Newly Diagnosed Multiple Myeloma Pts Research Articles

Patterns of Total Costs of Care for Newly Diagnosed Multiple Myeloma (MM) Patients

Introduction: As clinical evidence has mounted in support of novel agents and longer treatment (Tx) durations for patients (pts) with newly diagnosed multiple myeloma (NDMM), questions have arisen regarding the economic impact of extending time to progression (TTP) in these pts, and the cost consequences once pts relapse and move to a second line of Tx. Previous analysis showed that relapsed myeloma pts incurred higher monthly costs once they advanced to later lines of Tx (Gaultney, 2013). There is limited information on the cost patterns of MM pts before and after their first relapse. A claims analysis was performed to evaluate the patterns of total direct costs of care, from Tx initiation until progression, for NDMM patients and for newly relapsed patients treated with novel agents, utilizing time to next therapy (TTNT) as a proxy measure for progression.Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million lives annually. NDMM patients were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM] code 203.0X), with the first such claim used to define the index date. Inclusion criteria required a minimum of 12 months’ pre-index enrollment and 6 months’ post-index continuous enrollment between 2006 and 2012. Pts with claims for stem cell transplantation (SCT) were excluded, to avoid confounding results from various factors based on timing, costs, and site of care of SCT. The analysis focused on NDMM and relapsed MM pts receiving lenalidomide (LEN)- or bortezomib (BORT)- based Tx, where complete claim history was available from Tx onset to initiation of subsequent Tx. Using methods similar to those described by Gaultney, patients’ average monthly costs were determined, including medical (inpatient, ambulatory, and emergency room) and pharmacy (index and other drugs) costs, and total cost patterns over quarterly time periods were calculated. Average Charlson comorbidity scores were determined to compare baseline measures between pt groups.Results: 897 NDMM pts and 280 relapsed MM pts were identified with complete data through initiation of subsequent Tx. Monthly total direct costs for NDMM pts were $15,400 in the first 3 months (mos) of Tx, and declined each quarter, reaching approximately $5,000/mo at 18+ mos. At relapse, monthly costs increased to over $12,000 for the first 3 mos and followed a quarterly pattern of reduction similar to that seen for NDMM pts (Fig 1). Quarterly cost reduction patterns were consistent for patients treated with LEN or BORT for both NDMM and relapsed pts. Pts’ total monthly NDMM costs over the full TTNT period averaged $8,942 with LEN vs. $11,139 for BORT (due to 54% higher monthly medical costs for BORT), while monthly drug costs were nearly identical (Table 1). The baseline Charlson comorbidity index was similar between Tx groups in both lines of Tx. [Display omitted] Table 1: Direct monthly costs for NDMM pts [Display omitted] Conclusions: For a population of NDMM pts receiving either LEN- or BORT-based Tx without SCT, followed until TTNT, total direct monthly costs per pt declined steadily over time, decreasing by 68% from the initial quarter to the period post 18 mos. Costs spiked when pts began 2nd-line therapy, then followed a similar pattern of decline over time. This pattern may suggest that further extending the TTP for NDMM pts may also yield economic benefits for each month extended before relapse. Patterns of cost decline were similar between the LEN and BORT groups, for NDMM and for relapsed patients, although mean monthly total costs were lower for NDMM pts receiving LEN-based Tx due to lower medical costs and similar drug costs. DisclosuresArikian:Genesis Research: Consultancy. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients . Milentijevic:Celgene Corporation: Consultancy. Binder:Celgene Corporation: Employment, Equity Ownership. Monzini:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene Corporation: Employment. Nagarwala:Celgene Corporation: Employment. Hussein:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Surinach:Genesis Research LLC: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.

Phase 2 Study of Lenalidomide in Combination with Low-Dose Dexamethasone in Japanese Transplantation-Ineligible Newly-Diagnosed Multiple Myeloma Patients

Introduction: Lenalidomide (LEN) plus low-dose dexamethasone (Rd) has been shown to be effective and to have a manageable safety profile in non-Japanese patients (pts) with newly diagnosed multiple myeloma (NDMM) (Rajkumar, Lancet Oncol 2010). Recently, the FIRST trial showed prolonged progression-free survival (PFS) and favorable overall survival (OS) benefits for pts who were administered continuous Rd until progressive disease (PD) vs. the standard of care melphalan-prednisolone-thalidomide (Facon, Blood 2013). In Japan, the combination of melphalan- prednisolone -Velcade®(MPV) is the current standard of care for transplant-ineligible NDMM pts. However, prolonged treatment (Tx) with MPV is associated with increased toxicity including peripheral neuropathy (PN) and bone marrow suppression. Consequently, continuous Tx with MPV may have limited benefits due to toxicity and related Tx discontinuation. MM-025 is a phase 2, multicenter, open-label, registration, single-arm trial. It aimed to evaluate the efficacy and safety of the continuous Rd regimen in Japanese NDMM pts who are transplant-ineligible.Methods: The study enrolled Japanese NDMM pts who were aged ≥ 65 years (yrs), or were not candidates for hematopoietic stem cell transplantation. Pts with an ECOG performance status (PS) score > 2 or with grade ≥ 2 PN were excluded from the study. Tx consisted of LEN (25 mg once daily on days 1–21 of each 28-day cycle) and dexamethasone (40 mg for pts aged ≤ 75 yrs or 20 mg for pts aged > 75 yrs, once daily on days 1, 8, 15, and 22 of each 28-day cycle) until PD or discontinuation. The dose of LEN was adjusted according to baseline renal function: 25 mg/day for pts with normal or mild renal impairment (RI) (creatinine clearance [CrCl] ≥ 60 mL/min); 10 mg/day for moderate RI (CrCl ≥ 30 to < 60 mL/min); and 15 mg every other day for those with severe RI (CrCl < 30 mL/min, not requiring dialysis). Pts who discontinued Tx were followed up every 2 months (mos) for ≥ 5 yrs from the start of Tx. The primary endpoint was overall response rate (ORR; defined as complete response [CR] + very good partial response [VGPR] + partial response [PR]) based on the IMWG criteria. The secondary endpoints included time to response (TTR), duration of response (DOR), PFS, OS, and safety. Statistical analyses included the one-sample binomial test for ORR and Kaplan-Meier analysis for DOR, PFS, and OS. The data cutoff date for this analysis was November 2013.Results: A total of 26 pts were enrolled. Of these, 46.2% of pts (n = 12) were aged > 75 yrs, 50.0% (n = 13) were male, 19.2% (n = 5) had ISS stage III disease, 23.1% (n = 6) had an ECOG PS score of 2, and 7.7% (n = 2) had severe RI (CrCl < 30 mL/min). With a median follow-up of 7.4 mos, the median Tx duration was 6.4 mos. The ORR was 83.3%, including VGPRs (12.5%) (n=3) and PRs (70.8%) (n=17). The median TTR was 2.0 mos. Due to the short follow-up DOR, PFS, and OS were not reached at data cutoff. The most common grade 3–4 adverse events (AEs; reported in > 10% of pts) were anemia (19.2%), neutropenia (15.4%), and rash (11.5%). The most frequently reported AEs (≥ 20% incidence) were rash, constipation, anemia, nasopharyngitis, and insomnia. A total of 8 pts (30.8%) discontinued the study: 4 due to AEs, 3 through the investigator’s decision and 1 due to protocol deviation. No deaths, thromboembolic events, or second primary malignancies were reported.Conclusion: Continuous Rd was effective and well tolerated by Japanese transplant-ineligible NDMM pts. These findings are consistent with those reported in the FIRST trial (Facon, Blood 2013) and support the use of the Rd combination regimen as a first-line Tx for this pt group. DisclosuresOff Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Taniwaki:Celgene Corporation: Honoraria, Research Funding. Iida:Celgene K.K.: Honoraria, Research Funding. Matsumura:Celgene: Honoraria. Ogaki:Celgene K.K.: Employment. Midorikawa:Celgene K.K.: Employment. Houck:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.

