Predictors of Overall Survival for Multiple Myeloma Patients Depending on Transplant Status According to a Retrospective, Non-Interventional Study in Norway

Abstract Introduction Multiple myeloma (MM) is the second most common hematological malignancy in Europe and the US. The median survival after diagnosis is approximately 4-5 years (Röllig et al The Lancet 2015), with recent improvement observed in younger (Kyle et al Expert Rev Hematol 2014) and older patients (Kumar et al Leukemia 2013). The improvement in outcomes of MM patients is largely due to the introduction of autologous stem cell transplant (ASCT) and novel treatments including proteasome inhibitors and immunomodulators. Norwegian guidelines state that the preferred frontline treatment for MM patients under 65-70 years old is ASCT, but this option may be limited by comorbidity. Here, we report results from a retrospective, non-interventional study using data collected at the MM registry at Oslo University Hospital (OUS), Norway. The aim was to describe patient and disease characteristics, overall survival (OS), and potential predictors of death for the study population in Norway. Methods The study period was from 1 Jan 2008 to 31 Dec 2015. Patients (n=169) aged 18 years or older at MM diagnosis and who were treated at OUS (ASCT or not) or in 1 of 5 regional hospitals (ASCT only, with ASCT received at OUS and other treatments received locally), during the study period, were included. Study entry was defined as date of MM diagnosis and follow-up started from study entry. End of follow-up occurred at the first of: end of study period, loss to follow-up, or death. Variables used were part of routine practice. Descriptive analysis was done at diagnosis for the overall population, for patients who received ASCT (n=100), and for those who did not receive ASCT at any time during the study period (n=69). At treatment line 1, Cox models were used to identify potential predictors for OS. Results In the study, 55.6% of patients were diagnosed with MM at OUS and 25 of those patients (14.8% of total population) received ASCT. Patients who did not receive ASCT were older and included a larger percentage of women than in the transplant cohort (mean age non-ASCT 73.1±11.2 with 55.1% women and for ASCT 55.5±6.7 years with 45.0% women). More MM patients were diagnosed with Bence Jones (BJ) (21.9% of patients) or IgG type myeloma (54.4% of patients) than IgA type (20.1% of patients) (Table 1). Of transplant patients, more were of International Staging System (ISS) stage I or stage II than stage III MM, though 35.0% of patients were of unknown stage. Most non-transplant patients had unknown ISS stage, followed by stages II and III and the least number of patients were of stage I. Of the CRAB symptoms at diagnosis, most ASCT patients showed no hypercalcemia (80.0%), no renal impairment (90.0%), or no anemia (68.0%), and 34.0% presented with skeletal destruction (Table 1). Similarly, most non-transplant patients had no hypercalcemia (87.0%) and no renal impairment (79.7%) at diagnosis. Anemia and skeletal destruction were not measured in 24.6% of non-transplant patients. Of those with recorded results, more non-transplant patients had skeletal destruction than not and approximately the same number of non-transplant patients presented with anemia than not. High-risk cytogenic abnormalities, a criterion of the revised (R)-ISS, was unknown for most patients (80.5%). Median OS from start of treatment line 1 was 75.93 (90% confidence interval (CI): 68.23 to not reached) months for transplant patients and 34.20 (90% CI: 25.57-42.16) months for non-transplant patients. Variables including age group, sex, CRAB symptoms at diagnosis, type of first therapy, and type of MM at diagnosis were included in the Cox models per cohort, if they had a missingness of <20%. Hypercalcemia at diagnosis was a significant predictor for OS for the transplant cohort, while anemia at diagnosis gave a decreased risk of death. Hypercalcemia as well belonging to the older age groups (e.g., 61-70 years and 71-80 years) were significant predictors of death for the non-transplant patients (Table 2). Conclusions For MM patients in Norway, overall survival was much greater for patients receiving transplant in the first line. Hypercalcemia at diagnosis predicted death for both transplant and non-transplant cohorts and anemia at diagnosis was identified as a decreased risk of death for transplant patients, but not well-recorded for non-transplant patients. Belonging to an older age group (>71 or 80 years old) also was a significant predictor of death, but only for non-transplant patients. Disclosures Schjesvold: Oncopeptides: Consultancy; Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Bayer: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria. Jenna:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Sõnajalg:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Leval:Janssen-Cilag: Employment. Rana:Janssen-Cilag: Employment. Castren-Kortekangas:Janssen-Cilag: Employment. Borgsten:Janssen-Cilag: Employment.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Patient Related Factors Have an Indepedent Impact on Overall Survival in Myelodysplastic Syndrome Patients: A Report of the MDS-Can Registry

Blood ◽

10.1182/blood.v124.21.165.165 ◽

2014 ◽

Vol 124 (21) ◽

pp. 165-165

Author(s):

Rena Buckstein ◽

Richard A. Wells ◽

Nancy Zhu ◽

Thomas J. Nevill ◽

Heather A Leitch ◽

...

