Reduction Of Free Light Chains Research Articles

Early Reduction of Serum-Free Light Chains Associates with Renal Recovery in Myeloma Kidney

Myeloma kidney is the major cause of severe irreversible renal failure in patients with multiple myeloma. This tubulointerstitial injury is a direct consequence of high concentrations of circulating monoclonal free light chains (FLCs) produced by a clonal expansion of plasma cells. Early reduction of serum FLCs associates with renal recovery, but the target threshold of reduction to facilitate renal recovery is unknown. To determine the relationship between the achieved FLC reduction and renal recovery, we identified 39 patients with biopsy-proven myeloma kidney, the majority of whom had severe renal failure at presentation (median estimated GFR 9 ml/min per 1.73 m²). In a multivariable analysis incorporating demographic, hematologic, and renal variables, only the achieved FLC reduction significantly predicted renal recovery (P = 0.003). The relationship between renal recovery and FLC reduction was linear with no absolute threshold for FLC reduction. A 60% reduction in FLCs by day 21 associated with recovery of renal function for 80% of the population. Patient survival strongly associated with renal recovery: the median survival was 42.7 months (range 0 to 80) among those who recovered function compared with 7.8 months (range 0 to 54) among those who did not (P < 0.02). Cox-regression analysis demonstrated that the first presentation of myeloma, the kappa isotype of FLC, and renal recovery were independent predictors of survival. In conclusion, recovery of renal function in myeloma kidney depends on early reduction of serum FLCs, and this recovery associates with a significant survival advantage.

Online high-efficiency haemodiafiltration achieves higher serum free light chain removal than high-flux haemodialysis in multiple myeloma patients: preliminary quantitative study

Fast reduction of serum free light chain (FLC) levels correlate with renal recovery in cast nephropathy. Because convection has the capacity to remove proteins of higher molecular weights, we hypothesized that haemodiafiltration (HDF) would be superior to haemodialysis (HD) for FLC clearance. We retrospectively identified all renal replacement therapy (RRT) sessions performed in multiple myeloma patients with pre- and post-treatment FLC measurements during a 2-year period. Using kinetic modelling, we calculated reduction percentages corrected for net ultrafiltration, effective clearances, net mass removal and Kt/V for both kappa (κ) and lambda (λ) serum FLC. We analysed 27 (10 HD and 17 HDF) RRT sessions realized in a total of six subjects. HDF resulted in higher FLC removal rates when compared to HD. Moreover, high-efficiency (i.e. substitution volume > 15 L/session) HDF demonstrated median efficient FLC clearances roughly twice superior to high-flux HD for both κ (59.0 versus 33.8 mL/min, respectively; P < 0.01) and λ (40.5 versus 19.7 mL/min, respectively; P = 0.02) FLC. In post-dilution HDF treatments, corrected FLC reduction percentages positively correlated with substitution volumes. Total plasma proteins increased during RRT in the HDF group. This preliminary quantitative study demonstrates the superiority of high-efficiency HDF over high-flux HD for serum FLC removal in multiple myeloma patients on RRT. No negative impact on total plasma proteins was noted.

High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma

Recently, we demonstrated immunological and clinical responses to a RHAMM-R3 peptide vaccine in patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. To improve the outcome of the vaccine, a second cohort was vaccinated with a higher dose of 1,000 microg peptide. Nine patients received four vaccinations subcutaneously at a biweekly interval. Immunomonitoring of cytotoxic CD8(+) as well as regulatory CD4(+) T cells was performed by flow cytometry as well as by enzyme-linked immunospot (ELISpot) assays. Parameters of clinical response were assessed. In 4 of 9 patients (44%) we detected positive immunological responses. These patients showed an increase of CD8(+)RHAMM-R3_tetramer(+)/CD45RA(+)/CCR7(-)/CD27(-)/CD28(-) effector T cells and an increase of R3-specific CD8+ T cells. Two of these patients showed a significant decrease of regulatory T cells (Tregs). In one patient without response Tregs frequency increased from 5 to 16%. Three patients showed clinical effects: one patient with myelodysplastic syndrome RAEB-1 showed a reduction of leukemic blasts in the bone marrow, another myelodysplastic syndrome patient an improvement of peripheral blood counts and one patient with multiple myeloma a reduction of free light chains. Clinical and immunological reactions were lower in this cohort than in the 300 microg cohort. High-dose RHAMM-R3 peptide vaccination induced immunological responses and positive clinical effects. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematologic malignancies. However, higher doses of peptide did not improve the frequency and intensity of immune responses in this trial.