Relationship Between Lenalidomide Dose Modification and Time to Next Treatment in Newly Diagnosed Multiple Myeloma Patients

Introduction: Multiple clinical studies in patients (pts) with newly diagnosed multiple myeloma (NDMM) have shown benefits from continuous lenalidomide (LEN) treatment (Tx), including extended progression-free survival (PFS), time to progression (TTP), and overall survival (OS) (Facon, Blood 2013; Palumbo, NEJM 2012). Dose modifications are commonly utilized by physicians as part of continuous Tx plans to sustain control of disease while managing toxicities. Previous analysis has shown that dose modification of LEN was associated with longer duration of therapy (DOT) relative to non-dose modification, in the real-world setting (Lang, Blood 2013). This study aimed to evaluate whether LEN dose modification is associated with a longer TTP in NDMM pts, utilizing time to next therapy (TTNT) as a proxy measure available from claims data.Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million lives annually. NDMM pts were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM code 203.0X), with the first such claim used to define the index date. A minimum of 12 months’ pre-index enrollment and 6 months’ post-index continuous enrollment between Jan 1 2006 and December 31 2012 was required. The analysis focused on NDMM pts treated with LEN who did not have claims for stem cell transplantation (SCT), to avoid DOT limitations imposed by fixed-length induction Tx. Median DOT and TTNT were compared in NDMM pts with and without LEN dose modifications (dose increase or decrease). Charlson comorbidity scores were determined to compare baseline measures between the groups.Results: Of the 1,360 pts who met the inclusion criteria, 470 (35%) had LEN dose modifications, including 154 pts with at least one dose increase and 421 pts with at least one dose decrease. The majority of pts had an initial dose of 25mg. The median DOT was 447 days in pts with LEN dose modification and 182 days in those pts with no dose modification (p < 0.001). The median DOT in pts with dose modification was consistent regardless of whether they experienced a dose increase or decrease, with no significant difference. The median TTNT in pts with LEN dose modification was 3.5 yrs compared to 2.0 yrs in pts without dose modification (p < 0.001; Figure 1). Charlson comorbidity scores were similar in pts with and without LEN dose modification. [Display omitted] Conclusions: For non-SCT NDMM patients treated with LEN, dose modifications during their treatment were associated with a doubling of the median therapy duration and a 71% longer median TNTT, compared to pts without LEN dose modification. The DOT and TTNT in pts with dose modification were similar to median values reported for the LEN continuous Tx arm of the FIRST clinical trial (Facon, Blood 2013). This analysis suggests that LEN dose modification in the Tx of NDMM may be an effective tool in the real-world setting for pts to achieve sustained disease Tx and the associated prolonged time to progression, based on the proxy measure of TTNT. DisclosuresUsmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients. Binder:Celgene Corporation: Employment, Equity Ownership. Milentijevic:Celgene Corporation: Consultancy. Hu:Celgene: Employment. Nagarwala:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Arikian:Genesis Research: Consultancy. Surinach:Genesis Research LLC: Consultancy. Harwin:Celgene Corporation: Honoraria.

Impact of Renal Impairment (RI) on Outcomes after Treatment (Tx) with Lenalidomide and Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): First Trial Results

Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P < 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes.Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and < 80 mL/min), 23% had moderate RI (≥ 30 and < 50 mL/min), and 9% had severe RI (< 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484).Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P < 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P < 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl < 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, < 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3).Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. [Display omitted] [Display omitted] [Display omitted] DisclosuresDimopoulos:Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin: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; Sandoz: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Minimal Residual Disease (MRD) Testing in Newly Diagnosed Multiple myeloma (MM) Patients: A Prospective Head-to-Head Assessment of Cell-Based, Molecular, and Molecular-Imaging Modalities

