High-dose Melphalan And Autologous Stem Cell Transplantation Research Articles

Nationwide implementation of lenalidomide maintenance in multiple myeloma: A retrospective, real-world study.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy.

The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT.

Lenalidomide Maintenance in Multiple Myeloma: A Retrospective, Nationwide, Real-World Study

Introduction: Lenalidomide maintenance (LM) has shown progression-free (PFS) and overall survival (OS) benefit in clinical trials and is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved for all patients treated with HDM-ASCT since June 2019 and is publicly funded. That LM was made available nationwide simultaneous across all regions creates a unique opportunity to study the real-world use pattern, efficacy, and adverse effects of LM in an unselected, population-based cohort without referral bias. Methods: Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Baseline clinical characteristics were acquired from the Danish MM Registry. To avoid the risk of guarantee-time bias, several strategies were applied. Early discontinuation of LM was studied using landmark analysis at 6 months after initiation of LM. For comparison with the pre-LM cohort, survival time was calculated from date of ASCT to progression or death for PFS and death of any cause for OS. Cox proportional hazards regression was used to calculate hazard ratios. Multivariate adjustment was made for age and sex as well as known risk factors for worse outcome: ISS and high-risk cytogenetics. Results: Lenalidomide maintenance cohort: Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy, and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. During follow up, 119 (32.7%) patients had an event of progressive disease or death and 38 died. Only 1 death was related to Covid-19. To study the impact of early discontinuation of LM on clinical outcomes a 6-month landmark analysis was conducted. Early discontinuation did not negatively impact PFS, HR 0.92 (95% CI: 0.50, 1.70) or OS, HR 1.12 (0.25, 5.12). Results were similar in a 12-month landmark analysis. Comparison to the pre-lenalidomide maintenance cohort: A cohort of 364 multiple myeloma patients treated before the introduction of lenalidomide maintenance was used as comparison (pre-LM cohort). In that we take advantage of the randomness in being treated for MM in the years before and after the approval of lenalidomide. As the inclusion to either cohort was solely defined by the date of HDM-ASCT baseline characteristics were well balanced as expected with a median age of 61.1 vs 61.8 in the LM cohort and pre-LM cohort, respectively. By chance the dates of inclusion resulted in equal numbers of participants in both cohorts. We confirmed that lenalidomide maintenance was not routinely used before the approval in June 2019 by reviewing the electronic records of all patients treated with HDM-ASCT between January and June 2019. Of these, only 3 (7%) received LM, and in each case, LM was initiated just prior to approval. The LM cohort had similar PFS, HR 0.82 (0.65, 1.04), and OS HR 1.22 (0.78, 1.89) compared to the pre-LM cohort in unadjusted analysis, Figure 1. Results were similar after multivariate adjustment. The 3-year PFS and OS rates in the LM cohort were 61% (95 CI: 55%, 67%) and 86% (95 CI: 82%, 91%), respectively, while the pre-LM cohort had a 3-year PFS of 55% (50%, 60%) and a 3-year OS of 89% (86%, 93%). Conclusion: In this study encompassing all Danish patients with MM treated with HDM-ASCT since the introduction LM, we found that LM was initiated in approximately three out of four patients. One third of patients treated with LM discontinued this treatment within the first year, mainly due to toxicity. Early discontinuation of LM was not associated with worse clinical outcomes. When comparing post-transplantation PFS and OS in two cohorts of patients treated before and after the approval of LM, respectively, we found no differences.

Safety and Efficacy of Propylene Glycol-Free Melphalan in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Results of a Phase II Study

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis.

Tracking the Evolution of Therapy-Related Myeloid Neoplasms Using Chemotherapy Signatures

