Improved Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) for Light Chain (AL) Amyloidosis: A Center for International Blood and Marrow Transplant Registry (CIBMTR) Study

Abstract Background: Light chain (AL) amyloidosis is a rare plasma cell neoplasm associated with systemic amyloid deposition leading to organ dysfunction and death without treatment. The use of AHCT in AL amyloidosis remains controversial as a prospective randomized control trial suggested inferior outcomes when compared with standard chemotherapy, driven primarily by high peri-transplant mortality (TRM) up to 24%. Improved patient selection criteria, supportive care and risk-adapted therapy have reduced TRM in recent single center studies. We analyzed trends and prognostic factors associated with AHCT outcomes in AL amyloidosis patients. Methods: We identified 1532 AL amyloidosis patients who underwent AHCT following high dose melphalan (MEL) within 24 months of diagnosis between 1995 and 2012 from the CIBMTR database. A subset of patients with more complete level of research data reported between 2001 and 2012 was analyzed for multivariate analysis (n=354). The primary endpoints were day30 and day100 mortality, hematologic progression free survival (PFS), hematologic relapse/progression and overall survival (OS). Data regarding cardiac, renal, hepatic and neurologic amyloid involvement was collected. Hematologic and organ response and progression were defined based on the 2004 uniform consensus criteria. Results: The median age at transplant was 57 years, with 61% males. AHCT was performed within 6 months of diagnosis in 66% patients. Karnofsky performance score (KPS) was <80 in 14%, HCT-CI was ≥ 3 in 20% and 69% had a lambda isotype. Organ involvement included renal, cardiac, hepatic and autonomic nervous system involvement in 74%, 38%, 16% and 11% respectively. Coexistent myeloma (>10% bone marrow plasma cells) was seen in 14%. Progressively higher numbers of patients received AHCT from 1995-2000 (n=140) to 2001-2006 (n=595) and 2007-2012 (n=800). The majority were untreated pre-transplant (77%) while 8% received melphalan, 6% thalidomide and 4% each received lenalidomide and bortezomib based pre-AHCT therapy. The median CD34 cell dose infused was 4.4 X 106/kg cells (IQR 3.3-6.2). MEL dose reduction was common (60% received < MEL 180 mg/m2 and 38% < MEL 140 mg/m2). The median length of hospital stay was 17 days (IQR 13-23). The median follow-up of patients from the time of transplant was 61 months (range 3-145). Day100 response included hematologic complete response, CR (12%), partial response, PR (26%), stable disease, SD (23%), and renal response (12%) with an ultimate best response of hematologic CR (33%), PR (28%), SD (19%) and renal response in 31%. Table 1 shows day30 and day100 mortality and OS at 1, 3 and 5 years showing steady declines in mortality rates and improvements in survival in successive time cohorts. Figure 1 shows the 5 year OS in each of the time cohorts. On multivariate analysis, albumin ≥ 3 g/dl at diagnosis, KPS ≥80, pre-transplant anti-plasma cell therapy and MEL ≥180 mg/m2 were associated with lower hematologic relapse/progression. KPS ≥80 and predominant renal involvement were associated with superior hematologic PFS while KPS ≥80 and < 2 organ involvement correlated with OS. Table 1 Outcomes of AHCT in AL amyloidosis. Values are expressed as probabilities with 95% confidence intervals. 1995-2000 N=140 2001-2006 N=595 2007-2012 N=800 Day 30 mortality 11 (7-17) 5 (4-7) 3 (2-4) Day 100 mortality 20 (14-27) 11 (8-13) 5 (4-7) 1 year survival 75 (67-82) 85 (81-87) 90 (88-92) 3 year survival 64 (56-72) 72 (68-75) 83 (80-86) 5 year survival 55 (46-63) 61 (57-65) 77 (72-82) Conclusions: There has been a significant improvement in survival of AL patients after AHCT driven primarily by a reduction in early peri-transplant mortality. Limited organ involvement, higher KPS, use of pre-transplant therapy and higher dose melphalan conditioning contributed to superior outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Baseline Serum Albumin and Proteinuria Predict Renal Response after Autologous Stem Cell Transplantation in AL Amyloidosis.

