VTD Arm Research Articles

First-Line Use of Daratumumab in Patients with Multiple Myeloma Shows Delayed Neutrophil and Platelet Engraftment after Autologous Stem Cell Transplantation: Results from a Real-Life Single-Center Study.

This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m2. These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes.

CD16, CD57 and DNAM-1 Positive NK Cells Predict MRD Negativity in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Bortezomib, Thalidomide and Dexamethasone

Introduction: Daratumumab-based quadruplets are the current standard of care for newly diagnosed transplant-eligible multiple myeloma (MM) patients, because of improved depth of response and survival, compared with triplet regimens without daratumumab. Since one of the primary mechanisms of action of daratumumab is the induction of antibody-dependent cellular cytotoxicity (ADCC) via the Fc-gamma receptor CD16 on natural killer (NK) cells, it is crucial to understand the role of NK cells in combination therapy. We therefore set out to comprehensively profile NK cells by flow cytometry in newly diagnosed MM (NDMM) patients treated with either daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTD) or VTD. Methods: A subset of NDMM patients (n = 152) who were treated in the Cassiopeia trial (EudraCT: 2014-004781-15) was included in this immunomonitoring analysis. In this trial, patients were first randomized to receive either four induction cycles and two consolidation cycles of D-VTD or VTD in conjunction with autologous stem cell transplantation (ASCT). In the second part of this trial, patients who achieved partial response or better at day 100 post-ASCT were randomized to either receive daratumumab maintenance or observation for the duration of two years. Bone marrow (BM) and peripheral blood (PB) samples were collected at study entry (baseline), and for PB at additional time points: cycle 1 day 28, cycle 4 day 28, day 100 (post-ASCT) and week 52 (maintenance). All baseline BM and PB samples and a selection of longitudinal PB samples were profiled by flow cytometry, with a focus on NK cell phenotype (CD56, CD16, CD57, DNAM-1, TIGIT, KLRG1, PD1, TIM3, NKG2A, NKG2C, NKG2D). To identify NK cell profiles associated with minimal residual disease (MRD) negativity, baseline PB and BM data were compared between MM patients based on MRD status after consolidation. Additionally, longitudinal data of PB samples collected during treatment were assessed to understand the impact of D-VTD and VTD on NK cell profiles. Results: In this cohort, 49 patients out of 77 (64%) randomized to the D-VTD arm achieved MRD negativity post-consolidation, while this was the case in 28 out of 75 patients (37%) in the VTD arm (fisher exact-test, p = 0.008). Patients with a higher proportion of BM-residing NK cells expressing the ADCC receptor CD16 (median 86 vs 72%, p = 0.007), the activating receptor DNAM-1 (median 94 vs 89%, p = 0.029), or the maturation marker CD57 (median 58 vs 48 %, p = 0.049) at baseline were more likely to achieve MRD-negativity post-consolidation in the D-VTD arm (Figure 1). Notably, this association was not present in the VTD arm. Although not significant, we found a similar trend for CD16 in PB in the D-VTD arm. During D-VTD treatment, we observed an increase in the proportion of CD56 bright and NKG2A + in PB NK-cells, and a corresponding decline in cells expressing CD16, CD57 and DNAM-1 (linear mixed effect model (LME) p <0.001). During VTD treatment we also observed a decrease in CD16 + NK-cells and an increase in CD56 bright and NKG2A + NK-cells (LME p <0.05), although these changes were more pronounced in the D-VTD arm. In patients who were assigned D-VTD at the first randomization and were subsequently randomized to the observation arm, we observed a restoration of the proportion of CD16 +, CD57 +, and CD56 bright NK cells to baseline values at week 52 after ASCT (Figure 2). As expected, the daratumumab associated NK cell changes persisted in the group that was randomized to the daratumumab maintenance arm. Conclusion: This study highlights the importance of NK cell immunophenotypic profiles in bone marrow as predictive markers for MRD negativity in NDMM patients treated with D-VTD in in conjunction with ASCT. Additionally, our findings illustrate that NK cell changes associated with daratumumab return to baseline levels after treatment cessation, indicating the potential for sequential NK cell-based therapies. In conclusion, this study not only provides valuable insights into the role of NK cells in the treatment of NDMM patients with D-VTD and ASCT, but also indicates that further research to optimize NK cell function in the context of combination therapies is warranted.

Autologous STEM Cell Collection after Daratumumab, Bortezomib, Thalidomide and Dexamethasone Versus Bortezomib, Thalidomide and Dexamethasone in NEWLY Diagnosed Multiple Myeloma: A Real-Life Monocentric Italian Experience

