ALBERT

Description: Background: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

Description: Background: The clinical course of follicular lymphoma (FL) is characterized by a slow progression over years with continuous relapses despite good response to initial treatment. The median overall survival is 10 to more than 15 years. Standard therapy for patients requiring treatment consists of an anti-CD 20 antibody combined with chemotherapy followed by antibody maintenance. With this combination a 1-year-PFS of 93% was seen in the GLSG-2000 trial (Hiddemann et al, Blood 2005). Because of the substantial side effects of chemotherapy such as infections, secondary malignancies and impairment of the stem cell reserve novel "chemotherapy-free" treatment approaches could substantially improve the treatment tolerability in FL. The BTK-inhibitor ibrutinib has demonstrated promising activity in patients with iNHL, CLL and MCL. Anticipating the recent reports on a superior activity of obinutuzumab as compared to rituximab in the GALLIUM trial (Marcus et al., NEJM 2017), the GLSG initiated a phase II study combining ibrutinib and obinutuzumab to explore the efficacy and safety of this "chemotherapy-free" alternative. Methods: ALTERNATIVE is a prospective multicenter single-arm phase 2 study of the combination of ibrutinib and obinutuzumab in 98 patients with previously untreated FL and a high tumor burden (defined by modified GELF criteria) in need of treatment. Induction comprises 6 cycles of obinutuzumab at a dose of 1000 mg by intravenous infusion on days 1, 8, 15 of cycle 1 and on day 1 of cycles 2-6 to be given every 21 days. Ibrutinib is administered orally at a dose of 560 mg once daily throughout all 6 cycles. In patients with at least partial response (defined by Cheson Response Criteria 2007) after the end of induction, maintenance with obinutuzumab (1000mg every 8 weeks) plus ibrutinib (560mg daily) is given for an additional 24 months. In patients remaining MRD positive at 30 months ibrutinib is continued for another 12 months in an extended maintenance setting without obinutuzumab. The primary efficacy endpoint is the rate of investigator-assessed PFS one year after registration. Response rates at end of induction, after one year and after end of maintenance, duration of response, percentage of progression during induction and maintenance, time to treatment failure, overall survival, duration of molecular remission in MRD negative patients and safety are key secondary endpoints. Results: 98 patients with advanced stage FL were included, The median age was 59 years (29-81), 60% were male and 40% had a high risk FLIPI, 90% stage III/IV disease and 10% were stage II with a high tumor burden. Response to in induction was 90% (87/97) with 85% (82/97) PR and 5% (5/97) CR. 5 patients (5%) progressed during induction. Of the 82 patients with PR after end of induction, 8 patients achieved a CR during the first 6 months of maintenance treatment. 95 patients were evaluable for the primary endpoint of 1-year-PFS and 76 patients (80%) remained alive and free of progression at this timepoint. 18 patients progressed in the first year, two of whom died due to progressive disease. One additional death was caused by a non-lymphoma related event. An MRD-marker was found in 65 patients. MRD at the end of induction was evaluable for 63 patients. 44 patients (70%) were MRD negative after induction treatment. Of the 42 patients with follow-up MRD peripheral blood or bone marrow samples, 35 (83%) were MRD negative one year after registration. Therapy was generally well tolerated. Most common adverse events were diarrhea in 30% of patients, rash in 25% and fatigue and nasopharyngitis (common cold) in 23% and 20%, respectively. Concerning hematotoxicity grade 3-4 neutropenia and thrombopenia were seen in 8% and 4% of patients, respectively. Severe (〉=grade 3) infectious complications were rare (6% pneumonia/bronchitis, 2% sepsis, 7% other infections). Conclusions: The chemotherapy - free combination of ibrutinib and obinutuzumab showed high anti-lymyphoma activity with high overall response rates and a high proportion of MRD