Zeldenrust, Steven R.

Abstract Background: Light chain Amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in major organs and/or soft tissue. An observational study on natural history and outcome of localized immunoglobulin light-chain amyloidosis without vital organ (liver, heart, kidney, peripheral and autonomic nervous system) involvement has shown extremely low rate of progression (1%) to systemic amyloidosis at a median follow-up of 74.4 months (Mahmood S et al. The Lancet Haematology; 2015; 6:e241-e250). There is, however, limited evidence in published literature on natural history of AL amyloidosis confined to fat and/or bone marrow biopsy, without involvement of vital organs or other soft tissues. Methods: We retrospectively identified patients with AL amyloidosis limited to fat and/or bone marrow aspirate in a single-institution database. Patients were evaluated for progression to systemic amyloidosis. Statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Results: We identified 117 patients, with a median age of 70 years, who had light chain amyloidosis detected in abdominal fat aspirate and/or bone marrow biopsy, without systemic involvement. Amyloid was seen in fat only in 39%, marrow only in 54% and in both sites in 7%. The median follow up was 45.6 months (95% CI-38.1-57.7) from detection of amyloid. Of these, 64% were alive at the time of analysis. Among 117 patients, 65 were treated for a diagnosis of another plasma cell disorder made prior to or concurrent with detection of amyloid. The remaining 52 patients only had isolated fat or marrow amyloid. Among 65 patients with another diagnosis of plasma cell disorder requiring treatment, 3 progressed to systemic amyloidosis, one each with cardiac, renal and lymph node (LN) involvement detected at 32, 42 and 65 months respectively from the detection of amyloid. The first 2 patients had underlying multiple myeloma, and the third patient with LN involvement had underlying Waldenström macroglobulinemia. Among 52 patients without another diagnosis of a plasma cell disorder requiring treatment, at a median follow up of 32 months, no progression to systemic amyloidosis was observed. Median overall survival (OS) in 117 patients from detection of amyloid, using Kaplan-Meier survival estimates, was 60.2 months (95% CI-48.9-146.1). Conclusion: Our study highlights the fact that isolated amyloidosis detected in fat and/or bone marrow aspirate, in the absence of another plasma cell dyscrasias that require therapy, is unlikely to progress to systemic amyloidosis. Watchful waiting might be considered in such patients after a thorough evaluation to rule out systemic involvement. Disclosures Gertz: Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Abbvie: Research Funding; Millenium: Consultancy, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Abstract Abstract 2970 Background: Over a quarter of patients (pts) with symptomatic multiple myeloma (MM) have some degree of renal insufficiency at the time of diagnosis. Multiple studies show that presence of renal failure is strong predictor of inferior overall survival in MM. With effective therapy, renal function improves in a considerable number of patients. It is not clear if the return of renal function to normal levels will improve their outcome to that expected for patients without renal dysfunction. Methods: We evaluated 1478 patients with newly diagnosed myeloma seen at Mayo Clinic within 90 days of diagnosis, between January 1999 and January 2009. We examined these patients for improvement in renal function and identified the lowest serum creatinine obtained during the disease course. The outcomes were analyzed with respect to the renal function improvements. Results: The median age at diagnosis was 64 years (range; 22–93) and 50% were male. The median estimated follow up for the entire cohort was 53 months, with 781 patients alive at the time of analysis with a median follow of 3 years. The serum creatinine was over 1.5 mg/dL at diagnosis in 333 (22.5%) pts and over 2.5 mg/dL in 148 (10%) pts. The median overall survival for the 333 patients was 37 mos (95% CI; 28, 40) compared to 56 mos (95% CI; 51, 63) for those < 1.5 mg/dL; P < 0.001. Among the 333 pts with baseline Cr > 1.5 mg/dl, any improvement in Cr was seen in 263 (79%) including an improvement of at least 0.5 mg/dL in 208 (62%) pts. Among the 263 pts with any improvement, the median time to lowest Cr was 4 months (range; 1–13). The median survival of the group of patients with Cr <= 1.5 mg/dl, over 1.5 mg/dL at diagnosis but improved to <= 1.5 mg/dL, or remained >1.5 mg/dL were 56., 40 and 27 mos respectively; P < 0.001, Figure). We then examined the impact of renal function improvement in the group of patients where the baseline Cr was >2.5 mg/dL. The median OS for the 42 (out of 148 pts with Cr > 2.5 at diagnosis) who had improved to <=1.5 mg/dL was 40 mos compared to 56 mos for those with a Cr <= 1.5 mg/dL at diagnosis and 27.4 mos for the 106 pts