Tandem Autologous Stem Cell Transplantation Research Articles

Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.

Early Mortality Risk in Patients with Multiple Myeloma

BACKGROUND: Advances in treatment has improved greatly survival of multiple myeloma in the last two decades, and this improvement has been endorsed by wider use of novel drugs and tandem autologous stem cell transplantation. However, still there were cases died earlier post diagnosis OBJECTIVES: To study the risk factors of early mortality in patients with multiple myeloma In Kurdistan region of Iraq PATIENTS AND METHODS: A 176 cases that were diagnosed with symptomatic multiple myeloma between (January 2012 – July 2019) in cancer centers in Kurdistan region of Iraq. A total of 152 were continued within the study through their recorded sheet. Their data were analysed to determine what are the main risk factors that have an impact on early mortality among our myeloma patients. RESULTS: Among the total of 152 studied patients nine of them (5.9%) died early. The highest proportion (32.2%) of the sample aged 60-69 years, more than half (57.2%) of the them were male. The majority of the patients (80.9%) have been diagnosed during 2016-2019. The incidence of early death was 8.7% among patients who didn’t take the cytotoxic treatment compared with 1.7% of patients who took that treatment, but the difference was not significant (p = 0.089). The early death rate was significantly high (22.2%) among patients who didn’t take the immunomodulatory drugs, versus 2.4% of patients who took the immunomodulatory drugs (p = 0.001). The incidence of early mortality was 9.6% among patients with lactate dehydrogenase of ≥ 250 U/L compared with 0%

Relapse from MRD Negativity As Indication for Treatment in Multiple Myeloma - the Remnant Study

Background: Early intervention can reduce the rate of progression and improve overall survival (OS) in smouldering multiple myeloma (SMM) patients (pts) (1, 2). The most powerful predictor of prognosis in active MM is whether pts achieve minimal residual disease (MRD) negativity in bone marrow with treatment (3), however treating MRD relapse has not been evaluated in a randomized fashion. The REMNANT study will evaluate whether treating MRD relapse after first line (1.L) treatment prolongs progression free survival (PFS) and OS for MM pts versus treating relapse after 1.L. treatment at progressive disease (PD) (4). To establish a homogenous group of MRD negative pts after 1.L treatment including autologous stem cell transplantation (ASCT), pts are enrolled at diagnosis and treated with Norwegian standard of care (SOC) 1.L treatment. MRD negative pts will move on to the randomized part. Methods: The REMNANT study is an academic, multicenter, open-label, randomized phase II/III study of NDMM pts eligible for ASCT (see Figure 1). 391 pts across Norway will be included in the phase II part of the study and receive SOC 1.L treatment according to Norwegian national guidelines; VRd (V: 1,3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO Days 1, 2, 4, 5, 8, 9, 11, 12) for 4 pre-transplant induction and 4 post-transplant consolidation cycles (all 21-d cycles). After induction pts will undergo tandem or single ASCT, depending on toxicity and response to first ASCT. The primary endpoint of the phase 2 part of the study is the number of pts who achieve MRD negative (Euroflow NGF 10 -5) complete response (CR) 30-45 days post consolidation. Safety evaluations and pts-reported outcome assessment will be measured. Pts (176) achieving MRD negative CR will be randomly assigned in a 1:1 ratio to receive 2.L treatment at MRD reappearance (arm A) or at progressive disease (PD) as defined by the IMWG criteria (4) (arm B). Randomization will be stratified by R-ISS stage at diagnosis and single vs tandem ASCT. Pts in arm A will be followed with MRD assessment every 4 month and start 2.L treatment at loss of MRD negative CR. Pts in arm B will be followed up by standard criteria and start 2.L treatment at PD. Both arms will receive the same 2.L treatment; KdD (all 28-d cycles) (K: 70mg/m2 iv Days 1,8,15 d: 40 mg Days 1, 8, 15, 22 D: 1800 mg SC Days 1, 8, 15 during C 1-2, Days 1, 8 during cycle 3-6, Day 1 from cycle 7,). 2.L treatment will continue until disease progression, unacceptable AEs or patient withdrawal. In arm A MRD Euroflow will be assessed after 6 and 18 months of 2L therapy. In arm B MRD Euroflow will be assessed if &amp;gt;CR is achieved but not before 6 months of 2 L therapy, and again after 12 consecutive months. The co-primary endpoint is progression and death by any cause (PFS) and death by any cause alone (OS). Secondary endpoints includes TTNT and the proportion pf pts who achieve MRD negative CR during 2.L treatment in arm A and arm B, safety evaluations and pts-reported outcome. The trial is approved and will start enrollment Q3 2020. 1. Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F, Corral LL, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(8):1127-36. 2. Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. 2020;38(11):1126-37. 3. Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis. JAMA Oncol. 2017;3(1):28-35.5. 4. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e46. Disclosures Schjesvold: Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy. OffLabel Disclosure: Carfilzomib-dexamethason-daratumumab (KdD) as second line treatment