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

Abstract 4352AL 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.

Improving Outcomes in Patients with Renal Failure Secondary to Multiple Myeloma: Results From ChAR2M2.

Abstract 1875Poster Board I-900 Study purpose:To explore how free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) has been adopted into clinical practice for the management of renal failure secondary to multiple myeloma. Describing treatment patterns and the laboratory and clinical outcomes associated with its use. Methods:A chart audit of patients treated with FLC removal by HCO-HD, using the Gambro HCO 1100 dialyser, was performed in 16 dialysis centers across 9 countries. Patient demographics, treatment patterns and dialysis side-effects were recorded. In addition, the following outcomes were measured: dialysis independence and reductions in serum FLCs concentrations at 12 and 21 days. Results:Data for 66 patients was entered. Patients had an average age of 65.1 (SD×10.1); 42 of them (63.64%) were male and 24 (36.36%) were female. Sixteen (24%) presented with relapsing myeloma and 50 (76%) had de novo disease. On average, each patient received 13 HCO-HD sessions (SD×8). Forty-one patients became dialysis independent (62.12%), after an average of 12 sessions. Dialysis related side-effects were reported in 6% of all patients. Forty patients (60.61%) were reported to have a sustained reduction in serum FLC concentrations by day 12. By day 21 this had increased to forty-one (62.12%). Among the patients who achieved a sustained reduction in serum FLC concentrations, 28 (70%) had a decline in FLC levels of more than 50% by day 12 and 34 (82.93%) by day 21. Among patients who achieved sustained reduction of more than 50% in serum FLC concentrations by day 12, 75% became dialysis independent. In comparison only 53% of those with a reduction of less than 50% became dialysis independent (p×0.007). Furthermore, among patients who achieved sustained FLC reduction of greater than 75%, 81% became dialysis independent. The rate of dialysis independence was also significantly higher in patients with de novo disease compared with those with relapsing myeloma (64% versus 56%, p×0.04). Conclusion:Free light chain removal by HCO-HD was well tolerated and associated with a very high rate of dialysis independence in patients with renal failure secondary to multiple myeloma. Rates of renal recovery were greater in patients with de novo myeloma and those who achieved an early reduction in serum FLC concentrations. Disclosures:No relevant conflicts of interest to declare.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

Therapy Response by Decrease of Free Light Chain Concentration in Multiple Myeloma Patients Treated with Bortezomib/Doxorubicin/Dexamethasone as First-Line Therapy.

Incorporation of new drugs such as the proteasome inhibitor bortezomib in the treatment of multiple myeloma (MM) has increased response rates. However, the challenge is to find the optimal combination of drugs and to change therapy as early as possible in case of suboptimal response. Therefore, we analyzed retrospectively the concentrations of serum free light chains (FLC) before, during and after therapy with bortezomib/doxorubicin/dexamethasone. In order to evaluate their prognostic value we compared the FLC kinetics to therapy response according to the International Uniform Response Criteria. Sixteen patients with newly diagnosed symptomatic MM (IgG/kappa: 9, IgG/lambda: 2, IgA/lambda: 1, IgA/kappa: 1, IgD/lambda: 1, IgD/kappa: 1, light chain kappa: 1) who received 4 cycles of bortezomib/doxorubicin and dexamethasone as initial therapy from November 2005 to June 2007 were analyzed. All patients showed a decrease in the FLC and/or a change of the quotient kappa/lambda towards the normal value after therapy. Reduction of FLC concentration ranged from 2.4- to 840-fold. Marked reduction could be observed after the first cycle of therapy. Seven patients revealed good response (sCR, CR or VGPR). In six of them, the decrease in FLC concentration was at least 20-fold, in one patient 2.9-fold. This patient had only a moderate increase of FLC concentration before therapy (below four times upper limit of normal). Two patients did not achieve good response (SD: 1, PD: 1); they had only a slight reduction in FLC (2.4- and 2.5-fold, respectively) although their initial FLC concentration was high. In parallel to the reduction of FLC, the serum concentration of immunoglobulins decreased. However, lowering of FLC occurred earlier and was more pronounced. Measurement of FLC concentration provides more rapid information for treatment monitoring than immunoglobulins and thus may be helpful to change therapy as early as possible in case of suboptimal response.