Introduction Patients with clonal hematopoiesis (CH) are at risk for therapy-related Myeloid Neoplasm (tMN), especially patients with multiple myeloma (MM) undergoing high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). Exposure to distinct chemotherapies, such as melphalan, introduces hundreds of mutations in human cells measurable as highly penetrant mutational signatures. The impact of these mutations on tMN development is poorly understood. Methods To characterize the genomic impact of distinct chemotherapies, we analyzed a cohort of 40 tMN whole genomes (WGS) from 39 patients exposed to cytotoxic chemo (and/or radiation). 13 of 16 patients who received HDM-ASCT had underlying MM. Results We compiled single nucleotide variants (SNV) and performed mutational signature analysis to identify the mutational processes in each tumor. Overall, only platinum and melphalan were associated with mutational signatures. All 10 tMN with prior platinum exposure bore a platinum signature (SBS31/SBS35) while only 6 of 16 post-HDM-ASCT (37.5%) bore the melphalan signature (SBS-MM1). As detection of chemo-signatures in bulk whole genomes is contingent on a single cell expanding to clonal dominance (Pich, Nat Gen 2019), this differential signature presence suggests that CH may escape exposure to melphalan via leukapheresis and be reinfused to expand to tMN. Support for this model comes from 1) confirmation via targeted sequencing (MSK-IMPACT) of pre-existent CH variants in 8/11 tested pre-ASCT samples/apheresis products that became clonal in tMN , 2) detection of platinum but not melphalan signatures in 3 neoplasms with sequential exposure to both agents, and 3) detection of SBS-MM1 in two tumors without an escape route (tMN post-oral melphalan and a newly sequenced post-HDM-ASCT transitional cell carcinoma). The mutational burden of melphalan signature-positive tMN was higher than those without (p=0.009). We next compared 298 de novo AML exomes (Beat AML) and 21 genomes (TCGA) to tMN genomes. De novo AML and tMN lacking chemo-induced mutagenesis shared a similar CNV landscape, while tMN harboring chemo-signatures were enriched for aneuploidies including deletions of 5q, 7q, 17p, and gains in 19p13.2 (FDR<0.01). Chromothripsis was enriched in tMN with chemo-signatures (p<0.001), with five patients having focal amplifications (median 7; range 5-12, copies) of the SMARCA4 gene locus. Furthermore, chemo-signature-positive cases had a higher prevalence of TP53 loss (10/16, 62.5%) compared to signature-negative cases (3/23, 13%; Fisher, p=0.002). Strikingly, among those receiving HDM-ASCT, all six cases with the SBS-MM1 signature had TP53 loss as compared to 2/10 (20%) without the signature (Fisher, p = 0.007). This stark difference indicates that loss of TP53 may allow precursors to survive direct exposure to a myeloablative dose of melphalan and acquire chemo-mediated aberrations, while precursors with unperturbed TP53 may preferentially be reinfused with ASCT and/or or be selected by milder chemotherapy. Finally, we used chemo-induced mutations duplicated with large chromosomal gains to establish if these events were either acquired or pre-existing (i.e., selected) in relation to chemotherapy. According to this new workflow, if chemo-mutations are duplicated within a chromosomal gain, they must have been present prior to the event (i.e., gain was acquired after exposure). Conversely, the presence of only non-duplicated clonal or subclonal chemo-mutations indicates the chromosomal gain occurred prior to exposure (i.e., gain was selected). We demonstrated that several aneuploidies and chromothriptic events are acquired following exposure to chemotherapy. Conclusion Only a fraction (37.5%) of tMN cases harbor the highly penetrant SBS-MM1 melphalan mutational signature as compared to 100% of post-platinum cases. This further elucidates a novel mode of malignant progression for tMN that is not reliant on direct mutagenesis or even direct exposure to chemotherapy where CH may be reinfused to expand to tMN post-myeloablative therapy. Conversely, in cases with chemo-induced mutagenesis, copy number gains and complex SV are acquired following cytotoxic therapy. For patients treated with HDM-ASCT, TP53-mutant CH-status appears to influence these routes of progression, providing insight into the interaction of HD-melphalan and CH for patients with MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modified High-Dose versus High-Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m2) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.

Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N=635), we retrospective studied patients treated with carfilzomib (N=251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N=150) and after daratumumab (Da-Car; N=101) with those not treated with carfilzomib (N=384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p=0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies.

Recognizing the Existence of Heparin Induced Thrombocytopenia and Thrombosis in the Setting of High-Dose Melphalan and Autologous Stem Cell Transplantation: A Single Institution Case Series