Impact of Daratumumab on Stem Cell Collection, Graft Composition and Engraftment Among Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as &amp;lt; 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC &amp;gt;1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count &amp;gt;20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Results of Autologous Stem Cell Transplantation in Multiple Myeloma Patients with Renal Failure

Introduction According to the Russian register renal impairment at the time of diagnosis was noted in every fifth patient with multiple myeloma (MM). Timely induction therapy followed by autologous stem cell transplantation (ASCT) in some cases contributes to the reversibility of renal failure. Although ASCT appears safe in patients with mild and moderate renal impairment, there are limited data in those with severe acute kidney injury. These patients are often considered to be unfit for ASCT. The aim of the study To study the efficacy and safety of high dose therapy followed by ASCT in patients with MM and renal failure and to evaluate the results of the treatment depending on the severity of acute kidney injury. Materials and methods A retrospective single-center study was performed, including 59 (28 males, 31females) MM patients with renal failure at the time of diagnosis aged 19 to 65 years (median 53) underwent ASCT during a period from 2014 to 2019. Hematologic response and renal response was defined according to International Myeloma Working Group criteria. At the time of diagnosis median of serum creatinine level was 450 μmol/L, and median of glomerular filtration rate (GFR) was 10 ml/min/1.73 m2 (CKD-EPI). 18 patients (30,5%) were dialysis-dependent. Induction therapy included bortezomib-containing regimens in all patients, immunomodulatory drugs were used in 9 patients (15%). Before ASCT overall response rate (CR, VGPR, PR) was documented in 55 patients (93%), median of serum creatinine level was 143 μmol/L, median of GFR increased to 40 ml/min/1.73 m2. Renal response was achieved in 48 patients (81%), in 10 cases dialysis was stopped. 8 patients (13,5%) were dialysis-dependent at the time of ASCT. 43 patients (73%) underwent a single and 16 patients (27%) underwent a tandem ASCT (Mel 140-200 mg/m2). The analysis of such parameters as neutrophil and platelet recovery, a requirement for transfusion therapy was carried out in 2 subgroups: subgroup A - patients without dialysis at the time of ASCT (n = 51), subgroup B - dialysis-dependent patients at the time of ASCT (n = 8). Statistical analysis was done using Statistica 10. Survival curves were constructed using the Kaplan-Meier method. Frequency analysis (Fisher's test) was used. Results Median delay for neutrophil recovery was 14 days and 15 days for platelet recovery in subgroups A and B. Platelet concentrate transfusion was required for all patients of both subgroups in a comparable amount. In patients from subgroup B (dialysis-dependent) compared to those from subgroup A (dialysis independent) significant differences was observed in a requirement of red blood cell transfusions (100% vs 37%, p = 0.001). There was no transplant-related mortality. At 100 days after ASCT overall response rate (CR, VGPR, PR) was achieved in 57 patients (96,6%), median of serum creatinine level was 130 μmol/L, and median of GFR was 50 ml/min/1.73 m2. Renal response was achieved in 49 patients (83%); in one case dialysis was stopped after ASCT (Fig. 1). At one year after ASCT median of serum creatinine level was 127 μmol /L, and median of GFR was 46 ml/min/1.73 m2 (Table 1). Seven patients (12%) remained dialysis-dependent. After a median follow-up of 36 months 5-year overall survival was 60%, and 5-year progression-free survival (PFS) was 40%. The analysis of PFS dependent on the severity of acute kidney injury demonstrated that the 5-year PFS of patients who were dialysis-dependent at the time of diagnosis did not differ from that in patients with mild and moderate renal impairment (42% vs 39%, respectively). Conclusion ASCT is feasible and safe method of treatment in MM patients with severe kidney injury. Dialysis-dependent patients during the early post-transplant period significantly more often require red blood cell transfusions (p = 0.001). Induction therapy followed by ASCT allowed reducing a requirement for dialysis from 30.5% at the time of diagnosis to 12% after ASCT (Fig. 2). In our study 11 of 18 MM patients (61%) became dialysis independent. Overall, this work confirmed no difference in PFS dependent on the severity of acute kidney injury; dialysis-dependent myeloma patients should not be excluded from high dose therapy followed by ASCT. Disclosures No relevant conflicts of interest to declare.

