ALBERT

Description: Background: Survival of patients (pts) with multiple myeloma (MM) decreases with increased age (Pulte, Oncologist, 2011). In addition, MM pts with advanced disease who have exhausted treatment (Tx) with novel agents have a poor prognosis (Kumar, Leukemia, 2012). Pomalidomide (POM) is a new oral agent with antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). In the pivotal MM-003 trial, POM in combination with low-dose dexamethasone (LoDEX) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits vs. high-dose dexamethasone, with a tolerable safety profile in refractory or relapsed and refractory MM (RRMM; Dimopoulos, Blood, 2013). In MM-003, significant PFS and OS benefits with POM + LoDEX Tx were seen in different age groups; tolerability and dose intensity were not affected by age (Weisel, Blood, 2013). STRATUS is a multicenter, single-arm, open-label, European, phase 3b trial to further evaluate safety and efficacy of POM + LoDEX in a large pt population. This analysis examines outcomes by age (≤ 65 vs. 〉 65 yrs, and ≤ 70 vs. 〉 70 yrs). Methods: Eligible pts had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), having previous BORT and LEN failure and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to the last prior Tx line. Pts with Eastern Cooperative Oncology Group performance status 〉 2 were excluded. Pts received 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged 〉 75 yrs) once weekly. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. Tx continued until PD or unacceptable toxicity. The primary endpoint was safety; the secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. Outcomes were analyzed by pt age at baseline (≤ 65 vs. 〉 65 yrs, and ≤ 70 vs. 〉 70 yrs). Results: As of March 17th, 2014, a total of 456 pts have been enrolled, and 452 had received POM + LoDEX; 48% were aged ≤ 65 yrs, 52% were 〉 65 yrs, 71% were ≤ 70 yrs, and 29% were 〉 70 yrs. Pts were heavily pretreated (median 4-5 prior Tx depending on age subgroup). Median follow-up was 6.8 mos. Younger pts (≤ 65 yrs) were more likely to have better renal function (creatinine clearance ≥ 60 mL/min; 80%) than those aged 〉 65 (49%). Median relative dose intensity was similar independent of age (range, 0.95-0.97 mg/day). The most common grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) across age groups were neutropenia, anemia, thrombocytopenia, and pneumonia (Table). Gr 3-4 deep vein thrombosis (DVT) with prophylaxis was 1% in each subgroup. Discontinuations of POM due to TEAEs were low in pts aged ≤ 65 (0.9%), 〉 65 (3.0%), ≤ 70 (1.3%), and 〉 70 (3.8%) yrs. Outcomes by age are summarized in the Table. ORR was consistent for pts aged ≤ 65 (38%), 〉 65 (32%), ≤ 70 (35%), and 〉 70 (34%) yrs; DORs were 5.1, 6.8, and 5.8 mos and not estimable (NE) in these pt populations, respectively. Median PFS and median OS were similar across all age groups (PFS range, 4.0-4.9 mos, OS range, 10.6-11.5 mos). Conclusions: The data reported here further demonstrate the tolerability and efficacy of POM + LoDEX in pts with RRMM in the age subgroups analyzed (≤ 65 vs. 〉 65 yrs and ≤ 70 vs. 〉 70 yrs). Safety profiles were consistent, while dose intensity was similar across age groups. PFS, OS, and response rates were comparable with those previously reported in trials of POM + LoDEX in pts with RRMM and reinforce 4 mg POM as an appropriate starting dose irrespective of age. These data support POM + LoDEX as a standard Tx option for pts with refractory or RRMM regardless of age. Table 1. Age ≤ 65 yrs (n = 215) Age 〉 65 yrs (n = 237) Age ≤ 70 yrs (n = 319) Age 〉 70 yrs (n = 133) Grade 3-4 TEAEs, % Neutropenia Anemia Thrombocytopenia Pneumonia 38 30 22 13 41 24 16 10 38 29 21 11 44 23 15 11 Grade 3-4 EOI, % DVT/PE PN 1

