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The outcomes of patients with primary plasma cell leukemia (pPCL) after undergoing hematopoietic cell transplantation (HCT) in the novel agent era are unknown. We report outcomes of 348 patients with pPCL receiving autologous (auto-) HCT (n = 277) and allogeneic (allo-) HCT (n = 71) between 2008 and 2015. Median age was 60 years and 56 years for auto- and allo-HCT respectively. For auto-HCT, the 4-year outcomes were: non-relapse mortality (NRM) 7% (4-11%), relapse (REL) 76% (69-82%), progression-free survival (PFS) 17% (13-23%), and overall survival (OS) 28% (22-35%). Karnofsky performance status (KPS) > 90 and ≥very good partial response (VGPR) predicted superior OS in multi-variate analysis for auto-HCT. For allo-HCT, the 4-year outcomes were: NRM 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%). Compared with prior CIBMTR pPCL patients (1995-2006), inferior survival was noted in the current cohort (3-year OS, 39% vs. 38% in allo-HCT, and 62% vs. 35% in auto-HCT) respectively. However, we noted an increased HCT utilization, from 12% (7-21%) in 1995 to 46% (34-64%) in 2009 using SEER data (available till 2009). Despite modern induction translating to higher proportion receiving HCT, the outcomes remain poor in pPCL patients, mainly derived by high relapse rates post-HCT.

The bidirectional relationship between cancer and chronic kidney disease (CKD) is complex. Patients with cancer, particularly those with hematological malignancies such as multiple myeloma and lymphoma, are at increased risk of developing acute kidney injury and CKD. On the other hand, emerging evidence from large observational registry analyses have consistently shown that cancer risk is increased by at least 2- to 3-fold in kidney transplant recipients, and the observed increased risk occurs not only in those who have received kidney transplants but also in those on dialysis and with mild- to moderate-stage CKD. The interactions between cancer and CKD have raised major therapeutic and clinical challenges in the management of these patients. Given the magnitude of the problem and uncertainties, and current controversies within the existing evidence, Kidney Disease: Improving Global Outcomes (KDIGO) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology to identify key management issues in nephrology relevant to patients with malignancy. This report covers the discussed controversies in kidney disease in hematological malignancies, as well as cancer after kidney transplantation. An overview of future research priorities is also discussed.

Multiple myeloma (MM) is a common plasma cell malignancy, which is responsible for significant mortality, often related to severe renal impairment (RI). Kidney injury can limit therapeutic choices and may often translate into poor outcomes, but it remains potentially reversible in a proportion of patients. The most accessible, conventional markers of RI are subject to several shortfalls, among which are the delayed onset following kidney insult, multiple interfering factors, and lesser sensitivity to mild changes in glomerular filtration. Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C have accumulated large interest in MM-RI due to being very sensitive markers of renal injury, as well as indicators of tubular-glomerular axis impairment. Of interest, recent data suggest that prediction of acute kidney injury may be aided by urinary tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), which both act to induce G1 cell cycle arrest, reflective of a state of pre-injury, and thus may be superior to other measures of kidney insult (NGAL, kidney injury molecule ((KIM-1)). Moreover, TIMP-2 seems to be a biomarker dedicated to distal tubular cells, whereas insulin-like growth factor-binding protein 7 (IGFBP7) secretion has been found in proximal tubule cells. IGFBP7 can also identify a subsection of the normal proximal nephron, even, maybe the one that is responding to insult. They may be adopted into a conceptual screening panel for MM-RI. Unfortunately, no biomarker is ideal (influence of non-renal, biologic factors), and novel measures are limited by economic constraints, availability, lack of standardization. With the emergence of more advanced diagnostic and prognostic MM models, markers reflective of disease processes (including RI) are of high interest. Candidate molecules also include peptidome markers.

This study determined whether 85 patients with multiple myeloma (MM) double-refractory to primary induction therapy with triplet regimens had a homogenous prognosis. The overall response rate (ORR) after the second-line therapy was 51%. Patients who proceeded to immediate autologous stem cell transplantation (ASCT) had better ORR than those who received conventional therapies (62% vs. 31%). The ORR for patients who had ASCT directly after the frontline therapy was higher than for those treated with other regimens as the second line therapy (91% vs. 45%) and offered ASCT as the third-line therapy (91% vs. 55%). The median progression-free survival (PFS) after the second-line therapy and median overall survival were 21.6 months and 35.6 months, respectively. ASCT after the second line treatment (HR = 0.24) was an independent predictor of PFS. Eligible patients with primary refractory MM achieve the most benefit from ASCT, also performed immediately after first line induction therapy.

Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been defined by an absolute number of circulating PCs exceeding 2.0 × 109/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops de novo, and secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition, there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival (OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL. The prognosis of secondary PCL is extremely poor, with OS of only 1 month.

Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder implicated as a precursor of multiple myeloma (MM), while smoldering multiple myeloma (SMM) is a malignant plasma cell disorder without evidence of a myeloma-defining event(s) (MDE). This is a review article of both disorders outlining their current definition and management according to the current standard of care. We focus on the pathogenesis of MM and the role of MGUS and SMM in the development of active MM. MGUS is a benign disorder and, subsequently, is followed by observation. In contrast, for SMM, although the current standard of care is “watch and wait”, this paper will explore the circumstances in which treatment should be considered to prevent MDE.

© 2020 Kidney Disease:Improving Global Outcomes (KDIGO)The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.

Summary Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220–260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose–response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.

PRIMeR is the first U.S.-based ancillary study of MRD assessment by multiparameter flow cytometry (MFC). Patients were enrolled on a national 3-arm RCT (BMT CTN 0702, STAMiNA trial, ClinicalTrials.gov Identifier: NCT01109004) comparing 1) tandem auto-HCT, 2) single auto-HCT and 3) single auto-HCT, 4 cycles of lenalidomide, bortezomib, dexamethasone consolidation (auto+RVD); all 3 treatment arms included continuous lenalidomide maintenance until MM progression. STAMiNA opened to accrual before PRIMeR initiated, therefore 437 of 758 patients enrolled in STAMiNA provided consent and at least one analyzable sample for MRD by MFC to PRIMeR. Disease responses and progressions were adjudicated by an independent review committee. All analyses of treatment arm were performed using intent-to-treat. The MFC panel included 10 monoclonal antibodies (CD38, CD138, CD45, CD56, CD19, CD20, CD27, CD28, kappa, lambda) measured via 3 tubes of 6 colors each with a target of analyzing 2.5 × 105-1.5 × 106 events, depending on sample quality and quantity, yielding a sensitivity of 10−5 to 10−6. All samples were interpreted by two experienced flow cytometrists who were blinded to treatment arm and other patient, disease and treatment characteristics. MRD was assessed at Baseline/pre-AutoHCT (BL), Pre-maintenance (PM), and 1 year (Y1) post AutoHCT with the primary endpoint of MRD negative at Y1. At a median follow-up of 38 months, there was no significant difference in PFS or OS by treatment arm in the subset of PRIMeR patients. Univariate analysis demonstrated that being MRD negative at PM and Y1 was associated with better PFS, and at Y1, patients who were MRD negative also had longer OS (Table 1, Figures). Multivariate analysis of time to progression or death, adjusting for disease risk, demonstrated hazard ratios (HR) in MRD negative patients compared to MRD positive patients at BL, PM and Y1 were 0.66 (p=0.07), 0.48 (0