Keyword(s):

Overall Survival ◽

Physical Performance ◽

Predictive Factors ◽

Research Funding ◽

Performance Tests ◽

Related Factors ◽

Risk Of Death ◽

The Impact ◽

Very High

Abstract Introduction: MDS is a disease of the elderly; yet, the impact of clinical frailty (an age-related vulnerability state created by a multidimensional loss of reserves) and patient-reported outcomes on overall survival (OS) are unknown. Rockwood et al. have developed a simple 9-point clinical frailty scale (CFS) that correlated highly with the risk of death, institutionalization, worsening health and hospital use (Rockwood K., CMAJ 2005). In a prospective, national MDS registry, participants have undergone annual evaluations with the following: (a) 3 geriatric physical performance tests, (b) Charlson (CCI) and Della Porta comorbidity index (DP-CCI) scores, (c) graded frailty using the Rockwood CFS, (d) disability assessments with the Lawton Brody SIADL, and (e) QOL using the EORTC QLQ C-30 and the EQ-5D. The results of these frailty assessments and the effects of these patient-related factors and reported outcomes on OS, in addition to the IPSS/revised IPSS, will be presented. Methods: Overall survival was measured from time to enrollment. Results from physical performance tests were divided into quintiles with higher scores indicating better performance. We used univariate and multivariable Cox proportional hazard model to determine significant predictive factors of overall survival (OS). The variables considered included age, IPSS, R-IPSS, ferritin, LDH, transfusion dependence, hemoglobin (hgb), ECOG, frailty, CCI and DP-CCI, grip strength, 4 M walk test, stand-sit test, modified short physical performance battery (SPPB), Lawton Brody SIADL, time from diagnosis and selected QOL domains including the EQ-5D summary score, EORTC physical functioning, dyspnea and fatigue scores. Results: 453 MDS patients (pts) have been consented and enrolled locally since January 2008 (n=231) and nationally since January 2012 (n=222). Median time from diagnosis was 5.8 mos (IQR 1.4-21). Median age was 73 y (range, 26-95 y), 65% were male and the R-IPSS scores were very low (14%), low (46%), intermediate (24%), high (10%) and very high (6%). Thirty-three % of pts were transfusion dependent at enrollment. Median CCI and DP-CCI scores were 1 (0-12) and 0 (0-6) respectively with 18% and 24% falling into the highest category scores. Median frailty scale score (n=346) was 3 (1-9) with 25% having scores indicating moderate (4-5) or severe (6-9) frailty. The CCI and DP-CCI strongly correlated (r=0.6; p< .0001) with each other, while frailty significantly but modestly correlated with them (r=0.3-0.35, p<.0001). With a median follow up (from enrollment) of 15 mos (95% CI: 13-16), 159 (35%) pts have died and 28 pts lost to follow up. Actuarial survival was 41.0 mos (range, 33.6 - 48.5 mos). When considering patient related factors - age, frailty, comorbidity (both indices), sex, ECOG, the 10 x stand sit test, the SPPB, Lawton Brody SIADL, and all QOL domains considered above were significantly predictive of OS. The multivariable model with the highest R2 included R-IPSS (p=.0004), frailty (1-3 vs 4-9, p= .004), CCI (0-1 vs >2, p=.03) and EORTC fatigue (p=.01) as summarized in Table 1 below. A frailty score > 3 predicted for worse survival (figure 1: 2 year OS 68.5% vs. 83.8%) and further refined survival within the R-IPSS categories (Figure 2). Frailty was also the single most predictive factor for OS from the start of azacitidine therapy (not shown). Conclusions: Patient-related factors such as frailty and comorbidity (that evaluate physiologic reserve and global fitness) should be considered in addition to traditional MDS prognostic indices. Abstract 165. Table. Independent Covariate Predictive factors at baseline Coefficient SE p -value HR 95% CI of HR R2 (%) Time from diagnosis (months) * 0.0335 0.1076 0.7557 1.034 0.837 1.277 17.29% R-IPSS (5 categories) <.0001 Very high vs. very low 2.5701 0.7289 0.0004 13.066 3.131 54.524 High vs. very low 2.1156 0.6437 0.0010 8.294 2.349 29.285 Intermediate vs. very low 1.0466 0.6430 0.1036 2.848 0.808 10.043 Low vs. very low 0.6346 0.6181 0.3045 1.886 0.562 6.334 Frailty (1-3 vs. 4-9) -0.8323 0.2905 0.0042 0.435 0.246 0.769 Comorbidity Charlson (0-1 vs. ³2) -0.5915 0.2749 0.0314 0.553 0.323 0.949 EORTC fatigue * 0.3671 0.1546 0.0176 1.443 1.066 1.954 natural log-transformation was applied for normalizing distribution Figure 1 Overall survival by Frailty (n=346) Figure 1. Overall survival by Frailty (n=346) Figure 2 Overall Survival by Frailty and R-IPSS Figure 2. Overall Survival by Frailty and R-IPSS Disclosures Buckstein: Celgene Canada: Research Funding. Wells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Leitch:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Educational Grant Other, Honoraria, Research Funding. Shamy:Celgene: Honoraria, Other.