Background: Heparin induced thrombocytopenia and thrombosis (HIT/HITT) is a disorder characterized by transient hypercoagulability, with increased risk of venous or arterial thrombosis, related to the development of antibodies directed against the heparin-PF4 complex. HIT can occur in any patient receiving heparin but has rarely been described in the setting of high dose melphalan and autologous stem cell transplantation (HDM/SCT) so the true incidence in this population is unknown. Clinical suspicion of HIT in this setting is often clouded by the increased frequency of thrombocytopenia due to stem cell collection or high dose chemotherapy, as well as the increased risk of thrombosis in hematologic malignancies. We report five such cases, with clinically apparent and laboratory confirmed HIT that were diagnosed while undergoing treatment with high dose melphalan and autologous stem cell transplantation.Results: Five patients pursuing treatment with HDM/SCT were diagnosed with HIT during a five year period at our institution. Four patients were being treated for AL amyloidosis and one for multiple myeloma. The average patient age was 64 years (range, 59 to 69), including four males and 1 female. At the time of HIT diagnosis one patient was receiving prophylactic doses of enoxaparin due to a history of line-associated deep vein thrombosis. The other four patients had only been exposed to heparin as part of standard practice for central line placement, line flushes, or stem cell collection. Suspicion of HIT arose in all cases when the patient had delayed platelet recovery during the days following stem cell collection. Only one patient had proceeded with melphalan treatment before HIT was diagnosed. The average platelet nadir was 29, with a range of 6 to 68 x 109/L (Table 1). In two patients the development of thrombosis prompted the work-up for HIT: one with an internal jugular thrombosis and the other with limb threatening aortoiliac thrombosis requiring aortoiliac and femoral artery embolectomy with fasciotomy. All five patients had confirmation of diagnosis with heparin-PF4 antibody (optical density range, 0.5 to 3.3) and a positive serotonin release assay (SRA). Four patients were started on anticoagulation with fondaparinux or argatroban with appropriate platelet recovery in all patients. Three patients proceeded with HDM/SCT, while the remaining two patients received alternative therapies because the previously collected stem cells had been processed with heparin and could not be given to the patients.Conclusions: Herein we have describe five cases of HIT confirmed by the presence of a heparin-PF4 antibody and SRA testing. In all five cases the cause of thrombocytopenia was initially thought to be related to stem cell collection, which is known to cause a decline in platelets. It is notable that the platelet nadir in these patients, was frequently much lower than the nadir that is typically expected in HIT (50 to 80 x 109/L). Despite the development of thrombosis in two patients and the known increase in mortality in patients with HIT, the long term outcome in each of these patients was favorable. This is potentially attributable to rapid diagnosis, cessation of heparin, and initiation of alternative anticoagulation. In reaction to the initial cases, our institution has changed practices to eliminate heparin in the processing of stem cells so that all patients are able to receive their collected stem cells even in the setting of HIT. These cases highlight the existence of HIT during the process of HDM/SCT and the need for increased diligence in monitoring for unexpected thrombocytopenia or sluggish platelet recovery, in particular immediately after stem cell collection. Clinicians should have a low threshold to send diagnostic testing, begin alternative anticoagulation and postpone high dose chemotherapy in order to prevent life threatening complications. [Display omitted] DisclosuresSloan:Molecular Templates, Inc.: Consultancy; Stemline Pharmaceuticals: Consultancy.

Retrospective Analysis of High-Dose Melphalan and Autologous Stem Cell Transplantation for Systemic Light-Chain Amyloidosis: A Single Center 63 Cases

[Background]High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) show significant efficacy in systemic immunoglobulin light-chain (AL) amyloidosis. However, there have been few reports demonstrating efficacy of HDM/ASCT for AL amyloidosis patients in Asia, because of scarcity of AL amyloidosis. We retrospectively analyzed 63 cases of AL amyloidosis who received HDM/ASCT.[Patients and methods]We retrospectively analyzed 63 patients with AL amyloidosis who received HDM and ASCT between 2006 and 2017. Patients with plasma BNP<1000 pg/ml and <IVST 15mm were determined transplant eligible from 2007. The median age was 54 years old (range, 32-70). Cardiac, renal and gastrointestinal involvement were 24(38.1%), 42(66.7%) and 29(48%) patients, respectively. The percentage of more than 2 organ involvement was 69.8%. Cardiac response was defined as more than 30% of BNP decline. Because NTproBNP was measured only in limited number of patients, we used BNP instead of NTproBNP to analyze cardiac response. Also, BNP was well correlated to NTproBNP (spearman correlation = 0.922). Hematological and kidney response was defined as previously described (Comenzo RL et al, Leukemia, 2012). Briefly, a difference between the involved FLC and uninvolved FLC of 50mg/dl and more than 0.5g of 24-hour urine protein were defined as measurable for hematological and renal response.[Results]2-year and 4-year overall survival was 88.2% and 80.9%, respectively. Cardiac response was achieved in 9 of 22(40.9%). Hematological responses were evaluated in 25 cases and were 15(60%) sCR, 3(12%) VGPR and 6(24%) PR. More than 11mm of IVST affected worse OS(p=0.032) in line with previous reports. Also, more than 1mg/dl of serum creatinine (sCre) showed worse OS (p=0.022).Mortality within 100 days after ASCT was observed in 5 patients (1 MOF, 1 arrhythmia, 1 heart failure and 2 infection). 4 out of 5 patients showed cardiac involvement (median BNP value = 732.3).[Conclusions]Our analysis revealed comparable OS rate with other institutions in US and EU countries. Patients with cardiac involvement and higher sCre level showed worse prognosis. More than 11 mm of interventricular septum thickness (IVST) affected worse OS. Careful patient selection and experienced management are important for HDM/ASCT for AL amyloidosis. DisclosuresIshida:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; ONO: Honoraria; Celgene: Honoraria. Suzuki:Bristol-Myers K.K: Honoraria; Novarltis: Honoraria; Celgen: Honoraria; Ono: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria.

