Rajkumar, S. Vincent

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:KITE: 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; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Introduction Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p<0.001) and had a longer median time to best response (6 versus 4 months, p<0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p<0.0001) and had a longer median time to achieving best response (9 versus 4 months, p<0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p<0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p<0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.

Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with variable responses to different therapeutic regimens and wide spectrum of survival. Much of the heterogeneity in the outcomes appear to be related to the underlying primary genetic abnormality, which in the majority of patients consist of either translocations involving the heavy chain region on chromosome 14 (IgH translocation) or trisomies of odd numbered chromosomes. We hypothesized that the response to lenalidomide (Len) therapy would vary significantly based on the underlying molecular subtype of myeloma. Methods We examined a cohort of 518 patients with available FISH results, who had been exposed to Len-based regimens. Medical records were reviewed and data regarding the best response and time to next therapy following treatment with Len-based regimen was obtained. Data from the first use of Len was collected. Len was given in combination with dexamethasone (Dex) with or without alkylators in combination. Patients who received a combination of IMiD and bortezomib as their first exposure to Len were excluded. Patients were grouped according to whether FISH showed a trisomy or an IgH translocation. Results The median age was 62 (28-91), and the median estimated follow up from diagnosis was 52 months (95% CI; 50, 54) with 359 (69%) alive at the time of analysis. An IgH translocation was seen in 129 (30%) of patients and a trisomy in 268 (62%) of patients. IgH translocations included t(11;14) in 92 (18%), t(4;14) in 45 (9%), t(14;16) in 21 (4%); 34 (8%) had both translocations and trisomies. For the current analysis, we included only patients with either a translocation or trisomy (n=397) excluding those with neither or both of the abnormalities. The median time to start of Len from diagnosis was 0 months (range, 0-64). A PR or better was seen in 80% of patients with trisomy compared with 63% of the patients with translocation (p<0.001); and the response rate was similar among the different translocation types. The median TTNT was 28 months among trisomy pts compared with 17 months for translocated patients (p<0.001, figure). The median TTNT was similar across the different types of translocations (Figure). Among this group, 134 patients proceeded to an autologous SCT after Len induction. Among these patients, no difference was seen in terms of TTNT (29 months for patients with translocation vs. 28 months for those with trisomy (p=0.8). Finally, the TTNT was no different if Len was used with Dex or as part of an alkylator combination. Conclusion The current data supports the hypothesis that the underlying primary genetic abnormality can affect the response to a particular therapy. In this study response to Len was significantly higher in myeloma with trisomy compared with IgH translocated myeloma. Although the routine use of combinations of a proteasome inhibitor plus Len in frontline therapy in all patients with myeloma may overcome the lower response rate in IgH translocated patients, in most countries such a regimen is not approved or economically feasible. Based on our study, newly diagnosed patients with evidence of trisomy on FISH could be considered for a Len-based regimen such as lenalidomide-low dose dexamethasone. Additional studies should examine if use of bortezomib in patients with IgH translocation will lead to better outcomes compared with Len based therapies. Disclosures: Lacy: Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

Abstract The introduction of novel immunomodulatory drugs (IMiDs), such as lenalidomide, has drastically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib-based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis and apoptosis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). Additionally, we examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its putative downstream target interferon regulatory factor 4 (IRF4), both of which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that response to lenalidomide did not correlate with specific cytogenetic translocations. There were, however, distinct groups of lenalidomide-responsive and non-responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC-1 (IC50 = 2.6 μM versus 0.005 μM, p=0.004), but did not have an effect on the IC50 of the non-responsive HMCL DP-6 (p>0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN or IRF4 expression levels. In summary, our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. Additionally, while CRBN and IRF-4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment. These results suggest that the development of a new treatment paradigm based on cytogenetic subtype of MM alone may be insufficient, and that additional markers may need to be incorporated. Furthermore, the disconnect between our findings of expression of CRBN and IRF-4 in lenalidomide-treated HMCLs and patient data highlights the need for further investigation into the role of the bone marrow microenvironment on the regulation of these previously demonstrated markers of lenalidomide response. Disclosures: No relevant conflicts of interest to declare.