Introduction Monoclonal gammopathy of ocular significance (MGOS) is a rare subset of monoclonal gammopathy of clinical significance (MGCS) occurring secondary to plasma cell dyscrasia resulting in ocular manifestations. Given the rarity of these conditions, optimal management strategies are not defined; the approach is dependent upon the underlying cause of the monoclonal gammopathy and whether or not the patient's vision is affected. We report our review of 23 cases with MGOS, more specifically on paraproteinemic keratopathy (PPK) the most common form, to obtain a better understanding of the patient characteristics, diagnosis and treatments. Methods We report an international retrospective series of patients with MGOS. Data was collected on patients with MGOS:there were no other inclusion criteria besides monoclonal gammopathy with an ophthalmologic manifestation; however, this report focuses only on patients with PPK. Efficacy outcomes were the hematologic and the ocular responses in patients with PPK. Hematologic responses were reported according to the IMWG response criteria. The ophthalmologic response to treatment was assessed by each contributing physician and reported as either complete, partial or no sight recovery. Results We identified 23 patients with PPK in the setting of monoclonal gammopathy of unknown significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM) diagnosed between 2006 and 2019 in 7 countries. Table 1 summarizes the patients' characteristics. The ocular diagnosis was typically made at the same time or after the hematologic diagnosis. Eleven of 23 patients presented decreased vision. Four were treated by penetrating keratoplasty with or without systemic therapy, including chemotherapy with new generation anti-MM agents with or without autologous stem cell transplantation (ASCT). All patients with MM and 40% of those with other diagnoses such as SMM or MGUS received systemic therapy. In most cases, neither ocular nor hematologic treatment, even when ASCT was performed, afforded a durable improvement in the visual acuity despite initial responses. MGOS typically relapsed within one year of the initial response (Table 2). Conclusion To date, this is the largest retrospective study focusing on MGOS patients with monoclonal immunoglobulin deposits accumulating in the cornea and resulting in visual impairment. Further studies will be required to determine the optimal strategy to treat and prevent the relapse of ocular symptoms in patients with PPK and specifically to address the timing of keratoplasty and systemic chemotherapy and the role of maintenance therapy. Patients with corneal manifestation of unknown origin should undergo a hematologic check-up and patients with paraproteinemia should have a periodic ocular health assessment. Figure 1 Figure 1. Disclosures Garderet: Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. Gozzetti: AbbVie: Honoraria; Janssen: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Jurczyszyn: Janssen-Cilag, Amgen: Honoraria, Speakers Bureau.

Introduction: Prior studies have shown poorer outcomes in Black and Hispanic patients and in patients with lower median household income and education 1-5. In MM, we hypothesize that facility affiliation and case volume affects overall survival (OS) and rates of frontline treatment (including chemotherapy, immunotherapy, autologous stem cell transplant [ASCT] and palliative care). Methods: This is a retrospective analysis of 174,551 MM patients in the NCDB database, over the age of 18 years, between 2004-2016. Facility types include community cancer programs, comprehensive community cancer programs, academic/research cancer programs and integrated network cancer programs. High volume facilities had new MM cases per year ≥ 99 th percentile, and all other facilities were classified as low volume. Multivariable analyses used Cox proportional hazard analysis for OS and logistic regression for use of treatment, adjusted for age, sex, race, Hispanic origin, education, great circle distance, CCI score, and type of county (depending on population size). Kaplan-Meier method was used to estimate median OS, and the log rank test was used to compare OS across predictor variables. Results: The median age was 67 years (range 18-90) with 55% males, and 76% White vs 20% Black. In academic/research cancer programs, the median OS in high volume centers was 75.5 mo vs 50.2 mo in low volume centers (p Discussion: Our results show that academic/research cancer programs with high volumes have the best OS in MM. Additionally, academic/research cancer programs are more likely to give chemotherapy, immunotherapy, and ASCT, but less likely to give palliative care. We theorize that academic/research cancer programs with a high volume of cases likely have increased resources, which optimizes outcomes. Given that ~25% of patients with MM die in the first year 6, there is a recognized need to identify strategies to improve early outcomes in patients treated at community cancer programs and low volume facilities. Figure 1 Figure 1. Disclosures Lai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: Despite significant advancements in MM therapies, patients with quad-refractoriness (refractory to proteasome inhibitors: bortezomib and carfilzomib, and immunomodulatory drugs: lenalidomide and pomalidomide) and penta-refractoriness (additional refractoriness to CD-38+ monoclonal antibody daratumumab) have a poor prognosis in terms of short progression-free survival (PFS) and overall survival (OS). This is a retrospective, single institutional study comparing the outcomes of patients with quad and penta-refractory MM to patients who were quad and penta-exposed, but not refractory. Methods: Consecutive patients from the John Theurer Cancer Center at Hackensack Meridian School of Medicine who were quad and penta-exposed and/or refractory between the dates of 1/1/2015 and 3/1/2021 were identified. Quad-exposed was defined as having had prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide. Penta-exposed was defined as having prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide and daratumumab. Penta or quad refractory was defined as having stable disease (as best response) or progressive disease while on all of the above drugs, per International Myeloma Working Group (IMWG) definition of refractory. Patients were excluded if they had missing data or if they did not meet the above definitions. Baseline characteristics, high-risk status, ISS, treatment history, treatment response, drugs at first relapse and survival outcomes were obtained retrospectively from the electronic medical record and entered into database. High-risk cytogenetics were defined as the presence of t(4;14), t(14;16) or del 17p; 1q21 gain or amplification; 1p del; t(6;14); t(14;20). Baseline patients' characteristics were summarized descriptively by quad and penta-exposed groups. PFS and OS were estimated using the Kaplan-Meier method. Univariate and multivariable adjusted Cox proportional hazard regression models examined factors affecting OS. Results: A total of 162 patients met the inclusion criteria: 18/162 (11%) were quad or penta-exposed, 32/162 (20%) were quad-refractory, and 112/162 (69%) were penta-refractory. Median age was 62 (55-69), IgG subtype (59%), and 62/162 (38.5%) had high-risk cytogenetics. The median number of lines prior was 6 (range 4-8) among all patients, and 7 (range 5-9) in the penta-refractory group. 133/162 (82.1%) had prior autologous-stem cell transplant (ASCT). Extramedullary disease was present in 40/162 (25.2%). Plasma cell leukemia was present in 14/162 (8.8%). For those who were penta-refractory, the median time from quad to penta-refractory status was 10.2 months (95% confidence interval (CI), 3.57-16.57). See Table 1. Figure 1 shows PFS and OS from the time of becoming quad or penta-exposed or refractory (T0 ). The median PFS after T0 was 11.86 months (95% CI, 6.5-26.6) for combined quad and penta-exposed, compared to 3.88 months (95% CI, 2.99-5.17) for quad and penta-refractory patients. With a median follow-up of 5.14 months (Range, 0-52.4), the median OS for all patients was 7.43 months (95% CI, 5.8- 12.94). (Figure 1A). With a median follow-up time of 4.45 months (Range, 0-52.38), the median OS for patients who were quad or penta-refractory was 5.97 months [95% CI. 4.44-8.23], compared to OS not reached (NR) for quad or penta-exposed, with a median follow-up of 11.86 months. (Figure 1B). At least one subsequent treatment regimen was employed after T0 in 85% of the patients. (Figure 1C). Multivariable adjusted analysis (Table 2) revealed that patients ≥62 had inferior OS compared to those < 62 (p -value=0.046). Furthermore, patients who had ≤10 months between becoming quad- and penta-refractory had inferior OS compared to patients with >10 months (p=0.031). OS was not significantly affected by high risk versus standard cytogenetics or drugs used at first relapse. Conclusion: MM patients with quad and penta-refractory disease have significantly worse outcomes compared to patients with quad and penta-exposed MM: older age (> 62 years) and a short interval (< 10 months) between becoming quad and penta-refractory confer an adverse prognosis. Prospective studies are required to confirm these findings. Penta and quad-refractory multiple myeloma continues to represent a vulnerable population with an unmet need for therapeutic approaches. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3,256) and relapsing early post-AHCT (1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

