ALBERT

Description: Background There is ample data for the response rates and clinical outcomes for patients with newly diagnosed multiple myeloma (MM) treated with first-line lenalidomide and dexamethasone (LEN/DEX). Phase II and III studies have reported objective response rates (ORR) in the range of 70-90%.  However, extrapolating from clinical trials to ‘real world' clinical practice is sometimes difficult. This is particularly so when it comes to large city hospital systems such as Jackson Memorial Hospital (JMH) in Miami, Florida. JMH is the third-largest public hospital and third-largest teaching hospital in the United States. Patients are primarily uninsured or insured through Medicaid. Additionally, one might surmise, that for a medication like LEN- with a relatively narrow therapeutic index, high cost, and cumbersome prescribing/dispensing requirements- outcomes in the ‘real world' might be inferior to those cited in clinical study. We endeavored to explore such outcomes in JMH to determine whether the benefits of this high cost drug in this setting are concordant with published data. Methods We conducted a retrospective analysis of all patients enrolled into the Celgene patient assistance program and prescribed LEN from January 1, 2010 through July 30, 2013 at JMH. We identified 96 patients enrolled into this program, 35 patients received LEN/DEX as first-line therapy for MM and are evaluable for this analysis. The primary end-point for analysis was response at 4 months. Results Medical records of 35 patients were reviewed. The mean age was 59 (46-75), majority of patients were female (60%), and 29% were black. Consistent with our patient population, 71.4% of patients were Hispanic, 44% were uninsured, and 64% had Medicaid. IgG (60%) was the most common heavy chain involved while 3 patients had light chain disease only. The majority of patients (88.6%) had stage III disease by the Durie-Salmon criteria, and 37.1% had ISS stage III disease. Cytogenetic studies were evaluable in 30 patients: 66.7% were standard-risk, 30% intermediate-risk and 3.3 % high-risk according to mSMART risk classification. At 4-month follow-up, 26 (74.3%) patients had an OR: 6 (17.1%) patients had CR, 7 (20%) had VGPR, and 13 (37.1%) had PR. 6 (17.1%) patients had progressive disease, change in therapy, or were lost to follow-up. There were no documented deep venous thromboses, a known risk of LEN therapy. Only 8 patients (23%) underwent autologous stem cell transplant following primary therapy. Conclusion Responses with upfront LEN/DEX in MM at JMH, were relatively similar to published data in large clinical studies. This provides support for the extrapolation of data from well supported clinical trials at fully-resourced medical institutions, for an oral chemotherapy drug with significant potential toxicities and logistical barriers, to a primarily Medicaid patient population in a county hospital. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, therefore forcing the nuclear retention and re-activation of cell cycle regulators such as p53, FOXO, IkB, and Rb. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, which induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (TCR-MM). Patients with TCR-MM often present with plasmacytomas along with serological markers of MM. Methods: Here we analyzed the effects of Sel-dex in patients from the STORM study who had baseline plasmacytomas. Results: 122 patients were in enrolled in the STORM study including 27 with a baseline plasmacytoma. The majority of plasmacytomas were soft tissue (22 patients) and 5 patients had soft tissue disease extension from a bone (rib (2), iliac (2), sacral vertebral). The median age of patients with plasmacytomas was 64 years, the median prior therapies were 7 (range 4 - 15), and 8/27 patients with a plasmacytoma had high risk cytogenetics. Of the 27 patients, 11 patients did not have a follow up plasmacytoma assessment: 6 were not evaluable for response as they came off therapy due to clinical progression and/or adverse events, 4 had stable disease (SD) with no evidence of plasmacytoma change, and 1 had progressive disease (PD) on serum M-protein with no evidence of plasmacytoma change. Sixteen of the 27 patients did have follow-up plasmacytoma assessments (methods of measurements included PET, CT, MRI or Clinical). The median days from baseline plasmacytoma evaluation to follow up was 41 days (range 22 - 119). Five patients had objective responses, based upon para-protein and plasmacytoma reductions according to IMWG criteria (1 very good partial response [VGPR], 4 partial responses [PR]) for an ORR of 18.5%. In addition, 2 patients had a minimal response (MR), 4 had SD and 5 had objective PD. Among the 5 patients with ≥PR, 3 plasmacytomas completely resolved, 1 showed near complete resolution, and another showed size reduction with no metabolic activity on PET. Of the 2 patients with a MR, 1 plasmacytoma completely resolved and 1 showed reduced PET uptake. Among the 4 patients with SD, 1 plasmacytomas completely resolved, 1 increased in size and 2 had unknown outcomes as they were assessed clinically. Among the 5 patients with PD, 1 plasmacytomas decreased in size, 1 increased in size, and 3 had unknown outcomes as they were assessed clinically. Conclusions: Of the 16 patients with TCR-MM and a follow up plasmacytoma assessment enrolled on STORM, 9/16 of the plasmacytomas either completely resolved or decreased in size and/or metabolic activity. Effects on plasmacytomas occurred in patients with objective responses (≥PR), as well as in patients with MR, SD and PD. These observations support the finding that Sel-dex is active in patients with plasmacytomas and heavily pretreated TCR-MM. Disclosures Yee: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Chari:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Oncoceutics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Nooka:Adaptive technologies: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Moreau:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lonial:Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Prothena: Research Funding; Amgen: Research Funding; Karyopharm: Honoraria; Alnylam: Honoraria, Research Funding; Sanofi: Research Funding; Merck: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hoffman:Celgene: Speakers Bureau. Costa:Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor. Biran:Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Picklesimer:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Li:Karyopharm Therapeutics: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy.