Predictors and outcomes of acute kidney injury during autologous stem cell transplantation in AL amyloidosis.

Acute kidney injury (AKI) is a common complication after high-dose melphalan and autologous stem cell transplantation (HDM/SCT) in patients with light chain (AL) amyloidosis. However, its incidence, predictors and outcomes are not well known. This observational study included 223 patients with AL amyloidosis who underwent HDM/SCT. AKI was defined as an increase in serum creatinine to ≥1.5 times the baseline occurring within the first 30 days of HDM/SCT. The median age was 58 years (range: 30-77). Kidney and cardiac involvement were present in 86.1% and 56.8%, respectively. The median estimated glomerular filtration rate (eGFR) was 83.5 mL/min/1.73 m2 (range: 9-213) and proteinuria was 2899 mg/day (range: 0-19 966). AKI occurred in 29.1% of patients. Dialysis was initiated in 15 patients (6.7%) and of these 12 (80%) were able to discontinue dialysis. Most of the episodes of AKI occurred within the first 2 weeks; with a median follow-up of 4.5 years (range: 0.1-16.5), AKI was associated with increased overall mortality [hazard rato (HR) = 4.53, 95% confidence interval (CI) 2-10.23]. The 10-year overall survival was 87.1% without AKI, versus 56.9% with AKI. AKI was also associated with an increased risk for end-stage kidney disease (ESKD) (HR = 4.6, 95% CI 1.44-14.38). The risk of developing ESKD at 10 years was 18.9% with AKI, versus 8.1% without AKI. Several risk factors were found and using multivariate logistic regression, a prediction model was developed that included three readily available variables: eGFR <60 mL/min/1.73 m2, interventricular septal thickness in diastole >12 mm and albumin <3 g/dL. This model was able to predict AKI development with an area under the curve of 0.8. AKI is common in the post-HDM/SCT period and it leads to increased risk for ESKD and death. Our prediction model is an easily deployable tool in clinical settings as part of the discussion with patients who are being prepared for HDM/SCT.

Left Atrial Mechanics Associates With Paroxysmal Atrial Fibrillation in Light-Chain Amyloidosis Following Stem Cell Transplantation

BackgroundAtrial fibrillation (AF) during high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) for light-chain (AL) amyloidosis confers significant morbidity. Traditional risk factors provide limited prediction for development of paroxysmal AF during this vulnerable period. ObjectivesWe sought to assess the association of clinical and echocardiographic parameters, including left atrial (LA) mechanics and development of AF in patients undergoing HDM/SCT therapy. MethodsBaseline echocardiograms, electrocardiograms, and electronic medical records were retrospectively assessed among patients with AL amyloidosis before HDM/SCT (n = 91). LA function analysis was performed using speckle-tracking echocardiography. ResultsIn this study, 42 patients (46%) had cardiac involvement; in the peri-transplant period, 12 (13%) developed AF (7 with cardiac involvement). No significant differences in age, sex, cardiac biomarkers, or cardiac risk factors were seen between patients with and without development of AF; one-third of patients with AF peri-transplant had previous AF. Although LA reservoir strain was reduced in patients with development of AF, time to peak strain rate indexed to R-R interval (TPSRI) (p = 0.001) was prolonged in patients with development of AF compared with sinus rhythm patients in the total cohort but also in subgroups with and without cardiac involvement. ConclusionsTPSRI, a parameter of mechanical dispersion in the early reservoir phase of LA function, is associated with development of AF among patients undergoing HDM/SCT for AL amyloidosis. These findings require validation in larger prospective cohorts.