Outcomes of Multiple Myeloma Patients with Del 17p Undergoing Autologous Stem Cell Transplantation

Outcomes of Multiple Myeloma Patients with Del 17p Undergoing Autologous Stem Cell Transplantation

Tandem Autologous Hematopoietic Stem Cell Transplantation in Very Young Patients with Multiple Myeloma.

Introduction Multiple myeloma (MM) in very young patients is uncommon, and no treatment guidelines exist for these patients. Patients and Methods We performed a retrospective analysis of five very young myeloma patients who underwent tandem autologous hematopoietic stem cell transplantation (HSCT). Results The median age was 37 years (range = 34–40 years). A median of two leukapheresis was performed (range = 1–4). The median number of hematopoietic stem cells collected was 5.4 × 10 6 /kg (4.4–8.2 × 10 6 /kg). During first transplant, four patients received melphalan of 200 mg/m 2 and one patient received melphalan of 140 mg/m 2 (due to renal failure) as conditioning regimen. Second transplant conditioning was melphalan of 200 mg/m 2 for one patient and melphalan of 140 mg/m 2 for remaining four patients. Two patients were in complete remission, and two were in very good partial remission and one patient progressed to active disease at the time of tandem autologous bone marrow transplant. All patients developed significant mucositis. Neutrophil and platelet recovery was longer in tandem autologous hematopoietic stem cell transplant. More viral infections were seen in tandem transplant. Day 30 and day 100 mortality was nil. Conclusion We present data on tandem autologous HSCTs in very young patients with MM in India. Responses continued to improve in this small series.

How I manage frontline transplant-eligible multiple myeloma in Italy.

The treatment of transplant-eligible multiple myeloma patients in Italy consists in an induction phase based on bortezomib plus thalidomide plus dexamethasone (VTd), followed by a single or tandem autologous stem cell transplantation (ASCT), followed by lenalidomide maintenance. This approach offers an overall response rate of 93% and a CR rate of 58% with acceptable toxicity. Lenalidomide maintenance adds a significant increase in disease control, with a progression free survival after ASCT of 53 months, and an overall survival of 86 months. Second primary malignancies represent the most concerning toxicity of lenalidomide maintenance with a 6.9% incidence. However, the benefit in terms of increased myeloma control largely outweigh this complication. The incorporation of daratumumab in this treatment schema will further improve these clinical results.

MM-196: Efficiency and Safety in Autologous Stem Cell Transplant Versus Tandem in Patients with Multiple Myeloma with New Diagnosis