Description: Introduction: Daratumumab is an IgG Kappa monoclonal antibody (mAB) to CD38, a surface glycoprotein expressed on plasma cells. It was approved in 2015 as monotherapy for Multiple Myeloma (MM) patients who failed three prior lines of therapy. Its approval was then expanded to second line and most recently first line. As such, patients are now getting earlier and longer exposure to this mAB. Disease response to daratumumab is monitored by demonstrating a fall in paraprotein levels. It is becoming widely appreciated that hypogammaglobulinemia (HGGE) ie. (IgG

Description: Abstract 2948 Systemic AL amyloidosis is a proteotoxic clonal plasma cell disorder in which amyloid-forming immunoglobulin light chains produced by the clonal plasma cells cause cellular toxicity and deposit as fibrils, leading to organ dysfunction and death, usually of a cardiac cause. Distinguishing AL from other types of amyloidosis such as senile systemic due to wildtype (ATTRwt), or hereditary due to mutant transthyretin (ATTRm), can be challenging and has significant clinical ramifications. The incidence of monoclonal gammopathies (MG) is increased in African-Americans and in older patients; patients in those categories who have ATTRwt or ATTRm are more likely to have MG and are therefore at increased risk of being misdiagnosed with AL and receiving cytotoxic chemotherapy inappropriately. Over a 6 year period at Memorial Sloan-Kettering Cancer Center, 369 consecutive patients with systemic amyloidosis were evaluated for clonal plasma cell disease and 30% of them were screened for hereditary ATTRm based on African-American race, dominant peripheral neuropathy or having been referred with a tissue diagnosis of amyloidosis without apparent MG. A mutant transthyretin was identified in 5.4% (20/369; 7 Ala60Thr, 4 Ile122Val (one homozygote), 4 Phe64Leu, 4 Val30Met and 1 Glu89Gln). In addition, ATTRwt was diagnosed in 4% (15/369). Of the 20 consecutive patients with mutant TTR, 10 had an associated gammopathy, 6 monoclonal and 4 polyclonal. Those with MG had 2 potential sources of amyloidogenic proteins - the light chains associated with the MG and the mutant TTR. We used several available approaches to establish a conclusive diagnosis, including immunohistochemistry (IHC) and more definitive typing via mass spectrometry (MS) and immunogold electron microscopy (IEM). Ultimately, 4 of the 6 with MG and mutant TTR were diagnosed with ATTRm, while the other 2 had AL amyloidosis and were treated with chemotherapy. Of note, one patient was initially thought to have ATTRm based on IHC, but then shown to have AL based on MS. Interestingly, none of the 15 consecutive patients with SSA had a gammopathy despite being an older cohort (med age 76.5 vs 64). This lends credence to the hypothesis that patients with TTR mutations may be at increased risk of developing gammopathies (50% in this series). The significance of this rate of coincidence is two-fold. First, the mutant TTR protein may be immunogenic, as has been suggested.1 Second, this heightens the need for diagnostic vigilance and willingness to perform direct tissue typing. Kindreds with hereditary disease may be at greater risk of being misdiagnosed and treated for AL then would be expected based on population wide incidence. Clinical diligence and use of the newest techniques for pathologic typing are essential.2 O'Nuallain B, Hrncic R, Wall JS, Weiss DT, Solomon A. Diagnostic and therapeutic potential of amyloid-reactive IgG antibodies contained in human sera. J Immunol. 2006 Jun 1;176(11):7071-8. Vrana J, Gamez J, Madden B, Theis J, Bergen H, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry based proteomic analysis in clinical biopsy specimens. Blood. 2009. Dec 3; 114(24):4957-9. Disclosures: Comenzo: Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding.

