Frontline Multiple Myeloma Research Articles

Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in High-Risk and/or Stage 23 Relapsed and/or Refractory Multiple Myeloma: A Retrospective Subset Analysis of the Phase 2 Study,

Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in High-Risk and/or Stage 23 Relapsed and/or Refractory Multiple Myeloma: A Retrospective Subset Analysis of the Phase 2 Study,

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 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. Considering 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.

Low Venous Thromboembolic Risk With Bortezomib in Multiple Myeloma and Potential Protective Effect With Thalidomide/Lenalidomide-based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens

Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE risk in MM is increased by various patient- and disease-related factors. The type of anti-MM therapy represents a key factor, with a substantially elevated VTE risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide or lenalidomide in combination with dexamethasone and/or chemotherapy; VTE risk with lenalidomide-dexamethasone is further increased with concomitant erythropoietin. By contrast, treatment with the proteasome inhibitor bortezomib, alone or in combination, does not increase VTE risk; rates of DVT/PE do not appear affected by the use of erythropoiesis-stimulating agents. Bortezomib has shown antihemostatic effects in patients with relapsed or refractory MM, which supports that it exerts antithrombotic actions and thus potentially provides a protective effect in combination with regimens with an elevated VTE risk. Herein, we review data from phase 3 trials of bortezomib- and/or IMiD-based therapy in frontline MM, together with other studies of novel combination regimens. Despite the confounding effect of variable VTE prophylaxis, bortezomib-based regimens were typically associated with DVT/PE rates of ≤5%, similar to those seen with melphalan-prednisone and dexamethasone, whereas IMiD-based bortezomib-free regimens were generally associated with higher rates. Direct comparisons of regimens of thrombogenic potential with or without bortezomib demonstrated lower VTE risk with bortezomib. Between-study comparisons of VTE risk support these findings. Taken together, these data confirm the low VTE risk associated with bortezomib and support a potential protective effect of bortezomib in combination with IMiD-based regimens associated with elevated VTE risk.

Myeloma therapy: pursuing the plasma cell

Sagar Lonial is to be heartily congratulated on having brought together an impressive array of established leaders in the field of multiple myeloma (MM) to produce a comprehensive review of this difficult disease and its management. The book is divided into seven sections dealing with all the major areas relevant to MM. The first section addresses ‘Biological considerations and multiple myeloma'. The chapter relating to the ‘Epidemiology of MM' (A Langston and D Francis) is a thoughtful summary of current understanding of this topic and discusses the intriguing issue of familial predisposition to MM, which is, as yet, unexplained, but clearly has significant importance to the pathophysiology of MM. The chapter that focuses on the tumour microenvironment (M Raab and K Anderson) nicely summarises the current state of knowledge concerning the inter-dependency of MM tumour cells and the bone marrow microenvironment. This is a current paradigm, championed by Professor Anderson's group at the Dana-Farber that has underpinned the development of the so-called ‘novel therapies', which has led to the significant advances in MM treatment. The chapter on cytogenetics (E Braggio, M Sebag and R Fonseca) is a detailed and thorough overview of the cytogenetic abnormalities found in MM and of their prognostic significance. The second section of the book addresses ‘conventional' cytotoxic treatments. The chapters by J-L Harousseau and A Palumbo are typically authoritative and logical overviews of the function of autologous stem cell transplantation and therapies for non-transplant eligible patients, respectively. A chapter by S Ailawadhi and A Chanan-Khan discusses the function of anthracyclines in MM and reminds us that ‘conventional' drugs still have activity in this disease and should not be discarded from the anti-MM armamentarium. The third section addresses the immune-based therapies in MM as well as comprehensive reviews about immunotherapy and antibody-based approaches, and the function of allogeneic transplantation is discussed (F Wang and E Waller). This issue remains, arguably, one of the most important in the treatment of MM. The chapter summarises the current data and we are left in no doubt that further work is required to define the role of this treatment in MM. Section four, in over 60 pages, comprises a ‘state of the art' overview of the data concerning the ‘novel agents': thalidomide, lenalidomide and bortezomib. Each chapter is authored by recognised experts in the field and describes the early development and later definitive clinical trial data that has led to the establishment of these agents into frontline MM care. Population-based data have shown that coincident with the advent of the ‘novel agents', there has been the single most important increment in outcome for patients with MM. Clearly, the next questions will involve issues concerning the most appropriate sequencing of these drugs, the most effective combinations, the continuing role for ASCT in the ‘novel agent era' and the best selection of therapy for specific groups of patients. Section five addresses ‘Current and Future Targets'. This is arguably the most stimulating section of the book and different chapters discuss, among others, hsp90, PI3K/Akt, mTOR, FGFR3 and HDAC inhibitors. Each chapter has been written by experts in the field and offer clear and insightful reviews of these emerging potential targets for therapy. For example, the chapter by C Mitsiades on hsp90 ranges from scientific rationale to early phase clinical trials in the area. The authors offer the hope that new-targeted therapies will be developed and describe the strong rationale for combining these agents with pre-existing ones (e.g. hsp90 inhibitors with bortezomib). Let us hope that these scientifically designed combinations will further improve outcomes for patients with MM. Section six addresses the most important area of supportive care in MM. The issues discussed include bone disease and its treatment with kyphoplasy and vertebroplasty, anaemia, functional imaging and renal impairment. The final section addresses ‘Other Plasma Cell Disorders'. These chapters comprise authoritative reviews on Waldenstrom's Macroglobulinemia, AL Amyloidosis, the mysterious POEMS syndrome and MGUS. Penned by recognised experts in the field, these chapters represent an excellent resource and reference. Overall, the book is an outstanding resource for clinicians working in the area of MM, which will have long-lasting value and relevance.

Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma (MM): Final results of a multicenter phase I/II study.

8016 Background: Bortezomib (VELCADE, Bz) or lenalidomide (REVLIMID, Len) plus dexamethasone (dex) demonstrate substantial activity in front-line MM; the three-drug combination has shown efficacy in the relapsed setting. This was the first prospective study of the three-drug regimen in front-line MM. Methods: Patients (pts) received eight 3-wk cycles of Bz 1.0–1.3 mg/m2 (d 1, 4, 8, 11), Len 15–25 mg (d 1–14), and dex 40 or 20 mg (d 1, 2, 4, 5, 8, 9, 11, 12) at 5 dose levels (phase I) and the maximum tolerated/planned dose (MTD; phase II). Responding pts could receive maintenance therapy or ASCT. Pts received prophylactic anticoagulants and anti-viral therapy. Primary endpoints were MTD and response rate. Results: 66 pts were treated (35 in phase II). Median age was 58 (range 22–86); 55% were men; 44%/47%/9% had ISS stage I/II/III MM; 68%/23%/9% had IgG/IgA /light chain MM; 57% had any of del 13q, del 17p, t(4;14), and t(11;14). Pts received a median of 10 cycles, including medians of 8, 10, and 8 cycles o...

Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens.

Abstract Abstract 1873 Poster Board I-898 Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep-vein thrombosis (DVT) and pulmonary embolism (PE). The VTE risk in MM is increased by various patient- and disease-related factors; however, type of anti-MM therapy represents a key factor, with a substantially elevated risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide (thal) or lenalidomide (len) in combination with dexamethasone (dex) and/or chemotherapy (Palumbo et al, Leukemia 2008); VTE risk with len-dex (RD) is further increased with concomitant erythropoietin (EPO). By contrast, treatment with the proteasome inhibitor bortezomib (btz), either alone or in combination, does not increase VTE risk. In the VISTA phase 3 trial of melphalan-prednisone (MP) vs btz plus MP (VMP) in previously untreated MM patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008), data from an updated safety analysis showed similar rates of DVT (VMP: 5/340 [1%], four grade 3; MP: 6/337 [2%], two grade 3) and PE (VMP: 4/340 [1%], two grade 4; MP: 3/337 [1%], one grade 3, two grade 4) between arms; as reported by Richardson et al (IMW 2009), rates of DVT/PE were not affected by use of erythropoiesis-stimulating agents, including EPO. These findings reflect those from the APEX phase 3 trial of single-agent btz vs high-dose dex in relapsed MM (Lonial et al, Br J Haematol 2008); rates of DVT/PE were low (0.6% vs 2.7%) and unaffected by concomitant EPO use, and VTE risk appeared lower with btz vs dex, controlling for EPO use (odds ratio 0.207, p=0.046). As previously reported, btz shows anti-hemostatic effects in patients with relapsed or refractory MM, resulting in a decrease in platelet count and significant reductions in agonist-induced platelet aggregation (Zangari et al, Haematologica 2008); these findings support btz exerting anti-thrombotic actions and thus potentially providing a protective effect in combination with regimens with elevated VTE risk. A review of data from phase 3 trials of btz- and/or IMiD-based therapy in frontline MM and other studies of novel combination regimens supports this hypothesis. Despite the confounding effect of variable VTE prophylaxis, btz-based regimens are associated with DVT/PE rates of 0–4% (Figure), similar to those seen with MP and dex alone (Palumbo et al, Leukemia 2008), whereas IMiD-based btz-free regimens are generally associated with substantially higher rates. Direct comparisons of regimens of thrombogenic potential with/without btz demonstrate lower VTE risk with btz; as previously reported, DVT rates of 0% vs 10% (p=0.0006) were seen with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) with vs without btz in an analysis of patients enrolled on two University of Arkansas trials (Zangari et al, ASH 2004). Palumbo et al (EHA 2009) also reported lower rates of VTE events with btz, thal, dex (VTD, ∼4.5%) and VMP—thal (VMPT, ∼2.7%) vs TD (7%) in a phase 3 randomized trial of aspirin, low molecular weight heparin, and warfarin as VTE prophylaxis, while in another phase 3 study Rosiñol et al (ASH 2008) showed a lower rate of thrombotic events with VTD vs TD (1.7% vs 13%, p=0.02, no prophylaxis). Indirect, between-study comparisons of VTE risk support these findings; in six phase 3 studies, TD was associated with 5.5–23% DVT/PE, while in two phase 3 studies, the rate with VTD was 1.7–4%. Similarly, rates were 6–12% in five phase 3 studies of MP-thal (MPT) vs 4% with VMPT (Palumbo et al, EHA 2009). Finally, len-low-dose dex (Rd) and RD resulted in DVT/PE rates of 12–27% in two phase 3 studies, whereas a rate of only 4% was reported in a phase 1/2 study of btz-RD (RVD) by Richardson et al (IMW 2009). Taken together, these findings confirm the low VTE risk associated with btz and support a potential protective effect of btz in combination with IMiD-based regimens associated with elevated VTE risk. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Fink:DOD Radioprotectants: Research Funding.