negativity at one year. While the combination of ibrutinib and obinutuzumab was associated with a low toxicity profile, the combination was inferior to the published results of conventional immunochemotherapies in terms of the primary efficacy endpoint (1-year-PFS). Further evaluations might demonstrate whether subgroups exist which particularly benefit clinically from this low toxicity regime. Figure Figure. Disclosures Schmidt: Celgene: Honoraria; Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Buske:Bayer: Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Viardot:Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Keller:BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; MSD: Consultancy; Celgene: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Hänel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Liersch:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Dürig:Celgene: Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Hoster:Roche Pharma AG: Other: Travel support, Research Funding; F. Hoffman-La Roche: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

Description: Introduction & Objectives: Primary Cutaneous Follicle Center Lymphoma (PCFCL) is a very indolent mature B-cell lymphoma that shares germinal center morphology with follicular lymphoma (FL) but lacks the characteristic t(14;18). Unlike FL, immunohistochemistry fails to detect expression of BCL2, CD10, and immunoglobulin in PCFCL. Therefore, we investigated expression of B-cell receptor (BCR) transcripts to gain insight into the immunobiology of PCFCL. Materials & Methods: Full-length heavy and light chain BCR transcripts of 13 histologically confirmed PCFCL were amplified using ARTISAN PCR and sequenced on the PacBio RSII system. BCR from 4 cases were sequenced to a depth of 〉2000 sequences per BCR transcript; the remaining cases to a median depth of 1663 sequences (range: 626-5301). BCR from 51 cases of FL and from peripheral B cells of 12 healthy donors were used as controls. Whole genome sequencing (WGS) and RNAseq were performed on 5 PCFCL on the Illumina HiSeq platform. Results: No PCFCL case carried a t(14;18). In addition to previously described CD79B mutations, an L265P mutation in MYD88 was identified in one case, and two PCFCL carried amplifications in chromosome 2 involving the proto-oncogene REL. ARTISAN PCR demonstrated expression of potentially functional VDJ and VJ genes with heavily mutated V regions (VDJ: 5.9-24.0%; VJ: 4.7-17.9%) in all PCFCL cases, which could be confirmed by RNAseq-based de novo BCR assembly. One PCFCL case expressed IgM, another IgA, and the remaining ten cases expressed IgG. PCFCL VDJ carried relatively long heavy chain CDR3 regions with a median of 19 amino acids (versus 17 in healthy donor PBMCs). In contrast to FL, only minimal intraclonal sequence variation (comparable to the known error rate of the used sequencing method) was observed in PCFCL VDJ and VJ sequences, indicating absence of ongoing somatic hypermutation (SHM). VDJ and/or VJ of 11 PCFCL (85%) carried at least one acquired N-linked glycosylation motifs, six PCFCL (46%) at least two, and one case four such motifs. 75% of acquired N-linked glycosylation motifs were found in different positions than the N-linked glycosylation motifs found in FL BCR (Figure). In contrast, only 17.5% and

Description: Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore whether HDT/ASCT is an effective frontline therapy for patients identified to be high-risk by clinical (i.e., FLIPI) or clinicogenetic risk models (i.e., m7-FLIPI, POD24-PI). Methods: We performed targeted DNA deep-sequencing of 〉150 genes in available diagnostic FL biopsies from 165 patients ≤60 years with advanced FL from the GLSG2000 trial who uniformly received R-CHOP as frontline treatment. Of these, 87 patients (53%) were randomized to receive consolidative HDT/ASCT, 78 (47%) were randomized to interferon maintenance. We performed intention-to-treat (ITT) survival and regression analyses to explore whether known clinical and clinicogenetic risk factors can be overcome by ASCT. Results: The HDT/ASCT and no-HDT/ASCT cohorts were balanced regarding age (48 vs 50 