Introduction In newly diagnosed multiple myeloma (NDMM) patients (pts), induction followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains the standard of care. The addition of an anti-CD38 antibody, daratumumab, to an established frontline protocol based on bortezomib, thalidomide and dexamethasone (D-VTd), improves efficacy but could hamper peripheral blood stem cell collection (PBCS). Methods The aim of our study is to evaluate the possible impact of the addition of daratumumab to induction therapy prior to ASCT on PBCS and hospitalization parameters a real-world population with NDMM. We hereby, retrospectively analyzed 28 NDMM pts who received 6 cycles of D-VTd as induction therapy before ASCT and compared them with a consecutive series of 32 VTD-treated NDMM pts who were matched for cytogenetic abnormalities and age, managed at the Hematology Department of Sapienza University in Rome. Results Patient baseline characteristics were equally distributed among both groups, as summarized in Table 1. After induction therapy, a combination of cyclophosphamide (CTX) with granulocyte colony stimulating factor (G-CSF) at standard dose of 10 mg/sqm/day was used as the first mobilizing regimen attempt in both groups. The median time between the last day of induction therapy and the first day of mobilization therapy was 30 days for D-VTd groups and 22 days for VTD groups (p=0.041). Overall, 94% of pts treated with VTd met the desired collection goal after first mobilization therapy, compared to 68% of pts treated with D-VTd (p=0.01). In the VTd arm, 1 pts required a second mobilization attempt, and 1 pts required a further one. In the D-VTd arm, 5 pts required a second mobilization attempt, and 4 pts also required a further one. Overall, 3 pts in the D-VTd arm did not meet the collection goal. In pts with impaired mobilization, plerixafor was used in 4/32 pts in the VTd arm (13%), compared to 29% of pts treated with D-VTd (p=0.195). In the D-VTd arm, 12/28 pts (43%) had received a higher dose of CTX as mobilization therapy (3 g/m 2) compared to the standard dose of 2.4 g/m 2 in 16/28 pts (57%). Nevertheless, no difference was observed in the rate of PBSC collection at the first attempt (p=0.7). No baseline clinical or disease characteristics were observed to have negative impact on the PBSC at first mobilization attempt, including treatment response at the end of induction therapy. Nevertheless, a significantly lower pre-mobilization level of platelet was detected in the group of D-VTd treated pts (173.000/mm 3 vs 210.000/mm 3, p=0.012) that did not meet the desired collection goal after first mobilization therapy. The median PBSC collection was 9.1x10 6 CD34+ cells/Kg in the whole cohort, with no significant difference in the two groups. A lower pre-mobilization level of neutrophils (p=0.028) and platelets (p=0.004) was observed in the D-VTd arm compared to the VTd arm, possibly reflecting prolonged daratumumab-related hematological toxicity. No significant difference was observed in the leucocyte (WBC) azimuth value in the two arms. However, the two groups reached this value on two different days. In the VTd arm the median day was 8, and in the D-VTd arm it was 11 (p=0.034). The use of G-CSF for more days did not result in an increase in CD34+ and the median azimuth value of CD34 was significantly lower in the D-VTd group than in the VTD group (p<0.001). The median collection volume from apheresis devices was significantly higher in the D-VTd group (372 ml) compared to VTd arm (301 ml) (p=0.05), possibly related to a higher WBC azimuth in D-VTd arm, resulting in a prolonged apheresis procedure. Pts receiving D-VTd had slightly delayed hematopoietic neutrophil (11 vs 14 days, p=0.030) and platelet (15 vs 14 days, p=0.018) engraftment, but no requiring a higher number of red cell (p=0.6) and platelet (p=0.3) transfusions and a longer hospitalization (20 vs 17 days, p=0.2) after the first ASCT, compared to pts treated with VTd. No difference in the two groups regarding rate of febrile neutropenia (65% vs 45%, p=0.2) and use of antibiotics (53% vs 57%, p=0.8) were observed. Conclusions In conclusion, frontline induction daratumumab-based therapy is likely to affect PBSC collection after first mobilization attempt, even if not clinically relevant, and potentially mitigated with higher use of plerixafor. Furthermore, the inclusion of daratumumab in pretransplant therapy regimens did not impair ASCT.

P-178: Impact of t(11;14) according to induction regimen in newly diagnosed transplant-eligible multiple myeloma patients: long term follow-up of GEM05MENOS65 and GEM2012 PETHEMA/GEM studies

<h3>Background</h3> t(11;14) is the most frequently IgH rearrengement in newly diagnosed multiple myeloma (NDMM) with a 15-20% prevalence and is considered a standard-risk cytogenetic abnormality (SR). However, t(11;14) is controversial since recent reports describe inferior outcomes in contrast to other SR patients. We analyze the long-term outcome of t(11;14) compared to the remaining SR population in transplant-eligible patients included in GEM05MENOS65 and GEM2012 spanish trials for NDMM. <h3>Methods</h3> 386 patients included in GEM05MENOS65 trial were randomized to receive induction with 6 cycles of thalidomide and dexamethasone (TD) vs. 6 cycles of VTD vs. 4 cycles of alternating chemotherapy (VBMCP/VBAD) plus 2 cycles of bortezomib (VBMCP/VBAD/B). 458 patients included in GEM2012 trial received induction with 6 cycles of VRD. <h3>Results</h3> From a total of 414 SR patients, 84 (20%) were positive for t(11;14) and 328 (80%) were SR non-t(11;14). There were no differences in baseline characteristics among groups. In the VBMCP/VBAD/B arm, there were no significant differences in ORR or CR rate after induction between patients with t(11;14) or other SR (ORR 93 vs. 85%, p=0.4; CR 21 vs. 16%, p=0.6). However, patients with t(11;14) treated with VTD had lower ORR and CR rates after induction than SR patients (ORR 85 vs. 97%, p=0.04; CR 15 vs. 38%, p=0.1). Patients with t(11;14) treated with TD had lower ORR and CR rates although the differences were not statistically significant (ORR 63 vs. 78%, p=0.2, CR 5 vs. 11%, p=0.4). In the VRD arm, patients with t(11;14) had similar ORR and CR compared to other SR (ORR 87 vs. 89%, p=0.8; CR 24 vs. 32%, p=0.3). With a median follow-up of 54.2 months, no differences in median PFS were observed in the VBMCP/VBAD/B arm (44 vs. 46 months; p=0.7). However, shorter PFS was observed in patients with t(11;14) in the TD (30 vs. 46 months; p=0.03) and VTD arms (28 vs. 72 months; p=0.003). With VRD, median PFS was not reached for patients with t(11;14) and SR non-t(11;14) (p=0.8). Among patients with t(11;14), VTD showed shorter median PFS compared to VRD (28 months vs. not reached, p<0.01). Patients with t(11;14) treated in the VBMCP/VBAD/B arm showed shorter median OS than SR patients (66 months vs. not reached; p=0.03). In contrast, median OS was not reached in patients with t(11;14) or SR in neither TD, VTD and VRD arms. <h3>Conclusion</h3> Thalidomide-based induction regimens (VTD/TD) are suboptimal in patients with t(11;14) concerning response rates and PFS than SR patients, although this does not impact on OS. In contrast, VRD showed similar ORR and PFS in patients with t(11;14) and SR. Despite this is a non-randomized comparison, VRD appears to be more effective than VTD in this subset of patients. Patients with t(11;14) receiving induction with chemotherapy have the same response and PFS than SR patients but display a shorter OS. These results should be confirmed in larger series.