Diagnostic and prognostic utility of the serum free light chain assay in patients with AL amyloidosis

Organ dysfunction in AL amyloidosis is related to the production and deposition of amyloidogenic monoclonal light chains. These pathological light chains can now be quantified using the recently developed serum free light chain assay. We retrospectively reviewed 31 patients with AL amyloidosis to determine the frequency of abnormal free light chain assay results at diagnosis and whether changes in the serum free light chain assay predict outcome after therapy. An abnormal free light chain assay was found in 30 of 31 patients (97%) at the time of diagnosis. In the subset of our patients who received treatment for AL amyloidosis, a >50% reduction of the pathological free light chain following treatment was shown to predict improved overall survival. In our series of analyses, achievement of greater magnitudes of reduction of the free light chain result did not appear to provide additional prognostic information, nor did the baseline free light chain result predict outcome. Our findings support the use of the free light chain assay in the diagnostic work-up of patients with suspected AL amyloidosis, and also as a sensitive biomarker of response to therapy.

Early Immunoglobulin Free Light Chain (FLC) Response Post Autologous Peripheral Blood Stem Cell Transplant Predicts for Hematologic Complete Response in Patients with Multiple Myeloma.

Background: FLC is a valuable diagnostic tool to monitor response in patients with AL and oligosecretory MM. It is also prognostic in patients with MGUS. Its value in patients with non-oligosecretory myeloma has not been defined. Because of the short half-life of free-light chains, an early drop in free-light chain might be predictive for long term outcome post PBSCT.Methods: Between 8/1/03 and 12/10/04, 45 patients with multiple myeloma and abnormal FLC ratios (less than 02.6 or greater 1.65), who were undergoing PBSCT consented to have waste serum from routine post-transplant daily blood draws collected and frozen for future FLC analysis. The immunoglobulin FLC assay (Binding Site, U.K.) was run on samples collected from day +1 until patients were dismissed from our transplant center. Hematologic response was coded according to standard IBMTR criteria at approximately 3 months status post transplant (BJH 1998). Two types of immunoglobulin FLC response were coded: 50% reduction (FLC50) and 90% reduction (FLC90) of the difference of the involved and uninvolved FLC (Leukemia 2006). Two time periods of FLC response were analyzed: early (day 7); and delayed (day 19, range 13 to 24). Endpoints analyzed were overall response (>=PR), complete response rate (CR), progression free survival (PFS), and overall survival (OS).Results: The median age of the myeloma group was 59 years, and 53% were male. Thirty-three patients were monoclonal kappa, and 12 lambda. Forty-two percent were transplanted in response/plateau, 22% were primary refractory, and 36% relapsed disease. The overall hematologic response rate was 93% with a CR rate of 33%. Twenty-five patients have relapsed at a median of 14.2 months. Twelve patients have died, and median overall survival for the group has not been reached at a median follow-up of 24.6 months. Forty-nine and 58 percent of patients had early and delayed FLC90, respectively. Early FLC90, but not delayed FLC90, predicted for complete response (p<0.001). Neither early nor delayed FLC90 predicted for either PFS or OS. In addition, 89% and 96% of patients had an early and delayed FLC50, respectively. FLC50 at either time point did not predict for overall response, CR, PFS, or OS.Conclusion: Immunoglobulin free light chain responses are seen within the first weeks post high dose chemotherapy with peripheral blood stem cell transplant. A 90% reduction in FLC seen within the first seven days predicts for complete response. However, this does not yet translate into prolonged PFS or OS, but with longer follow-up separation of the survival curves may be seen.

Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation

AbstractThe immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor protein has been crude. We evaluated the utility of the FLC assay in a retrospective analysis of patients with AL undergoing peripheral blood stem cell transplantation (PBSCT). Ninety-three such patients had serial FLC measurements performed. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were studied. There was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio. FLC measurements both before and after PBSCT are important predictors of patient outcome.

Correlation of Suppression of FDG PET Uptake with Serum Free Light Chain Levels - Both FDG PET-CT and Serum Clonal Free Light Chain Response Precede and Predict the Likelihood of Subsequent Complete Remission in Newly Diagnosed Multiple Myeloma.