Blood ◽

10.1182/blood.v106.11.1166.1166 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1166-1166

Author(s):

Nelson Leung ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

Mark R. Litzow ◽

Shaji K. Kumar ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Light Chain ◽

Al Amyloidosis ◽

Baseline Serum ◽

Monoclonal Protein ◽

Renal Response ◽

Hematologic Response ◽

Organ Response

Abstract Introduction: High dose melphalan followed by autologous stem cell transplantation (ASCT) is an effective treatment for patients with light chain associated (AL) amyloidosis. Longer patient survival and higher rates of organ response have now been documented by multiple studies. However, predictors of organ response remain unknown. Previously, we have reported the benefits of renal response after ASCT in this population. This study was conducted to investigate the characteristics that would predict renal response after ASCT. Methods: The study was performed retrospectively on consecutive patients that underwent ASCT at our institution from March of 1996 to December of 2004. Exclusion criteria include baseline proteinuria < 1 g/d, dialysis prior to ASCT and lack of laboratory data at follow up to determine renal response. Renal response was defined by > 50% reduction in baseline proteinuria with < 25% decline in renal function as measured by serum creatinine. Treatment related mortality and dialysis dependence prior to meeting criteria of response were viewed as treatment failures. Hematologic response was determined by 50% reduction of monoclonal protein (free light chain) or complete eradication if the monoclonal protein was too small to be quantified. Results: A total of 135 patients met criteria for study. Median age was 56.2 years at the time of transplant, 53.7% were male. Median baseline proteinuria and GFR were 6.4 g/d and 70 ml/min/1.73m2 respectively. Renal response was achieved in 35.6% of the patients while hematologic response was 71.1% in the 128 patients evaluated. Patient’s age, sex, albumin, GFR, proteinuria, conditioning regimen, and hematologic response were evaluated and the following were found to be associated with renal response: albumin (p = 0.001), proteinuria (p = 0.008), and hematologic response (p = 0.0002). The cutoff for albumin was found to be 1.6 mg/dl and proteinuria was 3.5 g/d. Multivariate analysis using a logistic regression model showed hematologic response and proteinuria to be independent predictors of renal response. The impact of proteinuria and hypoalbuminemia was then investigated together (Table 1). When combined, they were a better predictor then either one alone (Hazard ratio = 6.34 for combined, 3.43 for proteinuria, 3.32 for hypoalbuminemia). The combination was also a better independent predictor of renal response in the multivariate analysis. In this group of patients, renal response was associated with longer survival but hematologic response was not (p = 0.02). Discussion: Our study showed that besides hematologic response, baseline serum albumin and proteinuria are independent predictors of renal response in AL patients after ASCT. Hypoalbuminemia and nephrotic range proteinuria, both markers of the severity of renal disease, have strong negative impact on response. This implies that there may be a limit to the reversibility of organ damage even when hematologic response is achieved. This study also points out the importance of organ (renal) response in this disease as hematologic response alone did not predict long term outcome. Our results suggest ASCT should be done early for AL to insure optimal organ response and patient outcome. Table 1 The Effects of Hypoalbuminemia and Proteinuria on Renal Response after ASCT Hypoalbuminemia & Proteinuria No Renal Response Renal Response None 39.3% 60.7% One 66.2% 33.8% Both 81.8% 18.2%

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Serum Immunoglobulin Free Light Chain in Primary Amyloidosis: Prognostic Value and Correlations with Clinical Features

Blood ◽

10.1182/blood.v112.11.2733.2733 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2733-2733

Author(s):

Shaji Kumar ◽

Angela Dispenzieri ◽

Raynell Clark ◽

Dirk Larson ◽

Colin Colby ◽

...

Keyword(s):

Overall Survival ◽

Alkaline Phosphatase ◽

Heavy Chain ◽

Light Chain ◽

Renal Involvement ◽

Organ Involvement ◽

Entire Group ◽

Al Amyloidosis ◽

Lower Serum

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( > 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (> 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P < 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

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Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5601.5601 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5601-5601

Author(s):

Andrew J. Cowan ◽

David G. Coffey ◽

Teresa S. Hyun ◽

Pamela S. Becker ◽

Damian J. Green ◽

...