Mmprofiler with SKY92 Combined with ISS Identifies High and Low Risk Multiple Myeloma in the VTD Arm of Gimema-MMY-3006

SKY92 combined with ISS identifies high and low risk multiple myeloma in GIMEMA-MMY-3006 VTD armErik H. Van Beers*, Carolina Terragna*, Rowan Kuiper*, Marina Martello*, Elena Zamagni*, Giovanni Martinelli, Martin H. van Vliet*, Michele Cavo*.Introduction: Prior to this cohort, SKY92 demonstrated significance in several bortezomib-containing treatments (HOVON-65/GMMG-HD4, APEX, TT3, TT6) and thalidomide-containing treatments (HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, TT2, TT3, TT6, MRC-IX). It remains unknown how this GEP-signature predicts outcome in IMiD plus proteasome inhibitor (PI) treatment. GIMEMA-MMY-3006 is the first dataset in which the front-line VTD in NDMM patients has been evaluated by SKY92 and other prognostic markers.Methods: The GIMEMA-MMY-3006 trial (NCT01134484) compared bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy prior to the autologous stem cell transplantation (ASCT) in transplant eligible NDMM patients [1]. The current analysis compares prognostic value of t(4;14), del(13), del(17), GEP and clinical characteristics in the VTD arm (GSE58133; n=114). PFS and OS were evaluated at median follow up of 3.3yrs. GEP data (U133Plus2.0 CEL files) were batch processed and GEP classifiers were calculated as reported [2]. R-ISS was constructed as described in Palumbo et al. [3], except for the missing marker t(14;16) while SKY92-ISS was constructed as described in Kuiper et al. [4] except that four classes were reduced to three (high, low, and the rest).Results: This is the first report of SKY92 evaluated in a VTD setting. The prognostic values of three risk models (ISS, SKY92-ISS and R-ISS) were compared (Table 1). A total of 36 progressions and 18 deaths occurred in 114 cases. Univariate PFS (results will be presented at the meeting). For OS, univariate analysis showed SKY92, UAMS70, IFM15, del(17), ISS (IIIvsI) and SKY92-ISS were significant. Figure 1 shows Kaplan Meier analyses for SKY92, SKY92-ISS, and R-ISS. Multivariate analysis for OS - with SKY92, del(17) and R-ISS (high risk vs others) - significance was observerd for SKY92 (HR 3.48) but not for del(17) or R-ISS (Table 2). Among the 31 R-ISS-I there were no deaths and therefore no HR (between I and III) was calculated (Figure 1C). A comparison of Figure 1B and C shows that SKY92-ISS captured more high-risk patients than R-ISS (23 vs.6). Of the 19 t(4;14) cases, eleven were also SKY92 high-risk. Of the 8 del(17) cases, 5 were also SKY92 high-risk.Both SKY92-ISS and R-ISS identified low risk patients. SKY92-ISS identified 12 more low risk cases than R-ISS (43/114, 38%, 31/105, 30%, respectively). Figure 1D shows concordance between the risk scores and association with OS (top rows) at 2 and 4y after diagnosis. None of the signatures predicted all deaths at 2 or 4y. SKY92 predicted more deaths than other markers (Figure 1D). Similar to a previous study [1] the risk models were concordant for 2 high risk and 66 standard risk cases, while discordant for 46 remaining cases. SKY92 best identified hazard for a large proportion of cases (Table 1).Conclusions: In this upfront VTD setting we observe proportions of SKY92 high risk and low risk myeloma that are comparable with previous studies with other treatments containing either bortezomib or thalidomide. SKY92-ISS identifies high risk in 20% and low risk in 38% MM patients with HR = 4.0 between high and standard risk (Fig 1A) and HR = 10.7 between high and low risk (Fig 1B) compared with R-ISS the obtained HR = infinite as there were no deaths in low risk (Fig 1C). SKY92-ISS identified a larger faction of low risk cases (38%) compared with R-ISS (30%) yet retains a very large and significant hazard ratio of 10.7 reproducing earlier validation data [1].Figure 1. Prognostic marker performance in n=114 VTD treated multiple myeloma patients. Kaplan Meier analyses for OS were stratified by A) SKY92, B) SKY92-ISS or C) R-ISS. D) shows GEP signature predictions (rows) and their overlap across all 114 cases (columns). Standard Risk (blue), High Risk (yellow), Alive at follow up (Green), dead at follow up (Red), lost to follow up (Grey).