whose Cr did not decrease to <= 1.5 mg/dL; P < 0.001. Conclusion: The results of this study point toward improved outcome among patients with renal dysfunction in whom renal function improves. However, it shows that this improvement in renal function does not necessarily improve survival to that observed for the patients with a comparable level of serum creatinine at diagnosis. While early treatment of asymptomatic myeloma has been shown to have little impact on overall survival, a strategy of waiting for serious features of target organ damage to appear before initiation of treatment may have a negative impact on survival in some patients, especially patients with high light chain production who have a higher predilection for renal insufficiency. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

Abstract Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables. Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC). Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS. Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants. Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS. Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. Figure 1. Overall survival of 722 patients according to MCF<21%. Figure 1. Overall survival of 722 patients according to MCF<21%. Disclosures Kumar: AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Abstract Abstract 2797 Poster Board II-773 Background: Primary systemic amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in multiple organs leading to varying degree of dysfunction. Cardiac involvement is a common feature of AL, and when significant is highly predictive of poor outcome. The currently used prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro B-type Natriuretic peptide (NT-ProBNP) and is effective at predicting outcome in patients with AL. However, this is driven primarily by the degree of cardiac involvement and does not take into account the degree of plasma cell burden and its impact on the disease course. It is possible that some of the heterogeneity in outcome can be explained by the plasma cell characteristics rather than the degree of the end organ damage. Methods: We examined the baseline clinical and laboratory data from 2119 patients with AL who were seen at our institution with in 90 days of their diagnosis. The data were collected from a prospectively maintained data base, and additional testing was done for free light chain levels (FLC) on stored sera from patients seen before the routine introduction of FLC testing. Cox proportional hazards analysis was performed to estimate the prognostic values of different variables. Results: We first examined the impact of plasma cell clone related characteristics namely, difference between involved and uninvolved FLC (FLC-Diff), bone marrow plasma cell (BMPC) %, plasma cell labeling index (PCLI), beta 2 microglobulin (B2M), and presence of circulating plasma cells, on overall survival (OS) from diagnosis. All variables were dichotomized into high and low based on their median value (FLC-diff: 20 mg/dL, BMPC: 10%, PCLI as a continuous variable, B2M: 3 mg/dL and circulating cells: absent or present). While all were found to be prognostic for OS in univariate analysis; in a multivariate analysis incorporating a stepwise selection only B2M and FLC-diff were significant. We then used these two variables along with the cTnT and NT-ProBNP that are used in the current model to develop a staging system. The median values for all four variables were used for developing the scores. Patients were assigned a score of 1 for presence of each characteristic (FLC difference > 20 mg/dL, troponin-T > 0.02, NT-ProBNP > 1000, and B2M > 3) or 0 if the value was at or below the cutoff. The scores were added to obtain a composite prognostic score that grouped the 370 patients (who had all the variables available for analysis) into 5 groups with very different OS (4.4, 9.3, 24.4, 43, and not reached for stages 4, 3, 2, 1, and 0 respectively; Figure A). However, since the NT-ProBNP did not have independent impact on survival in a multivariable model incorporating all the four variables, we also examined a system that only included FLC-diff, cTnT and B2M. This system again allowed grouping of patients (n=450 with all three variables available) into four distinct groups with divergent outcome with OS of 4.6, 10.5, 36.8, and not reached for stages 3, 2, 1, and 0 respectively; (Figure B). Conclusion: Incorporation of plasma cell related measurements into the existing staging system using cardiac biomarkers allows better risk stratification of patients with AL amyloidosis. The system using FLC, B2M and troponin has the advantage of easily available laboratory values and can be widely adopted. Addition of NT-ProBNP into the system allows better refinement of the intermediate risk groups. This system will allow upfront risk stratification and development of risk-adapted therapies for patients with AL. Disclosures: Gertz: Genzyme: Research Funding.