Extended follow‐up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma

High-quality response to multiple myeloma (MM) therapy can be predictive for improved outcomes. Novel agents may improve the depth of responses and therefore prolong survival. We report on the extended follow-up of a phase II study in frontline MM of bortezomib alone and in combination with dexamethasone. Forty-nine previously untreated, symptomatic MM patients received bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, for up to six 3-week cycles. High-dose dexamethasone was added for patients not reaching either a partial response after cycle 2 or a complete response (CR) after cycle 4. The overall response rate in 48 evaluable patients was 90%, with 42% achieving at least a very good partial response, of which 19% were CR/near CR. Thirty-six patients received high-dose dexamethasone with 28 (77%) showing improved response. Twenty-seven patients have undergone successful stem-cell transplantation (SCT). After median follow-up of 49 months, 15 patients have died; median overall survival has still not been reached, with an estimated survival at 4 years of 67%. Overall survival with and without SCT was not different (P = 0.54). Grade 3/4 adverse events included neutropenia (10%), sensory neuropathy (6% grade 3), neuropathic pain (4% grade 3), and diarrhoea (4% grade 3). Bortezomib +/- dexamethasone is an effective and well-tolerated induction regimen for the frontline treatment of MM.

A268 Phase I/II Trial of Lenalidomide, Bortezomib, Doxil, and Dexamethasone in Front-Line Multiple Myeloma

A268 Phase I/II Trial of Lenalidomide, Bortezomib, Doxil, and Dexamethasone in Front-Line Multiple Myeloma

Role of autologous and allogeneic stem cell transplantation in myeloma

The treatment of multiple myeloma (MM), a largely incurable B-cell hematologic malignancy, is changing dramatically. Autologous stem cell transplantation (SCT) and the approval of two new classes of drugs, immunomodulators and proteosome inhibitors, have resulted in improved response rates and increased overall survivals. Thalidomide, bortezomib and lenalidomide have been combined with corticosteroids, alkylators and anthracyclines in front-line MM treatment. Phase 2 and preliminary phase 3 studies have reported very high response rates and complete response rates formerly seen only with SCT. When patients with MM who have received these new drugs then proceed to transplant, major response rates are further increased. Owing to limited follow-up, it is unclear whether these higher response rates translate into increased survival. Despite these improvements, the disease remains incurable for all but a small fraction of patients. Allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect but is limited by mortality. Mortality can be reduced through the use of lower intensity conditioning regimens but this comes at a cost of higher rates of disease progression and relapse. Strategies to improve outcomes of allogeneic transplants include more intensive, yet non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering, post-transplant maintenance and targeted conditioning therapies.

Erythropoiesis-Stimulating Agents Do Not Adversely Affect Long-Term Outcomes Nor Increase the Risk of Thromboembolic Events in Multiple Myeloma Patients Treated in the Phase III VISTA Trial.