Early Serum Free Light Chain Response after High-Dose Melphalan and Stem Cell Transplantation Predicts Hematologic Response in AL Amyloidosis

Introduction Immunoglobulin light chain (AL) amyloidosis is a rare disease caused by a clonal plasma cell dyscrasia producing monoclonal light chains that misfold and form amyloid fibrils which can deposit in a variety of tissues and organs. This deposition of amyloid fibrils can lead to progressive organ impairment, multi-organ failure, and death if left untreated. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) is known to improve patient outcomes with hematologic complete responses (CR) rates of 25-67%. Hematologic CR is currently defined as the absence of monoclonal protein in serum and urine by immunofixation electrophoreses and normal serum free light chain ratio (FLCR). Studies have shown that even among patients achieving a normal FLCR after initial therapy with HDM, persistent elevation of the involved FLC (hiFLC) predicts poor prognosis. Serum half-life of FLCs is approximately 2-6 hours, even with diminished glomerular filtration rates, and could be a tool for early treatment response evaluation. We sought to determine the extent to which early FLC responses after HDM/SCT predict hematologic complete response (CR) at 6 months. Methods We analyzed patients with AL amyloidosis who underwent HDM/SCT from 2012-2019 at Boston Medical Center. Exclusion criteria included death within 100 days, lack of FLC data at any time point, pre-SCT normal FLC concentrations and ratio, and chronic renal insufficiency (serum creatinine &amp;gt;1.3 mg/dL) with a normal FLC ratio. All subjects received a total of 140-200 mg/m2 melphalan IV in equally divided doses on days -3 and -2. Stem cells were infused on day 0. FLC measurements were obtained early in the peri-SCT period (&amp;lt; 1 month), at 6 months, and at 12 months after HDM/SCT. The patients were evaluated for response according to the consensus response criteria at 6 months. Statistical analysis to compare CR at 6 months and early post-SCT free light chain levels was performed by Chi-square with significance considered at p&amp;lt;0.05. Results Of the 113 patients with AL amyloidosis treated with HDM/SCT during the specified time period, 32 were excluded (4 died within 100 days of SCT, 15 had normal FLCs pre-SCT, 5 lacked data, and 8 had chronic renal insufficiency (Cr &amp;gt;1.3 mg/dL) with normal FLCR. A total of 81 subjects (females=30) were analyzed. Median follow-up from SCT was 27.6 months (range, 6-145). Median time of early post-SCT FLC measurement was 8 days (range, 7-30). Median age at diagnosis was 58 years (range 30-79) and the iFLC was lambda in 81.5% (n = 66) of patients. Median number of bone marrow plasma cells was 10% (range, 1-50). The mean absolute involved FLC was 196 mg/L ±221 prior to SCT, 60 mg/L ± 77 in the early post-SCT period, 92 mg/L ± 152 at 6 months post-SCT. In early post-SCT period, 39.5% (n=32) had iFLC &amp;lt;20 mg/L, 28% (n=16/57) had dFLC&amp;lt;10 mg/L, and 84% (n=48/57) had normal FLCR. Early post-SCT dFLC &amp;lt;10 mg/dL and early post-SCT iFLC &amp;lt;20 mg/L were statistically associated with prediction of hematologic CR at 6 months (p=0.025 and p=0.001, respectively). However, early post-SCT normal FLCR was not associated with predicting hematologic CR at 6 months. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of early post-SCT iFLC &amp;lt;20 mg/L, dFLC &amp;lt;10 mg/L and normal FLCR to predict hematologic CR at 6 months are presented in table 1. Conclusion This study concludes that achievement of dFLC &amp;lt;10 mg/L and iFLC &amp;lt;20 mg/L in the early post-SCT period is associated with prediction of hematologic CR at 6 months. Early post-SCT dFLC &amp;lt;10 mg/L could be considered a tool for early evaluation of treatment response following HDM/SCT in AL amyloidosis. Key words: immunoglobulin light chains; AL amyloidosis, HDM/SCT Disclosures Sarosiek: Spectrum: Research Funding. Sanchorawala:Caelum: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Janssen: Research Funding.

Modified High Dose Versus High Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

