VRD Induction Research Articles

Lenalidomide, doxorubicin hydrochloride and dexamethasone versus bortezomib, lenalidomide, and dexamethasone prior to scheduled stem cell transplant in newly diagnosed myeloma.

8001 Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.

High-Throughput Characterization and New Insight into the Role of Tumor Associated Macrophages (TAMs) in Multiple Myeloma (MM)

The advent of immunotherapy in MM urges the need for in-depth knowledge about immune cells towards improved characterization of patients' immune profiles. Based on few studies, TAMs were suggested to be abundant in the MM tumor microenvironment where they promote cell growth and chemoresistance. However, further investigation about TAMs is warranted because i) their potential to induce chemoresistance was not determined tacking into account the effect of bone marrow (BM) stroma; ii) their chemoprotective role may be altered by the introduction of monoclonal antibodies (mAb) that target MM cells through ADCP; and iii) TAMs have been characterized with low-throughput flow cytometry, and recent studies in other clinical settings have suggested that novel markers may be more informative to characterize TAMs.Here, we started by producing human M2-like macrophages (ie. phenotypically similar to TAMs in MM) and investigated their contribution to chemoresistance, with or without MM patients’ derived BM stroma (Panels A&B). In contrast to BM stroma, human derived M2-like macrophages were not capable to protect MM (RPMI-8226 and MM1S) cells against bortezomib or dexamethasone. Furthermore, whereas macrophages showed a trend (2.4 fold change, P=.06) to increase baseline MM cell growth (ie. Control in Panels A&B), it became irrelevant upon adding BM stroma to the culture (1.1 fold change, P=.52). No significant differences were observed in the presence of daratumumab or isatuximab, including ADCP that could have been potentially induced by the two anti-CD38 mAbs.Afterwards, based on novel 8-color multidimensional flow cytometry mAb combinations and automated maturation tools, we characterized with high-throughput resolution the BM monocytic/macrophage system by identifying up to 7 different maturation related cell subsets: monoblasts I, II and III, promonocytes, classic and intermediate monocytes, and three novel macrophages subsets identified according to SLAN expression, amongst others (Panels C&D). Accordingly, upon sensitive FACS-sorting we demonstrated that the 3 macrophage subsets had unique transcriptomes (Panel E) consistent with lower immune suppressive signatures from SLAN- into SLAN+ macrophages (eg. down-regulation of VCAN, ENTPD1 and STAB1).We then investigated whether the monocytic/macrophage BM system was truly altered in newly-diagnosed MM patients (n=30) by comparing it to that of healthy donors (HD; n=15). Our results show that total monocytic cells were increased in MM (although the distribution of different monocytic subsets was identical to HD); total intermediate monocytes were also increased in MM (Panel F). By contrast, the percentage of macrophages was identical between HD and MM patients but their subset distribution was significantly altered in MM, and was consistent with an accumulation of more immune suppressive SLAN- TAMs. Next, we investigated whether treatment altered TAMs composition by analyzing 10 patient longitudinal samples collected at diagnosis, after VRD induction, and after HDT/ASCT. Interestingly, we observed that while TAMs remained unaltered after VRD induction, there was a marked shift in their distribution after HDT/ASCT with an even greater accumulation of immune suppressive SLAN- TAMs (P=.08), at expenses of reduced numbers of SLAN+ TAMs (P=.01). Furthermore, chemoresistant MRD-positive patients (n=7/10) after HDT/ASCT showed a 2-fold increment in immune suppressive SLAN- TAMs vs MRD-negative cases.In conclusion, by taking into account the effect of MM patients' BM stroma we showed that TAMs do not induce significant tumor growth. TAMs do not protect MM cells from classic drugs, and MM cells with normal CD38 levels (ie. non lentiviral-transduced to express abnormally high levels of CD38) were not targeted by anti-CD38 mAbs via ADCP. We also showed that there is an expansion of classic and intermediate monocytes but not TAMs in MM; however, using multidimensional flow cytometry to identify novel TAM subsets we revealed that newly diagnosed patients are enriched with immune suppressive TAMs that become further expanded after therapy. Thus, improved monitoring of TAMs could help identifying patients less susceptible to benefit from immunotherapy due to an immune suppressive tumor microenvironment. [Display omitted] DisclosuresMateos:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

In the Era of Bortezomib-Based Chemotherapy the Presence of Minimal Residual Disease Predicts Progression Free Survival after Autologous Hematopoietic Cell Transplant