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Persistent Overall Survival Benefit and No Increased Risk of Second Malignancies With Bortezomib-Melphalan-Prednisone Versus Melphalan-Prednisone in Patients With Previously Untreated Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.6180 ◽

2013 ◽

Vol 31 (4) ◽

pp. 448-455 ◽

Cited By ~ 168

Author(s):

Jesús F. San Miguel ◽

Rudolf Schlag ◽

Nuriet K. Khuageva ◽

Meletios A. Dimopoulos ◽

Ofer Shpilberg ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Final Analysis ◽

Incidence Rates ◽

Phase Iii ◽

Second Primary ◽

Risk Of Death ◽

Increased Risk ◽

Second Primary Malignancies

Purpose This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. Patients and Methods In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients. Results After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. Conclusion VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.

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Bortezomib Plus Melphalan–Prednisone Continues to Demonstrate a Survival Benefit Vs Melphalan–Prednisone in the Phase III VISTA Trial in Previously Untreated Multiple Myeloma After 3 Years' Follow-up and Extensive Subsequent Therapy Use.

Blood ◽

10.1182/blood.v114.22.3859.3859 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3859-3859 ◽

Cited By ~ 2

Author(s):

Maria-Victoria Mateos ◽

Paul G Richardson ◽

Rudolf Schlag ◽

Nuriet K Khuageva ◽

Meletios A. Dimopoulos ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Ortho Biotech ◽

Equity Ownership

Abstract Abstract 3859 Poster Board III-795 The initial results of the pivotal, international, phase III VISTA trial demonstrated the superiority of bortezomib (Velcade®) plus melphalan–prednisone (VMP) versus MP alone across all efficacy end points, including overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008). We conducted a planned updated survival analysis of VISTA after a median >3 years of follow-up and with the majority of patients having received subsequent therapy. We confirmed the previously demonstrated OS benefit of VMP versus MP, examined the use of subsequent therapy and its efficacy following VMP and MP, and evaluated the survival of patients who had received subsequent therapy. Patients were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies. The median age of patients was 71 years, 30% were aged ≥75 years, 34% had ISS stage III MM, and 33% had β2-microglobulin >5.5 mg/L. After median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP vs MP (hazard ratio [HR] 0.653, p=0.0008); median OS was not estimable vs 43.1 months, and 3-year OS rates were 68.5% vs 54.0% with VMP vs MP, respectively. This OS benefit was seen consistently across patient subgroups predefined by baseline characteristics. Within the VMP arm, OS was longer among patients aged <75 vs ≥75 years (HR 1.664, p=0.011; 3-year OS: 74.1% vs 55.5%); by contrast, there were no significant differences, although there were trends to longer OS among patients with creatinine clearance ≥60 versus <60 mL/min (HR 1.291, p=0.238; 3-year OS: 74.5% vs 63.1%) and patients with standard- vs high-risk cytogenetics (HR 1.346, p=0.399; 3-year OS 71.6% vs 56.1%). At data cut-off (16 March 2009), 178 (52%) VMP and 233 (69%) MP patients had received subsequent therapy; median time to subsequent therapy (28.1 vs 19.2 months, HR 0.527, p<0.0001) and median treatment-free interval (17.6 vs 8.4 months, HR 0.543, p<0.0001) were superior with VMP vs MP. Receipt of and response to subsequent bortezomib-, thalidomide-, and lenalidomide-based therapy are summarized in the Table. Median survival from start of subsequent therapy following VMP and MP was 30.2 vs 21.9 months (HR 0.815, p=0.21) among all patients receiving subsequent therapy. This updated analysis of VISTA confirms that VMP results in significantly longer OS compared with MP, despite 50% of MP patients being rescued with bortezomib-based therapy in the relapsed setting. VMP treatment used upfront appears more beneficial than treating with conventional agents and saving bortezomib- and other novel-agent-based treatment until relapse. Subsequent therapies appeared similarly effective in the VMP and MP arms, with our analysis also demonstrating the benefit of retreatment with bortezomib-based therapies following VMP. In addition, post-relapse survival among all patients receiving subsequent therapy appeared longer following VMP, indicating that frontline bortezomib use does not induce more resistant relapses. Table Response among patients who received subsequent therapy VMP (N=178) MP (N=233) Received subsequent therapy containing:* Bortezomib, n (%) 43 (24) 116 (50) Thalidomide, n (%) 81 (46) 110 (47) Lenalidomide, n (%) 57 (32) 30 (13) Overall response rate (%) to subsequent therapy: Bortezomib-based 47 59 Thalidomide-based 41 53 Lenalidomide-based 59 52 * Patients could have received >1 agent, either in combination or separately in different subsequent lines of therapy Disclosures: Mateos: Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Kropff:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Millennium: Research Funding. Schots:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esseltine:Millennium: Employment, Equity Ownership. Liu:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Updated Results of a Phase 2 Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVd-lite) in Transplant-Ineligible Multiple Myeloma