Introduction: High dose melphalan and autologous stem cell transplantation (HDM/SCT) results in deep and durable responses and prolonged survival in highly selected patients with systemic immunoglobulin light chain (AL) amyloidosis. HDM/SCT is offered to select patients &amp;gt;65 years but melphalan dose is often reduced due to concerns for tolerability and toxicities in older patients. However, older adults are a diverse population and chronological age alone does not accurately predict chemotherapy tolerance. While both melphalan 140 mg/m2 (MEL-140) and 200 mg/m2 (MEL-200) are commonly used in clinical practice, there are very few studies comparing these two doses in older patients. Available studies suggest that MEL-140 may be associated with worse event-free survival and progression-free survival, but it is unclear whether this is confounding for increased co-morbidities and frailty in this group. We report transplant-related toxicities and outcomes in patients &amp;gt;65 years undergoing first HDM/SCT with MEL-140 versus MEL-200 within 12 months of diagnosis of AL amyloidosis. Methods: We analyzed transplant-related toxicities and outcomes of patients &amp;gt;65 years who received first HDM/SCT within 12 months of diagnosis between January 2011 and June 2020. We excluded patients receiving additional conditioning agents and those undergoing tandem or second transplantation. Patients were stratified based on melphalan dose. All statistical analyses were performed using GraphPad Prism version 8©. Independent (unpaired) t tests with unequal variance and a 95% confidence interval were used to calculate the two-tailed p values for continuous variables. Chi-squared tests were used to compare categorical variables. Hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (CI) and p values are reported. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and log-rank tests were used to compare the survival measurements of each group. In this cohort, PFS was defined as the time from SCT to hematologic progression, next line of therapy and/ or death, whichever came first. Transplant-related mortality was defined as death occurring within 100 days of SCT. Results: Forty patients were included in the final analysis with a median follow up of 55.0 months (range 7 - 109, n = 18) for surviving patients in both groups. Table 1 displays patient and disease characteristics, transplant-related toxicities, 2-year PFS and median OS. Patients receiving MEL-140 were older (69 versus 66 years, p &amp;lt;0.0001) and more likely to be male (82.6% versus 47.1%, p 0.0383). Karnofsky performance status (KPS) was similar in both groups. Median number of organs involved was 2 with 91.3% and 82.4% of patients having renal involvement in the MEL-140 and MEL-200 groups, respectively. For patients who underwent induction therapy with anti-plasma cell agents, 22.2% treated with MEL-140 and 50.0% treated with MEL-200 were in &amp;gt;VGPR prior to HDM/ SCT (p 0.3348). There was no transplant-related mortality observed in either group. Severe transplant-related toxicities (grade &amp;gt;3) were reported in 88.2% of the MEL-200 group versus 72.7% of the MEL-140 group (p 0.4260) but the frequency of various toxicities were different. Patients who underwent conditioning with MEL-200 were significantly more likely to experience febrile neutropenia, sepsis and infections (88.2%, n = 15 versus 50.0%, n = 11; OR 0.13, 95% CI 0.03 - 0.73, p 0.0173 [Table 2]). Notably, the 2-year PFS was almost twice as long in the MEL-200 group (82.5% versus 42.6%, p 0.0534 [Figure 1]). The median PFS was 12.1 months in the MEL-140 group but was not reached in the MEL-200 group. There was no difference in median OS among the two groups (not reached, p 0.1454). Conclusion: Our study results suggest that highly selected patients ≥65 years with good performance status can safely undergo melphalan at a dose of 200 mg/m2 prior to stem cell transplantation in AL amyloidosis although there may be an increased risk of febrile neutropenia, sepsis and infections. Additionally, the melphalan conditioning dose 140 mg/m2 is potentially associated with a significantly shorter progression-free survival than 200 mg/m2 in older patients undergoing HDM/SCT for AL amyloidosis. Disclosures Sanchorawala: Takeda: Research Funding; Caelum: Research Funding; Oncopeptide: Research Funding; Regeneron: Other: advisory board; Caleum: Other: advisory board; Proclara: Other: advisory board; Abbvie: Other: advisory board; UpToDate: Patents &amp; Royalties; Prothena: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Safety and Efficacy of Propylene Glycol-Free Melphalan (Evomela) in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Preliminary Results of a Phase II Study

