on a larger scale. A prospective analysis of patients with AL amyloidosis treated with HDM/SCT was performed to determine the extent to which early FLC responses predict hematologic complete response (CR). Exclusion criteria included initial normal FLC concentrations and ratios and chronic renal insufficiency (Cr>1.2 mg/dL) with a normal FLC ratio. Hematologic responses, as defined by standard traditional criteria, were determined at 6 and 12 months. Traditional criteria define hematologic CR as by normalization of bone marrow exam and absence of monoclonal gammopathy in urine and serum by immunofixation electrophoreses. Serum FLC concentrations were measured by a sensitive nephelometric analysis within 10 days and within 3 weeks of HDM/SCT. Complete response for serum FLC was defined as normalization of FLC concentration and ratio or normalization of the ratio in renal failure (Cr>1.2 mg/dL). Serum FLC levels or k/l FLC ratios were abnormal and informative in 124 patients (87%) prior to HDM/SCT, and these patients were included in subsequent analyses. One week after transplant, sensitivity of FLC to predict hematologic CR was 0.64, specificity was 0.67, positive predictive value (PPV) was 0.49, negative predictive value (NPV) was 0.79, positive likelihood ratio (LR) was 1.92, and negative LR was 0.54. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.36, specificity was 0.86, PPV was 0.54, NPV was 0.75, positive LR was 2.59, and negative LR was 0.74. Two to three weeks after transplant, sensitivity of FLC CR to predict hematologic CR was 0.72, specificity was 0.74, PPV was 0.57, NPV was 0.85, positive LR was 2.78, and negative LR was 0.38. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.34, specificity was 0.86, PPV was 0.52, NPV was 0.74, positive LR was 2.40, and negative LR was 0.77. Serum FLC concentrations within 3 weeks of HDM/SCT have poor predictive values and should not be used to predict hematologic CR. However, failure to reduce FLC concentrations by 90% has a somewhat higher negative predictive value and could be used to guide additional post-transplant management. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib and High Dose Melphalan Followed by Autologous Stem Cell Transplantation (BortHDM/SCT) for the Treatment of AL Amyloidosis: Results of a Feasibility Study.

Blood ◽

10.1182/blood.v114.22.4353.4353 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4353-4353 ◽

Cited By ~ 1

Author(s):

Vaishali Sanchorawala ◽

Lisa Yanarella ◽

Karen Quillen ◽

John Mark Sloan ◽

Nancy T. Andrea ◽

...

Keyword(s):

Stem Cell ◽

Clinical Improvement ◽

Light Chain ◽

Free Light Chain ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free ◽

Serum Free Light Chain

Abstract Abstract 4353 AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. Furthermore, we have observed in ∼ 500 patients treated with HDM/SCT that achievement of a hematologic complete response (CR), i.e. disappearance of monoclonal gammopathy, normalization of serum free light chain ratio and clonal plasma cell dyscrasia, is a critical determinant of clinical improvement and prolonged survival. Bortezomib (Bor) has been reported to have activity in patients with AL amyloidosis. Furthermore, a synergistic effect between bortezomib and melphalan has been demonstrated in vitro and in vivo. Thus, the combination of bortezomib and HDM is a logical approach to study. Because of the importance of hematologic CR in treatment outcome, we conducted a feasibility study to determine whether addition of bort to HDM/SCT would be tolerable and would increase hematologic CR rates. Additional objectives of the study were to determine overall survival. Eligibility for entry into the trial required diagnosis of AL amyloidosis, age > 18 years, and adequate performance status (SWOG ≤ 2) and cardiopulmonary function (LVEF > 45%, DLCO > 50%). Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 2.5 × 106 CD34+ cells/kg required for participation in the trial. Bortezomib was administered at 1 mg/m2 on D -6, D -3, D +1, and D +4 and HDM at 140-200 mg/ m2 in two divided doses on D -2 and D -1. From 10/2008 to 7/2009, 8 patients were enrolled (median age 57, range 46-68; median number of involved organs 2, range 1-4). Of the 8 patients enrolled, 1 patient was removed from the protocol because of cardiac arrhythmia during stem cell mobilization and collection phase that precluded treatment with HDM/SCT. Of the 7 patients who received BorHDM/SCT, there was no treatment-related mortality within 100 days of SCT and there were no unexpected hematologic or non-hematologic toxicities associated with addition of bortezomib to HDM/SCT. The median times to neutrophil and platelet engraftment was D +10 and D +14 after SCT, respectively. Of 6 patients evaluable for early responses, normalization of serum free light chain levels and ratio occurred in 5 of 6 (83%) by D +14 and one patient achieved a 45% reduction in serum free light chain concentration at D +14. Of the initial 2 patients with longer follow-up, both have achieved a hematologic CR at 6 months following BorHDM/SCT. Follow-up is ongoing and hematologic responses appear to be well-maintained. Thus, this pilot study demonstrates that bortHDM/SCT is tolerable for selected patients with AL amyloidosis and leads to a high rate of hematologic responses. Disclosures: Off Label Use: Bortezomib in the treatment of AL amyloidosis.