Blood ◽

10.1182/blood-2019-128000 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3178-3178 ◽

Cited By ~ 1

Author(s):

Elizabeth K. O'Donnell ◽

Jacob P. Laubach ◽

Andrew J. Yee ◽

Robert Redd ◽

Carol Ann Huff ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Future Perspective ◽

Low Grade ◽

Advisory Committees ◽

Grade 3

PURPOSE: This updated analysis examined survival outcomes after 60 months of follow-up in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with the 3-drug regimen of modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population. METHODS: RVD lite was administered over a 35-day cycle. Lenalidomide 15 mg was given orally days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; dexamethasone 20 mg orally day of and after bortezomib for 9 cycles followed by 6 cycles of consolidation. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal, and hematologic function. Primary objective was to evaluate overall response rate (ORR). Secondary objectives included evaluation of safety, progression free survival (PFS), overall survival (OS), and the pharmacokinetic (PK) profile of intravenous (IV) and SC bortezomib. RESULTS: Fifty-three eligible patients enrolled between 4/17/13 and 7/25/15; 50 received at least one dose of therapy. As previously reported, the median age at study entry was 72 years (range 65-91). ISS stage was I in 19 (38%), II in 17 (34%), and III in 14 (28%) pts. Fatigue was the most commonly reported toxicity occurring in 37 (74%) and was mostly grade 1 or 2 in 29 (58%). Other grade 3 or greater toxicities included hypophosphatemia in 17 (34%), neutropenia in 7 (14%), and rash in 5 (10%) pts. Low grade peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. There were statistically significant improvements in scores of physical functioning (p=0.013), future perspective (p=0.023) and disease symptoms (p=0.001). Patients reported fewer symptoms across all symptom domains with the exception of diarrhea. The ORR was 86% and 66% of patients achieved a very good partial response (VGPR) or better. The median time to response was 1.1 months. At a follow-up of 61 months, median PFS was 41.9 months (95% CI, 31.2 - ∞) and median OS not reached. The 5-year overall survival was 61.3%. Sixty-six percent of patients received lenalidomide maintenance. CONCLUSIONS: RVD lite is a well-tolerated and highly effective regimen in the transplant-ineligible population with robust PFS and OS. Our data demonstrate that the benefits of more effective combination strategies observed in younger, fitter, transplant-eligible patients can be effectively used in older, transplant-ineligible patients with modifications in dose and schedule, without compromising efficacy. Disclosures O'Donnell: Celgene: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Yee:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Munshi:Celgene: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Oncopep: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder . Richardson:Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raje:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy.