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P &lt;0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P&lt; 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P &lt;0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P &lt;0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

Peripheral Neuropathy in the Cassiopeia Study

Introduction Peripheral neuropathy (PNP) remains one of the most common adverse events during multiple myeloma (MM) treatment. The immunomodulatory agent thalidomide and proteasome inhibitor bortezomib are particularly prone to induce PNP (Dimopoulos MA et al., Leukemia., 2010). Both agents are part of standard treatment regimens for newly diagnosed transplant-eligible MM patients. PNP varies from mild symptoms to severe disability, depending on timely dose reduction or discontinuation of treatment. Currently, incidence or severity of PNP cannot be predicted. Therefore, it is of utmost importance to monitor incidence of PNP in different treatment combinations, and in order to identify risk factors for developing PNP. Aims To investigate the incidence of PNP in patients treated in the Cassiopeia trial, to evaluate the role of CD38 antibody (daratumumab) treatment in development of PNP, and to identify risk factors for the development of PNP. Methods We retrospectively analysed incidence of PNP grade 2 to 4, scored according to common terminology criteria for adverse events version 4 (CTCAE) in the Cassiopeia study, a phase III trial conducted by IFM/HOVON, investigating the efficacy of adding daratumumab to bortezomib, thalidomide and dexamethasone (VTD). 1074 newly diagnosed MM patients were randomised. Patients received 4 induction cycles and 2 post transplantation consolidation cycles of 28 days each. Cycles included subcutaneous bortezomib (1.3 mg/m2 days 1,4,8,11), oral thalidomide (100 mg daily), dexamethasone (20-40 mg) and daratumumab intravenously (16 mg/kg and weekly during induction cycles 1 and 2 and once every two weeks during induction cycles 3,4 and consolidation). This trial was registered as ClinicalTrials.gov NCT02541383 and was supported by the French IFM and Dutch HOVON groups (Moreau et al., Lancet, 2019). Multivariate analysis was performed including sex, age, arm, body mass index (BMI), cytogenetics, ISS stage, country, diabetes mellitus (DM), creatinine clearance, liver function, ECOG, baseline PNP and disease characteristics. Results Baseline characteristics in dara-VTD and VTD arms were similar. Overall, 380/1074 (35%) patients developed grade ≥2 PNP and 102/1074 (9%) patients developed grade ≥3 PNP. Multivariate analysis indicated that the cumulative incidence of PNP grade ≥2 was significantly lower in the dara-VTD arm (33%) when compared to the VTD arm (38%) (hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.59-0.91, P=0.004). Furthermore, risk factors associated with a higher cumulative incidence of PNP grade ≥2 included older age (HR=1.03; P=0.020), grade 1 PNP at baseline (HR= 2.75; P= 0.002) and higher BMI (HR=1.46, P=0.003 for BMI 25-30 to HR=2.02, P=0.004 for BMI &amp;gt; 35). Progression free survival (PFS) from the end of induction was similar (86% vs 80% at 2 years, HR = 0.74, 95% CI 0.41-1.33, P=0.32) for patients developing grade ≥2 PNP during induction (179 pts, 17%). An unexpected finding was the difference in cumulative incidence between countries participating in this trial: in the Netherlands 68/141 (49%) of patients developed grade ≥2 PNP, while in France this was 280/846 (33%) and in Belgium 31/87 (36%) (p&amp;lt;0.001). The protocol of the Cassiopeia trial included instructions of discontinuation and dose modification, when PNP grade ≥2 was observed. However, in a subset of patients reaching PNP grade ≥ 2 the (temporary) discontinuation or adjustment of dose as described in the treatment protocol had not been applied (respectively in 148/352 (42%) with PNP ≥ 2 and in 39/97 (40%) with PNP ≥3). Conclusions Despite bortezomib being administered subcutaneously and clear instructions on discontinuation and dose modification, we observed a clinically relevant incidence of grade ≥2 PNP (35%) and grade ≥3 PNP (9%) in patients treated in the Cassiopeia trial. Patients in the dara-VTD arm showed less grade ≥2 PNP, suggesting a possible positive effect of daratumumab. Risk factors for the development of grade ≥2 PNP included older age, PNP at baseline and BMI &amp;gt; 25. Differences in incidence between countries were observed, however no clear explanation was found. Furthermore, standard measures for grading PNP, such as CTCAE criteria, are subject to interpretation bias of both the patient and the treating physician. Continuous screening and correct grading of PNP and strict compliance with guidelines is warranted. Disclosures Moreau: Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Sonneveld:Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Real world outcomes with Bortezomib Thalidomide dexamethasone and Cyclophosphamide Bortezomib dexamethasone induction treatment for transplant eligible multiple myeloma patients in a Latin American country. A Retrospective Cohort Study from Grupo Argentino de Mieloma Múltiple.

Data about treatment outcomes and toxicity in Latin America are scarce. There are differences with central countries based on access to healthcare system and socioeconomic status. Argentinean Society of Hematology recommends bortezomib-based triplets for induction treatment of transplant eligible newly diagnosed multiple myeloma patients. Most common options are CyBorD (cyclophosphamide, bortezomib and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone). Main goal of our retrospective, multicentric study was to compare very good partial response rate (VGPR) or better after induction treatment in a real-world setting in Argentina. Secondary objectives included comparison of complete response (CR) post-induction and after bone marrow transplantation, grade 3-4 adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Three hundred twenty-two patients were included (median age at diagnosis: 57 years; 52% male; 28% had ISS3; 14% with high-risk cytogenetics; median follow up: 34 months). CyBorD was indicated in 74% and 26% received VTD. In VTD arm, 72.62% of patients achieved at least VGPR vs 53.36% receiving CyBorD (odds ratio, OR: 1.96 [95% confidence interval, CI: 1.08-3.57; P = .026] after adjusting by age, ISS [International Staging System], lactate dehydrogenase levels (LDH) and cytogenetic risk. Difference in VGPR was 19.26% (95% CI: 15-24). CR rate were 35.92% (VTD) vs 22.55% (CyBorD) (adjusted OR: 2.13 [95% CI: 1.12-4.05]). Difference in CR was 13.37% (95% CI: 9.6-17.53). Adverse events (AEs) were more common with VTD (69.05% vs 55.46% for CyBorD; P = .030), especially grade 3-4 neuropathy (P = .005) and thrombosis (P = .001). Thromboprophylaxis was inadequate in 20.24% of patients. Hematological AEs were more common with CyBorD, especially thrombocytopenia (P = .017). PFS and OS at 24 months were not different between treatments. In this real-world setting, VTD was associated with better CR and VGPR than CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina, based on safety profile. Frontline autologous stem cell transplantation improves quality of responses, especially in countries with limited access to new drugs.