Description: Multiple myeloma (MM) remains an incurable disease, despite that it has had a huge increase in survival in part due to new drugs as proteasome inhibitors and immunomodulatory drugs; however new therapeutic venues are required. Immune-based therapies are having an important relevance to control cancer, and are a new therapeutic armamentarium. Natural killer (NK) cells have an important role as natural control of tumor cells; based on that, NK cell infusions could be a novel treatment strategy to treat MM. By co-culture with the genetically modified cell line K562-mb15-41BBL it is possible to expand ex vivo large numbers of activated NK (NKAE) cells from MM patients. NK cell therapy has some challenges to be answered in real clinical practice: Could they be used out of transplantation setting? Could they be used with other anti-myeloma drugs? Could they be infused and expanded several times? To answer these questions we have designed a phase I clinical trial to make multiple infusions of autologous NKAE cells together with anti-myeloma drugs bortezomib or lenalidomide in MM (NCT02481934). Five MM patients on 2nd or later relapse have been enrolled in this phase I clinical trial to date. To activate and expand NK cell, peripheral blood mononuclear cell (PBMCs) were co-cultured with K562-mb15-41BBL cells and 100 IU/ml IL-2. We collected 200 ml of peripheral blood (PB) from patients every cycle (n=4) to produce autologous NKAEs under GMP conditions and cells were harvested on day 14 and 21 for infusions. Four cycles of pharmacological treatment with 2 infusions of 7.5x106 autologous NKAEs/kg on day 1 and 8 of each cycle were performed. NKAEs purity and T regulatory cells (Treg) were analyzed by flow cytometry. NK cells presence in PB was also assessed by PB smear examination before and after each infusion. Serum cytokines concentration was determined by cytometric bead assay. Safety of NKAE end products was verified by real time-PCR of c-MYC and telomerase on NKAE from the 2th and 3rd week of expansion. BCR-ABL PCR studies were performed on NKAE cultures and on PB samples from the patients after treatment. Three patients received lenalidomide-based treatment and 2 bortezomib-based treatment. Patients received a total of 35 NKAEs infusions. We have not observed any serious toxicity attributable to NKAE infusion. Two patients had grade II neutropenia, which did not require dose adjustment. The 5 MM patients enrolled had 23% (±11%) NK cells of PBMCs. We collected a mean of 21x106 NK cells from PB. After 1 week NKAEs number increased x13 with 71% of NKAEs, at 2nd week the fold of NKAE cells expansion was x30 with a purity of 92%. We collected 550x106 (±50x106) NKAEs from culture for the first infusion. At 3rd week NKAEs number increased 45 times (fig.1.A). NKAEs infusion was completely safe; expression of c-Myc and telomerase was not altered in NKAE end products. The expression of BCR-ABL disappeared from cultures after the first week, and was undetectable in PB after NKAE therapy. Contamination of autologous T cells on NKAE end products was not significant; less than 4%. NKAE cells were detectable on PB after infusions; percentage of PB NK cells increased a mean of 5% and expression of activatory receptors NKp30 and NKG2D and apoptosis ligands TRAIL and FasL increased on PBMCs after infusion. PB smear showed an increase fold of activated circulating lymphocytes change of x3.8 (p

Description: Background: Patients (pts) with multiple myeloma (MM) who have relapsed on or are refractory to treatment (Tx) with novel agents lenalidomide (LEN) and bortezomib (BORT) have few effective options for Tx and short overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a distinct oral IMiDs® immunomodulatory agent with direct antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia 2010; Mark, Leuk Res, 2014). POM has been approved in the United States and the European Union for the Tx of pts with ≥ 2 prior Tx, including LEN and BORT, and progressive disease (PD) on Tx (EU, in combination with low-dose dexamethasone [LoDEX]) or within 60 days of completion of the last line of Tx (US). Results from the pivotal phase 3 MM-003 trial demonstrated that POM + LoDEX significantly extended progression-free survival (PFS) and OS vs high-dose dexamethasone