Description: Background Multiple myeloma is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent metabolic complication of myeloma in patients, and excessive osteolysis plays a major contributory role in its pathogenesis. Hypercalcemia caused by increased blood levels of PTHrP have been found in patients with solid tumors and are uncommon in patients with hematologic malignancies including multiple myeloma. Here we present a unique case of a rare variant of multiple myeloma, IgG heavy chain disease, presenting with PTHrP associated hypercalcemia. Methods A retrospective chart review of one patient from 2011-2013 including clinical history, laboratory data, imaging, and pathology was performed. Results A 60 year old female with past medical history of stage IIA Hodgkin's lymphoma diagnosed in 1992, treated with total nodal radiation with recurrence in 1997 treated with 6 cycles of ABVD achieving complete remission. The patient was found to have hypercalcemia (11.0 mg/dL) and renal failure (1.29 mg/dL) in March 2011. Hypercalcemia workup revealed suppressed PTH (

Description: Abstract 2815 Poster Board II-791 Background: The clonal plasma cells in AL can be considered malignant because they contain cytogenetic abnormalities, including t(11;14) in 40% to 50% of cases (Blood 2001;98:2266; 2008;111:4700; Haematologica 2009;94:380). By gene expression profiling (GEP) they are also reported to overexpress CCND1 (Blood 2005;105:794). To assess the frequency and significance of differences in CCND1 expression in plasma cells from AL patients at diagnosis, we evaluated the differences in CCND1 expression in CD138+ plasma cells from newly diagnosed patients. We then correlated these differences with features of both the deposition and clonal plasma cell diseases, and with treatments, outcomes and overall survival. Methods: Newly diagnosed AL patients were evaluated and CD138+ cells selected and used for GEP with Affymetrix U133 PLUS2.0 arrays (Affymetrix; Santa Clara, CA) or qRT-PCR as previously described (JNCCN 2007;5:179; Blood 2008;111:549). qRT-PCR was performed using TaqMAN Gene Expression Assays with CCND1 (Hs00277039_m1) and RPLP0 (Hs99999902_m1) primers and probes (Applied Biosystems; Foster City, CA) and 2 myeloma cell lines as positive and negative controls (KMS-12BM, RPMI 8226) on an Mx 3000P platform and related software (Stratagene; La Jolla, CA). The comparative Ct method was used and the amount of target was normalized to the control (2-ΔΔCt) assuming an efficiency of 2. Statistical analyses were performed with GraphPad PRISM (GraphPad; La Jolla, CA). Results: CD138+ cells from 58 newly diagnosed AL patients were evaluated. With GEP (n=16), CCND1 median loge-transformed quantitative expression levels were 11.08 (range, 9.6-11.55) in five versus 4.163 (3.875-5.447) in eleven patients (P 〈 0.01). With qRT-PCR (n=42), relative CCND1 expression levels were 4.21 (1.76-17.24) in twenty versus 0.014 (0-0.99) in twenty-two patients (P 〈 0.0001). Overall, 43% (25/58) of patients were CCND1+ and did not differ from CCND1- patients with respect to organ involvement, troponin I, urine total protein, creatinine or alkaline phosphatase levels. The median BNP of CCND1+ patients was 252pg/ml (range 20-1880), significantly higher than that of CCND1- patients (109pg/ml (5-4210), P 〈 0.05). CCND1+ patients tended to have more plasma cells (13% versus 8%, P = 0.06), higher serum free light chain levels (23.3 versus 14mg/dl, P = 0.12) and more kappa clones (6/25 versus 2/33, P = 0.06), and had fewer intact immunoglobulin M-proteins (4/25 versus 22/33, P 〈 0.01). There were no differences in frequencies of treatment with stem cell transplant or oral melphalan/dexamethasone or in the rates of complete hematologic responses. CCND1+ patients survived a median of only 27 months compared