Context: Currently, the therapy of high doses of chemotherapy followed by autologous stem cell transplant (ASCT) is considered standard treatment for patients with newly diagnosed multiple myeloma (MM). However, recently it has been demonstrated that tandem transplant is useful in the subgroup of patients with high-risk myeloma. Objective: Evaluate the efficiency and safety of high-dose chemotherapy therapy followed by ASCT vs tandem in patients with high-risk multiple myeloma and plasma cell leukemia. Design: Retrospective cohort study Setting: Single-center study in a private referral hospital. Patients or other participants: Patients with a recent diagnosis of multiple myeloma according to the IMWG 2014 criteria and high-risk features or plasma cell leukemia that underwent a single or tandem ASCT at our center between 2009 and 2018 were included in the study. High-risk multiple myeloma was defined to patients who cytogenetic analysis of high risk and FISH with (17p); t(4;14); t(14;16) or alteration of chromosome 1 and/or extraosseous extramedullary disease. Main outcome measures: We analyzed the assessed overall survival (OS), event-free survival (EFS), event-free survival and treatment-related mortality (TRM). Results: We included a total of 54 patients, with a median follow-up of 48 months. Time from diagnosis of multiple myeloma to first transplant was 6.6 months and the time between one transplant and the other was 98 days in the tandem group. Patients treated with tandem did not have better OS; HR for mortality for patients treated with tandem transplant vs single transplant=0.8 or EFS (HR=0.76). Response rate was statistically significantly better with tandem (risk ratio=0.69), but with a statistically significant increase in TRM (risk ratio=1.71) Conclusions: The therapy of ASCT continues to be considered efficient and safe for patients with MM. The use of tandem did not result in improved OS or EFS and is associated with improved response rates but increased mortality; however, the tandem is a strategy in a group of patients with high-risk diseases.

MM-203: Outcomes of Multiple Myeloma Patients with Del 17p Undergoing Autologous Stem Cell Transplantation

Context: High-risk (HR) multiple myeloma (MM) is a subgroup of MM patients that is variably defined. Patients with 17p deletion are considered HR and their optimal treatment approach has not been determined. Various strategies have been suggested to improve outcomes in MM patients harboring del 17p, including tandem transplantation. Objective: Evaluate the outcomes of multiple myeloma patients harboring 17p deletion that underwent autologous stem cell transplants (ASCT). Design: Retrospective study. Setting: Referral center in the US (Mayo Clinic). Patients or other participants: 116 MM patients with 17p deletion that underwent ASCT at Mayo Clinic. Patients were defined as 17p-deleted if they met the following criteria: If 50 cells in the bone marrow sample and 10 abnormal cells with the deletion were identified (20%) or if the bone marrow sample had between 20-50 total cells and 20% abnormal cells with the deletion were identified. We excluded patients that relapsed prior to ASCT, patients that underwent ASCT more than 12 months from the diagnosis, and patients that underwent tandem ASCT. Main outcome measures: PFS, OS. Results: There was no difference in the OS or PFS between patients that received VRd (bortezomib, lenalidomide, and dexamethasone) versus VCd (bortezomib, cyclophosphamide, and dexamethasone) induction. There was no OS or PFS difference between immunomodulatory drug (IMiD)-based and proteasome inhibitor (PI)-based maintenance, but there was a PFS advantage to patients that received combined maintenance (includes two novel agents). The OS and PFS of the entire cohort were NR and 29 months, respectively, similar to the outcomes in the single transplant arm in 17p-deleted patients that were recently published (EMNO2/HO95). Conclusions: The outcomes of our patients were similar to that of the single-arm ASCT in the EMN02 trial, and no difference in outcomes were found between patients that received VRd and VCd inductions, suggesting that tandem transplants may be considered for 17p-deleted MM patients treated with VRd induction. Dual novel agent maintenance therapy is important in improving outcome.

Prospective Evaluation of Radiation Dose Escalation in Patients With High-Risk Neuroblastoma and Gross Residual Disease After Surgery: A Report From the Children's Oncology Group ANBL0532 Study.