7003 Background: The role of alloHCT and subsequent maintenance for the treatment of high-risk MM has not been fully defined. We evaluated the efficacy of ixazomib maintenance therapy after alloHCT using reduced intensity fludarabine/melphalan/bortezomib (Flu/Mel/Bort)-based conditioning regimen to treat patients with high risk MM. Methods: This phase 2 prospective multicenter trial (NCT#02440464) enrolled adults 70 years or younger, with either high-risk MM defined by cytogenetics or plasma cell leukemia (PCL) or relapse within 24 months after autologous HCT. Conditioning regimen consisted of Flu/Mel/Bort. Patients received HLA-matched donor unmanipulated peripheral blood grafts. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus methotrexate. Between days +60 and +120 after allogeneic HCT, patients were randomly assigned (1:1, stratified by number of prior progressions) to receive ixazomib at 3 mg orally on days 1, 8, 15 on a 28-day cycle or matching placebo for 12 cycles. The study aimed to enroll 138 patients with 110 patients achieving randomization for a progression-free survival (PFS) comparison ixazomib maintenance vs. placebo. Results: Fifty-seven patients from 15 centers were enrolled (2015-18), of whom 52 (91.2%) received allogeneic HCT, and 43 (82.7%) proceeded to randomization (21 assigned to ixazomib and 22 to placebo). Enrollment was delayed by a clinical hold after enrollment of 17 patients due to toxicity concerns related to the conditioning regimen. Remaining patients were enrolled after an amendment reduced bort to a single pre-HCT dose. These and other delays in enrollment led to premature study closure. Median age was 56 (range, 35-65) years, and 33 patients (57.9%) had high-risk MM with 9 patients (15.8%) with primary PCL. At 24 mo post alloHCT, PFS and OS among all alloHCT recipients was 52% and 85% respectively with a corresponding transplant-related mortality (TRM) of 11%. At 21 mo post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%) and OS (95% vs. 87%, p = 0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) or chronic GVHD at 12 months (69% vs 64%) were similar. Best response, incidence of progression for ixazomib vs. placebo groups were similar while cumulative incidence of transplant-related mortality (TRM) at 21 months was 0.0% and 4.5% (90%CI: 0.5-16.5%), respectively. Conclusions: AlloHCT with reduced intensity fludarabine/melphalan and a single pre-HCT dose of bortezomib is safe and can produce durable disease control in extremely high-risk patients. ixazomib maintenance after alloHCT could not be assessed as intended due to early termination of study, but there was no signal of an impact in outcomes. Clinical trial information: NCT02440464.

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and immunoglobulin M production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients that received adult alloHCT for WM/LPL. Data was obtained from the Center for International Blood and Marrow Transplant Research database (2001-2013). Patients received myeloablative (n=67) or reduced intensity conditioning (RIC; n=67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n=18) failed prior autologous hematopoietic cell transplantation. About half (n=82, 57%) had chemo-sensitive disease at the time of transplantation, while 22% had progressive disease. Progression free survival, overall survival, rate of relapse, and non-relapse mortality at 5-years were 46%, 52%, 24%, and 30% respectively. Patients with chemo-sensitive disease and better pre-transplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative 50% vs. RIC 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days −4 and −1 before transplantation with melphalan 200 mg/m2 given on day −2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

Summary Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open-label, single-institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide-refractory patients. Patients were considered lenalidomide-refractory if they had no clinical response (

Most patients eligible for allogeneic hematopoietic stem cell transplantation will require identification of an alternate (unrelated or mismatched related) donor. We explored the transplantation outcomes for a sequential series of 54 patients undergoing haploidentical donor transplantation (HAPLO) compared to those from a control group of patients receiving cells from matched or mismatched unrelated donors (URD) selected by diagnosis and stem cell source. Patients undergoing HAPLO transplantations received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (Cy). Day 15 neutrophil recovery was lower after HAPLO than in URD recipients (43% versus 77%, P .001), as was day 30 platelet recovery (67% versus 84%, P = .043). HAPLO patients receiving bone marrow achieved neutrophil engraftment at a median of 17 days and platelet engraftment at a median of 29 days, compared with 16 days and 24 days, respectively, for recipients of peripheral blood stem cells. The incidence of graft failure was similar for both HAPLO and URD recipients (P = .42). HAPLO recipients were more likely to reach donor CD3 chimerism95% by day 28 after transplantation (88% versus 62%, P = .003). The cumulative incidence of grades II to IV acute GVHD (aGVHD) at 6 months after transplantation did not differ for these 2 groups (63% for HAPLO and 53% for URD recipients; P = .269), nor did the cumulative incidence of severe grade III/IV aGVHD (13% for HAPLO and 8% for URD recipients; P = .44). The cumulative incidence of moderate or severe chronic GVHD at 2 years did not differ, with probabilities of 24% for HAPLO and 18% for URD recipients (P = .43). The cumulative incidence of cytomegalovirus reactivation by day 100 after transplantation did not differ (45% for HAPLO and 46% for URD recipients; P = .96). The HAPLO recipients experienced a lower incidence of Epstein-Barr virus reactivation by day 100 (6% versus 32%, P .001) but a higher incidence of Human Herpesvirus-6 reactivation (35% versus 10%, P = .001). Relapse risk, regimen-related mortality, progression-free survival, and overall survival probabilities did not differ between these 2 groups. These data support the use of HAPLO transplantation with post-transplantation Cy as an alternate transplantation technique for patients lacking HLA-matched sibling donors. Transplantation of peripheral blood stem cells does not appear to enhance the speed of neutrophil recovery. The different patterns of viral reactivation require additional studies to explain.

Allogeneic hematopoietic cell transplant (HCT) may improve long-term multiple myeloma (MM) control through the graft-versus-myeloma effect. The Blood and Marrow Transplant Clinical Trials Network 0102 trial was a biologic assignment trial comparing tandem autologous transplant (auto-auto) versus autologous followed by reduced-intensity allogeneic (auto-allo) transplant in patients with newly diagnosed MM with standard-risk (n = 625) or high-risk (n = 85; β2-microglobulin at diagnosis ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) disease. Although the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of the graft-versus-myeloma effect. Median follow-up of survivors was over 10 years. Among standard-risk patients there was no difference in PFS (hazard ratio [HR], 1.11; 95% confidence interval [CI], .93 to 1.35; P = .25) or OS (HR, 1.03; 95% CI, .82 to 1.28; P = .82). The 6-year PFS was 25% in the auto-auto arm versus 22% in the auto-allo arm (P = .32), and 6-year overall survival (OS) was 60% and 59%, respectively (P = .85). In the high-risk group, although there was no statistically significant difference in PFS (HR, .66; 95% CI, .41 to 1.07; P = .07) and OS (HR, 1.01; 95% CI, .60 to 1.71; P = .96), a reduction in 6-year risk of relapse of 77% versus 47% (P = .005) was reflected in better PFS of 13% versus 31% (P = .05) but similar OS, at 47% versus 51% (P = .69). Allogeneic HCT can lead to long-term disease control in patients with high-risk MM and needs to be explored in the context of modern therapy.