Keyword(s):

Mass Spectrometry ◽

Plasma Cell ◽

Light Chain ◽

Congo Red ◽

Plasma Cell Dyscrasia ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Immunoglobulin Light Chain ◽

Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

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Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan

Blood ◽

10.1182/blood-2007-05-090852 ◽

2008 ◽

Vol 111 (2) ◽

pp. 549-557 ◽

Cited By ~ 18

Author(s):

Ping Zhou ◽

Julie Teruya-Feldstein ◽

Ping Lu ◽

Martin Fleisher ◽

Adam Olshen ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Calcium Binding ◽

Plasma Cells ◽

Complete Response ◽

High Dose ◽

Al Amyloidosis ◽

Embryonic Fibroblasts ◽

Knock Out ◽

High Dose Melphalan

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

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Light chain amyloidosis

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2018.022 ◽

2018 ◽

Vol 10 (1) ◽

pp. e2018022 ◽

Cited By ~ 17

Author(s):

Paolo Milani ◽

Giampaolo Merlini ◽

Giovanni Palladini

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Molecular Mechanisms ◽

Cell Clone ◽

Renal Involvement ◽

Response To Therapy ◽

Al Amyloidosis ◽

Cell Transplant ◽

Cardiac Damage ◽

Risk Patients

Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic lights chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. This needs be risk adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.

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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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High Dose Melphalan and Autologous Stem Cell Transplantation In Light Chain and Light and Heavy Chain Deposition Disease: Hematologic and Renal Outcomes.

Blood ◽

10.1182/blood.v116.21.4597.4597 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4597-4597

Author(s):

David Telio ◽

John Shepherd ◽

Donna L. Forrest ◽

Michael J. Barnett ◽

Thomas J. Nevill ◽

...

Keyword(s):

Stem Cell ◽

Renal Disease ◽

Light Chain ◽

High Dose ◽

Al Amyloidosis ◽

Renal Response ◽

Deposition Disease ◽

Stage Renal Disease ◽

High Dose Melphalan

Abstract Abstract 4597 Introduction: Light chain deposition disease (LCDD) and light and heavy chain deposition disease (LHCDD) are plasma cell disorders characterized by pathologic aggregation and deposition of immunoglobulin components in tissues leading to organ dysfunction. Reported outcomes with conventional chemotherapy include high rates of end stage renal disease and death. High dose melphalan followed by autologous stem cell transplantation (ASCT) has been employed in an attempt to improve outcomes, but few published data are available to support this practice. Methods: We conducted a retrospective review of all patients within our institutional database treated with ASCT for LCDD or LHCDD. Diagnosis was based in all cases upon renal biopsy. Associated multiple myeloma (MM) was diagnosed if bone marrow plasma cells were > 10% with concomitant anemia, hypercalcemia or lytic bone disease. Filgrastim was used for peripheral blood stem cell mobilization. All patients received melphalan conditioning at a reduced dose of 140 mg/m2 (due to renal dysfunction) with the exception of one patient who received melphalan 200 mg/m2. Response to treatment was adapted from the International Consensus Criteria (Gertz et al. 2005) designed for use in AL amyloidosis except that bone marrow biopsies were not performed to confirm complete hematologic remission. A renal response was considered to have been reached if proteinura decreased from 50% of baseline with stable creatinine or if creatinine decreased by 50% from its peak value. Results: We identified eight patients (7 LCDD, 1 LHCDD) treated with ASCT between August 2006 and November 2009. The median age at diagnosis was 48 years (range 40–62). Two patients had associated MM. All patients had come to medical attention as a consequence of renal dysfunction. The median serum creatinine at presentation was 192 μ mol/L (119-444) with two patients meeting criteria for nephrotic syndrome and a third having anasarca with nephritic syndrome. No patients were found to have associated AL amyloidosis, myeloma cast nephropathy, or extrarenal LCDD. Left ventricular ejection fraction was normal in all patients and none had evidence of cardiac infiltration. Kappa light chain restriction was present in seven patients with lambda light chain restriction in the eighth. Median kappa FLC level at diagnosis was 528 mg/L (range 42–1290, normal 3.3–19.4). Induction therapy consisted of dexamethasone in five patients and dexamethasone with bortezomib in two patients; one patient proceeded directly to ASCT without induction therapy. At the time of ASCT, the median serum creatinine was 183 μ mol/L (122-298). Stem cell mobilization was uncomplicated and ASCT was tolerated with no treatment related deaths or requirement for ICU admission. Significant toxicities included engraftment syndrome requiring steroids (2), bacteremia (2), sepsis with hypotension (1), pneumonia (1), grade 3 mucositis (1) and edema requiring ultrafiltration (1). One patient with a pre-ASCT creatinine of 298 μ mol/L went on to develop end stage renal disease and dialysis dependence two months after ASCT. Hematologic response was CR in two, PR in four, and not assessable in two patients due to insufficiently elevated baseline M-protein quantity for response determination. Seven patients had a renal response. After a median follow up from ASCT of 18 months (1-39 months), only one patient had experienced disease progression with increasing kappa FLC level. With the exception of the one dialysis dependent patient, no patients had symptoms related to renal disease at last follow up. Conclusion: In selected patients with LCDD and LHCDD, high dose melphalan with ASCT produced a high rate of hematologic and renal response with acceptable toxicity. Longer follow up is needed to assess the durability of response. Disclosures: No relevant conflicts of interest to declare.