A primary objective of the Children's Oncology Group (COG) ANBL0532 phase III study was to assess the effect of increasing local dose of radiation to a residual primary tumor on the cumulative incidence of local progression (CILP) in patients with high-risk neuroblastoma. Newly diagnosed patients with high-risk neuroblastoma were randomly assigned or assigned to receive single or tandem autologous stem-cell transplantation (SCT) after induction chemotherapy. Local control consisted of surgical resection during induction chemotherapy and radiotherapy after last SCT. Patients received 21.6 Gy to the preoperative primary tumor volume. For patients with incomplete surgical resection, an additional boost of 14.4 Gy was delivered to the gross residual tumor, for a total dose of 36 Gy. CILP (primary end point) and event-free (EFS) and overall survival (OS; secondary end points) were compared with the COG A3973 historical cohort, in which all patients received single SCT and 21.6 Gy without a boost. For all patients in ANBL0532 receiving radiotherapy (n = 323), 5-year CILP, EFS, and OS rates were 11.2% ± 1.8%, 56.2% ± 3.4%, and 68.4% ± 3.2% compared with 7.1% ± 1.4% (P = .0590), 47.0% ± 3.5% (P = .0090), and 57.4% ± 3.5% (P = .0088) for all patients in A3973 receiving radiotherapy (n = 328), respectively. Five-year CILP, EFS, and OS rates for patients in A3973 with incomplete resection and radiotherapy (n = 47) were 10.6% ± 4.6%, 48.9% ± 10.1%, and 56.9% ± 10.0%, respectively. In comparison, 5-year CILP, EFS, and OS rates for patients in ANBL0532 who were randomly assigned or assigned to single SCT and received boost radiotherapy (n = 74) were 16.3% ± 4.3% (P = .4126), 50.9% ± 7.0% (P = .5084), and 68.1% ± 6.7% (P = .2835), respectively. Boost radiotherapy to gross residual tumor present at the end of induction did not significantly improve 5-year CILP. These results highlight the need for new strategies to decrease the risk of locoregional failure.

PARP Inhibition Synergizes with Melphalan but Does not Reverse Resistance Completely.

High-dose melphalan (MEL) and autologous stem cell transplantation (ASCT) is the standard of care in the treatment of multiple myeloma (MM). Resistance to MEL has been linked to increased DNA repair. Here we sought to identify whether inhibition of poly(ADP-ribose) polymerase (PARP) synergizes with MEL and can overcome resistance. We tested the synergistic cytotoxicity of 3 inhibitors of PARP (PARPi)-veliparib (VEL), olaparib (OLA), and niraparib (NIRA)-combined with MEL in RPMI8226 and U266 MM cell lines, as well as in their MEL resistance counterparts, RPMI8226-LR5 (LR5) and U266-LR6 (LR6). The addition of VEL, OLA, and NIRA to MEL reduced the half maximal inhibitory concentration (IC50) in RPMI8226 cells from 27.8 µM to 23.1 µM, 22.5 µM, and 18.0 µM, respectively. Similarly, the IC50 of MEL in U266 cells was decreased from 6.2 µM to 3.2 µM, 3.3 µM, and 3.0 µM, respectively. In LR5 and LR6 cells, PARPi did not reverse MEL resistance. We confirmed this in a NOD/SCID/gamma null xenograft mouse model with either MEL-sensitive (RPMI8226) or MEL-resistant (LR5) MM. Treatment with a MEL-VEL combination prolonged survival compared with MEL alone in RPMI8226 mice (107 days versus 67.5 days; P=.0009), but not in LR5 mice (41 versus 39 days; P=.09). We next tested whether 2 double-stranded DNA repair mechanisms, homologous recombination (HR) and nonhomologous end-joining (NHEJ), cause MEL resistance in LR5 and LR6 cells. In an HR assay, LR6 cells had a 4.5-fold greater HR capability than parent U226 cells (P=.05); however, LR5 cells had an equivalent HR ability as parent RPMI8226 cells. We hypothesized that NHEJ may be a mediator of MEL resistance in LR5 cells. Given that DNA-PK is integral to NHEJ and may be a therapeutic target, we treated LR5 cells with the DNA-PK inhibitor NU7026 in combination with MEL. Although NU7026 alone at 2.5 µM had no cytotoxicity, in combination it completely reversed resistance to MEL (MEL IC50, 46.4 µM versus 14.4 µM). We examined the clinical implications of our findings in a dataset of 414 patients treated with tandem ASCT. High PARP1 expressers had lower survival compared with patients with low expression (median 42.7 months versus median not reached; P=.003). We hypothesized that combined expression of the HR gene BRCA1, the NHEJ gene PRKDC (DNA-PK), and PARP1 may predict survival and found that overexpression of 0 (n=101), 1 or 2 (n=287), or all 3 (n=26) genes had a negative impact on median survival (undefined versus 57.8 months versus 14.8 months; P < .0001). Here we demonstrate that PARPi synergized with MEL, but that resistance (which may be due to HR and NHEJ pathways) is not completely reversed by PARPi. In addition, we observed that a 3-gene analysis may be tested to identify patients resistant or sensitive to high-dose MEL.