18F-labeled Fluorodeoxyglucose Positron Emission Tomography - computed tomography (PET-CT) imaging results from newly diagnosed patients with multiple myeloma (MM) were correlated with serum free light chain (FLC) results from Total Therapy 3 (TT3). Patients had baseline PET-CT scans and serum kappa and lamda FLC analysis at diagnosis and at 2, 14 and 30 days post first cycle of VDTPACE and at pre-transplant 1 of two planned autologous stem cell transplants (TX1), correlating PET-CT response, clonal and nonclonal FCL response, and likelihood of subsequent complete clinical response (CR). Patients were selected with serum clonal FLC levels above the normal range that had been enrolled for sufficient time for a complete response (CR) to be recorded. Correlations between the serum clonal and nonclonal FLC levels and PET-CT response defined by both reduction in number of PET-defined focal lesions (PET-FL) (5 mm or larger areas of circumscribed uptake visually definable above background activity) and reduction in the maximum standardized uptake value normalized to the patients' lean body mass (max SUV) were performed.Results: Reduction in FLC and PET-FL and max SUV are correlated, as was normalization of clonal FLC levels with likelihood of subsequent CR (Fig 1). The Spearman's correlation coefficient between percent reduction in clonal FLC and percent reduction in max SUV was 0.04 (n=49, p=0.79) at 2 days post-VDTPACE, 0.32 (n=48, p=0.028) at 30 days post-VDTPACE, and 0.52 (n=33, p=0.002) prior to TX1. The greatest reduction in max SUV occurred by 2 days post-VDTPACE while the maximum reduction in clonal FLC occurred at 30 days post-VDTPACE, indicating that the PET response lead and predicted the FLC response in near “real time.” While normalization of the clonal FLC levels at 30 days was strongly predictive of subsequent CR (p<0.001, n=125), normalization of the non-clonal FLC levels was not (p=0.41, n=124).Conclusion: We conclude that normalization of serum clonal FLC correlates both with improvement in FDG PET-CT scanning in both max SUV and number of PET-defined focal lesions and with likelihood of subsequent CR, though it “lags” behind FDG PET response by nearly a month, with FDG PET following the clinical course in near real time. [Display omitted]

Absolute Values of Serum Immunoglobulin Free Light Chains Predict for Survival in Patients with Primary Systemic Amyloidosis Undergoing Peripheral Blood Stem Cell Transplant.

Introduction: The immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor has been crude. There is now a test that reproducibly measures serum levels of FLC. We evaluated the utility of this assay in patients with AL undergoing peripheral blood stem cell transplant (PBSCT).Methods: Between March 1, 1996 and July 31, 2004, 98 patients with AL undergoing PBSCT had serial FLC measurements performed either prospectively or on stored sera. Patients who died before their 100 day evaluation were excluded because response could not be estimated. FLC levels were performed using Freelite™ reagents on a Dade-Behring Nephelometer. In order to pool the data of the monoclonal kappa and lambda patients, the clonal free light chain was considered the involved] immunoglobulin free light chain for the purpose of these analyses and is henceforth referred to as FLC. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were evaluated.Results: Pre-transplant, 94% of patients had an abnormal FLC ratio, with a median involved FLC of 152 mg/L [15.2 mg/dL]. Only 14% of 98 patients had a “measurable” serum M-spike (i.e. ≥ 10 g/L [1 g/dL]) on electrophoresis with a median of 1 g/L [0.1 g/dL]. Ten patients have died of their disease during a median follow-up time of 19.5 months, range 3.3 to 103 months. The 2- year and 4-year estimated survivals are 92% and 76%, respectively. Using the 75th percentile value of pre-PBSCT FLC (382 mg/L [38.2 g/dL]) as a grouping variable, there was a significantly higher risk of death 5.4 (95% confidence interval 1.5–19.3) in the patient quartile with the highest baseline FLC. Baseline FLC correlated with serum cardiac troponin T levels (rho 0.51, p<0.0001), suggesting that high FLC levels are associated with more advanced disease. After PBSCT, the median percent reduction of FLC was 81%. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. The hazard ratio for death for not achieving a post-transplant FLC of 20 mg/L [2 mg/dL] post-transplant was 5.1 (95% confidence interval 1.1–24.1). Of 91 patients evaluable for complete response by EBMT criteria, 45 had a complete hematological response. Sixty-five percent of the patients achieving a FLC level of less than 20 mg/L [2 mg/dL] also had a complete hematologic response. Free light chain response as defined by a post transplant FLC level 20mg/L [2 mg/dL] or lower was a more powerful predictor of survival than complete hematologic response, as defined by the EBMT multiple myeloma criteria. Post-PBSCT FLC level only weakly predicted for organ response, but median follow-up for surviving patients is relatively short at 19.6 months.Conclusion: FLC measurements both pre- and post-PBSCT are important predictors of patient outcome.