Background: Retrospective studies have shown that achieving minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) is predictive of outcomes in multiple myeloma (MM). Modern induction therapies including bortezomib (V), lenalidomide (R) followed by autologous hematopoietic cell transplant (AHCT) have resulted in substantial improvements in progression free survival (PFS) and overall survival (OS). The impact of bortezomib-based therapy on end of induction chemotherapy MRD status and post-AHCT MRD status is not well defined. We designed a prospective clinical trial (NCT01215344) to study the incidence of MRD negativity at end of induction and following AHCT, and its association with PFS and OS.Patients and Methods: Twenty patients with newly diagnosed, symptomatic MM were enrolled. They received four cycles of VRd induction therapy followed by AHCT. Dose modifications of VRd were controlled during the clinical trial. MRD status by MFC was evaluated at the end of induction chemotherapy and at day 100 post-AHCT. The MFC cut-off to determine MRD negativity was defined as 10-4. Outcomes analyzed included MM disease status, PFS and OS.Results: Three cohorts of patients were identified; patients achieving MRD negative status at the end of induction (cohort 1, 50%), those achieving MRD negative status only after AHCT (cohort 2, 15%) and patients never achieving MRD negative status (cohort 3, 35%). All patients achieving MRD negative status at the end of induction remained MRD negative post-AHCT. There were no significant differences in median age, renal function, disease stage, cytogenetic risk and maintenance chemotherapy post-AHCT between cohorts. The table summarizes characteristics of these cohorts.Patients who never achieved MRD negative status after AHCT had significantly shorter PFS (cohort 3) compared with patients who achieved MRD negative status (cohorts 1 and 2, p=0.008) (figure). The median PFS for cohort 3 was 2.64 years and not yet reached for the other cohorts. There were no significant differences in OS. Median follow-up for survivors was 2.53 years (range, 0.73-4.04).Conclusions: In this study, bortezomib-based therapy resulted in half of patients achieving MRD negative status with induction chemotherapy alone. AHCT improved the depth of response with 30% of patients who were MRD positive after induction therapy converting to MRD negativity following AHCT. Achieving a negative MRD state, pre- and at D100 post-AHCT resulted in improved PFS. These findings were independent of molecular cytogenetics or ISS stage. MRD positive status at day 100 post-AHCT is highly predictive of earlier disease progression, and may help identify patients for alternative management approaches. Delay of AHCT may be considered as a potential management option for patients with MRD negative status at the end of induction therapy, as being studied in the IFM DFCI study (NCT01208662). As some patients with MRD positive disease at the end of induction therapy become MRD negative with AHCT, these patients may benefit from AHCT and this population warrants further investigation.TableDescriptive analysisCohort 1 MRD -/- (%) (n=10)Cohort 2 MRD +/- (%) (n=3)Cohort 3 MRD +/+ (%) (n=7)Test StatisticMedian Age5554600.31ISS Stage III4033140.52DS Stage III8967600.14Median Serum creatinine0.900.600.880.10Serum M-spike2.01.92.10.80Bone marrow plasma cells1444140.18Cytogenetics0.37Standard risk40057Intermediate risk506743High risk10330 [Display omitted] DisclosuresCornell:Prothena: Research Funding. Jagasia:Takeda Inc: Research Funding.

A Single-Center Retrospective Comparison of Post-Transplant Outcomes in Patients Receiving VRD Vs. VD Vs. RD As Initial Therapy Prior to ASCT for Newly Diagnosed Multiple Myeloma (MM)