This multicenter retrospective study included 101 patients (median age 62 years) with secondary plasma cell leukemia (sPCL). The median time from initial multiple myeloma diagnosis to sPCL was 31 months. Fifty-five out of 72 patients (75%) who received any therapy were treated with immunomodulators (IMiDs) and/or proteasome inhibitors (PIs), and 14/72 (19%) underwent salvage autologous stem cell transplantation (ASCT). The overall response rate in patients who received ASCT or PI (either alone or in combination) was higher than in those who did not (93% vs. 36% and 60% vs. 30%, respectively). The median overall survival (OS) in patients who received therapy was 4.2 months (95% CI: 1.3; 8.0) with a 1-year OS of 19%. Platelet count ≤100 × 109/L at sPCL diagnosis was the only independent predictor of a poorer OS in treated patients (HR = 3.98, p = .0001). These findings suggest that patients with sPCL may benefit from salvage ASCT- and PI-based regimens.

Multiple myeloma (MM) is a malignancy of clonal plasma cells accounting for approximately 10% of haematological malignancies. MM mainly affects older patients, more often males and is more frequently seen in African Americans. The most frequent manifestations of MM are anaemia, osteolytic bone lesions, kidney failure and hypercalcemia. The anaemia develops secondary to suppression of erythropoiesis by cytokine networks, similarly to the mechanism of anaemia of chronic disease. The concomitant presence of kidney failure, especially chronic kidney disease (CKD) and MM per se, leading to anaemia of chronic disease (ACD) in combination, provoked us to pose the question about their reciprocal dependence and relationship with specific biomarkers; namely, soluble transferrin receptor (sTfR), growth differentiation factor 15 (GDF15), hepcidin 25 and zonulin. One or more of these are new biomarkers of ferric management may be utilized in the near future as prognostic predictors for patients with MM and kidney failure.

Introduction: While minimal residual disease (MRD) negativity is not yet an established regulatory surrogate for a clinical endpoint in multiple myeloma (MM), it does have value as a prognostic biomarker and in assessing disease status. Previously we reported results from a phase 1b trial that described the safety and efficacy of the triplet regimen carfilzomib (given weekly), lenalidomide, and dexamethasone (KRd) in patients with relapsed and/or refractory MM (RRMM) or newly diagnosed MM (NDMM) (Biran et al, Am J Hematol 2019;94:794-802; Alsina et al, Clin Lymphoma Myeloma Leuk 2019;19:Suppl E52). Here, we evaluate MRD status by flow cytometry after treatment with weekly KRd in this trial. Methods: A total of 56 patients with RRMM and 51 with NDMM were enrolled and treated with weekly KRd. Treatment was given in 28-day cycles. Carfilzomib was given on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 (also day 22 for cycle 1-8). In the NDMM cohort, patients were enrolled regardless of transplant eligibility, and treatment interruption for mobilization and collection with or without autologous stem cell transplant was allowed after cycle 4. Per the protocol, aspirate was collected for flow cytometry evaluation at two separate endpoints: at cycle 8 day 1 (C8D1); and at the time when laboratory data supported a response of complete response (CR) or better (on the basis of negative immunofixation on serum and urine). Sample quality was assessed by several measures (including the presence of mast cells, erythroid precursors, and immature B cells), and viability was determined using a flow assay. Adequate samples were tested for MRD using 8-color flow cytometry in two tubes, with a sensitivity of 10-5. MRD was reported as positive when a minimum of 2 x 106 CD138+ cells per tube were evaluated, and ≥ 20 abnormal events detected. Results: Overall, 58 of 79 (73.4%) study-specified samples were obtained and evaluated by flow cytometry. Of the NDMM patients, 15 had bone marrow aspirate evaluable for MRD at C8D1 (in total 22 patients were treated to C8D1), and 12 had bone marrow aspirate evaluable for MRD at the time of CR (14 patients achieved CR). At C8D1, 53% (8/15) of NDMM patients with flow data achieved MRD negativity, and at time of CR, 83% (10/12) of NDMM patients were MRD negative (the remaining patients with flow data were determined to be MRD positive). Among the 12 NDMM patients evaluated for MRD at time of CR, 17% had high-risk cytogenetics, 58% had standard-risk cytogenetics, and 25% had unknown cytogenetic risk status. Of the RRMM patients, 26 had bone marrow aspirate evaluable for MRD at C8D1 (30 patients were treated to C8D1), and five had bone marrow aspirate evaluable for MRD at the time of suspected CR or better (in total 13 patients achieved CR). Of RRMM patients with available flow data at time of CR, 40% (2/5) achieved MRD negativity, and of those with flow data at C8D1, 50% (13/26) achieved MRD negativity. Of all patient samples evaluated for MRD, 67% of NDMM and 48% of RRMM samples were MRD negative. The results reported here are directionally comparable to the rates of MRD-negative CRs observed in previous studies of twice-weekly KRd in NDMM (Jasielec J et al, Blood 2014;124:2127; Kazandjian D et al, JAMA Oncol 2018;4:1781-1783; Zimmerman T et al, Blood 2016;128:675). Our findings are limited by incomplete acquisition of samples to support a full MRD analysis per protocol (approximately 73% of the intended time point samples were acquired). Additionally, we reported MRD status without censoring for missing MRD data, as would be required to analyze MRD for a randomized controlled trial to eliminate acquisition bias. A robust comparison of MRD-negative CR rates between regimens would require an RCT with full MRD sampling, and sensitivity analyses that treat missing MRD data as MRD-positive (Chari A et al, Blood 2017;130:974-981; Voorhees PM et al, Blood 2020). Conclusions: We have previously shown that once-weekly KRd is active and has acceptable toxicity in both the RRMM and NDMM settings. We found that among MRD-evaluable patients who had a CR or better, MRD negativity rates were impressive in both the NDMM setting (83%) and in the RRMM setting (40%), suggesting that the weekly KRd regimen can induce MRD-negative CRs in both settings. Disclosures Landgren: Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Other; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Seattle Genetics: Research Funding. Alsina:Janssen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau. Biran:Janssen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; KAryopharma: Research Funding; Sanofi: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: reimbursement of travel and accommodation, Research Funding, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Janssen: Speakers Bureau; BMS: Speakers Bureau. Fang:Amgen: Current Employment, Current equity holder in publicly-traded company. Arnold:Amgen: Current Employment, Current equity holder in publicly-traded company. Kimball:Amgen: Current Employment, Current equity holder in publicly-traded company; WindMIL Therapeutics: Current equity holder in private company. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. OffLabel Disclosure: Carfilzomib is a proteasome inhibitor that can be used for the treatment of relapses/refractory multiple myeloma

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P .001) and 72% versus 85% (P .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Skin infiltration in multiple myeloma (skin MM) is a rare clinical problem. Only a few cases of skin involvement have been reported, primarily in single case reports. We analyzed and present the clinical outcomes, immunohistochemistry and cytogenetic features, and relevant laboratory data on 53 biopsy-proven skin MM cases. The median time from MM diagnosis to skin involvement was 2 years. There appears to be an overrepresentation of immunoglobulin class A (IgA) and light chain disease in skin MM. We found no correlation between CD56 negative MM and skin infiltration. We found that skin MM patients presented in all MM stages (i.e. ISS stages I to III), and there was no preferential cytogenetic abnormality. Patients with skin MM carry a very poor prognosis with a median overall survival (OS) of 8.5 months as time from skin involvement. Moreover, patients with IgA disease and plasmablastic morphology appear to have a worse OS.