Role of Second Stem Cell Transplant in Patients with Amyloidosis Who Are Refractory or Relapsing.

Introduction: Stem cell transplant is an increasingly widely applied technique for managing amyloidosis. As in multiple myeloma, the treatment would not be expected to be curative and patients would be expected to relapse in most instances. In addition, approximately one-third of patients fail to respond to initial therapy. The role of second transplantation in treatment failures or patients who relapse is reviewed.Patients: Of 242 patients undergoing high dose conditioning and stem cell transplantation for amyloidosis (AL) at the Mayo Clinic, 6 subsequently underwent a second transplant.Results: Patient 1, who had single organ renal amyloid nephrotic syndrome responded and relapsed at 73 months, received a second stem cell transplant achieving a hematologic complete response with normalization of a markedly elevated pre transplant free light chain (59 to 1.9 mg/dL) and is alive at 12 months. Patient 2 relapsed 42 months after transplant for single organ renal amyloidosis; the second stem cell transplant, has normalized his free light chain ratio reduced his urinary protein loss from 5450 to 1482 mg/day and he is alive 21 months following his second transplant (63 months overall). Patient 3 relapsed 34 months after a response of renal and cardiac amyloidosis. After transplant two, he failed to achieve a 50% reduction in his free light chain, began hemodialysis 7 months post transplant and died one year post transplant. Patient 4 with single organ cardiac involvement relapsed 30 months following his first transplant and died on day +5 of his second transplant of an acute pulmonary embolus. Patient 5 was a response failure after his first transplant, had a second transplant 35 months later, having failed Dexamethasone followed by Melphalan/Dexamethasone therapy, and died 3 months later of progressive disease. Patient 6 had single organ vascular involvement manifest by calf and thigh claudication and failed to respond with his first transplant with a persistently elevated free light chain. The second transplant was performed six months after the first without further free light chain reduction and persistent claudication at 11 months.Conclusion: Patients who failed to achieve a hematologic response after a first transplant appear not to benefit from a second course of high dose therapy. Among 4 patients who were previously responsive and relapsed, one achieved a hematologic complete response, one achieved a hematologic partial response, and two died. The two patients achieving a second hematologic response had the longest response duration (73 and 42 months) following their first transplant, and the second response presumably reflects favorable (indolent; non proliferative) biology of the underlying plasma cell dyscrasia. High dose therapy and stem cell transplant may be an effective salvage regimen for patients who responded to a first transplant and whose response lasted greater than 36 months.

Serum free light-chain responses after high-dose intravenous melphalan and autologous stem cell transplantation for AL (primary) amyloidosis

Serum free light-chain (FLC) concentrations were measured by a sensitive nephelometric immunoassay in 66 patients with AL amyloidosis before and after treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). At 1 year after HDM/SCT, 27 patients (41%) achieved a complete hematologic response (CR), that is, disappearance of the monoclonal gammopathy previously evident by immunofixation electrophoresis (IFE) in serum and urine and of plasma cell clonality in the bone marrow. Abnormally elevated FLC levels became normal in 27 patients (41%), and decreased by >90% in 37 (56%). Average improvements in FLC were 94% for patients who achieved a CR and 72% for those who did not (P=0.0001). However, a reduction in FLC of >90% was associated with a similar high likelihood of clinical improvement and prolonged survival, whether or not patients achieved a CR. While CR, as defined by standard criteria, is a more stringent indicator of hematologic response than are decreases in abnormally elevated FLC levels per se, these measures of hematologic response are complementary, and decreases in FLC are more readily detected early after treatment than are the changes in IFE and marrow studies required to determine CR.

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

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.