Abstract Introduction: Treatment of myeloma-associated anemia (both disease and treatment induced) includes erythropoiesis-stimulating agents (ESA) and/or red-blood-cell transfusions (RBCT). Limited data from patient subsets in retrospective studies have suggested that ESA may have a detrimental effect on outcomes, including reduced time-to- progression (TTP) and overall survival (OS), in patients with multiple myeloma (MM). Furthermore, ESA may increase the risk of deep-vein thrombosis (DVT) and pulmonary embolism (PE), especially in patients receiving immunomodulatory-based regimens and/or anthracyclines with glucocorticoids. Since the impact of ESA use on long-term outcomes and thromboembolic events in MM has not been extensively evaluated, we conducted a sub-analysis of the prospective multi-center, randomized, phase III VISTA trial in frontline MM (San Miguel et al. Blood 2007), to assess the potential impact of ESA use on TTP, OS and rates of DVT/PE. Methods: Patients were randomized to receive nine 6-week cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, and days 1, 8, 22, and 29, cycles 5–9) plus melphalan (9 mg/m2) and prednisone (60 mg/m2) administered on days 1–4 of each cycle (VMP; n=340) or melphalan–prednisone (MP; n=337) alone. No protocol-specified antithrombotic prophylaxis was required. Baseline characteristics, including age, sex and disease characteristics, were similar between ESA and non-ESA groups. Results: Median Hb level at the time of ESA initiation was 9.75 g/dl in the VMP arm and 9.30 g/dl in the MP arm; consistent with current guidelines that ESA should not be initiated until Hb is <10 g/dl. The incidence of treatment-emergent anemia (defined as Hb < 8.0 g/dl) was lower in the VMP arm (23%) than the MP arm (33%), and fewer patients in the VMP versus MP arm were treated with ESA (30% vs 39%, respectively; erythropoietins 20% vs 24% and darbepoietin 11% vs 18%, respectively), or RBCT (26% vs 35%, respectively), potentially reflecting greater anti-myeloma activity with VMP. Median TTP was similar between patients who received ESA and those who did not in both treatment groups (Table). While one-year OS rates were similar, 2-year OS rates appeared higher for patients receiving ESA (Table). TE complications were low in both treatment arms and were not affected by ESA use (3% vs 2% for VMP, and 3% vs 1% for MP, for patients receiving or not receiving ESA, respectively). Conclusions: Our post-hoc analysis from a large, well-controlled multicenter phase III trial in frontline MM shows that ESA use did not adversely impact long-term outcomes with VMP or MP, and may be associated with a survival benefit. Furthermore, ESA use did not appear to increase the risk of TE complications with VMP or MP. These data suggest that ESA can be safely administered with VMP/MP for the treatment of anemia in frontline MM patients. Prospective, randomized studies are needed to further investigate the relationship between ESA and RBCT use, other agents and long-term outcomes in MM patients. Table. TTP and OS rates by ESA and RBCT use and per treatment VMP (n=340) MP (n=337) + ESA (n=102) − ESA (n=238) + ESA (n=131) − ESA (n=206) NE=not evaluable TTP, months (95%CI) 19.9 (18.9, NE) NE (18.3, NE) 15.0 (13.5, 21.8) 17.5 (14.7, 19.0) 1-year survival rate % (95% CI) 92.0 (86.6, 97.3) 87.8 (83.5, 92.0) 82.6 (76.0, 89.2) 81.4 (75.9, 86.9) 2-year survival rate % (95% CI) 86.7 (77.9, 95.4) 80.8 (73.1, 88.4) 77.3 (68.5, 86.1) 65.4 (55.7, 75.2) + RBCT (n=87) − RBCT (n=253) + RBCT (n=117) − RBCT (n=220) TTP, months (95%CI) NE (24.0, NE) 21.7 (18.9, NE) 14.1 (10.8, 16.6) 18.0 (15.2, 20.0) 1-year survival rate % (95% CI) 80.9 (72.4, 89.3) 91.8 (88.4, 95.3) 71.0 (62.7, 79.4) 87.7 (83.2, 92.2) 2-year survival rate % (95% CI) 67.2 (50.4, 83.9) 88.3 (83.8, 92.8) 58.3 (47.4, 69.2) 76.1 (66.9, 85.3)

Lenalidomide, Bortezomib, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Encouraging Efficacy in High Risk Groups with Updated Results of a Phase I/II Study