Abstract Abstract 1892 Background: Primary or light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multi-organ deposition of immunoglobulin light chain derived amyloid fibrils. The survival of patients with amyloidosis is quite variable with median survival of 12–18 months in different series, and largely dependent on the number and severity of organs involved. In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL and risk adapted approaches to SCT has decreased treatment related mortality. It is not clear if the recent progress in risk stratification and treatment approaches have translated into improved survival for these patients. Methods: We studied two separate cohorts of patients; the first cohort consisting of 2118 patients with AL seen at Mayo Clinic over a 40-year period between November 1967 and August 2006 was used to examine the trends in overall survival from diagnosis during this time period. The second cohort of 443 patients seen between September 2006 and August 2009 were examined only for the changes in early mortality and for validation of a model for predicting early mortality developed using the first cohort of patients. Results: The estimated median follow up for the entire group was 7.8 years (95% CI; 7.1, 8.5). The patients were divided into 4 cohorts based on date of diagnosis; 1966–1976 (n=121), 1977–1986 (n=343), 1987–1996 (n=636) and 1997–2006 (n=1017). The median OS from diagnosis for the four cohorts were 0.9, 1.2, 1.2 and 1.5 years respectively, P < 0.001 (Figure 1). More importantly there was steady improvement in the long-term survival among these patients with 4-year survival estimates of 16%, 21%, 24% and 33% respectively. Next, we specifically looked at the survival trends within the last cohort (1996-2006), dividing the patients into three time periods; 1996–1999 (n=263), 2000–2003 (n=291) and 2003–2006 (n=463). While the OS from diagnosis was relatively unchanged between the first and second time periods (28 vs. 30% 4 year survival), there was significant improvement in the last three year period (42% survival at 4 years); P =0.02. Given the high early mortality in this disease, we specifically examined the one-year mortality among the entire patient cohort and found no clear improvement in terms of one-year mortality. Using logistic regression analysis, we identified cTnT > 0.01, NT-ProBNP > 4200 and Uric Acid > 8.0 mg/dL to be the best predictors of death within one year of diagnosis. The probability of death within one year for those with none, 1, 2, and 3 risk factors was 19, 38, 61, and 78% respectively, P < 0.01 (Figure 2). This model was further validated among patients seen during the most recent three years, September 2006 and August 2009. Conclusion: Survival in AL amyloidosis has improved over time, particularly in the recent years and likely reflects the recent improvements in therapy. However, early mortality remains a problem and baseline factors can be used to identify patients at risk for early mortality, who then can be targeted for risk adapted therapy approaches in clinical trials. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 1964 Background: Thalidomide (thal), lenalidomide (len) and pomalidomide (pom) have been shown to have considerable efficacy in patients with newly diagnosed as well as relapsed multiple myeloma (MM). They are often used as initial therapy in patients proceeding to stem cell transplant (SCT), and based on the initial response, are usually considered for salvage therapy during their disease course. However, the retreatment efficacy of these compounds is unknown. We conducted this study to ascertain the degree of response that can be obtained by retreatment with immunomodulatory compounds. Patients and Method: 410 patients with newly diagnosed MM who received either thalidomide-dexamethasone or lenalidomide-dexamethasone were studied. Of these, 183 patients received thalidomide, lenalidomide or pomalidomide (with or without dexamethasone) as one of the salvage regimens following relapse, and form the study group. We included all patients who received the repeat immunomodulatory therapy as salvage treatment at any time during the MM disease course. Results: The median (range) age of the MM patient group was 60 (29-80) years; 117 (64%) were male. Thalidomide and lenalidomide were used as initial therapy in 106 (58%) and 77 (42%) patients, respectively. Patients received a median of 2 treatments (range, 1–6) prior to salvage therapy; bortezomib was used as one of the salvage treatment (prior to the repeat immunomodulatory therapy) in 41 (22%) patients. An autologous stem cell transplant was performed in 118 (64%) patients after the initial immunomodulatory therapy. Almost one half (89; 49%) of the patients went off the first line therapy to undergo a SCT; whereas drug toxicity (26; 14%) and disease progression (21; 11%) were other causes requiring a treatment change. The compound used for salvage therapy was