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Lenalidomide/Melphalan / Dexamethasone Chemotherapy In 50 Patients With Newly Diagnosed Amyloid Light Chain Amyloidosis: First Results Of a Prospective Single Center Phase 2 Study (Leomex)

Blood ◽

10.1182/blood.v122.21.1993.1993 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1993-1993

Author(s):

Stefan O Schonland ◽

Tilmann Bochtler ◽

Axel Benner ◽

Marianne Gawlik ◽

Christoph Kimmich ◽

...

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Cardiac Amyloidosis ◽

High Dose ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Number Of Patients ◽

Plasma Cell Disorder ◽

Amyloid Light Chain ◽

Cell Disorder

Abstract Introduction Amyloid light chain (AL) amyloidosis is a rare and life-threatening protein-misfolding disorder that is causedin most cases by a monoclonal plasma cell disorder. The goal of chemotherapy is to normalize the involved free light chain in serum which leads to an improvement or at least stabilization of organ function in most of these patients. A major challenge is the high treatment-related mortalityand toxicity in patients with advanced cardiac amyloidosis. Study design We performed a prospective single centerphase 2 trial with50 patients not eligible for high-dose treatment.Main inclusion criteria were: newly diagnosed and biopsy proven AL amyloidosis, significant organ involvement, age < 75 yrs and creatinine clearance > 40 ml/min. Treatment schedule was 6 cycles of an oral treatment with lenalidomide 10 mg day 1-21, melphalan 0.15 mg/kg day 1-4 and dexamethasone 20 mg day 1-4 every 4 weeks (L-M-dex). Primary endpoint was the rate of complete remissions (CR) of the underlying plasma cell disorder after 6 treatment cycles. Patients who received at least 3 cycles were eligible for hematologic remission (HR=CR+PR) analysis (At the time of study initiation “very good partial remission”in AL amyloidosis was not yet defined). The study was financially supported by Celgene. Patients and Methods Fiftypatients were included between 2009 and 2012. The median age was 67 years. 74% of patients had cardiac involvement. Outcome was compared with a historical group of 53 AL patients who received M-dex between 2004 and 2009 and fulfilled the same in- and exclusion criteria (patient characteristics see table). Results Forty-five patients (90%) completed 3 cycles and 35 patients (70%) completed 6 treatment cycles; overall 253 cycles could be administered. Reasons of discontinuation were toxicity in 6 patients (including one treatment-related death in the first cycle) or AL progression (9 patients). Ninety adverse events (AE) ≥ CTC grade 3 were recorded including 16 severe AEs. Seventeen hematologic AEs were observed (neutropenia 76%, CTC grade 4 in 2 patients). Most common non-hematologic AE was worsening of cardiac function or symptoms of autonomic neuropathy (14 patients). Furthermore 8 patients suffered from an infection, one patient developed acute renal failure and one patient a deep vein thrombosis. HR was achieved in 78% of patients: CR in 9 (20%)and PR in 26 (58%) of45 evaluable patients, respectively. Organ response was observed in 5 patients at the end of the study (6 months after the end of treatment). In the historical M-dex group HR rate was lower (58%, p=0.06): CR in 6 (15%)andPR in 17(43%) of 40 evaluable patients. OS was significantly improved using L-M-dex (see figure 1, median OS not reached vs. 26 mo., p=0.03). There was also a trend for a better EFS in the L-M-dex group (see figure 2, median EFS 23 vs. 16 mo., p=0.06). Of note, 3 L-M-dex patients (6%) died within 3 months after start of chemotherapy compared to 10 patients (19%) in the M-dex-group. Conclusion This is the largest phase II trial usinglenalidomide, melphalan and dexamethason in newly diagnosed AL amyloidosis patients. Treatment was effective and feasible in this cohort of mostly elderlypatients. 78% of evaluable patients achieved a hematologic remission. The early death rate was low with 6% despite of inclusion of a high number of patients with advanced cardiac amyloidosis. Overall, toxicity was manageable in most patients. Further improvement of these results might be achieved by prolongation of therapy in patients who have responded to and tolerate this combination therapy well. Disclosures: Schonland: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: lenalidomide in amyloidosis. Hegenbart:Janssen: Honoraria.