Abstract 2042▪▪This icon denotes a clinically relevant abstract Background:The optimal pre-transplant induction therapy for newly diagnosed MM remains to be determined. Combinations of lenalidomide, bortezomib, and dexamethasone result in high response rates with acceptable toxicity in the majority of patients. The most commonly utilized regimens in the U.S. are lenalidomide and dexamethasone (RD); bortezomib and dexamethasone (VD); lenalidomide, bortezomib, and dexamethasone (VRD); and thalidomide and dexamethasone (TD). We sought to determine whether any of the common initial regimens is a superior first choice. Methods:This retrospective single center study examined MM patients < 70 who underwent their initial ASCT between 7/1/2008 to 6/30/2011. A chart review was conducted using the outpatient electronic medical record. Data was gathered on disease characteristics, induction regimens, disease response, and clinical course after ASCT. The primary outcome measures were progression-free survival (PFS), overall survival (OS), and event-free survival (EFS), all measured from day 0 of ASCT. The secondary outcome measures were number of distinct induction therapy regimens, time from start of induction therapy to ASCT, and disease response immediately prior to ASCT. Disease response was grouped as either ≥Very Good Partial Response (VGPR) or <VGPR. The observation period ended on 6/30/2012. Results:A total of 174 patients were included in the analysis. The initial regimen was RD for 80 patients (46%), VD for 43 patients (25%) and VRD for 30 patients (17%). Other regimens (mostly thalidomide-based) accounted for the remaining 12%. The TD regimen was inferior as initial therapy in terms of all outcome endpoints. The primary analysis, therefore, compared RD to VD to VRD. The baseline characteristics for these groups of patients (including gender, stage at diagnosis, serum creatinine at diagnosis) were similar for RD and VRD, but the VD group had more subjects with higher stage (p=0.018) and creatinine > 2 at diagnosis (p<0.001). Use of maintenance therapy after ASCT, usually with lenalidomide, was different between the groups (p<0.001), with more frequent use for patients who received VRD or RD as initial therapy (73% and 64% respectively) than for patients who received VD (26%). The frequency of changes in induction therapy was similar across groups (received > 1 induction regimen: RD 29%, VD 26%, VRD 17%, p=NS). The primary reason for a change in regimen was lack of response rather than toxicity. Response rates immediately before ASCT were not significantly different among regimens (≥VGPR: RD 51%, VD 63%, VRD 73%, p=0.08). EFS was similar for patients treated with the RD, VD, and VRD (EFS at 2 yr post-ASCT: RD 56%, VD 48%, VRD 70%, p=NS). With a median follow-up of 26.3 months after ASCT, there is no significant difference in PFS or OS (OS at 2 yr post-ASCT: RD 90%, VD 86%, VRD 96%). Conclusions:We compared three commonly used regimens for initial treatment of MM in the transplant eligible population to determine if one combination resulted in a better outcome than the others after ASCT. Although there was a trend towards higher pre-ASCT responses with VRD induction therapy, with approximately 2 years of median follow-up, survival was not significantly different when based on choice of initial therapy. These data support that in the current era of highly active induction regimens, choice among them can be made considering such factors as disease manifestations, potential toxicity and drug administration rather than response rates and survival differences. Longer follow-up of these patients as well as future prospective analyses will further clarify these results. Disclosures:Vogl:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Porter:Novatis: Patents & Royalties; Celgene: Honoraria; Genentech: Employment; Pfizer: Research Funding. Mangan:celgene: Speakers Bureau; millenium: Speakers Bureau. Stadtmauer:celgene: Consultancy; millenium: Consultancy.

Bortezomib, Lenalidomide, and Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Frontline Multiple Myeloma Patients: Updated Results of the IFM 2008 Phase II VRD Intensive Program

Abstract 1872 Background:Introduction of new drugs in the intensive pathway have markedly increased survival rates for MM patients within the last 10 years. Efforts to further improve response and survival are still needed, mainly by increasing the depth of tumor reduction and the duration of response. Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) combination demonstrated substantial activity in frontline MM (Richardson P et al., Blood 2010); the IFM reported primary results of the VRD regimen as induction and consolidation therapy in the transplant setting (Roussel M et al. ASH 2010). We currently present updated data of the IFM 2008 trial. Methods:This phase II study was conducted at 10 transplant centers in France, with enrollment between Sept. 7 and Dec. 15, 2009. Pts with symptomatic upfront MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (D1, 4, 8, 11), Len 25 mg/day (D1–14), and Dex 40 mg/day once a week (D1, 8 and 15). Stem cell collection (STC) was planned after high dose cyclophosphamide (3g/m2). All pts then proceeded to melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts received two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 15 mg/day. All pts received, unless contraindicated, anticoagulation for prevention of deep-vein thrombosis (DVT), and anti-viral therapy. Pts with grade ≥2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved after consolidation. The secondary endpoints were: response rate after 3 cycles of VRD as induction, after ASCT and after maintenance; safety profile of the program; feasibility and quality of STC; duration of response, PFS, and OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells for minimal residual disease (MRD) was performed before and after ASCT, after consolidation and after maintenance. Adverse events (AEs) were graded using the CTC for Adverse Events (AE) v4. Patients:Thirty-one pts were enrolled. Baseline characteristics were: median age= 58 (range 33–65); women= 55%; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 17p del in 18% and t(4;14) translocation in 11% among 27 assessable pts. Results:All pts but 7 remain on study program at data cut-off (01/08/11). One pt discontinued treatment due to mobilization failure, 5 pts stopped maintenance because of serious AE (1 extensive DVT unless efficient anticoagulation) or AEs ( 3 grade 3/4 neutropenia and/or thrombocytopenia, 1 grade 3 hypothyroidism) and 1 pt went off study because of progressive disease. Currently, Len maintenance is on going for 6 pts and 4 pts just completed their last cycle.Therefore, 30 pts are evaluable for response after consolidation, and 20 after maintenance. All results are summarized in table 1. In ITT analysis, the overall response rate (ORR) after consolidation is 94%, including 36% VGPR, 48% RC or better (9% CR, 39% sCR). Consolidation therapy with 2 VRD cycles upgraded response in 26% of pts but only 1 pt achieved MRD negative (among 24 assessed). At time of reporting, Len maintenance did not improve response rate but 1 pt get MRD negative. One pt progressed during maintenance phase and 2 pts turned into MRD positive again without evidence of relapse.Table 1:InductionASCTConsolidationMaintenancen%n%n%n%sRC51711361239838RC262639210RC+sRC723134215481048VGPR12398261136628RP1032723310210ORR2994289129941886SD26261315PD15Out of trial111Total31313121Considering the safety profile, 18 serious AEs were reported. There was no treatment-related mortality. The most common toxicities during consolidation therapy were: emergent PNY (23%), including 10% grade 1 and 13% grade 2; grade 3/4 neutropenia (17%), and thrombocytopenia (10%). The most common toxicities during Len maintenance were: grade 3/4 neutropenia (43%), and thrombocytopenia (10%); fatigue (13%); erythrodermia (10%); zona (10%). One extensive DVT and one pulmonary embolism were reported. There was no evidence of secondary malignancy. Conclusions:VRD consolidation plus Len maintenance after VRD induction and HDT produce high quality responses with 38% of sCR and is well tolerated in de novo MM pts. Updated efficacy and safety data will be presented at the meeting. Disclosures:Roussel:Janssen: Honoraria; Celgène: Honoraria. Off Label Use: bortezomib, lenalidomide and dexamethasone as induction and consolidation therapy lenalidomide maintenance. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Hulin:Celgene: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Leleu:celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Facon:celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Avet-Loiseau: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. Attal: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.

Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM 2008 Phase II Study

AbstractAbstract 624 Background:Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible MM patients (pts). Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response and survival in those pts are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Therefore, the IFM (Intergroupe Francophone du Myélome) decided to evaluate the Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) regimen as induction and consolidation therapy followed by Len maintenance in the transplant setting for newly diagnosed pts. Methods:This open-label phase II study was conducted at 10 IFM transplant centers, with enrollment between September and December 2009. Pts under 65 with symptomatic de novo MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (days 1, 4, 8, 11), Len 25 mg (days 1–14), and oral Dex 40 mg (days 1, 8 and 14). Stem cell collection was planned for all pts after high dose cyclophosphamide (3g/m2). All pts then proceeded to intensification prepared with melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts could receive two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 10–15 mg/day. All patients received, unless contraindicated, aspirin prophylaxis or alternative anticoagulation for prevention of deep-vein thrombosis (DVT), anti-viral therapy (valacyclovir) for herpes zoster prevention. Pts with ≥ grade 2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved 1 month after consolidation. The secondary endpoints were the response rate after 3 cycles of VRD, after ASCT and after consolidation; the safety profile of the program, the feasibility and quality of stem cell collection and dthe uration of response (DOR), PFS, OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells was performed before and after ASCT, and after consolidation. Toxicities were graded using the CTCAEv4. Patients:Thirty-one pts with symptomatic MM were enrolled. Baseline characteristics of the pts were: median age = 58 (range 33–65); 55% were women; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 13q deletion in 41% over 27 assessable pts; chromosome 17p del in 18% and t(4;14) translocation in 11%. Results:All pts but one remain on study program at data cut-off (01/08/10). The one pt had discontinued treatment at time of ASCT due to mobilization failure. Therefore, 31 pts are evaluable for response rates after induction therapy, 30 after ASCT and 13 after consolidation. All results are summarized in table 1. In Intent To Treat analysis, the overall response rate (ORR) after ASCT was 94%, including 32% VGPR, 13% CR and 23% sCR. Nine serious AEs were reported. There was no treatment-related mortality. The most common toxicities were: sensory PNY (45%), including 29% grade 1 and 16% grade 2; neuropathic pain (13%); GI tract symptoms (42%) including diarrhea (16%) and constipation (10%); fatigue (10%) and erythrodermia (9%). There was no grade 3/4 PNY. Grade 3/4 hematological toxicities included neutropenia (26%), and thrombocytopenia (6%). No DVT or pulmonary embolism was reported.Six of 31 pts (19%) have had difficulty with mobilization but only 1 pt did not undergo ASCT. Stem cell collection with plerixafor was successful in 4 pts. Median stem cell collection was 7.7 × 106 CD34+ cells/kg.Table 1:After InductionAfter ASCTAfter consolidationn%n%n%sRC413723526RC516413526RC+sRC92811351052VGPR8261032737≥ VGPR175421681789RP134282615ORR309729941894SD1313Total313018Out of trial131 Conclusions:VRD induction followed by ASCT and VRD consolidation produce high quality responses and is well tolerated in newly diagnosed MM pts under 65. Updated efficacy and safety data will be presented at the meeting. Disclosures:Roussel:Janssen: Consultancy, Research Funding, orator; Celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib, lenalidomide as induction and consolidation therapies in frontline MM pts. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.