Response Improvement Rather than Response Status after First Autologous Stem Cell Transplantation Is a Significant Prognostic Factor for Survival Benefit from Tandem Compared with Single Transplantation in Multiple Myeloma Patients

High-dose chemotherapy and autologous stem cell transplantation (ASCT) have provided effective treatment for patients with newly diagnosed multiple myeloma for more than 3 decades; however, which patients will benefit from tandem ASCT compared with single ASCT remains unclear. Here we retrospectively analyzed 978 trial and nontrial patients who underwent single or tandem ASCT in Heidelberg or other German-Speaking Myeloma Multicenter Group centers. Our results show that response improvement after first ASCT is a significant prognostic factor for progression-free survival benefit from tandem versus single ASCT (multivariable analysis, P=.002; hazard ratio, .64; 95% confidence interval, .48 to .85; P for interaction=.02). The depth of response after first ASCT and the cytogenetic profile did not have a significant prognostic effect on survival benefit from tandem ASCT. Our results suggest that it is not the response depth, but rather the response improvement after first ASCT is of prognostic significance regarding the benefit of tandem ASCT versus single ASCT.

Overcoming Melphalan Resistance By Targeting Crucial DNA Repair Pathways in Multiple Myeloma

High dose melphalan (MEL) and autologous stem cell transplant (ASCT) is the standard of care in the treatment of multiple myeloma (MM). Resistance to MEL has been linked to increased DNA repair. Here we sought to identify which DNA repair pathways lead to MEL resistance. As inhibitors of the single strand DNA repair enzyme PARP1 are clinically available, we first examined whether PARP1 gene expression affected clinical outcomes. In a dataset of 414 patients treated with tandem ASCT, high PARP1 expression lead to reduced survival compared to patients with low expression (42.7 months vs. median not reached, p=0.003). We therefore tested in vitro the cytotoxicity of PARPi with veliparib (VEL), olaparib (OLA) or niraparib (NIRA) in RPMI8226 and U266 MM cell lines as well as their MEL resistance counterparts, RPMI8226-LR5 (LR5) and U266-LR6 (LR6). At physiologic doses PARPi alone was not cytotoxic. However, the MEL IC50 in RPMI8226 cells decreased from 27.8 to 23.1, 22.5 and 18.0 µM with the addition of VEL, OLA and NIRA respectively. Similarly, MEL IC50 decreased in U266 cells from 6.2 to 3.2, 3.3 and 3.0 µM. However, in LR5 and LR6 cells, PARPi did not completely reverse MEL resistance. We confirmed this in a NOD/SCID/gamma null xenograft mouse model with either MEL sensitive (RPMI8226) or resistant (LR5) MM. Treatment with a MEL-VEL combination prolonged survival in RPMI8226 mice compared to MEL alone (107 vs. 67.5 days, p=0.0009), but not in LR5 mice (41 vs. 39 days, p=0.09). Next we tested whether the double strand DNA repair mechanisms, homologous recombination (HR) and non-homologous end joining (NHEJ), cause MEL resistance which is not overcome by PARPi. Using an HR assay, LR6 cells had 4.5 fold higher HR ability than parent U226 cells (p = 0.05) showing this to be a possible mechanism of resistance. However, LR5 cells had equivalent HR ability to parent RPMI8226 cells. We therefore hypothesized that NHEJ may be a mediator of MEL resistance in LR5 cells. As DNA-PK is integral to NHEJ and may be a therapeutic target, we treated LR5 cells with the DNA-PK inhibitor NU7026 in combination with MEL. Although NU7026 alone at 2.5 µM had no cytotoxicity, in combination it completely reversed resistance to MEL resulting in a lower IC50 than even parent RPMI8226 cells (46.4 vs. 14.4 µM). Based on our findings, we hypothesized that combined expression of the HR gene BRCA1, the NHEJ gene DNA-PK, and PARP1 may predict survival in patients undergoing ASCT. Using the same clinical dataset, we found that overexpression of 0 (n=101), 1-2 (n=287), or all 3 genes (n=26) strongly predicted median survival (undefined vs. 57.8 vs. 14.8 months, p Here we demonstrated that MEL resistance is not completely reversed by PARPi, while it may be overcome by targeting HR and NHEJ pathways. In addition, we observed that a 3 gene analysis pre-ASCT may help predict patients that are inherently resistant or sensitive to high dose MEL.

