γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

Diagnosis and Management of Multiple Myeloma: A Review.

IMPORTANCE: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. OBSERVATIONS: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers ß2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients. CONCLUSIONS AND RELEVANCE: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.

Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma.

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced-intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens.

Prolonged Lenalidomide Therapy Does Not Impact Autologous Peripheral Blood Stem Cell Mobilization and Collection in Multiple Myeloma Patients: A Single-Center Retrospective Analysis.

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.

Chimeric Antigen Receptor T Cells for Multiple Myeloma: The Journey So Far-And the Road Ahead.

ABSTRACT: Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy.

A clinical perspective on plasma cell leukemia; current status and future directions.

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/µL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

90Y-labeled anti-CD45 antibody allogeneic hematopoietic cell transplantation for high-risk multiple myeloma.

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 (90Y-DOTA-BC8) as conditioning. 90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation.

BACKGROUND: Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE). PATIENTS AND METHODS: This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL. RESULTS: The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 106 CD34+ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever. CONCLUSION: KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.

The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

Autologous Stem Cell Transplantation for Multiple Myeloma: Growth Factor Matters.

Engraftment syndrome (ES) is a known complication of autologous hematopoietic stem cell transplant during neutrophil recovery. There is a limited amount of data available comparing the incidence of ES with post-transplant granulocyte colony-stimulating factor versus granulocyte macrophage colony-stimulating factor (GM-CSF), specifically in patients with multiple myeloma. Our retrospective review of 156 patients at a single center showed that GM-CSF was associated with a higher incidence of ES compared with G-CSF (32% versus 8% of patients, P < .001) and that development of ES was associated with a 32.9% (P < .001) longer hospital stay. This suggests that the choice of growth factor could possibly contribute to the development of ES and the associated costs of increased medical care.

Factors affecting lymphocyte collection efficiency for the manufacture of chimeric antigen receptor T cells in adults with B-cell malignancies.

BACKGROUND: The clinical and procedural parameters that affect the optimal collection of lymphocytes for the production of chimeric antigen receptor (CAR) T cells remain undefined but are increasingly important, as commercial products are now available. We evaluated determinants of low lymphocyte collection efficiency (CE) and the rate of successful CAR T-cell manufacture in middle-aged and older adults with advanced B-cell malignancies. STUDY DESIGNS AND METHODS: Mononuclear cell collections using two apheresis platforms (COBE Spectra and Spectra Optia, Terumo BCT) from patients participating in a CD19-directed CAR T-cell therapy trial were reviewed. Patient- and disease-specific factors, peripheral blood counts, apheresis parameters, and product cell counts were analyzed to determine effects on lymphocyte CE. RESULTS: Ninety-two apheresis events from patients with acute lymphocytic leukemia (ALL) (n = 28), chronic lymphocytic leukemia (n = 18), and non-Hodgkin lymphoma (n = 46) were available for analysis. Forty-one collections (45%) had a lymphocyte CE of <40%. On multivariable analysis, age (every 10-year increase, odds ratio [OR] = 1.51; p = 0.034), disease type (chronic lymphocytic leukemia vs. ALL, OR = 0.24; p = 0.052; non-Hodgkin lymphoma vs. ALL, OR = 0.20; p = 0.009) and precollection platelets (every 10 × 103 /µL increase, OR = 1.07; p = 0.005) were appreciably associated with a lymphocyte CE of <40%. No major apheresis complications occurred. CONCLUSIONS: Lymphocyte collection at our center was well tolerated and 100% successful in manufacturing CD19-directed CAR T cells from adult patients with B-cell malignancies despite low CE in some patients. A diagnosis of ALL, advancing age, and higher preapheresis platelet counts were observed to be associated with low CE.

Pre-transplantation novel agent induction predicts progression-free survival for patients with immunoglobulin light-chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation.

INTRODUCTION: High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is an effective treatment modality for immunoglobulin light-chain (AL) amyloidosis; however, its application remains restricted to patients with good performance status and limited organ involvement. In recent years, the paradigm for AL amyloidosis has changed with the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). We hypothesized that use of novel agent induction regimens has improved outcomes for patients with AL amyloidosis undergoing HDM/SCT at our center. METHODS: All patients with AL amyloidosis, age ≥18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were included in this study. Any regimen administered within 6 months prior to HDM/SCT including an IMiD or a PI was considered a novel induction regimen. Use of induction regimen was evaluated in a Cox proportional hazard model for association with progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-five patients with AL amyloidosis underwent HDM/SCT. The median age was 57.2 years (range 39-74.4), 15 (33.3%) were women. The median number of organs involved was 2 (range 1-5), with 20 patients having only 1 (44.4%), 10 patients having 2 (22.2%), and 15 patients (33.3%) having ≥ 3 organs involved. Novel agent induction regimens were used prior to HDM/SCT in 21 patients (46.7%); these comprised PI in 13/21 (57.1%), IMiD alone in 6/21 (28.6%), PI and cyclophosphamide (CyBorD) in 3/21 (14.3%), and IMiD and PI in 3/21 (14.3%). Use of a novel agent induction regimen was associated with improved, but not OS. The 3-year PFS for patients who received a novel agent induction was 79%, while for those who did not was 53% (hazard ratio [HR] = 0.317, p = 0.048). The 3-year OS for patients who received novel agent induction regimens was 95%, while for those who did not was 71% (HR = 0.454, p = 0.247). DISCUSSION: Our data suggest that use of a novel agent induction regimen including an IMiD or PI prior to HDM/SCT for patients with AL amyloidosis could improve outcomes, with improvement in PFS. Although these results are limited by sample size and lack of randomization, these results support possible further investigation of novel agent induction regimens in the context of a prospective clinical trial.

Sudden death in a patient with bone marrow transplant by a fungus among us.

Mucormycosis is rare, presenting as breakthrough infection among haematological and transplant patients on prophylaxis with voriconazole. We report an unusual presentation of this infection, that which is pneumonia progressing to cardiac arrest. A 68-year-old woman with refractory acute myelogenous leukaemia on voriconazole prophylaxis was initially admitted for neutropenic fever and pneumonia. She was discharged improved on antibiotics and voriconazole for presumed aspergillosis. She returned after 1 month with the same presentation. She eventually improved on antibiotics and voriconazole, and eventually received bone marrow transplantation. Three days later, she developed pleuritic chest pain, dyspnoea, and hypoxia requiring intubation. An hour after intubation, the patient arrested and expired. Autopsy revealed Rhizopus pneumonitis with pulmonary infarction, and emboli to her cerebellum, heart, thyroid and kidney. Mucormycosis is an emerging, fatal infection that should be suspected in haematological and transplant patients who deteriorate on voriconazole.