*Equally ContributedIntroduction: Recent studies show better progression-free (PFS) and overall survival (OS) for newly diagnosed multiple myeloma (NDMM) pts achieving MRD negativity by multicolor flow cytometry (MFC) or next-generation sequencing (NGS). Here, we report on the comprehensive assessment of MRD in a uniformly treated cohort of 45 MM patients (Korde et al. ASH 2013).Methods: 45 NDMM pts were treated with 8 cycles of combination therapy (carfilzomib, lenalidomide and dexamethasone) followed by 2 years of maintenance lenalidomide. Median potential follow-up was 17.3 mos. All patients were evaluated by NGS by LymphoSIGHT™ method. Briefly, using universal primer sets, we amplified immunoglobulin heavy and kappa chain (IGH and IGK) variable, diversity, and joining (VDJ) gene segments from genomic DNA obtained from CD138+ BM cell lysate or cell free bone marrow (BM) aspirate at baseline. A MM clonotype was defined as an immunoglobulin rearrangement identified by NGS at a frequency >=5%. MRD assessment by NGS, MFC and PET was repeated when patients achieved a complete response (CR) or completed 8 cycles of therapy. In a subset of patients, we performed NGS in peripheral blood (plasma) at baseline and after 2 cycles of treatment.Results:40/45 (89%) of pts achieved VGPR or better after combination therapy. At least one clonal rearrangement was identified in 31/34 (91%) of BM CD138+ cell samples and in 34/45 (76%) of cell free BM aspirates; overall clonal rearrangement was detected in 37/45 (82%) bone marrow aspirates at baseline. Repeat MRD assessment at CR or the completion of 8 cycles in 32 pts show residual disease in cell free BM aspirates by NGS in 18 (56% of pts tested and 40% of the total study population). Estimated 12-mo and 18-mo PFS for MRD neg vs. pos by NGS was 100% vs 94% and 100% vs 84%, respectively (p=0.025). MFC testing for MRD was feasible in 43/44 pts (98%). PFS probabilities at 12-mo and 18-mo for flow neg vs pos was 100% vs 79% and 100% vs 63%, respectively (p=0.0022). Among pts assessed by both MRD methods (n=31), 23 samples were concordant (9 pos and 14 neg); among 8 discordant cases, all were positive by sequencing and negative by flow (p=0.0078). Abnormal PET scans were noted in 38/45 (84%) of pts at baseline. 24/43 (56%) pts at CR or after 8 cycles of CRd had a neg/dec PET response and 19/43 (44%) pts had a pos/partial PET response. At 12-mo and 18-mo, PFS by a neg/dec PET response vs pos/partial PET response was 100% vs 89% and 92% vs 89%, respectively (p=0.54). Furthermore, in 14 pts, we performed NGS in peripheral blood samples collected at baseline. At least one MM clonotype identified in baseline BM was detectable in corresponding plasma sample in 13/14 pts. Number of myeloma-specific molecules per million diploid genomes in the plasma was 3-log fold lower than in the BM (median 252 vs 730,950 MM specific clonal molecules per million diploid genomes). After 2 cycles of CRd treatment, 12/13 pts were still pos by serum electrophoresis and/or immunofixation while only 1 had detectable myeloma clonotypes in the plasma.Conclusions: This prospective evaluation of MRD testing in MM has several key findings: 1. Detection of myeloma-specific clonotypes by NGS of the Immunoglobulin VDJ segments in the BM is feasible in majority of pts with NDMM. 2. MRD detection by NGS compares favorably to MFC since all pts with residual disease by MFC are also MRD positive by sequencing; an additional 8 pts who were MRD negative by flow MFC were MRD positive by sequencing. 3. MRD negativity by MFC and NGS are both associated with significantly better PFS. 4. Detection of myeloma-specific clonotypes by NGS of the immunoglobulin VDJ segments (i.e. cell free DNA) in the peripheral blood plasma is feasible in NDMM pts at diagnosis; however, since tumor load in the plasma is >2000-fold lower than in the BM; using standard volumes of peripheral blood (plasma), the levels of myeloma-specific clonotypes were too low to be quantified already after 2 cycles of combination therapy. This was true despite presence of positive serum electrophoresis and/or immunofixation. Additional studies to understand the dynamics of the myeloma clonotype level in peripheral blood plasma are necessary to determine optimal MRD testing regimen. DisclosuresFaham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Moorhead:Sequenta, Inc.: Employment.

Connect MM®—the Multiple Myeloma (MM) Disease Registry: Incidence of Second Primary Malignancies (SPM)

▪Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts.Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff).Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM.Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated.Table 1Incidence rates (per 100 PYa) by treatment exposureIR per 100 PY (95% CI)SPMLEN-Exposed(n = 977)Non–LEN Exposed(n = 466)Invasive0.85 (0.61-1.19)1.16 (0.72-1.86)Hematologic0.17 (0.08-0.36)0.47 (0.22-0.99)Solid tumor0.67 (0.46-0.98)0.68 (0.36-1.26)NMSC0.50 (0.32-0.77)0.41 (0.18-0.91)a PY of exposure is the sum of exposure of all pts. DisclosuresRifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity’s Board of Directors or advisory committees; DMC Millennium: Membership on an entity’s Board of Directors or advisory committees; IRC J&J: Membership on an entity’s Board of Directors or advisory committees.

Healthcare Resource Utilization Trends over Time with Continuous Lenalidomide Treatment (Tx) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM)

Introduction: Multiple myeloma (MM) is an incurable hematologic condition that is associated with high Tx costs. Resource consumption is driven by hospitalization and medical utilization, which is highest during periods of uncontrolled disease, such as after diagnosis and during relapses (De Portu 2013). In the pivotal phase 3 FIRST trial, continuous Tx with lenalidomide plus low-dose dexamethasone (Rd) was compared with fixed-duration Rd (Rd18) or fixed-duration combination Tx with melphalan, prednisone, and thalidomide (MPT), each for 18 months (mos), in NDMM pts who were ineligible for stem cell transplantation. Continuous Rd extended progression-free survival (PFS) and overall survival (interim analysis) vs. MPT. However, it is still unclear whether extending Tx duration with Rd adversely affects healthcare resource utilization. This analysis quantifies the rates of hospitalizations and medical utilization with continuous Rd over time based on data collected in the FIRST trial.Methods: The FIRST trial (N = 1,623) was a pivotal multinational, randomized, open-label study with a median follow up of 37 mos. Non-protocol-driven resource-use data was collected until subjects discontinued study Tx. To assess whether continuous Rd increases healthcare resource utilization over time, the rates of resource utilization for subjects treated with continuous Rd (N = 535) were plotted for up to 48 mos. In addition, hospitalization and medical utilization rates during the Tx period (18 mos) were estimated and compared between the 2 fixed-duration Tx arms.Results: Resource utilization amongst pts treated with continuous Rd declined over time (Figure). The annualized hospitalization rate in the first 3 mos was 3.2 times higher than the average rate for the remaining 45 mos of follow-up (2.02 vs. 0.62), and 4.2 times higher for medical utilization (5.66 vs. 1.34). After 4 years (yrs) of continuous Rd Tx, hospitalization and medical utilization rates were estimated to be 83% and 84% lower than those observed in the first 3 mos of Tx, reflecting the long-term disease control observed with continuous Rd in the FIRST trial. The highest hospitalization rates were associated with infections (0.20 per patient year), cardiovascular disorders (0.06), and respiratory and thoracic disorders (0.05). The mean (standard deviation) length of stay per admission was 14.08 (21.19) days. The highest medical utilization rates were associated with blood transfusions (0.76 interventions per patient year), general imaging procedures (0.21), respiratory and thoracic imaging procedures (0.20), and therapeutic interventions (0.09).The hospitalization rates for the fixed dose Tx arms were 0.91 (Rd18) and 0.79 (MPT) per patient year of follow-up during the Tx period of 18 mos, resulting in a rate ratio (RR) of 1.15 (1.01–1.30). The equivalent rates for medical utilization were 3.00 (Rd18) and 2.86 (MPT) medical interventions per patient year (RR = 1.05 [0.98–1.12]).Conclusions: The rates of resource utilization among pts treated with continuous Rd dropped substantially after the first 3 mos of Tx, and then gradually declined as Tx duration increased. The findings suggest that continuous Tx with Rd does not further increase resource utilization in hospitalizations and medical utilization compared to fixed-duration Tx. A comparison between the 2 fixed arms showed a 15% increase in hospitalization with Rd18 vs. MPT, and no differences in medical utilization between the 2 arms. A limitation of this analysis is that the resources were collected only while pts were receiving their respective Txs. Future analysis should include all costs generated by healthcare resources throughout pts Tx, including Tx-free intervals, and the costs associated with relapses. [Display omitted] DisclosuresWeisel:BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Vogl:Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding; Celgene Corporation: Consultancy. Delforge:Janssen: Honoraria; Celgene Corporation: Honoraria. Song:Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Dimopoulos:Celgene Corporation: Consultancy, Honoraria. Cavenagh:Celgene Corporation: Honoraria. Hulin:Celgene Corporation: Honoraria. Foá:Celgene Corporation: Consultancy. Oriol:Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Guo:Celgene Corporation: Consultancy. Monzini:Celgene Corporation: Employment, Equity Ownership. Van Oostendorp:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Facon:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Impact of Response Quality on Survival Outcomes in Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): Results from the First Trial