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in <1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Background: Autologous stem cell transplantation is an effective therapy for patients with multiple myeloma. We and others have previously reported the influence of lenalidomide based regimens on the ability to harvest adequate number of stem cells for successful transplantation. In order to identify factors predicting for poor mobilization we studied a large group of patients who underwent an attempt at stem cell mobilization after receiving lenalidomide and dexamethasone as primary therapy for myeloma. Methods: We identified sequential patients who received lenalidomide and dexamethasone as initial therapy for their myeloma and then underwent stem cell mobilization for immediate or future stem cell transplantation. Patients who received any other regimen prior to the stem cell mobilization were excluded. Between July 2004 and May 2008, 106 patients, satisfying the above criteria were identified from the Mayo Clinic transplant database. Medical records and collection sheets were examined for the data. Results: The median (range) age at mobilization was 60 yrs (29–75); 34 (32%) were over 65 yrs and 59 (55%) were males. The median duration of lenalidomide therapy was 4 months (range; 1–13). The strategy for stem cell mobilization was GCSF alone in 92 patients (87%), cyclophosphamide (CTX) and GCSF in 11 pts and 3 pts received AMD3100 and GCSF. Among the GCSF mobilized patients, 10 pts (11%) failed to collect at least 2.5 million cells required for one transplant, including 8 patients who never achieved the minimum peripheral count threshold to initiate the collection. Two of the 11 pts undergoing primary mobilization with CTX/GCSF failed to collect any cells, while all of the 3 pts mobilized with AMD3100 were successful. Five of these pts subsequently underwent successful salvage mobilization with CTX/GCSF, 1 with AMD3100, one failed to mobilize with CTX and the rest did not repeat mobilization. Given that the total CD34 collection and the number of days of collection are influenced by the CD34 goal, we examined patient characteristics that correlated with the CD34 collections over the first 2 days. Increasing patient age and the duration of lenalidomide therapy, both correlated with decreasing 2-day CD34 collection, while the time between last dose of lenalidomide and the start of GCSF had no effect. We then performed ROC analysis to find best cut-off points that predicted the inability to collect adequate (2.5 million) CD34 cells in 3 days. Lenalidomide therapy of more than 4 months (P =0.03) and age > 63 yrs (P = 0.04) best predicted inability to achieve this endpoint. In addition, a peripheral blood CD34 count < 5/uL on day 5 after start of GCSF was highly predictive of failure to reach this endpoint. Conclusions: Inability to collect adequate stem cells with lenalidomide appears to be related to patient age and the duration of lenalidomide therapy. We recommend early stem cell collection and storage, if a delayed transplantation approach is taken. Patients receiving more than 4 cycles of therapy and those over 65 years should undergo mobilization with CTX+G-CSF, rather than G-CSF alone. Majority of the patients who fail G-CSF based collection can be mobilized using CTX and G-CSF. Early identification of failures after G-CSF administration using the peripheral CD34 counts can potentially allow salvage using strategies such as AMD3100.

Abstract Abstract 636 Cellular vaccine may offer additional benefit as consolidative therapy after autologous stem cell transplant (ASCT) for multiple myeloma (MM). We have reported previously from two phase II studies the survival of MM patients who received APC8020 (autologous antigen presenting cell vaccine) after ASCT (Lacy, AJH '09, (84): 799; Lin, ASH annual meeting 2010, abstract 1958). To determine if there was an outcome advantage for additional consolidative vaccine therapy after ASCT, we performed this matched case control analysis comparing the survival of patients who received ASCT only (control) at Mayo Clinic to those who received APC8020 after ASCT in the same time period. Forty-three study patients accrued between July 1998 and March 2002 were eligible for matching. To reduce bias from disease risks and transplant-related mortality, control patients were required to be alive and progression free six months after transplant and have a M-spike value of < 2g/dL at 4 mos (1st study) or 9 mos (2nd study) after transplant, similar to post-ASCT patients who were enrolled in the two APC8020 studies. A total of 111 control patients were eligible for matching. Control patients were matched to study patients by age (+/− 5 yrs), ISS (International Staging System) stage, and plasma cell labeling index (PLCI, either >= 3 or < 3). A matched control was not identified for one study patient. Of the remaining 42 study patients, all had at least one matched control patient. Thirty-two patients had 2 matched controls. Cox proportional hazards analysis showed that there was no statistically significant difference in time to progression between the study and control patients (HR 1.54, 95% CI 0.92 – 2.58, p = 0.1). However the overall survival is significantly improved among the study patients (HR 0.54, 95% CI 0.30 – 0.99, p = 0.05). This analysis is the only known report of long-term follow-up of the largest group of MM patients treated with APC8020 vaccine. While many current prognostic tests were not available at the time of the initial vaccine studies, the control patients in this analysis were matched by known disease risks that are still in use today. The survival advantage in study patients remained statistically significant compared to matched controls. Interestingly, the time to progression is unchanged between study and control patients. This is similar to other reports of vaccine therapy such as in sipuleucel-T (Provenge™) in prostate cancer where an overall survival benefit is seen without change in progression-free survival. A larger, randomized phase III study is needed to confirm the encouraging survival benefit of this treatment modality in MM. Further insight into the mechanisms of action of APC8020 is needed to improve our understanding of the role of this therapy in the context of current practice of MM maintenance therapies. Disclosures: Sims: Dendreon Corporation: Employment.