thalidomide, lenalidomide or pomalidomide in 40 (22%), 129 (70%) and 14 (8%) patients, respectively. The responses to salvage therapy based on the initial therapy and the salvage regimen are as shown in Table 1. Overall, 67 (37%) patients achieved a partial response or better and 73 (40%) patients achieved less than a partial response (stable and progressive disease) to repeat immunomodulatory therapy, while the remaining 43 (23%) had non evaluable disease response. Conclusions: Retreatment with an immunomodulatory therapy, especially a different compound, was associated with excellent response rates. Lowest response rates were seen in patients retreated with thalidomide after having received lenalidomide as their initial therapy after the diagnosis of MM. This information is valuable in deciding on the choice of repeat therapy with immunomodulatory compounds in patients with relapsed disease. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Abstract 2803 Poster Board II-779 Background. The rate of asymptomatic amyloidosis (asym-amyloidosis) detected in patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. This topic is significant because unrecognized AL may be associated with increased mortality may change the patient's management. The objective of the present investigation was to evaluate the number and clinical significance of asym-amyloidosis in MM and SM patients at the time of the diagnostic bone marrow (BM) biopsy for MM. Materials and Methods. The study population was selected from the Mayo Clinic Dysproteinemia database and consisted of consecutive patients with an established diagnosis of MM or SMM without recognition of symptomatic AL. Bone marrow biopsies at diagnosis of MM or SMM were retrospectively stained with Congo Red and reviewed by a single pathologist. A patient was considered to have asym-amyloid if Congo Red staining with apple green birefringence was found. Results. Biopsies from 144 (M 84, F 59) patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years. No differences were found regarding hemoglobin, platelets, prothrombin time, serum and urine proteins, serum albumin, alkaline phosphate, creatinine and β2-microglobulin among MM and SMM patients. At a median follow-up 76 months (range 0-216), 32% patients were alive, 65% dead and 2.7% lost to follow-up. Immunoglobulin isotypes were as follows: 96/144 (67%) had IgG 23/144 (16%) IgA, 12/144 (8%) had light chain only, 1/77 (1%) had IgD, none had IgM and 12/144 (8%) had biclonal or indeterminate; 84/144 (58%) were κ restricted. The presence of amyloid was found in only 2 cases (1%, 95% CI – 0.6 to 3.2), 1 in MM and 1 in SMM group. Neither of these patients had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, 1 (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months of follow-up. Characteristics of these three patients are shown in table 1. Conclusions. We found only 2 cases (1%) of amyloidosis in the 144 cases of MM or SMM. Our estimates are lower than the rates which have been reported by others, perhaps because of our high level of suspicion for amyloid at our Amyloidosis Center. These data do not support the need for searching for asym-amyloidosis in patients with newly diagnosed MM or SMM as long as they have no clinical features of AL. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT. Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein &lt; 100 mg/24 hours. Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant. Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.

Abstract Background: Autologous stem cell transplantation (SCT) improves survival in patients (pts) with multiple myeloma (MM). We have previously demonstrated that the degree of response at transplant does not impact on the outcome of transplant. However, newer induction regimens such as thalidomide and dexamethasone (Thal-Dex) result in higher response rates compared to previously used regimens such as single agent dexamethasone or vincristine, doxorubicin, and dexamethasone (VAD). We examined the outcome of SCT following three different induction therapies for newly diagnosed MM, namely VAD, single agent Dex, and Thal-Dex. Patients and Methods: 340 patients with MM who received their SCT within 12 mos of diagnosis (median 5.8, range 3–12) were studied. Patients receiving more than one induction therapy as well as those in whom thalidomide was added to dexamethasone for lack of response were excluded from the analysis. There were 105 pts in the VAD group, 140 in the Dex group and 95 in the Thal-Dex group. Responses were defined using standard criteria. Results: The study cohort consisted of 209 males (59%), with a median age of 57 years (range 30–76) at transplant. Baseline characteristics were similar in the 3 groups, except for lower age in the VAD group (median 55.8) compared to Dex (59.6) and Thal Dex (57.4) and shorter time to transplant in the Dex group (5.4 m) compared to VAD (6.4) and Thal Dex (5.9). Markers of disease activity