PF598 STEM CELL YIELD AND TRANSPLANTATION IN TRANSPLANT‐ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS RECEIVING DARATUMUMAB + BORTEZOMIB/THALIDOMIDE/DEXAMETHASONE (D‐VTD): PHASE 3 CASSIOPEIA STUDY

Background:High‐dose therapy (HDT) followed by autologous stem‐cell transplantation (ASCT) is the standard of care in transplant‐eligible newly diagnosed multiple myeloma (NDMM). In the phase 3 CASSIOPEIA study, daratumumab + standard‐of‐care regimen VTd (D‐VTd) significantly improved stringent complete response (sCR), complete response or better (≥CR), and minimal residual disease (MRD)‐negative rates and reduced the risk of progression or death versus VTd in NDMM patients who were eligible for transplant.Aims:Here, we assessed stem cell yield and transplantation results among patients receiving D‐VTd versus VTd induction prior to HDT and ASCT in Part 1 of the CASSIOPEIA trial.Methods:In Part 1, transplant‐eligible NDMM patients ages 18–65 years were randomized 1:1 to 4 pre‐transplant induction and 2 post‐transplant consolidation cycles of D‐VTd or VTd alone. After induction, patients underwent stem cell mobilization with cyclophosphamide 3 g/m2 (recommended dose) and granulocyte colony‐stimulating factor (G‐CSF). Peripheral blood stem cells were harvested based on response to mobilization. Plerixafor was administered if stem cell collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m2 IV was given as HDT prior to ASCT.Results:A total of 1,085 patients were randomized to D‐VTd (n = 543) or VTd (n = 542). Among patients who completed mobilization (D‐VTd, 506; VTd, 492), more patients in the D‐VTd arm received plerixafor during mobilization than in the VTd arm (21.7% vs 7.9%). Patients underwent a median (range) of 2 (1–6) versus 1 (1–4) days of apheresis for D‐VTd versus VTd. The median number of CD34+ cells collected was lower in patients receiving D‐VTd versus VTd (6.3 × 106/kg vs 8.9 × 106/kg). Nevertheless, a similar percentage of intention‐to‐treat patients receiving D‐VTd versus VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34+ cells transplanted for D‐VTd versus VTd was 3.3 × 106/kg versus 4.3 × 106/kg. Hematopoietic reconstitution rates were high and similar in transplanted patients receiving D‐VTd versus VTd (99.8% vs 99.6%). For D‐VTd versus VTd, a median (range) of 13.0 (6–54) versus 13.0 (4–43) days was required to achieve sustained absolute neutrophil counts &gt;500 cells/mm3, and a median (range) of 14.0 (2–56) versus 12.0 (1–47) days was required to achieve sustained platelets &gt;20,000 cells/mm3 without transfusion.Summary/Conclusion:Stem cell mobilization and collection was feasible with D‐VTd induction. Adding daratumumab to VTd allowed successful transplantation in patients with NDMM who were transplant eligible.

PF594 BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE VS BORTEZOMIB-THALIDOMIDE-DEXAMETHASONE INDUCTION: INTEGRATED ANALYSIS OF RANDOMIZED CONTROLLED TRIALS IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA

Background: European and US guidelines recommend VRD and VTD for pts with TE NDMM. However, no RCTs have directly compared VRD vs VTD to date. Aims: To evaluate efficacy and safety of VRD vs VTD in TE NDMM via integrated analysis. Methods: Prospective, phase 3 RCTs evaluating VRD or VTD induction (every 3 or 4 wks) in TE NDMM before ASCT were included if they met pre-defined eligibility criteria (including access to pt-level data). Primary endpoint was noninferiority of ≥ VGPR rate post induction. Secondary endpoints included safety and ≥ VGPR rate during induction and post ASCT. Exploratory endpoints were PFS and MRD negativity. Statistical methods were based on propensity score (PS). Pts with missing baseline values for the variables used for the PS analyses were excluded. Results: Four studies met the eligibility criteria: VRD, PETHEMA GEM (GEM)2012 and IFM 2009; VTD, GEM2005 and IFM 2013–04. GEM2005 and GEM2012, used for the primary analysis, had a symmetrical induction design (six 4-wk cycles then ASCT). IFM studies were considered supportive due to their variable number of cycles (3 VRD cycles before ASCT vs 8 VRD cycles in IFM 2009 and 4 VTD cycles before ASCT in IFM 2013–04). IFM analyses compared the IFM 2009 VRD non-ASCT of vs IFM 2013–04 VTD arm. The VRD and VTD PS-stratified cohorts of the GEM and IFM studies had no clinically meaningful differences in baseline characteristics. The integrated analysis met its primary endpoint (non-inferiority) and demonstrated a statistically significant and clinically relevant ≥ VGPR rate improvement after 6 cycles of induction with VRD vs VTD (66.3% vs 51.2%; P = .00281; Figure) in the GEM studies. IFM non-inferiority results had similar ≥ VGPR rates for VRD vs VTD by 4 cycles (12 wks; 57.1% vs 56.5%). Responses deepened during induction in the GEM studies. Among the 378 VRD pts who started cycle 6, ≥ VGPR rate increased from 54.5% by 3 cycles of induction to 62.7% by 4 cycles, and to 70.1% by 6 cycles and post induction. Of the 111 VTD pts, these rates were 35.1%, 40.5%, and 55.9%, respectively. The ≥ VGPR rate post-ASCT (74.4% vs 53.5%) and MRD negativity (10–4) rates post induction (46.7% vs 34.9%) and post ASCT (62.4% vs 47.3%) support the benefit of VRD vs VTD. Safety was as previously reported for these studies. Peripheral neuropathy (PN) can limit VRD and VTD Tx duration. In GEM studies, SC vs IV administration of BORT may have contributed to lower rates of PN (grouped term) with VRD vs VTD (grade 3/4, 5.5% vs 15.4%; grade ≥ 2, 20.7% vs 44.6%). TEAEs led to dose reduction (21.6% vs 35.4%) and study or Tx discontinuation (3.1% vs 9.2%) less frequently in the VRD vs VTD cohorts. In IFM studies, TEAEs led to dose reduction more frequently (32.9% vs 18.3%) and Tx discontinuation less frequently (6.5% vs 11.2%) with VRD vs VTD. Grade 3/4 PN (grouped term) was 5.9% vs 15.4%, whereas grade ≥ 2 events were similar (30.3% vs 27.2%), which may reflect BORT administration in these IFM studies (IV for VRD vs SC for VTD, respectively).Summary/Conclusion: Six cycles of VRD induction led to a significantly higher ≥ VGPR rate than VTD in TE NDMM. Deepening responses and MRD negativity further support the benefit of VRD over VTD. TEAEs in the GEM and IFM studies were generally consistent with the known safety profiles of the individual agents. TEAEs with the VRD regimen were manageable, and the overall tolerability profile compared well with VTD, with lower rates of TEAEs leading to discontinuation. This analysis supports the favorable benefit-risk profile with VRD over VTD as induction Tx in TE pts with NDMM.

S874 EFFICACY OF DARATUMUMAB + BORTEZOMIB/THALIDOMIDE/DEXAMETHASONE (D‐VTD) IN TRANSPLANT‐ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA BASED ON MINIMAL RESIDUAL DISEASE STATUS: ANALYSIS OF CASSIOPEIA

Background:VTd is considered a standard of care for patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible. The CD38‐targeted monoclonal antibody daratumumab (DARA) demonstrated a significant reduction in the risk of progression or death and improvement in stringent complete response (sCR), CR or better (≥CR), and minimal residual disease (MRD)‐negative rates when added to VTd in transplant‐eligible NDMM patients in the phase 3 CASSIOPEIA study.Aims:Determine MRD status and its association with progression‐free survival (PFS) in transplant‐eligible NDMM patients receiving D‐VTd versus VTd as pre‐transplant induction and post‐transplant consolidation in CASSIOPEIA.Methods:Transplant‐eligible NDMM patients were randomized 1:1 to 4 cycles of pre‐autologous stem‐cell transplant (ASCT) induction and 2 cycles of post‐ASCT consolidation with DARA + VTd or VTd. Analyses of MRD were performed on bone marrow aspirates after induction and after consolidation (at Day 100 post‐ASCT) for all patients, regardless of response. MRD was assessed primarily by EuroFlow‐based multiparametric flow cytometry (MFC) and, based on sample yield, secondarily with next‐generation sequencing (NGS; Adaptive clonoSEQ® Assay). Here, we report post‐induction and post‐consolidation MFC results (10−5 sensitivity threshold) and post‐consolidation NGS results (10−6).Results:A cohort of 1,085 patients received D‐VTd (n = 543) or VTd (n = 542). The post‐induction MRD‐negative rate (MFC, 10−5) was significantly higher for the D‐VTd arm versus the VTd arm (34.6% vs 23.1%; P &lt; 0.0001; Table). Similarly, post‐consolidation MRD‐negative rates by MFC (10−5) and NGS (10−6) were significantly higher for patients receiving D‐VTd versus VTd (63.7% vs 43.5% and 39.1% vs 22.8%, respectively; P &lt; 0.0001 for both analyses; Table). Post‐consolidation MRD‐negative rates (MFC, 10−5) were consistent across patient subgroups, including ISS stage III or high‐risk cytogenetics.Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in patients reaching MRD negativity (HR, 0.31; 95% CI, 0.20–0.50; P &lt; 0.0001), and D‐VTd showed additional PFS benefit versus VTd alone (HR, 0.48; 95% CI, 0.30–0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented.Summary/Conclusion:The addition of DARA to VTd during induction and consolidation deepened responses, as demonstrated by significant increases in MRD‐negative rates. Deepened post‐consolidation responses with D‐VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in patients with NDMM who were transplant eligible.image

S145 PHASE 3 RANDOMIZED STUDY OF DARATUMUMAB + BORTEZOMIB/THALIDOMIDE/DEXAMETHASONE (D-VTD) VERSUS VTD IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: PART 1 CASSIOPEIA RESULTS