Abstract Abstract 2877 FLC assay measures circulating unbound k and l light chains and is of diagnostic and prognostic value in plasma cell disorders. Normalization of FLC ratio is considered a higher level of complete response (CR) in MM but this has not been well validated prospectively. HLC is a novel antibody based assay that targets the unique junctional epitopes between the heavy chain and light chain constant regions of intact immunoglobulin (Ig) molecules. It separately measures in pairs the light chain types of each immunoglobulin class generating ratios of monoclonal Ig/background polyclonal Ig concentrations (i.e IgGκ/IgGλ, IgAκ/IgAλ and IgMκ/IgMλ); potentially simplifying assessment of monoclonal protein response. To assess the prognostic impact of these assays and to correlate them with electrophoretic/immunofixation (SPE/IFE) assessment, we analyzed 497 stored serum samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 clinical trial, sponsored by the NHLBI and NCI, of tandem autologous (autoHCT) vs. tandem autoHCT- allogeneic (alloHCT). Samples were collected prior to the first autoHCT and analyzed for FLC (Freelite™) and HLC (Hevylite™) at The Binding Site, UK. Corresponding disease status determination was centrally performed by an expert data review committee using uniform response criteria and correlated with FLC and HLC results. HLC remission was defined as normalization of composite heavy and light chain ratios across all 3 measured heavy/light chain pairs or the normalization of clonal isotype with normal ratios of uninvolved pairs. The demographics of 497 patients with HLC/FLC samples at baseline were concordant with the main study and showed similar patient proportions from the 2 study arms. Of the 211 pts with baseline SPE response better than or equal to a very good partial response (>VGPR), 188 also had an HLC remission (Sensitivity=89%). Comparison of the HLC remission with the >VGPR disease state also identified a specificity of 52%, positive predictive value (PPV) of 58% and a negative predictive value (NPV) of 87%. Similarly, all 56 patients in complete remission (CR) by SPE/IFE were in HLC remission. Compared with conventional CR assessment, sensitivity of HLC remission was 100%, specificity 39%, PPV and NPV values of 17% and 100% respectively. FLC remission correlated with >VGPR disease state had a sensitivity of 47%, specificity of 81% and a PPV and NPV of 64% and 67% respectively. Multivariate models for post transplant progression free survival (PFS) indicated that baseline disease response (>VGPR vs. partial remission (PR) or<PR) was associated with longer PFS. Adjusted models including baseline response, myeloma stage and study arm were used to compare the predictive utility of HLC and FLC assays. There was a lower risk of treatment failure (HR 0.74, p=0.02) and superior PFS for patients who achieved an HLC remission. When stratified by baseline disease response states, there was no additional prognostic impact for HLC remissions on PFS. Normalization of FLC ratio among patients with >VGPR disease state did not impact PFS (HR 0.96, p=0.83). Abnormal HLC after induction therapy has a high negative predictive value (100%) for identifying patients not achieving CR by uniform response criteria and is also associated with shorter PFS after transplant. FLC ratio normalization had no impact suggesting that stringent CR criteria may need further validation. Disclosures: Krishnan: Celgene: Speakers Bureau; Millenium: Speakers Bureau. Alvi:the binding site: Employment. Harding:The Binding Site Group Ltd: Employment. Maloney:Cellgene: Consultancy.