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IgD Amyloidosis: An Unrecognized Entity

Blood ◽

10.1182/blood.v118.21.5079.5079 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5079-5079

Author(s):

Morie Abraham Gertz ◽

Francis K Buadi ◽

Suzanne R Hayman ◽

David Dingli ◽

Angela Dispenzieri ◽

...

Keyword(s):

Light Chain ◽

Conflicts Of Interest ◽

Demographic Data ◽

Performance Status ◽

Renal Involvement ◽

Renal Amyloidosis ◽

Al Amyloidosis ◽

Liver Size ◽

Monoclonal Protein ◽

Monoclonal Proteins

Abstract 5079 Introduction: IgD monoclonal proteins are rare. They are not seen as a MGUS and are present in 1% to 2% of patients with myeloma. In light chain amyloidosis (AL), IgD monoclonal proteins are rare. When an IgD protein is found, amyloidosis is often omitted from the differential diagnosis. An IgD protein in amyloidosis has been reported in single cases but never as a patient series. We report IgD AL in 53. Patients & Methods: Clinical and demographic data for patients were retrieved from the patient records. Factors of interest were compared between patients who did and did not have an IgD protein. Results: Among 3,955 patients with AL amyloidosis seen, 53 patients (1.3%) had a serum IgD monoclonal protein. (Table 1) A serum monoclonal protein peak was visible on SPE in only 14, and only 5 had an M spike greater than 1 g/dL. On immunofixation of the serum, the IgD light chain was k in 11, λ in 35, and uncertain in 6; 1 patient had a biclonal D λ and G k protein. A urine monoclonal protein was detected in 43 of 51 patients; urinary immunofixation detected a λ light chain in 33 and a k light chain in 10. Biopsy of tissues showed amyloid deposits in the bone marrow in 47% and in the fat aspirate in 73%. Six patients (age 47–63 years) underwent autologous SCT. Four had renal & two had cardiac AL. All 6 had hematologic PR, 4 CR, and 4 had organ response. One patient had relapse of disease and is now on dialysis, and another had relapse and is alive with salvage chemotherapy. One patient had disease relapse and died of progressive GI amyloidosis at 22 months. The other 5 are alive at a median of 68 months (range, 7.5–83.5 months). We compared the 53 patients with IgD amyloidosis with 144 patients with non-IgD amyloidosis. (Table 2) Findings that were significantly different between groups included a lower frequency of renal amyloidosis (P=.005) and a lower prevalence of cardiac amyloidosis (P=.047). There was a higher serum albumin level (P=.04) related to the lower level of proteinuria. No difference in survival was seen between the groups. (Figure). Variables that might affect survival—liver size, performance status, septal thickness, serum creatinine level, and β2-microglobulin level—were not different between groups. Conclusions: IgD AL patients have a lower frequency of renal involvement and possibly also of cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have AL associated with another monoclonal protein. IgD monoclonal proteins are so closely linked to the diagnosis of multiple myeloma in the mind of a clinician that the possibility of amyloidosis may be overlooked. Disclosures: No relevant conflicts of interest to declare.