High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

Purpose The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m2 to 140 mg/m2) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P 1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P

Renal dysfunction negatively impacts outcomes in patients with multiple myeloma (MM). Few treatment options are currently available for patients with MM and comorbid renal dysfunction, and as they are generally excluded from clinical trials, data on the use of immunomodulatory drugs in this population are scarce. In this paper, we describe a case series of five women with MM and severe renal dysfunction or dialysis dependency who were refractory to both bortezomib and either lenalidomide or thalidomide and were treated with full-dose (4 mg) pomalidomide. As part of their treatment regimen, these patients also received carfilzomib and dexamethasone with or without cyclophosphamide. All five patients achieved at least a partial response to pomalidomide-based therapy, which was relatively well tolerated. Our findings suggest that pomalidomide may represent a valuable and tolerable treatment option for MM patients with severe renal impairment. The fact that pomalidomide is extensively metabolized prior to urinary excretion may explain the improved tolerability of pomalidomide versus lenalidomide in such patients. Copyright © 2016 John Wiley & Sons, Ltd.

Introduction: Over the past decade, the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) has dramatically improved the progression-free and overall survival of patients with multiple myeloma (MM). Ixazomib, a second-generation oral reversible 20S PI, is one of the first oral PIs in development for patients with MM.Areas covered: The current literature examining the outcomes of MM patients treated with ixazomib. A literature search using PubMed and abstracts presented at international conferences was conducted to include relevant preclinical and prospective clinical trials using ixazomib in MM. Preclinical studies have demonstrated both independent and synergistic antitumor activity of ixazomib. Phase I and II studies have established safety and efficacy of ixazomib in once and twice weekly dosing in the upfront and relapsed/refractory disease in transplant and non-transplant eligible populations. Commonly seen adverse events include cytopenias, skin toxicities and gastrointe...

Waldenstrom macroglobulinemia (WM) is an incurable disease with frequent relapse after frontline therapy [1]. With one approved agent (ibrutinib) and no standard of care [1,2], new treatment option...

Background: Panobinostat (pano) is a pan histone deacetylase inhibitor (HDAC-i) FDA-approved for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy, including both btz and an immunomodulatory agent (IMiD). This retrospective study evaluates efficacy and safety of pano combined with other FDA-approved agents used in relapsed/refractory (RR) MM. Methods: From February 2015-July 2017, 47 consecutive patients with RRMM treated with commercial pano identified in the EMR were reviewed. Results: Median age was 58.7 (27-78) years with 55% men. 41 (87%) were Durie-Salmon Stage 3. 12 (26%) had high-risk FISH: t(14;16), t(4;14), del 17p, and gain 1q21. Median number of prior lines was 6 (2-14). 38 (81%) were RR to the last line of therapy. 29 (62%) were btz-refractory, 36 (77%) lenalidomide-refractory, 36 (77%) pomalidomide-refractory, and 36 (77%) carfilzomib-refractory. 33 (70%) were refractory to carfilzomib with an IMiD. 15 (32%) had prior daratumumab and 7 (15%) had prior HDAC-i therapy. Median pano cycles was 3 (0.25-18). ORR (≥PR) was 25.0% and clinical benefit rate (≥MR) was 38.6%. Median duration of response (≥SD) was 4.3 months. Median PFS was 2.4 months (95% CI: [1.61,4.01]). Median OS from initiation of pano through 1/16/19 was 6.25 months (95% CI: [5.10,12.95]). Three patients discontinued pano due to toxicity. Grade 3-4 non-hematologic toxicities were diarrhea (N=1), and respiratory failure (N=2). Grade 3-4 hematologic adverse events (AEs) occurred in 19 (40%) patients, 12 (26%) with anemia,15 (32%) with neutropenia, and 13 (28%) with thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, febrile neutropenia, heart failure exacerbation, and dyspnea in 4 patients, respectively. PFS is negatively associated with a greater number of lines of treatment prior to initiating pano (HR 1.21: 95% CI 1.02-1.4). High-risk FISH (HR 0.71: 95% CI 0.31-1.60) and being refractory to the last prior line of therapy (HR 0.51: 95% CI 0.17-1.60) show no significant association with PFS. Conclusion: Use of pano outside of the FDA indication, in combination with PI and IMiD-based regimens, has activity and is well tolerated in heavily pretreated RRMM patients.

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.

8506 Background: STaMINA was a phase III trial comparing progression-free survival (PFS) among 758 pts randomized to: 1. second autoHCT then lenalidomide (Len) maintenance (Auto/Auto, n = 247); 2. consolidation with Len/bortezomib/ dexamethasone (RVD) followed by Len maintenance (Auto/RVD, 254); 3. Len maintenance (Auto/Len, 257). All three arms were similar (Stadtmauer JCO 2018). Len maintenance was designed to continue for 3 years and amended to allow continuation until disease progression through a follow up protocol (07LT, NCT#02322320). We report 6 yr follow up for STaMINA and the results of Len discontinuation beyond 3 years. Methods: 07LT was offered to pts who were progression-free at 38 mo; completed planned Len maintenance and were within 4 years of BMT CTN 0702 follow up. Among 431 07LT eligible patients, 273 enrolled and 179 opted to continue maintenance until disease progression. All patients enrolled in STaMINA were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and long-term outcomes for patients not enrolled on 07LT (N = 166) were available through this mechanism. Before combining 07LT data and CIBMTR data for LTFU analysis, outcomes in both databases were analyzed separately and confirmed to be comparable. Results: Using intent-to-treat (ITT), 6yr PFS and overall survival (OS) was the same among Auto/Auto (43.9%; 73.1%), Auto/RVD (39.7%, 74.9%) and Auto/Len (40.9%, 76.4%)(p = 0.6; p = 0.8). Protocol defined high risk disease, (HR = 1.53, p < 0.0001) and age (p = 0.03) were adverse risks for PFS. In as treated analysis, 6yr PFS were 49.4%, 39.7% and 38.6% for Auto/auto (170), Auto/RVD (222) and Auto/Len (361), respectively (p = 0.01). 6yr PFS in high risk pts as treated analysis were 43.6% and 26% for Auto/auto and Auto/Len, respectively (p = 0.03). Landmark analysis at 38 mo included 215 pts who continued Len maintenance (either on 07LT study or commercial Len) vs. 207 who stopped. Baseline demographics; study arm on 0702, induction pre-autoHCT were similar. Len discontinuation after 38 mo was associated with inferior PFS (79.5% vs. 61% at 5yr; HR = 1.91, p = 0.0004) but similar OS. Incidence of all second primary malignancies (SPM)(81 cases with 43 heme-malignancies) was associated with age. Conclusions: Long term outcomes are similar using ITT, but as treated analysis suggested a PFS benefit for tandem autoHCT, driven mainly by pts with high risk MM. Len discontinuation even at 38 mo was associated with inferior PFS. Clinical trial information: NCT02322320 .