Abstract Background: Bortezomib (VELCADE®, Bz) is approved for the treatment of patients (pts) with multiple myeloma (MM). Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥1 prior therapy. Len/Bz±Dex is active and well tolerated in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in front-line MM. The aims of this phase l/ll study were to determine the maximum tolerated dose of Len/Bz/Dex (RVD) and to assess safety and efficacy in previously untreated MM pts. Methods: Pts received Len 15–25 mg on days 1–14, Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on days 1, 2, 4, 5, 8, 9, 11, 12, for up to eight 21-day cycles, initially at four planned dose levels (Len/Bz: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs; Grade (G) ≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Based on safety data, dose level 4M (Len/Bz 25/1.3) was added with a reduced Dex (20/10 mg) starting dose. Pts with G≥2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts with at least partial response (≥PR) could proceed to autologous stem cell transplant (ASCT) after ≥4 cycles. Results: 68 pts have been enrolled to date: 33 in phase l, including 17 pts at the maximum planned dose (MPD, dose level 4M) and 35 in phase ll (at MPD). Data are available for 66 pts (median age 58 yrs, 55% men, 67% IgG MM, 50% with ISS stage II/III). Pts have received a median of 10 cycles; 46 have completed all 8 cycles, 39 have discontinued/completed therapy. Two DLTs of G3 hyperglycemia due to high-dose Dex were seen at dose level 4. Dose reductions in cycle 2 and beyond have occurred in overall/dose levels 1–4 for: Len 16/8 pts, Bz 23/8 pts, and Dex 19/15 pts. Toxicities to date have been manageable, including all G3/4 hematological toxicities (3–15%), G3 hypophosphatemia (8%) and deep vein thrombosis/pulmonary embolism (5%, with daily aspirin), with no G4 PNY, and no treatment-related mortality. The overall response rate (ORR; ≥ PR) is 98%, including 71% ≥ VGPR and 36% CR/nCR; at MPD, ORR is 100%. Efficacy was independent of baseline cytogenetics or ISS stage (Table). ORR and ≥ VGPR rates were similar regardless of the absence or presence of deletion 13q or translocation 4;14; ORR rates ranged from 86% to 100% and ≥ VGPR rates ranged from 57% to 75%. Pts from all three ISS categories achieved ORR ranging from 97% to 100% and ≥ VGPR ranging from 51% to 80%; of note, the 10 pts with ISS stage III disease had an ORR of 100% and ≥ VGPR rate of 80%. Median stem cell collection in 21/23 pts was 6.2 × 106 CD34+ cells/kg after a median of 6 cycles of therapy; 15 pts have proceeded to ASCT, with the transplant course in each case reported as unremarkable. Two of 23 pts (9%) have had difficulty with mobilization. After a median follow-up of 8 months, median time to progression, progression-free survival, and overall survival have not been reached. Conclusions: RVD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at Len 25 mg, Bz 1.3 mg/m2, and Dex 20 mg, with phase ll enrollment now complete and 100% ORR reported at the MPD. Stem cell mobilization has been successful in almost all pts, with transplant course in pts otherwise unremarkable. Updated efficacy and ASCT data will be presented at the meeting. Responses by cytogenetic status (normal, abnormal [deletion 13q or t(4;14)]), and ISS stage Normal Abnormal No Del 13q With Del 13q No t(4;14) With t(4;14) * pts with available data n* (63) 39 24 52 7 49 10 ≥ PR 100% 96% 100% 86% 98% 100% P 0.381 0.119 1.00 ≥ VGPR 69% 79% 75% 57% 73% 70% P 0.560 0.375 1.00 ISS I ISS II ISS III n* (64) 33 21 10 ≥ PR 97% 100% 100% P 0.385 ≥ VGPR 51% 57% 80% P 0.421

Bortezomib (BOR) and High Dose Melphalan (HDM) as Conditioning Regimen Before Autologous Stem Cell Transplantation (ASCT) for De Novo Multiple Myeloma (MM): Final Results of the IFM Phase II Study VEL/MEL