Absolute Lymphocyte Count Recovery Following Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

<h3>Introduction</h3> Absolute lymphocyte count (ALC) recovery following autologous stem cell transplant(ASCT) has been shown to be an important factor for overall and progression free survival. This is thought to be mediated by improved immune reconstitution resulting in decreased adverse events. <h3>Objectives</h3> Our primary aim was to investigate the role of ALC recovery at day 30 (D30) following ASCT in the overall survival(OS) and progression free survival(PFS) in patients treated for multiple myeloma(MM). Our secondary aim was to evaluate the correlation between infused CD3 content and ALC D30. <h3>Methods</h3> Two hundred forty-six patients were identified from our center's CIBMTR database who underwent ASCT between 2000-2010 for MM. Following manual chart review one hundred twenty-five met criteria for inclusion in analysis. ALC D30 was defined as the closest ALC to D30 post ASCT +/- 7 days. Patients who did not have D30 ALC data (n= 87) or underwent tandem ASCT (n=25) were excluded. Descriptive data is available in Table 1. The cohort was split into two groups with ALC ≥ 500 cells x10^6/cu mm or ALC < 500 cells x10^6/cu mm. Albumin was categorized into high and low, consistent with R-IPSS. Descriptive statistics were summarized for all variables. Univariable and multivariable Cox Proportional Hazard regression models were fitted to examine the association between the ALC D30 and the PFS and OS. <h3>Results</h3> ALC D30 failed to show an association with either PFS or OS in the univariable and multivariable analyses. The Median PFS time in ALC ≥500 group was 23.7 months (95%CI: 18.4 - 29.7) compared to 30.1 months (95% CI: 15.5 – 70.5) in the ALC < 500 group, p = 0.72. One year OS rates were 98%(CI: 92%-99%) and 96%(CI: 72%-99%) in ALC ≥ 500 and ALC < 500 groups, respectively (figure 2). Previously identified factors such as age at transplant and Karnofsky performance score also failed to show associations with both PFS and OS. In the multivariable analysis, albumin and disease response status following ASCT were significantly associated with improved OS but not with PFS, Table 2. Infused CD3+ showed a weak correlation to ALC D30, r = 0.25, p=0.004. <h3>Conclusions</h3> Our study failed to show an association between ALC D30 recovery and OS or PFS in patients with MM undergoing ASCT. Previously identified factors such as age also did not show an association with OS and PFS in our study. Data on induction regimens was not collected for this study and maintenance therapy was not administered or data was unavailable for a large portion of our dataset which may contribute to the discrepancy with previously reported studies. CD3+ dose of cells infused showed a weak but statistically significant correlation with ALC D30.

Blood product administration during high risk neuroblastoma therapy

The increasing intensity of high-risk neuroblastoma (HR NB) treatment over the last decades has resulted in improved survival at the expense of prolonging therapy and exposure to additional potentially toxic agents. Anemia and thrombocytopenia requiring transfusion are common during therapy for HR NB. Risks of cumulative red blood cell and platelet transfusions are incompletely defined in pediatric oncology patients, however, risks of transfusional iron overload are well described in other populations. This study aimed to determine the number of packed red blood cell (pRBC) and platelet transfusions throughout treatment for HR NB and how these numbers have changed with modern therapy. We performed a retrospective review of 92 patients with HR NB from June 2002 until September 2017. Patients received a median of 20 pRBC and 32 platelet transfusions. Our results demonstrated large numbers of transfusions with significantly increased blood product exposures among patients who received intensified therapy, either with additional induction chemotherapy, tandem autologous stem cell transplants, or dinutuximab plus cytokines with isotretinoin. Similar volumes of pRBC transfusions have been associated with iron overload in other populations and warrant further discussion of guidelines for long-term follow up of HR NB patients.