Background: The discovery that gut microbial dysbiosis correlated with prognosis, immune reconstitution and development of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell transplantation (allo-SCT) highlights the clinical relevance of the gut microbiome in shaping anti-tumor immune responses. Treatment of allo-SCT patients with antibiotics has recently been associated with increased GVHD mortality (Routy et al. 2017). Based on these studies and the association of distinct gut bacteria with increased efficacy to PD-1 blockade in patients with solid tumors (Derosa et al. 2018), we performed a retrospective analysis to determine if infection treated with antibiotics affected the outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: A list of all MM patients treated at our institution between January 2012 through December 2015 was obtained and 1095 patients were identified. A comprehensive review of the electronic medical record (EMR) of the first 142 who received ASCT was performed. Information was collected from diagnosis to the date of last contact. Baseline characteristics, treatment history, transplant course, antibiotic treatment, and infection severity using common terminology criteria for adverse event (CTCAE) version 4 were reviewed. Prophylactic antibiotics were excluded. Response was measured and defined using the International Myeloma Working Group Criteria. Progression free survival (PFS) and overall survival (OS) were estimated using log rank tests. Cox hazard stepwise regression model examined for multiple factors affecting PFS and OS using the Akaike information criterion. Results: Of the 142 patients, 93 (65%) were Durie Salmon (DS) III, 20 (14%) were Revised International Staging System (R-ISS) III, 44 (31%) had high-risk cytogenetics, and 76 (54%) were male. The median age at diagnosis was 60. Although there was a similar frequency of DS III (67% vs 61%) and high-risk cytogenetics (35% vs 25%) among patients in the antibiotic and non-antibiotic treated groups, there was an over-representation of R-ISS 3 (19% v 4%) patients in the antibiotic-treated group. Treatment with antibiotics was associated with decreased median PFS (2.38 vs 6.58 years (yrs), p =0.00003) (Figure 1a) and decreased median OS (7.43 vs 17.39 yrs, p = Multivariate analysis demonstrated progression risk associated with beta-lactam use (HR-2.25, 95% CI, 1.31 - 3.85, p = 0.003), and DSS III (HR-2.28, 95% CI, 1.23 - 4.21, p = 0.009). Multivariate analysis demonstrated increased mortality associated with antibiotic treatment (HR-5.70, 95% CI, 1.34 - 34.29, p = 0.019) and decreased mortality risk with age younger than 65 (HR-0.24, 95% CI, 0.07 - 0.81, p = 0.022). For both PFS and OS, there was no statistical significance demonstrated in multivariate analysis for gender, fluoroquinolone treatment, high risk cytogenetics, R-ISS 3, or CTCAE grade. Conclusion: In this preliminary study, antibiotic use and infection severity predicted for decreased PFS and OS compared to patients who did not receive antibiotics in MM patients undergoing ASCT. Treatment with at least 2 classes of antibiotics-fluoroquinolones and beta-lactams, predicted for decreased PFS and OS. Multivariate analysis showed increased progression risk with beta lactams and DSS III as well as increased mortality risk with antibiotic treatment and advanced age. The study was limited by its relatively small sample size, retrospective nature, and the high correlation among infection and antibiotic groups that affected the multivariate analysis. Work is underway at our institution to further elucidate the impact of antibiotics on microbial diversity and patient survival. Disclosures Goldberg: COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. 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. Biran:Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

Background: Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Adequate HPSC after multiple cycles of dose-intense melphalan (mel) can be harvested, cryopreserved, and stored to allow for such future transplants. Many investigators reported sustained CD34+ cell viability using in vitro assays such as colony forming units (CFU-GM) potency of HPSCs after long term storage. Data on engraftment outcomes using these products demonstrating in vivo viability are limited. This study describes a large single center experience evaluating the engraftment potential of HPSC used in salvage transplantation after long-term storage in patients with MM, in comparison to initial treatment. Study Design and Methods: We conducted a retrospective chart review of patients with MM undergoing salvage HSCT, whose initial cell collection occurred between January 2002 and May 2016. This review identified 59 patients, all conditioned for initial transplants with dose-intense Mel 200 mg/m2, and who received autologous HPSC stored > 1 year after initial HSCT. HPSC were cryopreserved and stored in vapor phase liquid nitrogen at a temperature of ≤-150°C. Conditioning regimens for salvage transplants were mel (n=11), mel/bortezomib (bor) (n=32), mel/bor/thalidomide (n=6), BEAM (n=1), and Super BEAM (n=9). Patients who received a planned tandem transplant only (less than a year apart) were excluded. For patients receiving tandem HSCT followed by salvage HSCT, the first of the tandem HSCTs was considered for this analysis (n=5). Differences in CD34+ cell doses and days to engraftment between first and salvage transplant were tested using a paired 2-tailed t-test. Univariate and multivariable linear regressions were used to determine association between storage time and days to engraftment. Results: From 2002 to 2017, transplant data from 59 MM patients were analyzed (Table 1). Forty-nine (83%) patients had a Salmon Durie stage IIIA or IIIB at first diagnosis. The median age at first diagnosis was 57.5 (range, 36-73) years. A median collection dose of 16.0 × 106 CD34+ cells per kilogram (range, 7.9-62.5) was reached during HPSC collection with a median of 3 collections (range, 1-7) per patient. All 59 patients collected upon first mobilization attempt. The median age of patients at time of first and salvage transplants was 59 and 62 years, respectively. As predicted, the patient's age at salvage transplant was significantly greater than the age at first transplant (p500 /uL) at a median of 11 days after both the first and salvage transplant (ranges, 9-18 and 8-15 respectively, p=0.041) (Figure 1). The median time to sustained platelet engraftment (>20 x 109/L) was 13 days (range, 9-36) after first HSCT and 14 days (range 8-45) after salvage HSCT (p=0.842) (Figure 1). The CD34 dose for the salvage transplant was significantly higher than the first transplant, with patients undergoing the first HSCT receiving a median CD34+ cell dose of 5.3 × 106/kg (range 3.0-14.1), compared to a median of 6.1 × 106/kg (range 3.4-13.8) for the salvage HSCT (p=0.04). There was no association between the CD34 dose infused and days to ANC (p=0.755) or platelet (p=0.669) engraftment. After adjusting for age at transplant and CD34 dose, there was no association between duration of cryopreservation and days to ANC (p=0.658) and platelet (p=0.725) engraftment (Figure 2). There were no graft failures reported in either the first or salvage HSCT. Conclusion: Long-term cryopreservation did not affect engraftment outcomes in patients with MM receiving salvage autologous HSCT, despite the addition of salvage chemotherapy. There was no association between engraftment kinetics and storage duration in patients receiving a salvage transplant when controlling for CD34 dose and recipient age. Although it is possible that these cell products may have lost HPSC viability but still contained more than adequate viable HSC for HSCT, there was no evidence of delayed engraftment, particularly of platelets, suggestive of low numbers of viable HSCT. Disclosures Biran: Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership. Siegel:Takeda: 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; Bristol-Myers Squibb Company: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy.