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Real-World Differences in Characteristics and Survival of Relapsed AML Patients with and without Transplant

Blood ◽

10.1182/blood-2018-99-118621 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2297-2297

Author(s):

Abdalla Aly ◽

Saurabh Ray ◽

Anuj Shah ◽

Marc Botteman

Keyword(s):

Overall Survival ◽

Real World ◽

Research Funding ◽

Cell Transplant ◽

Employment Equity ◽

Risk Of Death ◽

Hazard Ratios ◽

Equity Ownership ◽

To Receive

Abstract Background: Some AML patients, particularly those relapsing rapidly, may not get a chance to receive a potentially curative stem cell transplant (SCT) due to early death, among other reasons. This study compares the differences in characteristics and survival of relapsed AML patients with and without SCT, as observed in a real-world setting. Methods: Relapsed AML patients aged 66-75 years were identified from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database by medical claims associated with ICD-9 code 205.02 (2009-2014). Patients were followed from relapse to the earliest of death, SCT, or end of follow-up. Baseline characteristics were compared between relapsed AML patients with and without SCT. The SCT rates were estimated after adjusting for the competing risk of death. The Fine and Gray method was used to identify predictors of receiving SCT and were reported in terms of sub-distribution hazard ratios (SHR) and 95% confidence intervals (CI). Kaplan-Meier estimates (reported in terms of median and 6-, 12-, and 24-months survival rates, tested with a log Rank test statistic) and a Cox proportional hazards model adjusting for age, sex, race, Census region, marital status, urban location, Charlson comorbidity index (CCI), and diagnosis year (reported in terms of hazard ratios (HR) and 95% CI) was used to assess the difference in survival between patients with and without SCT. Results: Of the 474 relapsed AML patients (median age, 70 years, median follow up, 4.4 months, male, 55%) included in the study, 8% received SCT, 80% died without having SCT and 12% were administratively censored. Patients were less likely to receive SCT if they were 71-75 years old (SHR 0.28, 95% CI (0.19 to 0.41; P <.001) and had higher comorbidity with CCI >3 (SHR 0.16, 95% CI (0.06 to 0.44; P <.001). The median overall survival was 16.1 months for patients with SCT vs. 4.1 months for those without SCT (log rank P <.001; adjusted HR 0.52, 95% CI (047 - 0.57; P <.001)). The 6-, 12-, and 24-month overall survival for all relapsed AML patients was 42%, 26%, and 12%, respectively. For patients with SCT, the 6-, 12-, and 24-month overall survival was 84%, 59%, and 43%, respectively. For patients without SCT, the 6-, 12-, and 24-month overall survival was 39%, 23%, and 12%, respectively. Conclusions: Relapsed AML patients who received SCT experienced significantly longer survival compared to those who did not receive SCT in this elderly study population. However, only 8% of all relapsed AML patients received SCT. Therapies that bridge more patients to SCT are expected to improve overall survival in this high unmet need population. Disclosures Aly: AstraZeneca: Research Funding; Celgene: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Research Funding; Daiichi Sankyo Incorporated: Research Funding. Ray:Daiichi Sankyo Incorporated: Employment, Equity Ownership. Shah:Celgene: Research Funding; Pharmerit International: Employment, Research Funding; Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Celgene: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding.

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Changes in Uninvolved Immunoglobulins during Multiple Myeloma Therapy

Blood ◽

10.1182/blood.v128.22.3251.3251 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3251-3251

Author(s):

Praful Ravi ◽

Shaji Kumar ◽

Wilson I Gonsalves ◽

Francis K Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Treatment Response ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Advisory Committees ◽