to 60 months for CCND1- patients (P = 0.02) and had a risk of death of 2.86 (CI 1.18-6.94). Conclusions: Significant differences in CCND1 expression in the plasma cells of AL patients at diagnosis can be appreciated by GEP and qRT-PCR and clearly define two groups, CCND1+ and CCND1-, that differ in baseline BNP levels and features of the clonal plasma cell disease. Despite similar treatments and initial responses, CCND1+ patients have poorer overall survival, possibly due to asymptomatic cardiac involvement at diagnosis and low-level persistence of clonal plasma cells despite treatment, hypotheses that merit prospective evaluation. Disclosures: Comenzo: Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 4043 Cyclin D1 (CCND1) overexpression in AL plasma cells (PC) is associated with patient characteristics such as production of free immunoglobulin (Ig) light chains (FLC) without an intact M-protein (that is, without partner Ig heavy chains), increased cardiac biomarkers and shorter survival (Amyloid 2010;17(S1):61a; Blood 2008;111:4700; Haematologica 2009;94:380). The molecular ramifications of CCND1 overexpression within AL PC clones have not been described. To study these associations, we used CD138+ AL PC from 69 untreated AL patients at diagnosis for (1) gene expression profiling (GEP, Affymetrix U133A 2.0) (n=16), (2) qRT-PCR to validate GEP findings (n=53), and (3) clonal IgVL germline donor gene identification (n=69) by established methods (Blood 2008;111:549; Blood 2001;98:714). By GEP, all cases displayed significant overexpression of the appropriate isotypic IgVL constant region gene, confirming the preponderance of clonal AL PC. Five cases were CCND1hi and 11 CCND1lo, and a supervised analysis of CCND1hi vs CCND1lo transcriptomes showed that in CCND1hi PC among the most down-regulated genes were IGHG1, IGHG3 and CCND2 while among the most up-regulated ones (after CCND1) were FAM129A, WARS, SEC63, PDIA6 and SEL1L. By RT-PCR all 53 cases used for qRT-PCR displayed prominent amplification of spliced and unspliced XBP1, confirming PC derivation. By qRT-PCR, median CCND1 expression was 1.51 (range, 0–19.36) with 27 cases above (CCND1hi) and 26 below the median (CCND1lo) with clear-cut quartile differences (25% 0.02, 75% 4.78). We examined PDIA6 and SEL1L expression by qRT-PCR, and found that both correlated with CCND1 expression (PDIA6, P=0.018, r=0.452; SEL1L, P=0.038, r=0.395). In addition, PDIA6 and SEL1L values above and below the CCND1 median differed significantly (P=0.01, P=0.04). The genes up-regulated in CCND1hi cases are involved in endoplasmic reticulum (ER) and protein control processes: WARS in protein production, FAM129A in autophagy, SEC63 in ER protein transport, PDIA6 in catalysis of disulfide bonds and SEL1L in modifying misfolded proteins and channeling them to cytosolic proteasomes. We then identified the clonal IgVL germline donor genes in the CCND1hi (n=32) and CCND1lo (n=37) AL PC clones. We knew that CCND1hi clones displayed biased Ig light chain restriction with 10/12 κ and 22/57 λ cases being CCND1hi (p=0.009, Fisher's exact). Surprisingly, we also identified biased λ family use as only 6/27 λ1 and λ2 cases were CCND1hi compared to 16/30 λ3 and λ6 cases (P=0.03). Overall these results confirm that CCND1hi AL PC clones express significantly higher levels of important ER protein quality control genes than CCND1lo clones, possibly due to CCND1hi AL PC clones adapting to the production of FLC without partner Ig heavy chains. Moreover, CCND1hi AL PC clones display a biased clonal IgVL germline donor gene repertoire, raising questions about the origin of CCND1hi clones since germline gene selection is an early and CCND1 overexpression likely a late event in malignant clonal PC emergence. Disclosures: No relevant conflicts of interest to declare.