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: 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; Celgene: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

Introduction: Patients (pts) with high-risk multiple myeloma (HRMM) experience early disease progression post autologous stem cell transplant (ASCT). The median progression free survival (PFS) for HRMM pts undergoing ASCT with lenalidomide (len) maintenance ranges between 27 and 42 months in high risk pts and 22 months in ultra-high risk, defined by two or more adverse cytogenetic abnormalities such as: gain(1q), t(4;14), t(14;16),t(14;20), or del(17p)( Chakraborty et al, Leukemia,2018 and Jackson et al, Lancet, 2018). Elotuzumab, a humanized IgG kappa monoclonal antibody against SLAM-F7 (CS-1), is approved in combination with len and dexamethasone (ERd) in pts with relapsed MM (Dimopoulus et al, BJH, 2017). It directly activates natural killer (NK) cells and mediates myeloma cell death by antibody-dependent cell mediated cytoxicity. We hypothesized that administration of ERd as post-ASCT consolidation will enhance an immune-competent phenotype, by restoring NK cells and effector T-cell populations at a time of maximal disease de-bulking, and will ultimately improve outcomes among pts with HRMM. Methods: Thirty-one HRMM patients who achieved stable disease or better were treated beginning at 30-90 days post ASCT with ERd (29/31 pts) or elotuzumab/pomalidomide )/dex (EPd) (2/31 pts) between September 2016 and February 2019. With institutional review board approval, electronic medical records were reviewed for baseline characteristics, treatment history, adverse events (AE) while on therapy as defined by common terminology criteria for adverse events (CTCAE), and survival outcomes. Treatment with ERd or EPd was administered for 4 consecutive 28-day cycles per standard dosing regimens with a tapering or discontinuation of corticosteroids per investigator discretion with cycles 3 and 4. HRMM was defined by any of the following: ISS or Revised-ISS stage 3, CD-138 selected FISH with del 17p, 1q21 gain, t(4;14), t(14;16), and t(14;20), cytogenetics with 13q del or complex karyotype, and/or high-risk gene expression profile score. Ultra-HR pts were defined by having both del 13q and 1q21 gain by FISH based on recent unpublished COMPASS data. Minimal residual disease (MRD) was evaluated upon achievement of very good partial remission or complete remission using 10-color multiparametric flow cytometry. PFS was measured using the log-rank test. Response criteria was defined per International Myeloma Working Group criteria. Results: Baseline characteristics of all 31 patients are shown in Table 1. Thirty-four percent were ISS-3, 71% (22/31 pts) had high-risk FISH, of which 19% were ultra-high risk (6/22 pts). Seven pts (22.6%) underwent tandem-ASCT pre-consolidation. Of the 8 pts who had GEP testing, 2 (25%) were high risk. Best response to treatment by cycle is depicted in Table 2. Consolidative ERd/EPd deepened response compared to post-ASCT with 71.4% vs 19.4% achieving stringent complete remission (sCR). Post-consolidation, 19.3% vs 12.9%, pre-consolidation, achieved MRD negativity. With a median follow-up of 24.8 months, median PFS was 31.4 months (Figure 1). There was no significant association between median PFS and variables such as tandem ASCT and ultra-HR using multivariate cox regression. Although all pts experienced at least one AE while on therapy, only 1 patient (3.22%) experienced a grade 3 AE. Hematologic AEs included: anemia (48%), neutropenia (45%), and thrombocytopenia (52%), while the most common non-hematologic AEs included: fatigue (32%), malaise (23%), and back pain (19%). One patient experienced a serious AE (SAE) which was PCP pneumonia requiring hospitalization, resulting in early discontinuation from therapy. There was no treatment-related mortality. Conclusion: ERd or EPd as 4 months of fixed duration consolidation therapy post-ASCT resulted in a median PFS of 31.4 months amongst pts with HRMM, similar to or perhaps surpassing historical reports of HRMM pts receiving lenalidomide maintenance until progression. This therapy may offer comparable, if not superior, outcomes while having the advantage of allowing for significant time without therapy and perhaps improving quality of life and financial toxicity. This study is limited due to its retrospective nature. Larger prospective studies evaluating fixed duration ERd/EPd in HRMM patients post ASCT should be conducted. Disclosures Rowley: Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Siegel:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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; Celgene: 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. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck: Research Funding.

Engraftment syndrome (ES) is a well-defined entity characterized by non-infectious fever and other clinical manifestations including skin rash, pulmonary infiltrates, diarrhea, weight gain and neurological symptoms which happens in the setting of autologous HSCT during early neutrophil recovery phase. (Spitzer ,2001).These clinical manifestations usually occur immediately before or at the time of neutrophil engraftment possibly due to the release of inflammatory cytokines. ES may require therapy with corticosteroids and other immunosuppressive drugs. Our study cohort included 645 patients with multiple myeloma treated with autologous stem cell transplantation between January 2010 and June 2019. The majority of patients had a single autologous transplant (80%), 18 % received a second autologous transplant and 3 patients had a third autologous transplant. Fifty seven percent of patients were male, 61 % had IgG myeloma and 50 percent had standard risk cytogenetics. Sixty three percent of patients were under the age of 65 years. ES was defined as a combination of at least 2 symptoms not attributed to other causes, including non-infectious fever, diarrhea, skin rash, pulmonary infiltrates or hepatic dysfunction, occurring from 3 days prior to 10 days post engraftment. (Cornell ,2015).One hundred and ninety seven patients in this cohort met the criteria for engraftment syndrome of whom 173 were treated with corticosteroids and 9 required the addition of tacrolimus or cyclosporine. Univariate and multivariate statistical analyses were performed looking at risk factors for the development of ES and the overall effect of ES on patient outcome. Results of our univariate analysis showed that age >65, female sex, use of plerixafor were significant risk factors for developing engraftment syndrome while use of cyclophosphamide-based mobilization had significantly reduced risk. Multivariate analysis using Gray Fine model revealed that patients over 65 years were twice as likely to develop ES than patients who were younger than 65 years (HR=1.881, CI: 1.405 to 2.518). Females had a 36% higher risk of ES than male patients (HR=1.355, CI: 1.011 to 1.815). Patients who were infused with more than 7x106 CD34+ cells/kg had a 40% reduced risk of developing ES (HR=0.559, CI: 0.385 to 0.812). Receiving the new formulation of melphalan: EVOMELAⓇ, as preparative regimen, was associated with a 60% increased risk of developing ES compared to patients treated with the standard formulation (HR=1.597, CI: 1.116 to 2.285). The use of plerixafor was found to be a risk factor for ES even when adjusted for age(HR=1.463,CI:1.024 to 2.089). Follow- up of patients that did not develop ES (n=445) had a median of 59 months (IQR: 29.0 -80.0months), range: 0 - 136 months. Follow-up time of patients that developed ES (n=197) was 41.0 months (IQR: 16.0 - 66.0 months), range: 0.0 - 131 months.An overall survival analysis of patients who developed engraftment syndrome showed a trend for improved survival in patients who did not develop engraftment syndrome, however this did not meet statistical significance and PFS curves were similar with no statistically significant difference between the two groups. Our study of this large cohort of patients suggests that selection of mobilization regimen and conditioning chemotherapy could decrease the incidence of ES, thereby decreasing morbidity and prolonged hospital stay. There can also be a consideration for pre-emptive treatment of patients in the very high risk category based on age, gender and available cell dose. Disclosures Siegel: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; 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. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Goy:Takeda: Other: Grants outside of the submitted work; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Autologous hematopoietic cell transplantation (AHCT) is an effective treatment to achieve deep and durable remission in multiple myeloma (MM). Typically, AHCT is offered to patients Methods: We analyzed the outcomes of 15,999 MM patients aged 20 years and older from the USA who received a single AHCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017 and reported to the CIBMTR. Multivariate analysis was performed for non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards model with age at transplant in decades as the main effect. Hazard ratio (HR) with 95% confidence intervals (CI) are reported. Because of the large sample size, a p-value of Results: Table 1 shows patient, disease and treatment characteristics by age group at diagnosis. All age groups had similar distribution of gender, race, ethnicity, Karnofsky performance score (KPS), comorbidity index (HCT-CI), stage III by Durie-Salmon/International Staging System. There was a higher proportion of high-risk cytogenetics in patients ≥70 years (30%), compared to age group 40-49 years (24%) and 20-39 years (20%) in this population. Older patients were more likely to be White compared to younger patients: 85% ≥70 compared to 64% 20-39 years. While 82% of the overall population received melphalan 200 mg/m2, 58% of the ≥70% received Mel 140 mg/m2. There were more ASCT performed in the ≥70-year age group in 2017 (28%) compared to 2013 (15%). Univariate outcomes by age groups shown in Table 2 revealed that 100-day NRM was higher in ≥70 years at 1% compared to younger patients (p Conclusions: This is the largest study of AHCT in older adults with MM. More MM patients ≥70 years are being transplanted in the US over time. While our data may highlight referral and access biases regarding which older patients may be referred for ASCT, our results confirm that patients ≥70 years can undergo transplant safely and achieve similar benefits as 60-69 years' old patients. Our results also suggest that melphalan 200 mg/m2 may be given safely in the ≥70 years population. While melphalan conditioning dose 140 mg/m2 in the ≥70 group is associated with worse outcomes, this is likely a surrogate for higher frailty and comorbidities in this cohort of patients. Our analysis confirms that AHCT has similar benefits in terms of disease control (REL and PFS) in both young and older MM patients. This benefit is seen even in a contemporaneous era where proteasome inhibitors and/or immunomodulator drugs are used in upfront treatment. Thus, AHCT remains a safe consolidation therapy across all age groups of MM patients. Disclosures Hari: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Shah:Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Genzyme: Other: Speaker; Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees.