Percentage Difference ◽

Lower Likelihood

Abstract Background Suppression of uninvolved immunoglobulins is a common finding in multiple myeloma and the preservation of uninvolved immunoglobulins at diagnosis is associated with improved progression-free and overall survival. However, little is known about the impact of myeloma treatment on levels of uninvolved immunoglobulins, and the link between changes in uninvolved immunoglobulins during therapy and treatment response, disease progression and survival. Methods We identified patients who received therapy for newly diagnosed multiple myeloma at our institution between 2001 and 2014, and who had data available on absolute lymphocyte count (ALC) and quantitative uninvolved immunoglobulins (Ig) before commencing treatment. The ALC and levels of uninvolved Ig after 4 cycles of therapy were abstracted from the electronic medical record; patients who switched or stopped treatment, or died, before this time point were excluded. To assess change in ALC, the percentage difference in ALC between baseline and 4 cycles was calculated; for uninvolved Ig, the average of the percentage difference between baseline and 4 cycles for each uninvolved Ig (IgA and IgM for IgG myeloma, IgG and IgM for IgA myeloma, IgG and IgA for IgM and IgD myeloma, and IgG, IgM and IgA for light-chain only myeloma) was calculated. Treatment response at 4 cycles was retrospectively assigned according to International Myeloma Working Group criteria. Time to treatment failure (TTF) was defined as time from start of initial therapy to start of next line of therapy or death (if no additional treatment was received). A landmark analysis was used to calculate overall survival (OS) from the date of follow-up after 4 cycles of therapy. The Kruskal-Wallis, Chi-Square, and log rank tests were used to detect differences in medians, proportions, and survival times respectively. Results A total of 421 patients were included in this analysis. The median age was 63 years (range 33-91), 254 patients (60.3%) were male and median follow-up was 6.5 years (95% CI 5.6-7.3); the vast majority of patients had IgG (n=247 [58.7%]), IgA (n=98 [23.3%]) or light-chain only myeloma (n=68 [16.2%]). First line therapy comprised of pulse-dose dexamethasone (DEX, n=92 [21.9%]), lenalidomide-dexamethasone (RD, n=176 [41.8%]), bortezomib-dexamethasone (VD, n=22 [5.2%]), bortezomib-cyclophosphamide-dexamethasone (VCD, n=84 [20.0%]), and bortezomib-lenalidomide-dexamethasone (VRD, n=47 [11.2%]). Across the entire cohort, the median change in ALC and uninvolved Ig after 4 cycles of treatment was -11.0% (range: -92.7 to +718.8) and +9.0% (-77.7 to +1094.4) respectively; treatment with VCD was associated with the greatest median declines in ALC (DEX: -0.1%; RD: -9.9%; VD: -20.8%; VCD: -40.9%; VRD: -15.3%) and uninvolved Ig (DEX: -0.5%; RD: +15.5%; VD: +44.0%; VCD: -14.0%; VRD: +76.0%, both p<0.001). Conversion from suppression to normalization of the primary uninvolved Ig (IgA in IgG myeloma, and IgG in all other myeloma types) after 4 cycles was seen more frequently with the use of RD (13.1%) and VRD (12.8%) compared to DEX (4.7%), VCD (1.3%), or VD (4.8%), χ2=21.8, p=0.040. When considering only patients in whom the primary uninvolved Ig remained suppressed between baseline and 4 cycles, a ≥25% reduction in the primary uninvolved Ig occurred more frequently with the use of DEX (51.5%) and VCD (34.5%) compared to RD (24.8%), VD (23.5%) or VRD (25.7%), χ2=15.1, p=0.005 (Table 1). Although an average reduction in uninvolved Ig between baseline and 4 cycles (ΔIg<0) was independently associated with a lower likelihood of achieving very good partial response (VGPR) of better on multivariate analysis adjusting for age, sex and treatment regimen (OR=0.40 [0.24-0.63], p<0.001), there were no differences in TTF (2.0yrs vs. 2.0yrs, p=0.783) or OS (8.0yrs vs. 8.0yrs, p=0.721) between patients with ΔIg<0 (n=169) and those with ΔIg≥0 (n=222). Conclusions Myeloma treatments produce differential impacts on immune parameters, with VCD causing the greatest reduction in lymphocytes and uninvolved Ig, implying general targeting of plasma cells, in comparison to lenalidomide, which appeared to be more tumor-specific with relative sparing of lymphocytes and uninvolved Ig. While an average decrease in uninvolved Ig was an independent predictor of a lower likelihood of achieving VGPR or better after 4 cycles of therapy, it was not associated with a shorter TTF or poorer OS. Disclosures Kumar: BMS: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; Millennium: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Dispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding.

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Analysis of 179 Patients with Newly Diagnosed Multiple Myeloma (MM) Treated with Novel Agents Followed by Autologous Stem Cell Transplantation (ASCT): a Retrospective Study

Blood ◽

10.1182/blood.v116.21.1343.1343 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1343-1343

Author(s):

Joyce Habib ◽

Neil Dunavin ◽

Gary Phillips ◽

Patrick Elder ◽

Meaghan Tranovich ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Research Funding ◽