Description: High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic light-chain amyloidosis (AL) and a risk-adapted approach to MEL dosing minimizes transplant-related mortality (BJH2007; 139). The depth and duration of hematologic response to treatment with SCT or conventional chemotherapy have been shown to correlate with overall survival (OS). Patients who do not achieve a complete hematologic response (CR) after SCT and are initially observed have a median OS of 24 months (Leukemia Lymphoma2000;37:245). In an effort to improve the OS of those not achieving CR, and based partly on trials in multiple myeloma showing benefit, we have explored adding early adjuvant therapy (AT) to the treatment of AL patients with persistent clonal plasma cell disease post-SCT. We have enrolled patients on two consecutive SCT+AT protocols, the first utilizing adjuvant dexamethasone (Dex) +/− Thalidomide (Thal) and the second Dex + Bortezomib (Bort). AT was added at 2 or 3 months post-SCT for those with partial hematologic response or stable hematologic disease. We assessed the outcomes on these protocols with respect to AT-related mortality, hospitalizations in the first year post-SCT, immune recovery and OS. Sixty-four patients enrolled on these trials and 59 survived 2 to 3 months post-SCT to be evaluated for hematologic response. Seventeen were observed without AT while 42 received AT (10 Dex, 21 Dex+Thal, 11 Dex+Bort). There were no deaths due to AT. Thirteen of the 42 patients receiving AT (31%) were hospitalized during the first year post-SCT (6 with pneumonia [5 viral, 1 fungal]; 1 with sinusitis and S. pneumo bacteremia; 3 with congestive heart failure; 2 with pulmonary emboli; 1 with avascular necrosis of the hip) as compared to 2 hospitalizations (1 with engraftment syndrome; 1 with diarrheal illness) in the 17 patients not receiving AT (12%; p= 0.23 by χ2). At 1 year post-SCT median absolute lymphocyte counts (ALC) and IgG levels were lower in the AT group (ALC: 1.0 (0.4–2.9) vs 1.7 (0.9–5.1), p=0.01; IgG: 569 (205–1650) vs 867 (635–1200), p=0.04, two-tailed Mann-Whitney), and IgA recovery at 1 year was impaired in the AT group as well (p=0.07). Twenty-four of the 42 patients receiving AT (57%) had improved hematologic responses, including 10 of 11 patients receiving Dex+Bort, with 13 of 42 achieving CR (31%). Median overall survival has not been reached for those with CR to SCT and is 59 months for those who received AT (p=0.06). In sum, AL patients in this series receiving early AT post-SCT were more frequently hospitalized in the first year and had impaired immune recovery. However, over half of the AT patients had improved hematologic responses and, as a cohort, the median overall survival of AT patients was more than twice that of historical controls receiving SCT followed by observation alone.

Description: Abstract 316 Introduction: Hematopoietic stem cell migration out of the bone marrow is essential for effective and successful stem cell transplantation. Sympathetic nervous system signaling has been shown to regulate hematopoietic stem cell egress from bone marrow. Ablation of adrenergic neurotransmission in animal models indicates that norepinephrine signaling controls granulocyte colony stimulating factor (G-CSF) -induced osteoblast suppression, CXCL-12 (or stromal derived factor-1 (SDF-1)) down regulation and hematopoietic progenitor cell mobilization (Katayama Y, et al. Cell 2006). In addition, β adrenergic agonists and antagonists enhance and reduce stem cell mobilization, respectively. High dose therapy and stem cell rescue following G-CSF mobilization is a standard approach to the treatment of patients with light chain (AL) amyloidosis. In patients with AL amyloidosis, we prospectively studied the relationship between catecholamine levels and the efficiency of stem cell collection. Methods: In AL amyloidosis patients enrolled on a phase II clinical trial using G-CSF mobilization and high dose melphalan conditioning, 24 h urine samples were collected and analyzed for epinephrine, norepinephrine and dopamine excretion before G-CSF administration and after stem cell collection was completed. Statistical analysis included the Spearman Rank Coefficient (r), Wilcoxon Rank Sum test and Signed rank test. Results: In 39 patients with AL Amyloidosis collected on study, median CD34+ cells collected per kg was 8.3 × 106 (IQR 5,12.3) in a median of 2 (IQR 2,3) collections. The median number of CD34+ cells infused on day 0 was 4.7 × 106 (IQR 3.8, 6) per kg and time to neutrophil engraftment (ANC 〉 500 × 2 days) was 9 (IQR 9, 11) days. Baseline urinary excretion of epinephrine and dopamine correlated with total number of CD34+ cells per kg collected (r = 0.33, P = 0.005; and r = 0.47, P = 0.05, respectively). An optimal collection outcome defined as 〉 5 × 106CD34+ cells in 2 collections was achieved by 25/39 patients and was associated with higher baseline epinephrine (median 7 versus 4mcg/24h, P = 0.02) and dopamine (median 220 versus 156mcg/24h, P = 0.05) but not norepinephrine levels. When comparing baseline and post collection catecholamine levels, only dopamine values changed significantly from before to after stem cell collection (P =