years), sex (49% vs 64% male patients), high-risk FL International Prognostic Index (FLIPI; 25% vs 29%), Eastern Cooperative Oncology Group Performance Score 〉1 (6% vs 5%) and mutation status of EZH2 (23% vs 18%) and TP53 (3% vs 3%). The incidence of POD24 was not significantly lower in the HDT/ASCT cohort (8% vs 14%, p=0.32). After a median follow-up of 7.5 years, 5-year failure-free survival (FFS) rates in the HDT/ASCT and no-HDT/ASCT cohorts were 77% and 69% (HR 0.7, p=0.16), 5-year OS rates were 95% and 90% (HR 0.6, p=0.21), respectively. The high-risk cohorts identified by FLIPI, m7-FLIPI, and POD24-PI comprised 27% (n=45), 18% (n=29) and 22% (n=37) of patients, respectively (Fig. A). The m7-FLIPI reclassified 10% (n=16) of patients from high-risk FLIPI to low-risk m7-FLIPI. The POD24-PI reclassified 5% (n=9) of patients from high-risk FLIPI to low-risk POD24-PI; one patient was reclassified from low-risk FLIPI to high-risk POD24-PI. Patients identified to be high-risk by all three indices had shorter FFS (FLIPI: HR 2.8, p=0.0002; m7-FLIPI: HR 3.0, p=0.0003; POD24-PI: HR 2.5, p=0.0013), but OS was not different (FLIPI: HR 1.4, p=0.47; m7-FLIPI: HR 1.5, p=0.45; POD24-PI: HR 1.5, p=0.47). The risk to develop POD24 was increased in high-risk patients (FLIPI: OR 4.4, p=0.007; m7-FLIPI: OR 4.8, p=0.005; POD24-PI: OR 4.3, p=0.008). Consolidative HDT/ASCT did not prolong FFS in high-risk patients as defined by FLIPI (HR 1.2, p=0.67), m7-FLIPI (HR 1.2, p=0.70; Fig. B) and POD24-PI (HR 1.3, p=0.63; Fig. B). Similarly, OS was not significantly improved in all three high-risk cohorts (FLIPI: HR 0.2, p=0.13; m7-FLIPI: HR n/a, p〉0.99; and POD24-PI: HR 0.3, p=0.22). In low-risk patients, HDT/ASCT was associated with a non-significant trend towards prolonged FFS (FLIPI: HR 0.5, p=0.061; m7-FLIPI: HR 0.6, p=0.16; POD24-PI: HR 0.5, p=0.068; Fig. B), but again OS was not significantly different (FLIPI: HR 0.8, p=0.69; m7-FLIPI: HR 0.8, p=0.66; and POD24-PI: HR 0.7, p=0.52). Conclusions: Our ITT-analysis confirms that consolidative HDT/ASCT should not be offered to unselected cohorts of patients with previously untreated, advanced FL after R-CHOP. Also, our current clinicogenetic risk models are not optimized to select high-risk patients who may benefit from frontline HDT/ASCT. The fraction of patients identified to be high-risk by FLIPI, m7-FLIPI and POD24-PI is low when applied to younger, medically fit patients. Moreover, the fraction of patients being reclassified by integrating gene mutation data is low in this patient cohort. Therefore, we are developing specific stratification algorithms for younger, medically fit patients who are eligible for dose-intensified approaches. Figure. Figure. Disclosures Klapper: F.Hoffman-La Roche: Honoraria, Research Funding; HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Dreyling:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Hoster:F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Weigert:Roche: Research Funding; Novartis: Research Funding.

Description: Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD). Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study. Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309. Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period. Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. Disclosures Collins: Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Introduction High-dose chemotherapy and stem cell transplant (SCT) remains a standard of care in medically fit patients (pts) with newly diagnosed (ND) MM. Induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks among the most effective regimens and VRD/SCT was superior to VRD alone in an RCT. In a phase 2 study, we demonstrated RAD induction (lenalidomide 25 mg d1-21; Adriamycin 9 mg/m2 iv d1-4; dexamethasone 40 mg d 1-4 and 17-20 every 4 weeks) followed by SCT to be safe and effective (Knop et al., Leukemia 2017). Therefore, we decided to compare RAD versus (vs) VRD (lenalidomide 25 mg, d1-14; subcutaneous bortezomib 1.3 mg/m2 d 1, 4, 8, 11; dexamethasone 20 mg d 1+2, 4+5, 8+9, 11+12 every 3 weeks) induction (3 cycles each) in an RCT. MethodsThe current