Progression Free Survival ◽

Novel Agents ◽

Genetic Profile ◽

Newly Diagnosed ◽

Free Survival

Abstract Abstract 1343 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States with an estimated 20,580 new cases in 2009. Over the past decade, the introduction of novel agents (thalidomide, lenalidomide and bortezomib) have played a pivotal role in improving response rates, duration of response, overall survival (OS) and quality of life. In this study we describe a single center experience with novel agents used for induction followed by high dose chemotherapy (HDT) and first autologous stem cell transplant (ASCT) in patients with MM. Method: A retrospective review of the medical records of 179 newly diagnosed patients with MM seen between October 2006 and December 2009 at The Ohio State University was performed. All patients received novel therapy containing thalidomide, bortezomib or lenalidomide as part of an induction regimen followed by ASCT. All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to plot progression free survival and overall survival. Results: Of the 181 patients seen, 2 were excluded because they did not receive a novel agent as part of induction treatment. Of the 179 patients analyzed, median age was 56.8 years (29-80) with 30% of patients older than 60 years. African American represented 19%. Fifty-nine percent were male, 80% had Durie-Salmon (DS) stage III while 25%, 28%, 18% represented International prognostic score (IPS) stage I, II, and III respectively with 27% unknown. Median comorbidity index score was 2 (2-7) and median Karnofsky performance score (KPS) was 90% (70-100). Thirty percent had high risk genetic profile, and 73% received one line of treatment before ASCT. The median time from diagnosis to ASCT was 8.33 months (4-58). The overall response rate (ORR) prior to transplant was 84% (9% complete (CR), 29% very good partial (VGPR), and 46% partial (PR)). The ORR post ASCT was 89% (CR 45%, VGPR 22%, PR 21%). Non relapse mortality was 1% and 3% at 100 days and 1 year respectively. At a median follow up of 31 months (7-90), 69 patients (38%) had relapsed. Median progression free survival (PFS) was 29 months with 1 and 3 years PFS of 79.3% and 61.5% respectively (Fig. 1). The OS was not reached. One and 3 years OS were 93% and 88% respectively (Fig. 1). Univariate analysis showed that time to transplant > 12 months was associated with poor outcome and decreased overall survival (HR 3.30, p = 0.008). High risk genetic profile was also found to be associated with decreased overall survival although this was not statistically significant (HR 2.31, p = 0.070). Multivariate analysis found that only time to transplant > 12 months was an independent predictor of decreased OS. Significant predictors for disease progression were high risk genetic profile and time to transplant > 12 months in patients receiving 2 or more treatments before ASCT. Conclusion: Induction with novel agents followed by HDT and ASCT improves CR rate, in our case from 9% to 45%. Median PFS (29 months) was comparable to other published data. OS was not been reached after a median follow up of 31 months. Predictors of progression include high risk genetic profile and time to transplant > 12 months. The only significant predictor for survival was time to transplant. Our study suggests that an early transplant may improve OS and PFS. An extended analysis will be presented at the meeting. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

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Long-Term Survivorship with Active Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-120152 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1912-1912

Author(s):

Brett Grieb ◽

Jithma Prasad Abeykoon ◽

Saurabh Zanwar ◽

S. Vincent Rajkumar ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Short Term ◽

Advisory Committees ◽

Entire Cohort ◽

Long Term Survivors

Abstract Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been attained. Prior literature has used 10 years as a cutoff for "long-term survivorship". In this study, we have assessed the biological disease characteristics and outcomes of long-term survivors with MM (≥10 years from active disease). Methods All patients with active MM evaluated at the Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study after approval of the Institutional Review Board. Patients with smoldering multiple myeloma were excluded. The overall survival (OS) was calculated from the time of symptomatic disease requiring treatment. Patients were then divided into two cohorts: (1) long-term survivors, which included patients who had an overall survival of at least 10 years; and (2) short-term survivors, which included patients who had an overall survival of less than 5 years from the diagnosis of active MM. The baseline characteristics between these two groups were compared using Wilcoxon, chi-square, and Fisher's exact test as applicable. All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using Log-Rank test. Results During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. The median follow-up for the entire cohort was 12.6 years (95% CI: 12.5-13.4).The median OS for the entire cohort was 4.4 years (95% CI: 4.2-4.7 years). Three-hundred and ninety nine (18.7%) patients survived at least 10 years whereas 872 patients (41%) survived less than 5 years from the date of initial diagnosis. The median OS was 14.1 years for the long-term survivors (95% CI: 13.9-14.6 years) and 2.1 years for the short-term survivors (95% CI: 1.8-2.2 years). The clinical features at diagnosis comparing long-term survivors and short-term survivors are shown in Table 1. Among long-term survivors (n=399), based on the available data regarding remission and ongoing treatment status, 331 patients were categorized into 6 cohorts (Table 2). The MM specific survival data of these 6 cohorts is depicted in Table 2.Figure 1 shows survival outcomes from the 10-year landmark. Of the 6 cohorts, 38 patients in Cohort 1 and 19 patients in Cohort 2 (total 57; 17% of long term survivors, ~3% of the entire cohort ) have been off therapy for at least 5 years and remain in remission, representing a distinct group of patients with 100% 15-year survival. Conclusion In our large database with prolonged follow-up, long-term survivors appear to have distinct baseline characteristics, but also constitute a heterogenous group of patients with disparate outcomes. A small subset (17% of long-term survivors) was identified that may represent patients closest to being considered as 'operationally cured'. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; annexon: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