Tandem Autologous Hematopoietic Stem Cell Transplantation for Treatment of Adult T-Cell Lymphoblastic Lymphoma: A Multiple Center Prospective Study in Southwestern China

Background: T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and lack of a standard treatment regimen. Accordingly, this study evaluated the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) treatment for adult T-LBL and assessed factors affecting survival. Methods: Newly-diagnosed adult T-LBL patients (n=181) were divided into three groups: chemotherapy (no HSCT) group (89 patients), single auto-HSCT group (46 patients), and tandem auto-HSCT group (46 patients). The measurement of primary outcome was progression-free survival (PFS). The secondary outcomes were progression/relapse rate and overall survival (OS). Additionally, this study analyzed factors influencing toxicities related to tandem auto-HSCT treatment and patient prognosis. Results: The 3-year progression/relapse rate of the tandem auto-HSCT group was significantly lower than that of the single auto-HSCT group and chemotherapy group (26.5% vs 53.1% and 57.6%, p < 0.05). The 3-year PFS rate and OS rate of the tandem auto-HSCT group (73.5% and 76.3%, respectively) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%, respectively, p < 0.05) and the chemotherapy group (42.3% and 56.1%, respectively, p < 0.05). In the tandem auto-HSCT group, age and disease status after the first transplantation impacted the OS and PFS. Multivariate analysis identified disease status after the first transplantation as the only independent prognostic factor for outcome in T-LBL treated with tandem-HSCT. Conclusions: Tandem auto-HSCT improves long-term survival of adult T-LBL patients compared to recipients of chemotherapy alone or chemotherapy plus single auto-HSCT, and disease status after the first transplantation is an independent prognostic indicator for these patients. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No.81370594, 81070388, 81270569, 81600166), the Scientific and Technological Innovation Program of Chongqing social undertakings and people's livelihood guarantee (cstc2016shms-ztzx10003), and Youth Innovation Project of Military Medicine of Chinese People’s Liberation Army (No.13QNP116). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was performed in accordance with the Declaration of Helsinki and local laws. The protocol was approved by the ethic committee of each center, and written informed consent was obtained from all patients.

Tandem autologous hematopoietic stem cell transplantation for treatment of adult T-cell lymphoblastic lymphoma: a multiple center prospective study in China.

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and no standard treatment regimen. In this study, we assessed the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) for adult T-LBL and evaluated prognostic factors affecting survival. A total of 181 newly-diagnosed adult T-LBL patients were enrolled: 89 patients were treated with chemotherapy alone, 46 were allocated to the single auto-HSCT group, 46 were treated with tandem auto-HSCT. Median follow-up time was 37 months; the 3-year progression/relapse rate of the tandem auto- HSCT group was significantly lower than that of the single auto-HSCT and chemotherapy groups (26.5% vs. 53.1% and 54.8%). The 3-year progression- free survival (PFS) and overall survival (OS) rates of the tandem auto- HSCT group (73.5% and 76.3%) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%) and the chemotherapy group (45.1% and 57.1%). In the tandem auto-HSCT group, age and disease status after the first transplant impacted OS and PFS. Multivariate analysis identified that disease status after the first transplant was the only independent prognostic factor for patients treated with tandem-HSCT. In addition, diagnostic models of the initial CD8+CD28+/CD8+CD28– T-cell ratio in predicting the disease status were found to be significant. Taken together, tandem auto- HSCT can be considered an optimal strategy for adult T-LBL patients. (Study registered at: ChiCTR-ONN-16008480).

The timing of plerixafor addition to G-Csf and chemotherapy affects immunological recovery after autologous stem cell transplant in multiple myeloma.

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34+ cell count. We evaluated the number of CD34+, CD34+/CD38-, CD3+, CD4+, CD8+, CD19+, CD56+/CD3-, CD4+/CD25+/FOXP3+, and CD138+/CD38+ cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 106 CD34+ cells/Kg (IQ 7.7-13.4). Patients with <20/µL CD34+ cells at plerixafor administration (18/33) had a significantly higher CD34+ cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34+ cells. A similar CD34+ and immune graft composition was reported. A higher number of CD3+ and CD8+ cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34+ cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.

EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, &gt;3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or &gt;3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.