in this pt population (San Miguel, Lancet Oncol, 2013). STRATUS is a multicenter, single-arm, open-label phase 3b trial with 〉 85 sites across Europe designed to further evaluate safety and efficacy of POM + LoDEX in a large pt population (N = 456 at data cutoff). Methods: Eligible pts had refractory or relapsed and refractory disease (PD during or within 60 days of last line of Tx), previous BORT and LEN Tx failure, and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last prior line of Tx. Key exclusion criteria included absolute neutrophil count 〈 800/μL , platelet count 〈 75,000 or 〈 30,000/μL (for pts with 〈 50% or ≥ 50% of bone marrow nucleated cells as plasma cells, respectively), creatinine clearance 〈 45 mL/min, hemoglobin 〈 8 g/dL, and peripheral neuropathy ≥ grade (Gr) 2. POM was administered at 4 mg D1-21 of a 28-day cycle in combination with LoDEX 40 mg/day (20 mg for pts aged 〉 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent. The primary endpoint was safety, and key secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, OS, and cytogenetic analyses. STRATUS is registered with ClinicalTrials.gov (NCT01712789) and EudraCT (2012-001888-78). Results: As of March 17, 2014, 456 pts were enrolled and 452 had received POM + LoDEX; median age was 66 yrs (range, 37-88 yrs); median time since diagnosis was 4.9 yrs (range, 0.3-22.6 yrs). Pts were heavily pretreated with a median of 5 prior Tx (range, 2-18); 78% were refractory to BORT and LEN. Median follow-up was 6.8 mos with a median of 4 cycles received. Median PFS and OS were 4.3 mos and 10.9 mos, respectively (Figure 1). The ORR was 35%, with 6% of pts achieving ≥ very good partial response (VGPR); median DOR was 6.0 mos. Similar PFS (4.2 and 3.9 mos), OS (10.9 mos for each), and ORR (34% and 33%) were achieved in pts refractory to prior LEN (n = 427) or LEN and BORT (n = 356), respectively. In addition, PFS (4.3 and 3.9 mos), OS (11.5 mos and not estimable), and ORR (27% and 37%) were consistent in pts with LEN (N = 172) or BORT (N = 189) as last prior treatment, respectively. The most frequent Gr 3-4 treatment-emergent adverse events (TEAEs) were hematologic, including neutropenia (39%), anemia (27%), and thrombocytopenia (19%); Gr 3-4 non-hematological toxicities included pneumonia (11%), fatigue (5%), and hypercalcemia (4%). Gr 3-4 deep vein thrombosis was low (1%) with prophylaxis, and peripheral neuropathy was 1%. Dose reductions of either POM or LoDEX due to TEAEs were required in 28% of pts; discontinuations due to TEAEs were infrequent (9%). Conclusions: Results from STRATUS, the largest POM + LoDEX clinical trial thus far, were consistent with those observed in the pivotal MM-003 trial, and confirm that this regimen has an acceptable safety and efficacy profile and shows substantial improvements in PFS and OS benefits. Combination therapy with POM and LoDEX represents a new standard of therapy for pts with refractory or relapsed and refractory MM in whom LEN and BORT Tx failed. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria. Palumbo:Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Weisel:BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Ocio:Celgene Corporation: Honoraria, Research Funding. Cavo:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Doyen:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Simcock:Celgene Corporation: Employment. Miller:Celgene: Employment, Equity Ownership. Slaughter:Celgene: Employment. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Daratumumab is a CD38-directed antibody increasingly used for the treatment of adult patients with multiple mieloma. The membrane of red blood cells express CD38 and thus samples from patients treated with daratumumab show agglutination in red blood cell antibody screen tests performed prior to transfusion. This interference hinders the detection of red blood cell alloantibodies. Published literature has described a method to eliminate CD38 in red blood cells with DTT (Chapuy, 2016). This technique is cumbersome, requires positive and negative controls as DTT destroys Kell antigens and can produce in vitro hemolysis. The increasing number of multiple myeloma patients treated with daratumumab poses the need for a simple and straightforward technique with applicability in standard transfusion centers. DaraEx (Inno-Train) is a new anti-CD38 neutralizing agent that overcomes daratumumab-induced interferences detected in pre-transfusion tests without the major drawbacks associated with the DTT technique. Our aim was to validate and implement DaraEx as the method of choice to solve daratumumab interferences detected in pre-transfusion screen tests in a tertiary care center. A two-step approach using in vitro and in vivo samples was designed to validate the new method. First, we compared DaraEx efficacy in vitro to the reference DTT method in two samples spiked with daratumumab to achieve a concentration of 10mg/mL (Sample A: serum from a patient without known red blood cell alloantibodies; Sample B: serum from a patient with alloantibody anti-c). Red blood cells in the screen test (3 red blood cell screen; ID-DiaCell I-II-III) as well as positive (E+ red blood cells) and negative controls (K+ red blood cells) were treated with DTT 0.2M solution for 30 minutes at 37ºC and then washed four times with saline. In parallel, red blood cells in the screen test were incubated during 30 minutes at room temperature in a shaker (600rpm) with DaraEx. Red blood cells treated with each of these methods were used for indirect antiglobulin test with our gel card system (BioRad; IH-1000). Preference of method in terms of time needed and result interpretation was evaluated by three hematologists specialized in blood banking and four different technicians. Secondly, we tested pre-transfusion samples from patients treated with daratumumab with the DaraEx technique to check in vivo efficacy. There was a 100% concordance between both techniques (DDT reference method and DaraEx new method) in both in vitro samples. All hematologists and technicians found the DaraEx technique less cumbersome in terms of processing and time to result (2 hours with DTT versus 1 hour with DaraEx) and the interpretation straightforward. Twelve samples with daratumumab-induced interference in pre-transfusion screen tests belonging to 5 patients were tested between January and July 2019. All the interferences detected resolved with DaraEx regardless of time from last daratumumab administration (range: 7-145 days; mean: 57 days). Figure 1 shows screen test with and without treatment with DaraEx in a patient sample. In our experience, DaraEx technique is a simple, fast and efficacious method, regardless of time from last daratumumab administration, to resolve interferences secondary to daratumumab administration without the major disadvantages associated with DTT. Figure 1 Disclosures García Gutiérrez: Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Description: Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P 〈 .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.

Description: Background: The broad use of immunomodulatory drugs (IMiDs) and the breakthrough of novel immunotherapies in MM, urge the optimization of immune monitoring to help tailoring treatment based on better prediction of patients' response according to their immune status. For example, current T cells immune monitoring is of limited value because the phenotype of tumor-reactive T cells is uncertain. Aims: To characterize the MM immune microenvironment at the single-cell level and to identify clinically relevant subsets for effective immune monitoring. Methods: We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering, in a large flow cytometry dataset of 86 newly-diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 clinical trial, including immune monitoring at diagnosis, after induction with bortezomib, lenalidomide, dexamethasone (VRD), autologous transplant and VRD consolidation. Immunophenotyping was performed using the first 8-color combination (CD19, CD27, CD38, CD45, CD56, CD81, CD117, CD138) of the next-generation flow (NGF) panel for MRD assessment. Results were then validated in additional 145 patients enrolled in the same trial. Deep characterization of T cells was performed using 17-color multidimensional flow cytometry (TIM3, CD160, TIGIT, CD57, CD8, PD1, CD45RA, CD56, BTLA, CD4, CD3, CD39, CD137, CTLA4, CCR7, CD16, CD27) and combined single-cell (sc) RNA/TCR sequencing (10xGenomics). Results: Simultaneous analysis of the entire dataset (n=333 files) unbiasedly identified 25 cell clusters (including 9 myeloid and 13 lymphocytes subsets) in the MM immune microenvironment. Afterwards, we correlated a total of 120 immune parameters derived from the cellular abundance of each cluster and specific cell ratios determined at all time points, with a total of 20 clinical parameters including the International Staging System (ISS) and FISH cytogenetics. Twelve variables had significant impact in progression-free survival (PFS) and the ratio between CD27- vs CD27+ T cells emerged as an independent prognostic factor (HR:0.09, p=0.04) together with the ISS in a Cox regression model. The 3-year PFS rates of patients with high vs low CD27-/CD27+ ratios were 94% vs 71% (p=0.02), respectively; these findings being confirmed in the validation dataset. Thus, we observed in the entire cohort (n=231) that a prognostic score including the CD27-/CD27+ T cell ratio (HR:0.21, p=0.013) and ISS (HR:1.41, p=0.015) outperformed each parameter alone (HR:0.06, p=0.007). To gain further insight into the biological significance of the CD27-/CD27+ T cell ratio, we performed scRNA/TCRseq in 44,969 lymphocytes from 9 MM patients. Downstream analysis unveiled that CD27- T cells were mostly CD8 and included senescent, effector and exhausted clusters. By contrast, CD27+ T cells were mainly CD4 and the remaining CD8 T cells had a predominant immune suppressive phenotype (ie. high GZMK, TIGIT, LAG3 and PD1 expression levels). Such T cell clustering was validated by 17-color multidimensional flow cytometry that confirmed the cellular distribution identified by scRNAseq, as well as higher reactivity for PD1, TIGIT, BTLA and TIM3 in CD27+ vs CD27- T cells. Simultaneous scTCRseq revealed a total of 90 different clonotypes (median of 12 per patient). Interestingly, most clonotypes where found in CD27- (74/90) as opposed to CD27+ T cells and, using the VDJB database, the CDR3 sequences of clonotypic effector/exhausted CD27- T cells were predicted to recognize MM-related epitopes such as MLANA, HM1.24 (CD319), TKT, or IMP2. In selected patients, we performed exome- and RNA-sequencing of tumor cells and analyzed their HLA profile. Using the T Cell Epitopes - MHC Binding Prediction tool from the IEDB Analysis Resource, we found expression of mutated genes (e.g. UBXN1, UPF2, GNB1L) predicted to bind MHC class I molecules on tumor cells and potentially recognized by autologous clonotypic CD27- T cells. Conclusion: We show for the first time that potential MM-reactive T cells are CD27-negative and that their abundance in the immune microenvironment of newly-diagnosed MM patients is prognostic, possibly due to their reactivation after treatment with IMiDs and autologous transplant. Because NGF is broadly used, these results are readily applicable for effective T cell immune monitoring. Disclosures Puig: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Takeda: Consultancy, Honoraria. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. Oriol:Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Rios:Janssen: 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. Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Amgen: Membership on an entity's Board of Directors or advisory committees. De La Rubia:Takeda: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy. Mateos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Takeda, Amgen, Celgene and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Key PointsVRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.