Introduction: Multiple myeloma (MM) remains incurable when treated with novel myeloma therapies in combination with high dose chemotherapy and autologous stem cell transplantation (ASCT). In contrast to the accelerated development of effective new drugs for induction, maintenance, and relapse, single-agent melphalan remains the standard for conditioning before ASCT. Is this phase II trial, we prospectively evaluated a conditioning regimen consisting of high-dose intravenous busulfan and melphalan followed by bortezomib (BUMELVEL), an agent shown to be potentially synergistic in combination with alkylating agents. We report our 7 year long term follow up with direct comparison to a contemporaneous CIBMTR cohort with the primary aim of both long term progression-free (PFS) and overall survival (OS). Methods: This phase I/II study was conducted between July 2009 and May 2012 at Loyola University Medical Center. MM patients with any disease response following induction were enrolled at time of stem cell transplantation. 43 patients received BUMELVEL conditioning followed by ASCT on the phase II portion of this study. Busfulan was administered intravenously (i.v.) daily for 4 days with the first 2 days (days −6 and −5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (days −4 and −3) adjusted to achieve a target AUC total of 20,000 μM·min determined by pharmacokinetic (PK) analysis. Melphalan at 140 mg/m2 and bortezomib at 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Maintenance therapy was not planned. Patients received prophylaxis for oral mucositis with palifermin. Data from this phase II clinical trial were compared against a matched control cohort of contemporaneous North American MM patients from the CIBMTR database (n = 162) receiving conditioning with single agent iv melphalan at a dose of 200mg/m2. The primary objectives of this study were median PFS and toxicities. Results: Baseline patient characteristics are described in Table 1. More patients in the BUMELVEL arm received greater than one line of therapy prior to transplant (53 v 33%). There were more standard risk patients per Mayo Stratification (Kumar et al, Mayo Clin Proc 2009) in the MEL200 group (78%) v the BUMELVEL group (40%). There was no difference in response rates at day 100 (p=0.48) but a trend toward improved response at 1 year in the BUMELVEL arm with 77% achieving a VGPR or better versus 60% in the MEL200 group (p-0.09). No patients in the BUMELVEL group received planned maintenance therapy post-transplant whereas 112 (69.6%) in the MEL200 control arm received planned post-transplant maintenance. Non-relapse mortality was 2% (range 0-9%) in the BUMELVEL group and 10 (6%, range 3-11) in the MEL200 but this was not statistically significant in both univariate and multivariate modeling (p=0.25). There were no episodes of sinusoidal obstructive syndrome in the BUMELVEL group and 37% of patients experienced grade 3 mucositis with no grade 4 mucositis. After a median of more than seven years of follow up, the five year PFS was 47% (95% CI; 32-62) in the BUMELVEL group versus 30% (95% CI; 23-37) in the MEL200 group (p=0.05) (Figure 1). Notably the 7-year PFS in the BUMELVEL group was 32% (range 18-48). In multivariate analysis for PFS, BUMELVEL conditioning (HR 0.65; 95% CI 0.44-0.97)(p=0.036), time from diagnosis to transplant of greater than versus less than 12 months (HR 1.64; 95% CI 1.18 - 2.27), and disease status at transplant CR versus other (p=0.006) were all predictive of PFS (table 2). OS was not different between the two groups with a 7 year survival of 64% (95% CI; 48-79) in the BUMELVEL group versus 55% (95% CI; 46-64%) in the MEL200 group (Figure 1) which was confirmed on multivariate analysis (p=0.33). Discussion: Similar to recent reports in the literature comparing busulfan and melphalan to melphalan alone (Bashir et al, Lancet Hem 2019), we show that although depth of response was similar between the BUMELVEL group and the historical MEL200 comparator, the BUMELVEL group experienced an improved PFS. Importantly, we report no cases of SOS and a low non-relapse mortality of only 2% (v 6% in the historical control) reinforcing that the preparatory regimen in myeloma can be intensified safely with improved duration of unmaintained PFS. These long term results confirm a sustained benefit of novel combination conditioning in MM and the need for novel transplant preparative regimens. Disclosures D'Souza: EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Stiff:Unum: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Amgen: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding.

A small proportion of patients with multiple myeloma (MM) are diagnosed at a very young age. The clinicopathological characteristics and prognosis of these patients are not well known. This analysis included 52 patients diagnosed with MM at the age of ≤30 years (range: 8-30 years). 68% of patients had International Scoring System (ISS) 1 MM; 22% presented with the light chain-only disease, and 48% with elevated serum lactate dehydrogenase (LDH). 85% of patients were treated with novel agents, and 62% received front-line autologous stem cell transplantation (ASCT). Overall response rate (ORR) to front-line treatment and ASCT were 71% and 90%, respectively. The group was followed-up for the median period of 86 months. The median overall survival (OS) was 166 months (95% CI: 53-222), with 5-year OS rate of 77% (95% CI: 61.0-87.9). This findings suggest that the prognosis in young MM patients may be as good if not better than in the general population of MM patients.

Monoclonal gammopathy of renal significance (MGRS) has introduced a new perspective to several well-known disease entities impacting nephrology, haematology and pathology. Given the constantly changing disease spectrum of these entities, it is clinically imperative to establish diagnostic and treatment pathways supported by evidence-based medicine. MGRS is a disease of the kidney, secondary to plasma cell clonal proliferation or immune dysfunction, requiring therapeutic intervention to eradicate the offending clone. To fully understand the disease(s), it is prerequisite to determine the significance of the findings. The diagnostic work up should be extensive due to the wide heterogeneity of clinical presentation, ultimately necessitating kidney biopsy. Particular patient profiles such as AL amyloidosis, which may be diagnosed through biopsies of other tissues/organs, may be an exception. Treatment decisions should be formulated by multi-disciplinary consensus: nephrologists, haematologists and pathologists. The ultimate goal in managing MGRS is eradication of the offending plasma cell clone which requires targeted chemotherapy and, in eligible cases, haematopoietic stem cell transplantation. We present a review of diagnostic procedures, treatment options and advances in the last few years in the management of MGRS in an effort to acquaint specialists with this new face of several older diseases.