Background: In the pivotal phase 3 FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd) improved progression-free survival (PFS), overall survival (OS), and response compared with fixed-duration treatment (Tx) with either Rd or the combination of melphalan-prednisone-thalidomide (MPT) in transplant-ineligible NDMM pts (Facon, Blood 2013). Here we examine if pts achieving complete remission (CR) or at least very good partial response (≥ VGPR) equally benefit from continuous Rd.Methods: Pts were randomized to continuous Rd until progressive disease (PD; N= 535); Rd for 18 cycles (72 weeks) (Rd18; N = 541); or MPT for 12 cycles (72 weeks) (N = 547). The primary endpoint was PFS (continuous Rd vs. MPT). The secondary endpoints included OS, response rate (assessed using IMWG criteria), time to response, duration of response (DOR), time to Tx failure, time to next antimyeloma Tx, health-related quality of life, and safety. With a data cutoff of May 24, 2013, the median follow-up was 37.0 months (mos).Results: In pts who achieved ≥ VGPR, median PFS was significantly longer (NR) with continuous Rd compared with Rd18 (31.0 mos; HR = 0.46; P < 0.01) or MPT (34.7 mos; HR = 0.55; P < 001). Even greater benefit of continuous Rd was observed compared with Rd18 or MPT in pts who achieved CR, where the median PFS with continuous Rd was NR vs. 45.2 mos with Rd18 (HR = 0.29; P < 0.01) and 44.6 mos with MPT (HR = 0.28; P < 0.01) (Table 1). In the intent-to-treat population, duration of response (DOR) was 35 mos with continuous Rd, which was significantly longer of almost a year vs. Rd18 (22.1 mos; HR = 0.60; P < 0.01) or MPT (22.3; HR = 0.63; P < 0.01). Importantly, the DOR was significantly longer with continuous Rd vs. Rd18 or MPT across all response categories, including pts with CR. Median duration of CR was NR vs. 43.6 mos in pts receiving continuous Rd vs. Rd18 (HR = 0.29; P < 0.01); ≥ VGPR, NR vs. 29.9 mos (HR = 0.46; P < 0.01); and ≥ PR, 35 mos vs. 22.1 mos (HR = 0.60; P < 0.01). In pts who achieved CR, 88% were disease-free after 36 mos with continuous Rd vs. 55% Rd18 and 54% MPT. In terms of OS, only interim data on continuous Rd vs. Rd18 or MPT on depth of response in the subgroups is presented in table 1.Conclusions: The DOR was significantly longer (12-18 mos) as was PFS in pts treated with continuous Rd vs. Rd18 or MPT regardless of the depth of response. The benefits of continuous Rd were more pronounced in pts who achieved a greater depth of response (≥ VGPR). These data suggest that continuing Tx after best response may further help in controlling the disease and delaying PD, especially in pts achieving CR. Longer follow-up may be needed to determine the impact of response quality on OS in pts receiving continuous Tx.Abstract 3458. Table 1PFS, DOR, and OS in pts with NDMMCR (n = 209)≥ VGPR (n = 618)≥ PR (n = 1140)≤ SD (n = 483)ITT pts (N = 1623)Median PFS (mos)RdNRNR37.73.727.4Rd1845.231.024.04.621.3MPT44.634.726.34.921.8PFS, HR (95% CI); P-valueRd vs. MPT0.28 (0.13–0.61); P < 0.010.55 (0.40–0.76); P < 0.010.67 (0.55–0.82); P < 0.011.60 (1.22–2.11); P < 0.010.68 (0.56–0.83); P < 0.01Rd vs. Rd180.29 (0.15–0.58); P < 0.010.46 (0.34–0.60); P < 0.010.60 (0.49–0.72); P < 0.011.10 (0.82–1.48); P = 0.530.68 (0.55–0.83); P < 0.01Median DOR (mos)RdNRNR35.0–35.0Rd1843.629.922.1–22.1MPT41.931.822.3–22.3DOR, HR (95% CI); P-valueRd vs. MPT0.27 (0.13–0.59); P < 0.010.54 (0.39–0.74); P < 0.010.63 (0.51–0.76); P < 0.01–0.63 (0.51–0.76); P < 0.01Rd vs. Rd180.29 (0.15–0.59); P < 0.010.46 (0.35–0.61); P < 0.010.60 (0.50–0.72); P < 0.01–0.60 (0.50–0.72); P < 0.01Median OS (mos)RdNRNR55.133.255.1Rd18NRNRNR26.853.6MPTNRNRNR31.648.2OS, HR (95% CI); P-valueRd vs. MPT0.59 (0.23–1.49); P = 0.260.77 (0.50–1.180; P = 0.230.85 (0.64–1.11); P = 0.230.98 (0.72–1.33); P = 0.890.78 (0.64–0.96); P < 0.02Rd vs. Rd180.84 (0.34–2.07); P = 0.710.82 (0.56–1.22); P = 0.330.90 (0.69–1.17); P = 0.450.97 (0.70–1.35); P = 0.850.90 (0.73–1.10); P =0.31CI, confidence interval; ITT, intent-to-treat. DisclosuresBahlis:Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Stoppa:Celgene, Janssen: Honoraria. Decaux:Celgene and Janssen-Cilag : Consultancy, Honoraria. Marit:Celgene, Janssen: Congress expenses Other. Demuynck:Janssen-Cilag: Honoraria. Ervin-Haynes:Celgene: Employment. Leupin:Celgene: Employment. Marek:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Facon:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone (Rd): The First Trial