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Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Blood ◽

10.1182/blood-2020-138500 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-26

Author(s):

Vanessa Fiorini Furtado ◽

Dina Brauneis ◽

Shayna Sarosiek ◽

Karen Quillen ◽

Vaishali Sanchorawala

Keyword(s):

Light Chain ◽

Research Funding ◽

Amyloid Fibrils ◽

Advisory Board ◽

Free Light Chain ◽

Light Chains ◽

High Dose ◽

Al Amyloidosis ◽

Serum Free Light Chain ◽

High Dose Melphalan

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine >1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (< 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p<0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr >1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC <20 mg/L, 28% (n=16/57) had dFLC<10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC <10 mg/dL and early post-SCT iFLC <20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC <20 mg/L, dFLC <10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC <10 mg/L and iFLC <20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC <10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents & Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

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B-Type Natriuretic Peptide (BNP) and Mitral Velocity E/A Ratio (MV E/A) Are Two Important Noninvasive Functional Indices of Cardiac AL Amyloidosis.

Blood ◽

10.1182/blood.v110.11.4773.4773 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4773-4773

Author(s):

Peter Kabos ◽

Qaiser Bashir ◽

Robert Chen ◽

JoAnn Lindenfeld ◽

Han Myint ◽

...

Keyword(s):

Stem Cell ◽

Right Ventricular ◽

Pulmonary Edema ◽

Light Chain ◽

Left Ventricular ◽

Pulmonary Complications ◽

Free Light Chain ◽

Al Amyloidosis ◽

Serum Free ◽

Serum Free Light Chain

Abstract Cardiac AL amyloidosis is characterized as global myocardial dysfunction, oftentimes complicated by pulmonary events during stem cell mobilization and autotransplant. Although BNP or N terminal proBNP has been shown to be prognostically significant for survival following autotransplant, pathophysiologic processes of the heart for elevated levels of these molecules are unclear. In the current study, we sought to evaluate functional cardiac indices assessed by two-dimensional and Doppler echocardiography and to correlate to BNP and clinical events. Evaluations were done on 39 serial echocardiogrmas obtained between July 2006 and July 2007 from 5 patients with established cardiac AL amyloidosis as a part of systemic amyloidosis (3 primary; 2 secondary to free kappa light chain multiple myeloma). Their median age was 78 years (range 48 to 80). One patient presented with pulmonary edema initially and three others developed pulmonary edema (n = 2) or congestion with pleural effusion (n = 1) during the course of therapy. Two patients underwent melphalan-based autotransplant, and three received melphalan 50 mg/m2 up to 2 cycles every 3 months without stem cell infusion. The median BNP at diagnosis was 1110 pg/mL (range, 115 to 2540); right ventricular diastolic diameter (RVDd) 3.8 cm (2.9 to 4.0); left ventricular end diastolic volume (LVEDV) 88 mL (50 to 125); ejection fraction 60% (53 to 77); MV E/A 2 (1.3 to 2.9); right ventricular systolic pressure (RVSP) 48 mmHg (40 to 68). In multiple regression analyses, BNP levels were most significantly correlated to the RVDd, β = 0.58, p < 0.05. The RVSP as a surrogate index of pulmonary arterial pressure was shown most dependent on the left ventricular diastolic filling assessed by the MV E/A (β = 0.93, p < 0.05) that in turn was dependent on the LVEDV (β = 2.68, p < 0.05). None of the myocardial wall measurements and left ventricular indices except these were found to be significant. Although the RVDd was dependent on the RVSP (β = −1.17, p < 0.05), both BNP and RVSP were independent of each other (β = −0.25, p = 0.6). RVSP levels were significantly elevated in 4 patients who had pulmonary complications: 50, 55, 57, 68 mmHg, respectively. The MV E/A was elevated at or above 2.5 at the time of these episodes: 2.5, 2.9, 2.9, 3.7, respectively. Decrease in both BNP and RVSP appeared to be minimally related to improving serum free light chain levels following therapy: β = 0.29, p = 0.08 and β = 0.34, p = 0.05, respectively. There was no correlation between the MV E/A and serum free light chain level either, β = 0.19, p = 0.3. The data suggests that the MV E/A and RVSP may be useful indices for monitoring patients for potential pulmonary complications, and the BNP appears to reflect more of the right-sided heart events. Further studies are needed to confirm the current findings.

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