Abstract Introduction: ASCT is recommended for young patients (pts) with newly diagnosed MM. The achievement of Complete Response (CR) or at least Very Good Partial Response (VGPR) is the main prognostic factor for survival after ASCT. However, only 40–50% of patients achieve CR and VGPR with current HDM regimen. BOR has demonstrated significant activity in relapsed/refractory pts, a synergistic effect with Melphalan (MEL) and a lack of prolonged hematological toxicity. The combination of BOR and HDM is therefore a logical approach to attempt to improve CR+VGPR rates after ASCT. Methods: In July 2007, the IFM initiated an open-label, multicenter, phase II study. Fifty-seven pts with symptomatic de novo MM were enrolled to receive BOR and HDM as conditioning regimen before ASCT. The choice of induction therapy was not specified in the protocol, and was made on an individual-patient basis by the treating clinician. BOR (1 mg/m2) was delivered on days −6, −3, +1, +4 and MEL (200 mg/m2) on day −2. Peripheral blood stem cells (median 4 × 106 CD34/kg, range 2–12) were infused on day 0. The primary endpoint was the CR+VGPR rates at 3 months post ASCT. The secondary endpoint was the safety profile of this regimen. Baseline characteristics of the pts were: median age = 58; ISS= 1 in 30, 2 in 15 and 3 in 12 cases; chromosome 13q deletion in 27 of 52 assessable; chromosome 17p del in 3 and t(4;14) translocation in 6. Twenty-nine pts received VAD induction therapy while 18 received a BOR-Dexamethasone (DEX) based regimen. Seven pts needed more than 2 lines of therapy to achieve response before ASCT and 3 pts had already received a first course of HDM. Overall response rates before ASCT were: CR=2, VGPR=6, partial response (PR)= 33 and stable disease (SD)=16. Results: All pts but one were assessed for response at 3 months after ASCT. Twenty pts (36%) achieved a CR and 17 (30%) a VGPR. One patient was non-responder. Among the 3 pts receiving a tandem ASCT, no CR or VGPR was observed after BOR+HDM. In the VAD induction group, 12 pts (43%) achieved CR and 7 (25%) VGPR. In the BOR-DEX based induction group, 7 pts (39%) achieved CR and 6 (33%) VGPR. All results are summarized in table 1. From the standpoint of safety, BOR did not increase hematological toxicity. Median duration of neutropenia (< 0.5 × 109/l) and thrombocytopenia (< 50 × 109/l) was 7 (range 1–15) and 8 (range 3–31) days respectively. Grade 3/4 extra-hematological toxicities were limited: mucositis in 22 cases (39%), peripheral neuropathy in 1 case. Other toxicities included: erythroderma in 30%, headache in 20%, hallucinations in 9% and grade 2 peripheral neuropathy in 3 cases (preexisting ASCT). Five serious adverse events were reported: 1 pulmonary embolism, 1 seizure, 1 acute cholecystis and 2 pneumonias. No toxic death was observed. Conclusions: These results suggest that BOR (1 mg/m2) and HDM is a safe and highly effective conditioning regimen in frontline MM pts with almost 70% achieving CR and VGPR. This compares favorably to the updated results of the IFM 2005/01 trial (comparing BOR-DEX versus VAD as induction prior to ASCT in de novo MM pts) reported in last ASH meeting (Harousseau et al.). A matched case-control study will be conducted between our cohort and the pts of the IFM 2005/01 trial. Table 1: IFM VEL/MEL IFM 2005/01 VAD n=28 BOR-DEX n=18 ≥ 2 lines n=7 VAD n=110 BOR-DEX n=112 CR 43% 39% 14% 20% 34% ≥ VGPR 68% 72% 71% 50% 64% ≥ PR 93% 100% 86% SD 7% 0 0 PD 0 0 14%

Safety and efficacy of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with newly diagnosed multiple myeloma (MM): A phase I/II study

8520 Background: Single-agent Bz and Len/Dex are approved for pts with relapsed MM following ≥1 prior therapy. Len/Bz±Dex is active in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in frontline MM. Primary objectives of this phase I/II study were to define the MTD and assess response rate to Len/Bz/Dex in previously untreated MM pts. Methods: Pts received Len 15–25mg on d 1–14, Bz 1.0–1.3mg/m2 on d 1, 4, 8, 11, and Dex 40/20mg (cycles 1–4/5–8) on day of and after Bz for up to eight 21-d cycles, initially at 4 planned dose levels (table). Dose escalation proceeded depending on dose-limiting toxicities (DLTs). Based on safety data, dose level 4M was added with a reduced Dex starting dose (20/10mg). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PN) were excluded. Responses were assessed by modified EBMT and Uniform Criteria. Pts with ≥PR could proceed to ASCT after ≥4 cycles. Results: 66 pts have been enrolled to date. Data are available on 53 pts (median age 58 yrs, 51% men, 68% IgG MM, 49% ISS Stage II/III): 33 in Phase I, including 17 at the maximum planned dose (dose level 4M), and 20 in Phase ll (at max planned dose). Pts have received a median of 6 cycles; 16 (32%) have completed all 8 cycles, 14 have discontinued. Two DLTs of G3 hyperglycemia due to high-dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred for Len in 12 pts, Bz in 11 pts, and Dex in 18 pts, mostly in dose levels 1–4. Toxicities have been manageable, with no unexpected toxicities, no G4 PN, 2 DVTs, and no treatment-related mortality. Response rate (≥PR) to date is 98% in 42 evaluable pts, including 52% CR/nCR/VGPR (table). After median follow-up of 4 months, median TTP, PFS, and OS have not been reached. Median stem cell collection in 7 pts was 11.5 x 106 CD34+ cells/kg. Conclusions: Len/Bz/Dex is very active and well tolerated in newly diagnosed MM pts. Phase II enrollment is almost complete. Updated response data will be presented. Responses by phase/dose level (subject to confirmation) Dose level Len/Bz/Dex starting dose Response-evaluable patients CR nCR VGPR PR RR Phase l 31 8 (26%) 3 (10%) 9 (29%) 10 (32%) 30 (97%) 1 15/1.0/40 3 1 1 1 3 2 15/1.3/40 3 2 1 3 3 20/1.3/40 3 1 2 3 4 25/1.3/40 6 1 3 2 6 4M 25/1.3/20 16 3 2 5 5 15 Phase II 25/1.3/20 11 1 (9%) 1 (9%) 9 (82%) 11 (100%) TOTAL 42 9 (21%) 3 (7%) 10 (24%) 19 (45%) 41 (98%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene, Millennium Pharmaceuticals Celgene, Millennium, Novartis Celgene, Millennium Celgene, Millennium, Novartis Celgene, Eli Lilly, Millennium, Novartis

Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs

The treatment of multiple myeloma (MM) is changing rapidly. During the last 10 years, higher rates of complete response (CR) and prolonged progression-free and overall survival have been seen with high-dose chemotherapy plus autologous stem-cell transplantation (HDT-ASCT). Achievement of CR and good partial response have been shown to be key prognostic factors for prolonged survival, with eradication of minimal residual disease seeming crucial to long-term disease-free survival. Until recently, high rates of CR and other major responses were primarily seen with HDT-ASCT, but insights into the biology of MM have led to the development and approval of new drugs with significant activity, and new induction regimens based on these novel agents are offering improved responses. Thalidomide, bortezomib, and lenalidomide have been combined with corticosteroids, alkylators, and anthracyclines in front-line MM treatment. Phase II studies have indicated that high rates of response and CR may be achieved. The substantial activity seen with these new drug combinations has prompted a re-examination of the role of SCT in MM treatment. Will achievement of major responses with these new regimens translate into improved survival after consolidation with transplantation? Will these improved induction regimens reduce the need for tandem transplantation, or does achievement of CR obviate the need for front-line transplantation altogether? To help address these questions, randomized trials are needed, as well as tests with improved sensitivity to better define depth of remission.

Bortezomib [VELCADE™], Pegylated Liposomal Doxorubicin [DOXIL/CAELYX®] and Dexamethasone in the Treatment of Previously Untreated Multiple Myeloma Patients: Impact on Quality-of-Life.

Abstract Introduction: Bortezomib in combination with liposomal doxorubicin has shown convincing activity as induction therapy in frontline multiple myeloma (MM) patients with CR rates exceeding those seen with conventional induction therapy. The impact of this treatment on patient Quality-of-Life (QOL), determined by overall health status, cancer and neurotoxicity specific questionnaires, is of clinical interest. Methods: Newly diagnosed Autologous Stem Cell Transplant (ASCT) eligible MM patients were recruited from nine centres across Canada to this single-arm, open-label, Phase II study. Patients received three to four 21-day cycles of DBd induction therapy (bortezomib 1.3mg/m2 days 1, 4, 8, 11 + pegylated liposomal doxorubicin 30 mg/m2 day 4 + pulsed dexamethasone 40mg days 1–4, 8–11, 15–18 Cycle 1 and days 1–4 cycles 2–4), depending on rapidity of CR achieved, and were then followed post ASCT. Patients completed the European Quality of Life Questionnaire (EQ-5D), the European Organization for Research and Treatment of Cancer’s 30-item Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx) prior to each cycle and at study termination. Results: Fifty patients were enrolled to fulfill the sample size requirement. Mean age was 56.0 (±8.7) years, and 68% of patients were male. Sixty-five percent of the patients had Stage III disease and all but two patients had secretory disease. Mean baseline β2-microglobulin level was 4.2 (1.5–25.4) mg/mL. Overall best response post-induction was 98% (≥ Minimal Response), with a corresponding 26.8% combined complete response (CR) + near CR rate. There was no significant change in the total EQ-5D score throughout the study when compared to baseline. There was a significant improvement at end of study in the mean EQ-5D VAS self-rated health status (Δ+5.14, p<0.05) compared to baseline. Although not significant, there was a trend towards an increase in the proportion of patients reporting no problem in the mobility and anxiety/depression EQ-5D dimensions over the course of induction therapy. There were also no significant changes observed in the EORTC QLQ-C30 scores. Throughout the study, the FACT/GOG-Ntx scores showed no statistically significant changes over time from baseline, in agreement with the overall clinical safety profile observed. The largest mean score change from baseline was at the end-of-study time point (Δ+1.79, SD±6.07, p=0.06). Conclusion: Although this study was not powered to detect changes in QOL, preliminary results indicate that there is a trend towards improvement in QOL outcomes in multiple myeloma patients being treated with the DBd induction regimen. These results corroborate the safety and tolerability profile observed in the study.

Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma

There are a number of reports in literature data on the long-term outcomes of patients with multiple myeloma treated with high-dose therapy and autologous stem cell transplantation (HDT/SCT). While in general these data support the association between maximal tumor response and overall survival or progression-free survival after HDT/SCT, some trials have failed to find such correlation and there is no recent comprehensive literature analysis of this issue. We, therefore, performed a comprehensive literature review to identify prospective and retrospective studies on HDT/SCT in frontline multiple myeloma in which long-term outcomes were reported according to best tumor response observed. Following a prospectively defined search strategy we identified 21 studies (10 prospective and 11 retrospective studies) in which outcomes of 4,990 HDT/SCT patients according to their best tumor response were reported. The majority of these studies indicated a correlation between maximal response during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). The conclusions in individual studies report on the association between maximal response following induction therapy and long-term outcomes were more heterogeneous, possibly due to the low rate of complete response after standard induction therapy in each individual study. We, therefore, performed two types of meta-analyses, one based on the p-values reported for these associations in the individual studies, and one based on the primary response and outcome data provided in the individual studies. Both meta-analyses indicated highly significant associations between maximal response (complete response/near complete response/very good partial response) during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). Both meta-analyses also provided evidence of highly significant associations between maximal response following induction therapy and long-term outcomes (overall survival and event-free/progression-free survival).

Bortezomib in Combination with High-Dose Dexamethasone (HD dex) and Erythropoietin (EPO) Does Not Result in an Increased Risk of Thromboembolic Complications.

Introduction: There is an increasing awareness of the risk of thromboembolic complications (TE) associated with multiple myeloma (MM) due to underlying patient- and disease-related factors as well as choice of therapy. Notably, prior TE, and use of HD dex, doxorubicin, concomitant EPO in combination with lenalidomide or thalidomide, have all been suggested to increase TE risk in MM patients (pts) and require more complex management strategies (Niesvizky et al., J Clin Oncol2006;24(Suppl):423s; Hussein, Thromb Haemost2006;95:924–30; Rajkumar et al, J Clin Oncol2006;24:431–6; Zangari et al, Blood2002;100:1168–71). Based on these reports, experience with another novel agent, bortezomib (btz), recently approved for second line MM, was studied. Methods: Adverse event data were examined from the phase 2 SUMMIT and CREST studies of btz ± dex in relapsed and/or refractory MM, and the phase 3 APEX study of btz vs dex in relapsed MM (1–3 prior lines of therapy). Rates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were calculated for pts receiving btz ± dex ± EPO in the phase 2 studies, and for pts receiving btz or dex ± EPO in the APEX study. Results: Data were analyzed for all 256 pts enrolled in SUMMIT and CREST, of whom 106 received added dex, and for 331 btz-treated and 332 dex-treated pts in APEX. Rates of DVT and/or PE were very low, with no notable differences when dex and/or EPO were given with btz (Table 1). In the APEX trial, overall odds ratio for the risk of DVT/PE according to EPO use = 1.670 (95% CI: 0.500, 5.580); P = 0.4051. Furthermore, there appeared to be a decrease in TE risk with btz vs dex, controlling for EPO use; odds ratio = 0.207 (95% CI: 0.044, 0.971), P = 0.0459. Summary: Btz plus dex and/or concomitant EPO does not appear to be associated with an elevated TE risk in this analysis. This observation is supported by two phase 2 studies of btz plus dex in 97 frontline MM pts, in which no TE was reported despite some concomitant EPO use (Jagannath et al, Blood2005;106(Suppl):231a; Harousseau et al, J Clin Oncol2005;23(Suppl):598s). Furthermore, btz appears to lower the risk of TE when used in combination with agents of known thrombogenic potential (Palumbo et al, Haematologica2006;91(s1):729; Ciolli et al, Haematologica2006;91(s1):764; Terpos et al, Haematologica2006;91(s1):223; Richardson et al, Blood2005;106(Suppl):365a; Zangari et al, Blood2004;104(Suppl):4914a). Table 1. Rates of DVT and PE with btz ± dex ± EPO in phase 2 and 3 trials of btz. Combined incidence in SUMMIT and CREST phase 2 trials Btz alone Plus dex EPO No EPO Total EPO No EPO Total *1 pt had both DVT and PE †2 pts had both DVT and PE (N=158) (N=98) (N=256) (N=74) (N=32) (N=106) DVT 3 (1.9%) – 3 (1.2%) – – – PE 1 (0.6%) 1 (1.0%) 2 (0.8%) – 1 (3.1%) 1 (0.9%) DVT/PE 3* (1.9%) 1 (1.0%) 4* (1.6%) – 1 (3.1%) 1 (0.9%) Incidence in APEX phase 3 trial Btz Dex EPO (N=137) No EPO (N=194) EPO (N=106) No EPO (N=226) DVT 1 (0.7%) – 2 (1.9%) 4 (1.8%) PE 1 (0.7%) – 1 (0.9%) 4 (1.8%) DVT/PE 2 (1.5%) – 3 (2.8%) 6† (2.7%)