Background: In the pivotal FIRST trial, a randomized, international, multicenter phase 3 study, continuous Rd compared with melphalan-prednisone-thalidomide (MPT) improved progression-free survival (PFS) which was the primary endpoint (HR = 0.72; P < 0.01). The interim overall survival (OS) analysis showed a 22% reduction in risk of death with continuous Rd vs. MPT (HR = 0.78; P = 0.02) (Facon, Blood 2013). This analysis evaluates outcomes based on age, which was a stratification parameter, and compared pts aged ≤ 75 yrs and > 75 yrs.Methods: Pts with NDMM were randomized to continuous Rd until progressive disease (PD) (N = 535); 18 cycles (72 weeks [wks]) of Rd (Rd18; N = 541); or 12 cycles (72 wks) of MPT (N = 547). Starting doses were reduced in pts aged > 75 yrs: dexamethasone (20 vs. 40 mg), melphalan (0.20 vs. 0.25 mg/kg), and thalidomide (100 vs 200 mg). The primary endpoint was PFS (continuous Rd vs. MPT) and the secondary endpoint were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety.Results: The proportion of pts aged > 75 yrs was > 34% across treatment (Tx) arms. In pts ≤ 75 yrs, 37% had ISS stage III vs. 51% in > 75 yrs. ECOG score ≥ 1 was observed in 74% and 69% of pts aged > 75 and ≤ 75 yrs, respectively. Severe renal impairment (CrCl < 30 mL/min) was observed in 14% of pts > 75 vs. 7% in ≤ 75 yrs. PFS and OS outcomes favored continuous Rd over MPT in both age groups. With a median follow-up of 37 months (mos), PFS was 27.4 mos in continuous Rd pts vs. 21.8 mos in MPT pts aged ≤ 75 yrs (HR = 0.68; P < 0.001); a trend for improved PFS was also seen for pts aged > 75 yrs (HR = 0.81; P = 0.11) (Table 1). PFS for continuous Rd vs. Rd18 pts was also increased in both age groups (HR = 0.68; P < 0.001 and HR = 0.75; P = 0.03, respectively). Response rates were consistently higher with continuous Rd vs. MPT in pts aged ≤ 75 yrs (77% vs. 66%; P < 0.001) and > 75 yrs (71% vs. 55%; P < 0.001). Duration of response with continuous Rd was longer vs. MPT in pts aged ≤ 75 yrs (40 vs. 22 mos) and pts > 75 yrs (31 vs. 24 mos). The interim analysis of OS showed an improved trend for continuous Rd vs. MPT in pts aged ≤ 75 yrs (HR = 0.77; P = 0.06) and > 75 yrs (HR = 0.80; P= 0.16). Grade 3–4 adverse events (AEs) in ≥ 10% of pts were similar across age subgroups (Table 2). Tx discontinuation due to AEs was comparable across the Tx groups and independent of age.Conclusions:Regardless of age (≤ 75 vs. > 75 yrs), continuous Rd was effective, increased PFS and interim OS, and was generally well tolerated vs. MPT in NDMM pts. Duration of response was improved with continuous Rd vs. MPT and Rd18, irrespective of age, and with a more profound benefit observed in younger pts. Continuous Rd represents a new clinical option and standard of care for these pts in the first-line setting.Abstract 81. Table 1PFS, OS and ResponseAged ≤ 75 yrsAged > 75 yrsAll ptsITT populationContinuous Rd (n = 349)Rd18 (n = 348)MPT (n = 359)Continuous Rd (n = 186)Rd18 (n = 193)MPT (n = 188)Continuous Rd (n = 535)Rd18 (n = 541)MPT (n = 547)Median PFS, mos27.421.321.821.219.419.225.520.721.2PFS HR (95% CI); P-valueContinuous Rd vs. Rd180.68 (0.55–0.83); P < 0.010.75 (0.58–0.98); P = 0.030.70 (0.60–0.82); P < 0.01Continuous Rd vs. MPT0.68 (0.56–0.83); P < 0.010.81 (0.62–1.05); P = 0.110.72 (0.61–0.85); P < 0.014-yr OS, %666158474739595651OS HR (95% CI); P-valueContinuous Rd vs. Rd180.88 (0.67–1.16); P = 0.360.94 (0.69–1.29); P = 0.700.90 (0.73–1.10); P = 0.31Continuous Rd vs. MPT0.77 (0.59–1.01); P = 0.060.80 (0.59–1.09); P = 0.160.78 (0.64–0.96); P = 0.02Response rate (≥ PR), %777766716655757362Duration of response (≥ PR), mos402322312024352222CI, confidence interval; ITT, intent to treat; PR, partial response.Table 2Grade 3–4 AEs Observed in ≥ 10% of PtsAged ≤ 75 yrsAged > 75 yrsSafety population, %Continuous Rd (n = 347)Rd18 (n = 348)MPT (n = 357)Continuous Rd (n = 185)Rd18 (n = 192)MPT (n = 184)Neutropenia282547282940Thrombocytopenia8913977Anemia181220192317Leukopenia5611458Infections292116292320DVT and/or PE1068784Peripheral sensory neuropathy1110108Tx discontinuation due to AEs281828322530DVT, deep-vein thrombosis; PE, pulmonary embolism. DisclosuresHulin:Celgene: Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Facon:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Belch:Janssen, Celgene, Onyx: Honoraria. Petrucci:Celgene, Janssen-Cilag, Sanofi, Bristol-Myers Squibb: Honoraria. Dührsen:Celgene: Honoraria, Research Funding. Song:Celgene: Consultancy, Honoraria, Research Funding. Houck:Celgene: Employment. Chen:Celgene: Employment. Ervin-Haynes:Celgene: Employment.

Prognostic and Predictive Gene Expression Profiling (GEP) Markers Confirmed in Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Treated Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts)