Background: VTd is a standard of care for transplant-eligible newly diagnosed multiple myeloma (NDMM) patients. Daratumumab (DARA), a CD38 mAb, significantly reduced the risk of progression or death and improved complete response (CR) and minimal residual disease (MRD)-negative rates in relapsed refractory multiple myeloma or transplant-ineligible NDMM in phase 3 studies. Aims: We report the primary and final analysis of Part 1 of the CASSIOPEIA trial for NDMM. Methods: In Part 1, transplant-eligible NDMM patients 18–65 years old were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-autologous stem cell transplantation {ASCT} induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1–2; T 100 mg PO QD; d 40–80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT therapy. The primary endpoint was the rate of post-consolidation stringent complete response (sCR) assessed at Day 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 patients (D-VTd, 543; VTd, 542) was randomized. The Day 100 post-ASCT sCR rate was significantly higher for the D-VTd arm versus the VTd arm (28.9% vs 20.3%; P = 0.0010; Table). With 18.8-months median follow-up, progression-free survival (PFS) from first randomization favored D-VTd with a hazard ratio (HR) of 0.47 (95% CI, 0.33-0.67; P < 0.0001; Figure). With median PFS not reached in either arm, 18-month PFS rates were 92.7% versus 84.6% for D-VTd versus VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). Overall survival is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23–0.80). The most common (≥10%) grade 3/4 treatment-emergent adverse events (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of patients.Summary/Conclusion: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in transplant-eligible NDMM. CASSIOPEIA is the first study to demonstrate the clinical benefit of daratumumab plus standard of care in transplant-eligible NDMM patients.

Bortezomib-Thalidomide-Dexamethasone Versus Thalidomide-Dexamethasone before and after Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Final Analysis of Phase 3 Gimema-MMY-3006 Study and Prognostic Score for Survival Outcomes

Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes. Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival. Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs. Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p Conclusions: With a follow up of 10 yrs, the final analysis of the GYMEMA MMY-3006 trial comparing VTD versus TD showed a persistent PFS benefit translating into extended OS for the VTD arm. A prognostic model based on cytogenetic, ISS stage and achievement of CR, identified three risk groups with statistically different long-term survival probabilities. Both IR and HR groups significantly benefited from VTD. A PFS time of 78 months predicted for long term survival outcomes in the LR and IR groups. Disclosures Tacchetti:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni:Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity9s Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Definitive Results of a Randomized Phase 3 Pethema/GEM Study

VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Definitive Results of a Randomized Phase 3 Pethema/GEM Study

Real World Outcomes with VTD and Cybord Induction Treatment for Transplant Eligible Multiple Myeloma Patients in a Latin American Country. Retrospective Cohort Study from Gamm (Grupo Argentino de Mieloma Multiple)

Introduction:There are scarce data regarding treatment outcomes and toxicity in Latin American countries. Argentina is the second largest country in the region and the fourth most populated one. National Guidelines from the Argentinean Society of Hematology (SAH) recommends the use of bortezomib based triplets for induction treatment in transplant eligible newly diagnosed Multiple Myeloma patients.Objective:To compare response rates and adverse events after induction treatment with Cyclophosphamide Bortezomib and Dexamethasone (CyBorD) or Bortezomib Thalidomide and Dexamethasone (VTD) outside of clinical trials in a Latin American country.Methods:Retrospective multicentric cohort study. All centers participating in the Argentinean Multiple Myeloma Study Group (GAMM) were invited to participate in the study.Eligible patients were 75 years of age or younger, with a diagnosis of Multiple Myeloma according to the IMWG 2014 criteria, transplant eligible, treated with at least one cycle of CyBorD or VTD as induction therapy in the time period from December 2012 until December 2017. Main exclusion criteria were amyloidosis, plasma cell leukemia and previous neuropathy.Patients were identified from local registries at each center and included consecutively in the study database. Epidemiological and clinical data were obtained from medical records and collected in a standardized clinical report form. Patients were followed from diagnosis until death or lost to follow up. Response was evaluated according to IMWG Response Criteria 2016. Adverse events were graded by CTCAE 4.3.Comparisons of response rates were performed using a Chi2 test and differences in rates were expressed as proportions with 95% confidence intervals (CI). Crude odds ratios (OR) and OR adjusted by potential confounders were calculated using a logistic regression model. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Stata 13 software was used.Results:A total of 322 patients from 15 centers in Argentina were included in the study. The median age at diagnosis was 57 years (range 26-74), 52% (167) of the patients were male, 18% (58) had renal failure, 28% (85) ISS 3 , 7% (22) extramedullary disease, and 14% (46) high risk cytogenetics. Median time of follow up was 34 months (IQR 21-58).CyBorD was the most common treatment, indicated as induction therapy in 74% (238) of the cases. The characteristics of the patients were similar in both groups except age and LDH levels.The median number of cycles was 5 (range 1-12). Bortezomib was administered once per week in 85% (272) of the patients and subcutaneously in 86% (276) with no differences between both treatment arms. The median cumulative cyclophosphamide dose per month was 1.5 g (IQR 1.5-2.4) and thalidomide dose per day was 100 mg.In the VTD arm, 72,62% (61) of the patients achieved at least very good partial response (VGPR) vs 53.36% (127) with CyBorD [OR of 2.31 (CI 1.35 - 3.99) p=0.002]. The difference in VGPR was 19.26% (CI 15 - 24). Complete response rate (CR) was 35.92% in patients treated with VTD vs 22.55% with CyBorD [OR of 1.87 (CI 1.04 - 3.35) p=0.03). The difference in CR was 13,37% (CI 9.6 -17.53). There was no difference in overall response rate (ORR) with 94.05% vs 91.18% (p=0.406).Adverse events were more common with VTD (69.05% vs 55.46% p=0.030), especially neuropathy grade 3 - 4 (7.14% vs 1.26% p=0.005) and thrombosis (13.10 % vs 3.36 % p=0.001). Deep venous thrombosis prophylaxis was inadequate in 20.24% of the patients. Hematologic adverse events were more common with CyBorD, especially thrombocytopenia (5.95% vs 16.39% p=0.017).Autologous stem cell transplantation (ASCT) was performed in 78% (249) of patients. There was 5% (17) stem cell mobilization failure, all in the CyBorD arm. Response rates after ASCT with VTD and CyBorD induction treatment were: 76.19 vs 73.11% VGPR (p=0.580) and 48.53% vs 40% CR (p=0.20). Maintenance treatment was indicated in 67.86% (57) and 65.13% (155) patients respectively (p=0.650).The PFS at 24 months was 83% (CI 71-90) with VTD vs 72% (CI 66-78) [(HR 0.92 (CI 0.59 - 1.42) p 0.715] and OS 96% (CI 87-99) vs 91% (86-94) respectively [(HR 1.2 (CI 0.62 - 2.32) p 0.587].Conclusions:VTD has better CR and VGPR compared to CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina based on safety profile. The optimal number of induction treatment cycles remains to be determined. [Display omitted] DisclosuresSchutz:Takeda: Honoraria, Research Funding; Sanofi Aventis: Research Funding; Roche: Research Funding; Glaxo: Research Funding; Janssen: Honoraria, Research Funding; Varifarma: Honoraria. Shanley:Brystol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Fantl:Janssen: Consultancy, Honoraria, Research Funding; Varifarma/Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Roche: Research Funding; Tecnofarma: Honoraria; BMS: Consultancy, Honoraria; Glaxo: Research Funding.

Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies

Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies

Integrated Analysis of Randomized Controlled Trials Evaluating Bortezomib + Lenalidomide + Dexamethasone or Bortezomib + Thalidomide + Dexamethasone Induction in Transplant-Eligible Newly Diagnosed Multiple Myeloma

Integrated Analysis of Randomized Controlled Trials Evaluating Bortezomib + Lenalidomide + Dexamethasone or Bortezomib + Thalidomide + Dexamethasone Induction in Transplant-Eligible Newly Diagnosed Multiple Myeloma

Bortezomib-Based Regimens As Consolidation Therapy after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Single Center Experience from Oran (Algeria)

INTRODUCTION:Autologous stem cell transplant (ASCT) is the standard of care in transplant-eligible multiple myeloma (MM) patients and is associated witha significant improvement in progression-free survival (PFS), complete remission rates (CR), and overall survival (OS). However, the majority ofpatientsrelapse.This study compares the efficacy of autologous hematopoietic stem cells followed by consolidation bybortezomibbased regimens to the no consolidation therapy in adult patients.PATIENTS AND METHODS:This is a retrospective study over a period of 7 years (2009-2015). All patients less than 65 years with a newly MM diagnosis were included. The protocol used in induction was VD (n=47) treatment whichconsisted of four 3-week cycles of 1.3 mg/m2 bortezomib administered subcutaneously (SC) on days 1, 4, 8, and 11 and 40 mg dexamethasone on days 1Ð4 and 9Ð12. Therapy with VTD was composed of four 3-week cycles of SC bortezomib and dexamethasone at the same doses and schedules as for the VD regimen plus 100 mg/day thalidomide administered orally. Therapy with VCD was composed of four 3-week cycles of SC bortezomib and dexamethasone at the same doses and schedules as for the VD regimen plus 500 mg/m2 cyclophosphamide administered orally on days 1, 8, and 15. Recommended concomitant medications included bisphosphonates, antibiotics, and antiviral prophylaxis. Acetyl salicylic acid was systematically used in the VTD arm. Stem cells were mobilized with 15 or 10 microg/kg G-CSF alone. Leukapheresis to harvest stem cells was performed on day -2 and -1. The grafts were kept in a conventional blood bank refrigerator at 4¡C until reinfusion on day 0. The target yield was 2 x106 CD34+ cells/kg. Following induction therapy, all patients had to proceed to ASCT. The conditioning regimen consisted of melphalan 200 mg/m2 in all patients.The consolidation regimen consisted of two cycles of VD or VCD or VTD after autologous stem- cell transplantation. In our study patients were divided into two groups: Group1 (ASCT plus consolidation) and Group 2 (ASCT alone).The therapeutic evaluation focused on the overall response (CR + VGPR) and progression free survival (PFS) and overall survival (OS) calculated by the Kaplan-Meier method.RESULTS:Over a period of 7 years, 153 patients were collected divided in two group: G1 (n=71) and G2 (n=82). Baseline characteristics are summarized in Table 1. No significant difference was observed between the 2 groups.In terms of CR, 58% of the patients in the G1 achieved a CR after consolidation vs 33% in the G2 after ASCT alone (p=0.007). In terms of VGPR, 31% of the patients in the G1 achieved a least a VGPR vs 17% in the G2 (p=0.04). The relapse rate was significantly lower in the G1 (10%) than the G2 (39%), (p=0.0001).The median follow-up period was 23,4 months. PFS was significantly higher in the G1, median no reached vs 37 months in the G2 (p=0.02) but no significant difference was observed in terms of OS rate between the 2 groups, 91% (G1) versus 82% (G2) at 27 months (p=0.7). CONCLUSIONWe conclude thatbortezomib-based regimens as consolidation therapy after ASCT in patients with MM was effective in the improvement of PFS and response rate. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial

AbstractThe Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

Bortezomib, Thalidomide and Dexamethasone (VTD) Is Superior to Bortezomib, Cyclophosphamide and Dexamethasone (VCD) Prior to Autologous Stem Cell Transplantation for Patients with De Novo Multiple Myeloma. Results of the Prospective IFM 2013-04 Trial

Bortezomib, Thalidomide and Dexamethasone (VTD) Is Superior to Bortezomib, Cyclophosphamide and Dexamethasone (VCD) Prior to Autologous Stem Cell Transplantation for Patients with De Novo Multiple Myeloma. Results of the Prospective IFM 2013-04 Trial