INTRODUCTION: High dose melphalan and autologous stem cell transplantation (HDM/SCT) is effective for treatment of selected patients with light-chain (AL) amyloidosis with adequate functional status and preserved organ function. Despite rigorous patient selection, approximately 21% of AL amyloidosis patients receiving treatment with HDM/SCT develop acute renal injury and up to 22% develop cardiac arrhythmias in the peri-transplant period. Patients with AL amyloidosis are at greater risk of organ dysfunction in the peri-transplant period due to pre-existing amyloid deposition. This toxicity is potentially exacerbated by the co-solvent propylene glycol found in melphalan hydrochloride. Propylene glycol is reported to lead to metabolic acidosis, sepsis-like syndrome, renal dysfunction, and cardiac arrhythmias. Therefore a clinical trial investigating the use of propylene glycol-free melphalan during HDM/SCT was developed to evaluate the effect on organ toxicity in AL amyloidosis patients (NCT02994784). PROTOCOL: This Phase II clinical trial began enrollment in April 2018. Eligibility criteria included the following: histologic diagnosis of systemic AL amyloidosis, involvement of ≥1 vital organ, eGFR of ≥30 mL/min, DLCO ≥50%, LVEF ≥40%, ECOG &lt;3, NYHA status &lt;3, and no prior HDM/SCT. Subjects underwent autologous stem cell transplantation per institutional guidelines, receiving the conditioning regimen of 140 or 200 mg/m2 propylene glycol-free melphalan via IV infusion on Days -3 and -2. Stem cell infusion occurred on Day 0. Primary objectives included evaluation for renal dysfunction (defined as a ≥1 mg/dL increase in creatinine or a doubling of creatinine to ≥1.5 mg/dL for ≥2 days), cardiac dysfunction (defined as development of new arrhythmia), and autonomic dysfunction (defined as a drop in SBP ≥20 mmHg on orthostatic measurements). Secondary objectives included evaluation of time to engraftment, treatment related mortality, overall hematologic response at 6 months after SCT, organ response at 12 months after SCT, and number of hospitalizations. RESULTS : At the time of data cut-off (July 1, 2019) 17 patients had been enrolled. Median age was 59 years (range, 44-76) with 11 (65%) males. Median number of prior therapies was 0 (range, 0-2). Median number of organ systems involved was 1 (range, 0-3). 13 (76%) and 7 (41%) patients had renal and cardiac involvement, respectively. Median NT-proBNP level was 396 pg/mL (range, 63-6220), urine protein excretion was 3.14 g/24 h (range, 0-22.9), serum creatinine was 0.93 mg/L (range, 0.72-2.07), and median dFLC was 51 mg/L (range, 2-700). In the 7 patients with relapsed/refractory disease, median time from last therapy was 2 months. Subjects received either 140 mg/m2 (n = 2) or 200 mg/m2 (n = 15) of propylene glycol-free melphalan. There have been 0 deaths during the peri-transplant period or follow-up. Per the protocol defined criteria, 2 patients (11%) developed acute renal dysfunction, 3 subjects (18%) developed orthostatic hypotension, and 3 patients (18%) experienced a new cardiac arrhythmia (atrial fibrillation or ventricular tachycardia) while on study. Median time to neutrophil engraftment was 10 days. Median time to platelet engraftment was 17.5 days. Peri-transplant hospitalization occurred in 14 subjects (82%) and median hospitalization was 5 days. The most common non-hematologic adverse events included nausea/vomiting (82%), fatigue (82%), and diarrhea (88%). Of the 8 subjects who have completed their 6 month follow-up the hematologic response rates are as follows: 4 CRs (50%), 2 VGPRs (25%), 1 PR (13%) and 1 stable disease (13%). CONCLUSION: In this ongoing trial investigating the safety of propylene glycol-free melphalan in patients with AL amyloidosis the cardiac toxicities appear comparable to historical data with 18% of patients developing a cardiac arrhythmia and with potentially improved renal toxicity (11%), although additional data are required to confirm this finding. Time to engraftment is similar to published data for HDM/SCT and no peri-transplant mortality has been seen. Hematologic responses are also comparable to historical controls (50% CR and 25% VGPR). Additional data will be obtained with ongoing patient enrollment to determine if there are significant differences in the safety of propylene glycol-free melphalan in this population of patients with high risk of organ dysfunction during HDM/SCT. Disclosures Sarosiek: Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Stemline: Consultancy; Abbvie: Other: Endpoint Review Committee. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. OffLabel Disclosure: propylene glycol-free melphalan is FDA approved for multiple myeloma, but not for AL amyloidosis (which has not FDA approved therapies)

MCT1 As Molecularly Validated Predictive Marker for Lenalidomide-Maintenance Therapy in Multiple Myeloma