Introduction High rates of complete response (CR) have previously been demonstrated in KRd-treated NDMM pts in a phase 1/2 trial (trial 1; NCT01029054) and a phase 2 trial that combined KRd with autologous stem cell transplant (ASCT) (trial 2; NCT01816971). Here, we report results of extended follow-up from the 2 trials and correlate response and PFS with GEP performed using the MMprofiler GEP assay, which provides results for the SKY92 signature, 7 virtual karyotyping markers (t[4;14], t[11;14], t[14;16]/t[14;20], gain[1q], del[13q], del[17p], H-MM [virtual gain(9q)]), and 3 clusters (MF, MS, CD2). Previously, a combination of 5 markers (SKY92, virtual gain[1q], virtual t[14;16]/t[14;20], MF and CD2 clusters) was identified that predicts improved outcomes when treated with the proteasome inhibitor (PI) bortezomib (van Vliet et al, EHA 2014). We evaluated the SKY92 prognostic signature, virtual karyotyping markers, and this 5-marker PI predictor signature in order to confirm these markers as predictive signatures in the KRd setting. Materials and Methods In the consecutive trials 1 and 2, pts received 4 cycles of KRd induction, followed by extended KRd treatment with deferred ASCT (trial 1; NCT01029054) or ASCT followed by extended KRd treatment (trial 2; NCT01816971). In both trials, pts received single-agent lenalidomide as maintenance after completion of KRd. The MMprofiler GEP assay was performed on RNA from CD138+ purified plasma cells. As depth of response with KRd is associated with improved time-to-event outcomes (Jasielec et al, ASH 2013), data were analyzed for associations between any of the MMprofiler markers and the groups that achieved ≥near CR (nCR) vs Results Based on a July 1, 2014 cutoff date, 91 pts were enrolled (53 in trial 1; 38 in trial 2). CD138+ RNA was available from 27 pts (16 from trial 1; 11 from pts in trial 2 who completed ≥4 KRd cycles). Pts with H-MM (virtual gain[9q]) were significantly less likely to achieve nCR (p=0.027) (Table 1). None of the other markers were found to have a statistically significant association with response; several markers, however, showed a trend for predictive value at the current sample size. PFS data were available for 16 pts (median follow-up: trial 1, 40 months [mo]; trial 2, 6.7 mo [with no events at the cutoff date]). Two markers were found to be significantly prognostic (Figure 1): SKY92 (5/16 pts [31%]; HR=5.7; p=0.023) and virtual gain (1q) (6/16 pts [38%]; HR=5.5; p=0.017). Virtual t(4;14) was marginally significant (HR=3.7, p=0.055). When considering the 5-marker PI predictor signature, none of the 16 pts were positive for virtual t(14;16)/t(14;20), MF or CD2 clusters. Combining the SKY92 and virtual gain(1q) markers identified a highly significant subgroup of high-risk pts (7/16; 44%) with a median PFS of 26 mo (HR=8.7; p=0.0088; Figure 1). In no-risk pts (9/16), estimated 4-year PFS was 78%. Conclusions Absence of H-MM (virtual gain[9q]) identified pts more likely to achieve ≥nCR by the end of 4 cycles of KRd, with other markers awaiting validation from ongoing enrollment to the KRd + ASCT trial. Based on combined SKY92 high-risk and virtual gain(1q) signatures, the MMprofiler assay detected a highly significant group of high-risk pts with inferior PFS compared to the no-risk group. Despite the inferior outcome, these high-risk pts appeared to have benefited from KRd when compared to historical data of treatment without PIs, suggesting that the 5-marker PI predictor signature (Van Vliet et al, EHA 2014) may also apply to carfilzomib-based treatment. We observed a 4-year PFS rate in no-risk pts in the KRd trials which trended higher than the historical outcome of the PAD arm in the HOVON65/GMMG-HD4 trial (78% vs 34%, respectively), suggesting a benefit for KRd without ASCT in this group of pts compared with other strategies with PIs; further study is needed, however. With ongoing enrollment into the KRd + ASCT trial, the findings reported here will be further validated. Updated results will be presented at the meeting. Acknowledgments This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project BioCHIP grant 03O-102. Disclosures van Vliet:SkylineDx: Employment. Vij:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria. Dumee:SkylineDx: Employment. Bosman:SkylineDx: Employment. deBest:SkylineDx: Employment. van Beers:SkylineDx: Employment. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; SkylineDX: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Health-related quality of life (HRQOL) in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM): Results from the first trial.

8516^ Background: In the pivotal FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd; [N = 535]) improved progression-free survival (PFS) and overall survival (OS) compared with 18 cycles of Rd (Rd 18; [N = 541] for and 12 cycles of melphalan-prednisone-thalidomide (MPT; [N = 547] for 72 weeks) (Facon, Blood 2013). This analysis evaluates HRQOL changes in these NDMM pts. Methods: HRQOL was assessed using the EORTC-QLQ-C30, QLQ-MY20, and EQ-5D validated questionnaires at baseline, end of cycle 1, then 3, 6, 12, 18 months (mos), and at study discontinuation. Cross sectional and longitudinal analyses were performed. Changes from baseline at each time-point were estimated with a focus on seven pre-selected and clinically-relevant domains (Global QOL, Physical Functioning, Pain, Fatigue, Disease Symptoms, Side Effects of Treatment, and Health Utility). Results: Questionnaire compliance was high (≥ 84%) at Cycle 1, 3 and 6 mos across treatment arms. At 12 and 18 mos, the compliance rates were l...

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

BackgroundRd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. MethodsPatients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). ResultsBetween October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71)At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). ConclusionIn a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures:Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Response To First-Line Treatment In Stem Cell Transplant (SCT) and Non-SCT Patients With Newly Diagnosed Multiple Myeloma Who Are Enrolled In The Connect MM Registry

IntroductionThe advent of new therapies for the treatment of multiple myeloma (MM) has resulted in improved clinical outcomes and patient (pt) survival. However, the best combination of agents from different drug classes and subsequent therapeutic strategies for pts with newly diagnosed MM (NDMM), while investigated, has not yet been established. The goal of the Connect(R) MM registry is to provide insight into the disease and explore the management and outcomes of pts with NDMM who are treated at community and academic sites in the United States. This analysis aims to describe the combinations used in NDMM outside the interventional clinical trial setting and the activity and outcome response to different regimens by class of therapeutic agents in clinical practice. MethodsConnect MM is an ongoing prospective, longitudinal, observational registry of NDMM pts. This multicenter US pt registry was initiated in 2009. Pts who were newly diagnosed with symptomatic MM within 2 months of enrollment were eligible to participate. Data were collected at baseline and every 3 months. Pts who had response data 12 months after enrollment, met CRAB criteria, and received treatment were eligible for this analysis. Treated pts were stratified according to SCT status. Data on baseline demographic and clinical characteristics, and initial therapies (proteasome inhibitors [PI], IMiD(R) immunomodulating agents, alkylating agents [AA], corticosteroids, and combinations) were collected. The overall response rate (ORR), as assessed by the site investigator, was defined as the best response during the course of initial therapy and is presented as cumulative ORR over 3, 6, and 12 months. ResultsAs of the data cutoff (April 15, 2013), 1494 pts were enrolled in the registry; 1312 pts met CRAB criteria and received treatment. Of these, 439 received SCT or were anticipated to receive (had undergone a stem cell harvest) SCT and 873 would not receive SCT (non-SCT). Mean (SD) age for SCT and non-SCT pts was 58.9 years (8.7) and 69.8 years (10.7), respectively. Majority of pts in both groups were male (62.0% vs 56.5%) and Caucasian (85.4% vs 81.4%). Among SCT pts, ISS stages were: I/II (55.1%), III (25.3%), and unknown (19.6%) and ECOG performance status (PS) was 0/1 (63.1.%), 2/3 (7.1%), and unknown (29.8%). Among non-SCT pts, ISS stages were: I/II (42.0.%), III (32.2%), and unknown (25.8%) and ECOG PS was 0/1 (56.6%), 2/3/4 (14.7%), and unknown (28.8%). ORR to initial therapy and 1-year survival for the 5 most commonly used regimens are presented in the Table. [Display omitted] A triplet regimen is 2 times more likely to be selected for SCT pts than for non-SCT pts, suggesting investigator bias in selecting more aggressive therapy for younger pts. For the 5 most commonly used regimens, 1-year survival was 97.9% for SCT pts and 83.3% for non-SCT pts. ConclusionOutside an interventional clinical trial setting, the most commonly used initial treatment regimens for NDMM were IMiD + PI + steroid for SCT pts and PI + steroid for non-SCT pts. Response rates were higher among SCT pts regardless of regimen. The investigator-assessed response rates were similar across the various combinations including 2 vs 3 drug combinations in SCT pts. Disclosures:Abonour:Celgene: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Off Label Use: This abstract will report on an observational study. There is no pre-specified use of drugs; treating physicians determined what drugs to use and some could be off-label. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Durie:Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Terebelo:Amgen: Honoraria; Millennium: Honoraria. Gasparetto:Celgene ( 2012): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium (2012): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Sullivan:Celgene: Employment. Srinivasan:Celgene: Employment. Nagarwala:Celgene: Employment. Rifkin:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Lenalidomide (LEN)-melphalan-prednisone induction followed by LEN maintenance (MPR-R) in newly diagnosed multiple myeloma (NDMM) elderly patients (Pts) with moderate renal impairment (RI): MM-015 trial post-hoc analysis.