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The Impact of Induction Regimen Choice on Transplant Outcome and Survival in Newly Diagnosed Multiple Myeloma in the Era of Novel Agents

Blood ◽

10.1182/blood.v126.23.3044.3044 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3044-3044

Author(s):

Rajshekhar Chakraborty ◽

Shaji Kumar ◽

Francis Buadi ◽

David Dingli ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Research Funding ◽

Novel Agents ◽

Agent Based ◽

Induction Regimen ◽

Baseline Characteristics ◽

The Impact ◽

Novel Agent

Abstract Background Induction with novel agents, including proteasome inhibitors and immunomodulators, prior to autologous stem cell transplantation (ASCT) is the standard of care frontline treatment of transplant-eligible patients with multiple myeloma (MM). Common novel agent-based induction regimens include three drug combinations with a backbone of bortezomib (V), thalidomide (T) and/or lenalidomide (R). There is limited information on the comparative efficacy of novel regimens used as part of initial therapy prior to an ASCT in terms of overall survival (OS). To address this question, we retrospectively analyzed 1096 consecutive patients undergoing ASCT for MM at Mayo Clinic. Methods Study patients included those who underwent first transplant within 12 months of diagnosis, did not receive more than one induction regimen, did not relapse prior to transplant and did not receive treatment for smoldering MM in the past. Baseline characteristics, response rates and survival data were extracted from an electronic medical record and statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Choice of induction regimen was almost exclusively made by the referring physician. Results Median age at diagnosis was 60.3 years (Interquartile range 53.9-65.9). ISS staging at diagnosis was available for 49.7% of patients, of which, 34.2%, 39.3% and 26.5% of patients had ISS stage 1, 2 and 3 disease, respectively. Estimated median follow up was 65.6 months (95% CI 58.3-73.3). Baseline characteristics of patients by initial treatment have been summarized in table 1. Major subgroups by induction therapy included patients receiving Cy-Bor-d (n=193, 17.6%), Vd (n=64, 5.83%), Rd (n=253, 23.1%), VRd (n=126, 34.6%), Td (n=157, 14.3%) and VAD or dexamethasone alone as the non-novel agent comparator group (n=229, 20.9%). Median overall survival (OS) was significantly different between novel agent-based and conventional regimens (Log-rank test; p=0.0029), which were 102.7 months (95% CI, 95.2-112.2) and 78.8 months (95% CI, 67.8-92.6) respectively. Median OS with each regimen is shown in table 1. Among novel agent-based regimens, there was no significant difference in median OS, except Td, which was inferior to Rd (HR 1.62; 95% CI 1.17-2.24). Conclusion We cannot demonstrate with overall survival as an endpoint that the doublets of Vd and Rd are inferior to VRd or Cy-bor-d. There were insufficient patients treated with VTd to be included. Our study shows that the choice of novel induction regimen prior to ASCT does not affect survival (with the exception of Td being inferior to Rd), reflecting the wide array of effective salvage options. However, further prospective randomized clinical trials comparing these regimens are required to validate these findings. Table 1. Baseline characteristics and overall survival. Baseline characteristics and survival Cy-Bor-d (n=193) Vd (n=64) Rd (n=253) VRd (n=126) Td (n=157) VAD or Dex (n=229) p-value Median age 61.9 62.15 60.8 60.8 59.3 58.5 0.0041 Sex (percent males) 56.48 57.81 56.92 61.91 57.96 59.82 0.9271 ISS at diagnosis 1:24.82% 2:40.69% 3:34.48% 1:29.73% 2:24.32% 3:45.94% 1:40% 2:43.78% 3:16.22% 1:41.76% 2:34.06% 3:24.18% 1:28% 2:36% 3:36% 1:20% 2:60% 3:20% 0.0005 Median follow-up (95% CI) 20.3 (17.1-22.7) 49.5 (44.7-55.7) 59 (54.5-67) 26.9 (22.8-30.7) 126.7 (120.2-132.9) 143.4 (132.5-152.6) <0.0001 Median OS Not reached (Estimated 5 year OS rate 75%) 97.2 months (95% CI, 66.6-NR) 112 months (95% CI, 97.4-124.3) Not reached (Estimated 5-year OS rate 77%) 81.1 months (95% CI, 59.1-99.1) 78.8 months (95% CI, 67.8-92.6) 0.0019 Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria.

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