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Minimal Residual Plasma Cell Content of Autulogous Grafts, Chemosensitivity to Induction or High Dose Therapy and Pre/Post Transplant PET Negativity Predict Long Term Disease Free Survival in Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.3024.3024 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3024-3024

Author(s):

Sule Mine Bakanay ◽

Klara Dalva ◽

Berna Elif Koksoy ◽

Erol Ayyildiz ◽

Muhit Ozcan ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Plasma Cell ◽

Light Chain ◽

Pet Imaging ◽

Plasma Cells ◽

Whole Body ◽

High Dose ◽

Aberrant Expression ◽

Number Of Patients

Abstract Abstract 3024 Introduction: High dose melphalan supported by autologous hematopoietic cell transplantation has been shown to prolong survival and decrease relapse rates compared to conventional chemotherapies in elligible patients with multiple myeloma (MM) but unfortunately relapses remain a problem. Various factors have been shown to affect the relapse after transplantation. Malignant plasma cells (PCs) have been documented to contaminate blood stem cell harvest products. Conflicting results have been reported regarding the levels of PC contamination in apheresis products from patients with MM undergoing transplantation (Tx) and their impact on relapse and survival. Aim of this study was to analyze post induction residual myeloma by flow cytometric detection of the graft and by whole body PET imaging. Method: Standard panel was set up with CD138FITC/CD38PE/CD45ECD/CD56PC5. CD45negCD56pos plasma cells were identified as abnormal plasma cells. If any aberrant expression [such as CD20(loss) CD27(loss) CD28 (gain), CD33(loss), CD34 (gain), CD81(loss), CD117(gain)] is detected at diagnosis, the corresponding antibody was also added to the panel. Univariate and multivariate analysis were performed by SPSS.16. Results: Apheresis products from 118 patients (female/male=53/65; median age at diagnosis= 55 (35–69)) were tested for the presence of abnormal PCs and the number of normal PCs. The number of patients in MM subtypes IgG/IgA/Light chain/non-secretory were 70/20/26/2. International scoring system I/II/III:50/38/30. Most patients (n=108) had received one or two lines of induction and 52 had bortezomib based therapies before transplantation. In univariate analysis age (> 55; ≤ 55), ISS (ISS1 vs ISS2 + ISS3), beta2 mcg (>3.5 and ≤ 3.5) and MM Subtype (light chain vs others) were significantly associated with response to Tx. Presence of abnormal PCs in the harvests did not significantly affect response to Tx or OS. However, both the presence of abnormal PCs and the amount of normal PCs > 7.6 ×105/kg was associated with shorter PFS. Fifty-five of the patients had pre and post-Tx PET-imaging done. On the other hand, post-Tx PET positivity negatively affected the PFS. Post-Tx PET positivity was also significantly associated with relapse at 12 months after transplantation. Pre and post-Tx disease status significantly influenced relapse after transplantation. In multivariate analysis, age, beta2 mcg and light chain myeloma continued to be significantly associated with response to transplantation. Abnormal PC contamination and the amount of normal PCs> 7.6 ×105/kg were not associated with pre-Tx PET positivity. Conclusions: Age, ISS, beta2 mcg, light chain disease are predictors of response to transplant. Response to the treatments before mobilization, response to Tx, post Tx PET positivity, graft plasma cell (abnormal or normal) content, serum LDH are predictors of PFS. Response (≥VGPR) during mobilization correlates with less abnormal plasma cells in the apheresis product. PC contamination of the graft does not prevent response to transplant. However, presence of abnormal PC in the apheresis product as well as PET positivity predicts shorter DFS compared to lack of residual disease by flow or PET imaging (11 vs 18 months). Disclosures: No relevant conflicts of interest to declare.

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