8544 Background: The MM-015 pivotal phase III trial showed significant PFS benefit for MPR-R (31 mos) vs. MPR (14 mos) or MP (13 mos; both p &lt; 0.001) followed by placebo in NDMM pts aged ≥ 65 years. As NDMM pts with RI have poor prognosis, this retrospective analysis studied the efficacy and safety of MPR-R in pts with creatinine clearance (CrCl) &lt; 60 mL/min. Methods: LEN starting dose for induction/maintenance was 10 mg/day (D1–21 of a 28-day cycle). Dose adjustments were not recommended for pts with RI. CrCl was calculated using the Cockcroft-Gault equation. Pts with severe RI (serum Cr &gt; 2.5 mg/dL [221 μmol/L]) were excluded from the trial. Results: Pts with CrCl &lt; 60 mL/min (median 47, interquartile range [IQR] 38–55) were included in this analysis: 51% MPR-R, 45% MPR, and 49% MP. Median PFS was significantly higher with MPR-R (26 mos [95% CI 14–48]) vs. MPR (13 mos [95% CI 12–15]) or MP (14 mos [95% CI 12–16]; both p &lt; 0.001). In a Cox proportional model of PFS, CrCl &lt; 60 mL/min was not identified as a negative prognostic factor (p = 0.69). The most common Gr 4 adverse events (AEs) were hematologic and occurred predominantly during induction and are shown in the Table for pts with or without moderate RI. The number of deaths on study was similar: 10% (MPR-R), 7% (MPR), and 8% (MP); deaths associated with RI or disease progression were reported in ≤ 1% of pts with RI across the arms. Conclusions: The benefit of continuous LEN treatment with MPR-R is not compromised in NDMM pts with moderate RI, consistent with the overall trial results. CrCl and AEs should be monitored closely in this population. Clinical trial information: NCT00405756. [Table: see text]

Effect of CMP, carfilzomib (CFZ) plus melphalan-prednisone (MP), on response rates in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): Results of a phase (Ph) I/II trial.

8513 Background: MP+thalidomide (MPT) and MP+bortezomib (MPV) have shown significant progression-free survival and overall survival (OS) benefits in NDMM pts &gt; 65 years (y) but are associated with peripheral neuropathy (PN). CFZ, a novel proteasome inhibitor, has shown promising activity and a favorable toxicity profile with low PN rates. Methods: This PhI/II study in NDMM &gt;65y was designed to determine maximum tolerated dose (MTD) of CMP and assess safety and efficacy. In PhI, CFZ was started at 20mg/m2, then escalated to 27, 36, and 45mg/m2, given IV in 42-day (D) cycles (C) on D1/2/8/9/22/23/29/30 for 9C. Melphalan 9mg/m² and prednisone 60mg/m² were given PO D1–4 of every 45-day cycle. MTD was based on dose-limiting toxicity (DLT) in C1 defined as any grade (G) 4 hematologic adverse event (AE), any hematologic AE preventing aministration of ≥ 2 C1 CFZ doses except G4 thrombocytopenia without bleeding or G4 neutropenia ≤7D, ≥G3 febrile neutropenia, or any ≥G3 nonhematologic AE. Results: As of Jan 6, 2013, 24 pts have been enrolled in PhI: 6 for each dose level. There were 2 DLTs at 45mg/m2(fever, hypotension) resulting in a MTD of 36mg/m². In PhII, 45 additional pts received CMP at 36mg/m² CFZ for N=69 total PhI/II pts (median age 74y). ORR was 89% with 51% ≥VGPR. With median follow-up of 12 mo, the projected 2y OS was 89.9%. CMP was well tolerated without PN ≥G2. Conclusions: These results compare favorably to those of MPV, MPT, MP+lenalidomide (R), and R+dex in similar pts (ORR 71% San Miguel NEnglJMed2008, 76% Facon Lancet2007, 80% Palumbo JClinOncol2007 and 85% Rajkumar LancetOncol2010, respectively). CFZ 36mg/m2 +MP is tolerable and effective in elderly NDMM pts. Treatment is ongoing. Final safety and efficacy data will be presented during the meeting. Clinical trial information: NCT01279694.

Early mortality (EM) for newly diagnosed multiple myeloma (NDMM) in the Connect MM U.S. registry.