pre-transplant, including B2M and marrow plasma cell percentage were higher in the Dex group compared to either VAD or Thal Dex. The proportion of patients with any response to induction therapy was lower in the Dex group compared to the other two. All pts in the Dex and the Thal-Dex groups received melphalan only conditioning compared to 70% in the VAD group, the rest receiving Melphalan/TBI. An objective response was achieved after SCT in 96%, 97%, and 98% of pts in the VAD, Dex and Thal-Dex groups respectively (P=0.8). A complete response to SCT was seen in 49% of patients in VAD group, 45% among those in the Dex group and 38% among those in the Thal Dex group (P=0.38). There was no difference in the median progression free survival after transplant (P=0.21) or overall survival from diagnosis (P=.34) between the three groups. The proportion free from progression at 2 years post transplant was 54%, 55% and 46% for Dex, VAD and Thal-Dex respectively. The proportion surviving at 4 years from diagnosis was 64%, 65.4% and 72% respectively for the three groups. Conclusion: We did not observe any difference in the response rates including complete responses to SCT in the three groups with nearly all pts in each group achieving a response. The progression free survival and overall survival appear to be comparable between the three groups. The results from initial therapy cannot be compared between the three regimens since the study population is restricted to patients reaching stem cell transplant. Within the limits of the study, there does not appear to be any long term impact of the initial therapy for the patients going onto an early stem cell transplant. Figure Figure

Abstract Immunoglobulin (Ig) light chain (LC)-associated amyloidosis (AL) is a fatal plasma cell (PC) disorder characterized by the overproduction of Ig light chains that deposit in an abnormal conformation as amyloid throughout the body. Lambda LC are involved in amyloid deposition 2–3 times more often than kappa LC, and certain LC Ig variable genes are more frequently involved than others and influence clinical presentation and outcome. AL is a potential complication of any immunoglobulin clonal process, but is most often pathologically associated with minimal clonal expansion of PC, as seen in monoclonal gammopathy of undetermined significance. It is much less commonly observed in patients with multiple myeloma (MM). Because of this, and to our knowledge, there are no cell lines that have been established from AL patients, an experimental tool that would be of great value in studying amyloid formation and the biology of amyloid producing PC. In this study, we have established two cell lines from a 50 yr old female initially diagnosed with AL. Upon initial diagnosis, the BM aspirate consisted of 27% IgG λPC with a PC labeling index (PCLI) of 1.9% and a κ to λratio of <0.1. Amyloid was present in periosteal vessel walls and in the fat aspirate. The first cell line, ALMC-1, was established from BM mononuclear cells isolated from the diagnostic aspirate. The patient received a peripheral blood stem cell transplant (PBSCT) 2 months later, but relapsed within 100 days post-PBSCT with symptomatic myeloma. At relapse, the patient’s BM aspirate consisted of 70% λ+ PC and a PCLI of 20%; the second cell line, ALMC-2 was established from this aspirate. IgVL and IgVH analysis revealed that both cell lines expressed identical sequences and used IgVλ 6–57*01, IgλJ3*02, and IgλC3*03: both used the IgVH VH3–21 gene and the extent of somatic mutation was approximately 4%. Both cell lines produce significant FLC, and studies are currently underway to characterize in vitro amyloid production. We next used fluorescence in situ hybridization (FISH) to identify the genetic defects in this patient’s tumor population before and after transition to symptomatic MM. The initial BM aspirate at time of diagnosis of AL revealed approximately 30% of the PC had clear evidence of c-MYC gene amplification. In the subsequent draws as well as in both cell lines, 100% c-MYC amplification was identified, consistent with clonal selection. FISH analysis also revealed that 40% of cells had p53 deletion upon initial diagnosis, whereas the subsequent samples and cell lines were 100% for p53 deletion. All cells also had an IgH translocation that did not involve any commonly observed chromosome partners. Lastly, we have characterized the cytokine responsiveness of both cell lines. Although some differences are observed between ALMC-1 and ALMC-2, IL-6 and IGF-1 stimulated growth in both cell lines to varying degrees and both lines expressed autocrine IGF-I. In summary, our initial characterization of ALMC-1 and ALMC-2 predicts that these unique cell lines will prove to be an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology. Insight gained from this model system may eventually have an impact in the clinical arena by providing a better understanding of this incurable disease.