Description: Background and Aim Most multiple myeloma (MM) patients will experience relapse due to the persistence of residual tumor cells, or MRD. We compared the prognostic value of traditional response criteria with MRD measured by three different methods: a sequencing-based method, termed the LymphoSIGHT™ platform, multiparameter flow cytometry (MFC) and ASO-PCR of Ig genes in a cohort of 133 uniformly-treated MM patients from the Spanish Myeloma Group trials. Methods Bone marrow samples were obtained from 133 patients at diagnostic and post-treatment time points on GEM clinical trials (GEM00 and GEM05). All 133 patients were either in CR or VGPR at the post-treatment time point. Using the sequencing assay, we identified clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, and IGK) genes in diagnostic samples. We then assessed MRD in follow-up samples, analyzing concordance between: sequencing, MFC and ASO-PCR of Ig genes MRD results, and comparing the prognostic value of each method with traditional response criteria. Results The sequencing assay detected the presence of a myeloma-specific gene rearrangement in diagnostic samples from 121 of 133 (91%) patients. We tested MRD in follow-up time points in 109 of the 121 patients. Of the 109 patients, 79 were positive by sequencing at MRD levels of 10-5 or higher and 30 were MRD negative. The Time to Tumor Progression (TTP) and Overall Survival (OS) were significantly longer in the MRD negative group compared with the MRD positive group by sequencing (TTP, median 80 vs. 31 months, p

Description: Abstract 2967 Zoledronic Acid (ZOL) has demonstrated up to half a year improvement in survival of multiple myeloma patients. This conjoins with prior experimental studies to support a potential anti-myeloma effect for bisphosphonates. However, the in vivo effect can be confounded with the concomitant use of chemotherapy and new drugs, as well as with competing risks that emerge from the beneficial effect of bisphosphonates on the skeletal related events and its relationship with survival. Accordingly, the real anti-tumor effect of ZOL remains to be elucidated in clinical practice, for example in patients free of the disturbing effect of chemotherapy. New therapies provide an 80–90% response rate in MM, although most patients ultimately relapse. During relapse, many patients show an initial re-positivization or re-growth of the M-component (biochemical relapse) that is usually not accompanied by clinical symptoms. The usual decision at this point is not to treat such patients. Thus, these asymptomatic patients represent a perfect group to explore the antitumor benefit of ZOL in the absence of any other cytotoxic therapy. Aim: To analyze the anti-tumor effect of ZOL in the absence of any other cytotoxic drug in MM patients under asymptomatic biochemical relapse. Primary end-point was Symptomatic Progression Free Survival (sPFS). Secondary evaluation variables were response rate, skeletal related events and time to next chemotherapy. Patients and methods: 192 patients are calculated to be recruited in a randomized, prospective, open label phase IV trial in which a group of patients receive ZOL (4 mg iv./4 wk, 12 doses) and Best Supportive Care (BSC) and the rest only BSC. All patients are monitorized every 4 wk. Results: This is an interim analysis corresponding to the first 93 patients included in the trial: 49 treated with ZOL and 44 without ZOL. Asymptomatic Biochemical Relapse was confirmed in all patients who had a median age of 68 yr (40–87) and a male female distribution of 50/43. M-component distribution was IgG (69%), IgA (29%) and only light chain (2%). Relapse had presented after 1, 2 or 33 lines of therapy in 67%, 22% and 11% of cases, respectively. Prior treatment had always included transplant (65%), bortezomib (33%), IMiDs (33%), or a combination of them. Lytic bone lesions were present in 66% of patients and one or two skeletal related events (SRE) had presented prior to the inclusion in the trial in 31% of cases. FISH/cytogenetics was abnormal in 49% of cases: t(11;14) 18%, Rb deletion (alone) 16%, del(p53) 9%, t(4;14) 6% and t(14;x) 4%. After randomization, both groups of patients were well balanced in terms of prognostic features, prior response, and time from diagnosis and relapse to the inclusion in the trial. 25 patients have completed the program and four terminated before completion due to patient refusal (n=2) and development of other diseases (n=2). 31 patients are still ongoing and 38 have progressed before 12 mo of treatment, with a median sPFS of 287 days (9.4 months) with similar results between the two arms (271 vs. 308 days for patients receiving or not receiving ZA, respectively; 12-month projected sPFS was 47% vs. 42%, respectively). Interestingly, patients not treated with ZOL progressed with more advanced bone disease (8 cases of new bone lesions or re-growth of prior lesions, 1 spinal cord compression, and 2 cases of hypercalcemia) vs. patients treated with ZOL (two cases re-growth of bone lesions, p

Description: Key Points In MM patients, stringent CR criteria, in particular the sFLC ratio, do not predict significantly better outcome among MM patients in conventional CR.