8596 Background: EM occurring ≤ 6 mos from diagnosis of MM has been reported in several NDMM studies. Incidence of EM in the pre-novel-therapy era was 10–14% of patients (pts); causes included infection/pneumonia, renal failure, refractory disease, and cardiac events. Identifying risk factors and improving response rates (RR) could lower EM. Established risk factors only have a sensitivity of 61% and specificity of 74%. Introduction of novel therapies is improving RRs and changing the profile of morbidity risk factors. Fewer indwelling catheters, better antibiotics, and bisphosphonates have reduced morbidity and mortality in MM. This analysis aims to better understand the causes of EM in this new era. Methods: Connect MM is a prospective observational registry of NDMM pts. Since 2009, 1494 pts in 228 US centers have been enrolled. Baseline characteristics were compared for pts who died ≤ 6 mos after enrollment vs pts who survived &gt; 6 mos. Multivariate logistic analyses identified significant associations between baseline characteristics and EM. Results: Most pts received novel therapies (91%). In the entire cohort, EM occurred in 103 pts (7%), of which 93 were treated (6.5%). EM associated characteristics by multivariate analyses (P&lt; 0.05) were: age, ISS disease stage, PS, history of hypertension, hypercalcemia, lower clonal bone marrow cells (subject to further study), and platelet count. Venous thromboembolism and cytogenetics were not risk factors. Causes of the 103 early deaths were: MM progression (38%), cardiac failure (13%), infection (7%), pneumonia (6%), renal failure (4%), sudden death (3%), vascular event, bleeding, pulmonary embolism (1% each), other (15%) and unknown (13%). Conclusions: It is important to recognize EM as a distinct entity in MM. Better understanding of the biology and pt characteristics is required to further reduce its incidence. This is the first assessment of EM in a registry where almost all pts received novel agents. Of the 103 early deaths, 38% were due to MM, representing a 2.6% incidence in the total cohort (under further review). Although the 7% EM in Connect MM is encouraging, there is still room for improvement. Additional analyses on improvements and causes of death should be performed.

A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide (Len) Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) ≥ 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (NDMM): Updated Results for Pts Aged 65–75 Yrs Enrolled in MM-015

A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide (Len) Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) ≥ 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (NDMM): Updated Results for Pts Aged 65–75 Yrs Enrolled in MM-015

Efficacy and improved toxicity profile of once a week bortezomib (BZ) with dexamethasone (dex) in newly diagnosed multiple myeloma (NDMM) patients (pts) with older age and comorbidities: Preliminary results of an ongoing clinical study.

8074^ Background: The current BZ regimen administered twice a week for 2 weeks with one week off is effective, however is inconvenient and associated with toxicities such as neuropathy. To improve convenience and compliance, we have investigated the efficacy and safety of a weekly BZ regimen. Methods: In this phase II multi-center single-arm study BZ is administered at 1.6 mg/m2 IV weekly for 4 weeks with 1 week off with dex 40mg PO on the day of and day after BZ for upto 6 cycles in NDMM pts not considered for autologous stem cell transplant in participating Veterans Hospitals (VA) nationwide. The objective is to evaluate overall response rate (ORR) and toxicity of this regimen. Results: Currently 41 pts (median age-71; range 50-89) have been enrolled at 12 VA Hospitals. Pts had significant co-morbidities including 83% with cardiovascular problems, 44% with respiratory problems, 66% with diabetes and/or hyperlipidemia, 51% with renal dysfunction, 15% with history of cancer. All pts were on at least 5 daily medications. Of the 41 pts enrolled, 33 pts have received at least 1 cycle of therapy and were evaluable for toxicity and efficacy. With a median of 4 cycles administered, this regimen was well tolerated. One pt developed grade 3 neuropathy while 3 pts experienced grade 1 and one patient with grade 1 neuropathy at diagnosis had increased to grade 2. Dex dose was reduced in 32% while BZ dose was reduced in 10% of the pts. Additionally, grade ≥1 asthenia was observed in 51%, constipation in 42%, diarrhea in 32%, anemia in 42%, and thrombocytopenia in 34%. Four pts have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with BZ. Of the pts who received at least 1 cycle of therapy, 64% pts achieved ≥PR; 15% CR/nCR and an additional 15% achieved VGPR. Including MR in the analysis, ORR was observed in 97% of the evaluable pts. On intent to treat analysis including all 41 pts, ORR was observed in 78% pts and ≥ PR in 51% pts. Conclusions: These preliminary results point to the effectiveness and tolerability of the once a week BZ regimen even in older pts with significant co-morbidities.

High Incidence of Thrombotic Events Observed in Patients Receiving Lenalidomide (L) + Dexamethasone (D) (LD) as First-Line Therapy for Multiple Myeloma (MM) without Aspirin (ASA) Prophylaxis.

Introduction: Lenalidomide (L) is an immunomodulatory compound, or IMiD®, which has impressive activity against both relapsed/refractory (RRMM) and newly diagnosed MM (NDMM). Although approximately 15% of NDMM patients (pts) treated with thalidomide (another IMiD®) plus dexamethasone (D)(TD) will develop thromboembolic events (TEEs), less is known about the thrombotic risk associated with LD. In 2 large Phase III studies comparing LD to D + placebo (P)(DP) in RRMM, which did not include routine thrombosis prophylaxis, the overall rate of TEEs in the LD groups were 8 and 14% versus 4% for those treated with DP. Here we describe an unexpectedly higher incidence of TEEs among the first 21 pts enrolled in a Southwest Oncology Group (SWOG) double-blinded Phase III study (S0232) comparing LD to DP in NDMM pts.Methods: Pts received L/P 25 mg/day on days 1–28 plus D 40 mg/day on days 1–4, 9–12, 17–20 for three 35-day induction cycles, followed by L/P 25 mg/day on days 1–21 plus D 40 mg/day on days 1–4, 15–18 in repeating 28-day maintenance cycles. The incidence of TEEs for pts on LD and DP were compared using Fisher's exact test (two-sided). Baseline clinical data were compared for pts who developed thromboses versus those who did not. Baseline labs, including hemoglobin, platelet count, PT, PTT, D-dimers, fibrinogen, vWF activity, Protein C, Protein S, activated protein C resistance, factor VIII level, and thrombin-antithrombin complexes, were also assessed.Results: Nine of 12 NDMM pts (75%) randomized to LD developed TEEs, compared to zero of 9 (0%) treated with DP (p = 0.0011). All events were lower extremity deep vein thromboses except for one ischemic stroke. Events occurred after a median of 50 days of therapy. There was no association between myeloma stage, pt age or gender, or M-protein Ig subtype and the risk of thrombosis. Although baseline fVIII and vWF levels were elevated in the majority of pts (median 169 and 164.5, respectively) neither these nor other coagulation lab findings correlated with the risk of thrombosis. In all cases except the one pt who suffered a stroke, LD was resumed after full anticoagulation was instituted.Discussion: The 75% incidence of thrombosis for the first 12 newly diagnosed pts treated with LD on S0232 was much higher than expected. No other predictive risk factors, including coagulation-related laboratory abnormalities, were identified. The incidence of thrombosis for pts with NDMM treated on a prior Phase II study of LD administered in 28-day cycles with daily ASA prophylaxis (325 mg/day) was extremely low. This experience, plus evidence that ASA (81 mg/day or 325 mg/day) reduces the risk of TEEs in pts treated with TD or T plus chemotherapy, prompted us to amend the protocol to include ASA 325 mg daily for all pts. The impact of ASA prophylaxis on the incidence of TEEs in pts enrolled subsequent to the 21 pts described here will be reported at the meeting.