study was set up according to a double 2x2-factorial design to enrol transplant-eligible pts up to 65 years. The post-induction (PI) complete response (CR) rate as per IMWG criteria was the efficacy co-primary endpoint. We hypothesized the CR rate following RAD to be non-inferior to VRD which was estimated to be 20%. The study was powered to confirm non-inferiority of RAD at a margin of 10% with a one-sided alpha level of .05. Cytogenetic characterization was performed by fluorescence in situ hybridization (FISH) from CD138-enriched plasma cells. Minimal residual disease (MRD) was assessed by second-generation eight-color flow cytometry (FC; EuroFlow protocol). Bone marrow (BM) samples from baseline and defined restaging time points were analyzed for an acquisition of ⩾107cells/sample. In a subgroup of 103 pts, we evaluated the applicability of comprehensive immunoglobulin (Ig) amplicon next generation sequencing (NGS) to detect molecular MRD markers and to compare the results with FC. NGS-based marker screening was performed in baseline BM. Sequencing libraries were prepared using 2-step PCR employing multiplex primer sets for IGH V-D-J (FR1, FR2 and FR3), IGH D-J and IGK loci (V-J and KDe). For MRD detection, we used 1-step library preparation with the same primer sets. Results476 pts with a median age of 55 (range, 32-65) years were randomized between 05/2012 and 06/2016 and 469 received at least one dose of study drug. High-risk (HR) FISH abnormalities comprised del17p (11.3% of pts); t(4;14) (11.7%); and t(14;16) (4.5%). 232 pts were randomized to receive RAD, and 237 to VRD, respectively. 90.5% of RAD vs 93.7% of VRD pts completed all 3 cycles. PI CR rate was 13.5% (95% CI, 9.4%-18.7%) with RAD vs 13.4% (95% CI, 9.3-18.5) with VRD, (P=.971). Rates of ≥VGPR were 40.6% (50% CI, 34.2%-47.3%) with RAD vs 48.9% (95% CI, 42.3-55.6%) with VRD (P=.076). In pts with HR cytogenetics, rates of ≥VGPR were 43.3% (RAD) vs. 59.3% (VRD; P=.096). From 317 pts with paired samples, 33/151 (21.9%) of RAD vs 45/166 (27.1%) of VRD pts were FC MRD negative (P=.169) following induction at a median sensitivity level of 6.73x10-6. 197/239 positive pts (82.4%%) had MRD levels above 0.01%, and 42 (17.6%), between 0.0001 and 0.01%. Flow MRD negativity as per IMWG MRD criteria (Kumar et al, Lancet Oncol 2016) was seen in 8/151 (5.2%) pts with RAD vs 6/166 (3.6%) with VRD (P=.27). The remainder of pts did not (yet) fulfil IMWG CR for various reasons. NGS marker screening identified at least 1 Ig marker in 98/103 evaluable patients. To date, 47/98 pts were analyzed for NGS MRD following induction. Four out of 47 (8.5%) subjects were sequencing negative (3/4 post-VRD) with all of them also being IMWG FC MRD negative. One VRD patient died during induction for a mortality rate of 0.2 %. 62.1% of RAD vs 55.3% of VRD pts experienced at least one serious adverse event (SAE; p=.16). SAEs with relationship to study drugs of at least °3 severity occurred in 26.3% (RAD) vs 23.6% (VRD) pts (p=.523). ConclusionsTo the best of our knowledge, this is the first RCT to compare two R-based triplets in SCT-eligible pts. The co-primary efficacy endpoint was met with identical PI CR rates of around 13% for RAD and VRD, respectively. However, a trend emerges to favor VRD over RAD in terms of at least VGPR including HR FISH subjects. Analysis of MRD by multicolor FC showed 5% of pts to be already IMWG flow MRD-negative. Results for all 98 pts evaluable for NGS MRD will be presented. As of yet, too few progression events have occurred to estimate the second co-primary endpoint, 3-year progression-free survival. Longitudinal response and MRD analysis are ongoing. Disclosures Langer: Celgene: Consultancy. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. Blau:Amgen: Other: Advisory board; BMS: Other: Advisory board; Novartis: Other: Advisory boards; Takeda: Other: Advisory board; Janssen: Other: Advisory board, Research Funding; Celgene: Other: Advisory board, Research Funding. Rollig:Janssen: Research Funding; Bayer: Research Funding. Dechow:AMGEN: Consultancy; Celgene: Honoraria. Gramatzki:Affimed: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.