Introduction: Lenalidomide-based maintenance therapy is the currently approved standard of care for multiple myeloma (MM) patients after high-dose melphalan and autologous stem cell transplantation (HD-Mel), which significantly prolongs progression-free (PFS) and overall survival (OS). For patients with del17p bortezomib based maintenance treatment is considered overcoming adverse prognosis of this aberration. Predictive markers of response to lenalidomide maintenance have remained elusive. We have previously shown that IMiDs exert their anti-MM activity via destabilization of MCT1 and CD147 and combined overexpression reduces response to lenalidomide-treatment in vitro and in an in vivo MM xenograft model (Eichner et al. Nature Medicine 2016). Methods: CD138-purified myeloma cell samples of 654 patients receiving high-dose melphalan therapy and autologous stem cell transplantation and either bortezomib (n=101), thalidomide (n=98) or lenalidomide (n=455) maintenance treatment were assessed by gene expression profiling (GEP) using U133 2.0 plus DNA microarrays, 316 by RNA-sequencing (RNA-seq). Expression of CD147 and MCT1 were assessed and correlated with PFS and OS data. Gene expression based risk scores, including UAMS70-gene, Rs-score and gene expression based proliferation index were assessed alongside routine iFISH-analysis. Survival curves and median time to progression were computed with nonparametric survival estimates for censored data using the Kaplan-Meier method. Difference between the curves were tested using the G-rho Log-rank test. Landmark analysis was performed by defining an alternative start point (landmark) at 12 months. In vitro, CD147 and MCT1 were lentivirally overexpressed in MM1S cells, which were subjected to lenalidomide or bortezomib treatment and proliferation analysis. Xenografted MM-tumors were followed by 18FDG-PET and analyzed by immunohistochemistry. Results: Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2months in MCT1high vs. MCT1low,P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance. Likewise, patients with thalidomide maintenance showed reduced PFS (34.8 vs. 43.7 months in MCT1high vs. MCT1low, P=.23) and significantly shorter OS (83.6 months vs. not reached (NR) months in MCT1high vs. MCT1low;P=.03). For bortezomib based maintenance, MCT1 expression had no significant impact on PFS (39.8 months vs. 32.6 months in MCT1high vs. MCT1low) and OS (125.8 months vs. 129.8 months in MCT1high vs. MCT1low). No association with other prognostic factors was found. As still differences between MCT1high vs. MCT1lowexpression myeloma cells might be attributed to undiscerned molecular factors and for functional validation, we lentivirally overexpressed CD147 and MCT1 in human myeloma cell lines. Overexpression of MCT1 significantly reduced cytotoxicity of lenalidomide, while no change was observed in MM cells treated with bortezomib. We subsequently validated our results in vivo. Functional investigations in the mechanism of MCT1 impact on cellular survival are ongoing. Conclusion: Taken together MCT1 expression as potential predictive marker for response to IMiD-based maintenance treatment. Both PFS and OS were significantly reduced in patients with high gene expression levels of MCT1. In vitro and in vivo (xenograft model), MCT1 overexpression reduced sensitivity to lenalidomide unlike bortezomib treatment. Disclosures Salwender: Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations. Bertsch:Sanofi: Other: travel support; Celgene: Other: travel support. Goldschmidt:Chugai: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Takeda: Consultancy, Honoraria; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria. Scheid:Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Bassermann:Celgene: Consultancy, Research Funding.

The frequency of chromosomal abnormalities in AL amyloidosis and their impact on treatment response.

e19539 Background: Chromosomal abnormalities (CA) found in AL amyloidosis (AL) are similar to those found in multiple myeloma (MM.) However, t(11;14) has been reported more frequently in AL, anywhere from 30% - 50% in studies. It has been reported that the presence of t(11;14) confers a lower hematologic response rate with bortezomib-based therapy (BBT) and a better hematologic response rate with high dose melphalan and autologous stem cell transplantation (HDM/SCT). Methods: We performed a retrospective review of 307 newly diagnosed patients seen at our center between January 2013 and December 2017, for whom interphase fluorescent in-situ hybridization (iFISH) data, performed on bone marrow aspirate using standard MM FISH probes on enriched plasma cells after magnetic separation, were available. Patients who already had iFISH performed prior to their visit with us were also included. We collected data on the incidence of CA, first line treatment, and hematologic response to this treatment. Results: Of the 307 patients, CA were not detected in 37%. 21% had t(11;14), 25% had 13q deletion, 21% had IgH rearrangements with an undetermined partner chromosome, and 11% had 1q21 gain. In those for whom initial treatment and hematologic response data were available, in patients with t(11;14), hematologic complete response (CR) was achieved by 18% following HDM/SCT and 27% following BBT. For those with 1q21 gain, CR was achieved by 33% following HDM/SCT and 19% following BBT. In contrast, hematologic CR was achieved by 47% following HDM/SCT and 40% following BBT for those who had no detectable CA with iFISH. Conclusions: Our study shows a lower incidence of t(11;14) in AL compared to other studies. This may be partly explained by the high number of patients with IgH rearrangements with undetermined partner chromosomes, some of whom may indeed harbor t(11;14). Our study also did not show a better hematologic response rate with HDM/SCT in t(11;14) patients compared with BBT. Hematologic response rates were much better both with HDM/SCT and BBT for those with no detected CA compared to patients who had t(11;14) or 1q21 gain.

Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-2009.

High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.

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.

Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome

Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS). Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance). In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.