Follow-up of Real Life Treated Multiple Myeloma Patients: Response, Disease Progression and Overall Survival,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3937-3937
Author(s):  
Hareth Nahi ◽  
Johan Liwing ◽  
Katarina Uttervall ◽  
Johan Andreasson ◽  
Astrid Gruber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Real Life ◽  
M Protein ◽  
Novel Agents ◽  
Response Distribution ◽  
Employment Equity ◽  
Study Population ◽  
Equity Ownership

Abstract Abstract 3937 Treatment results in clinical practice and in real life can be different from each other. Therefore, evaluating real life outcomes in Multiple Myeloma (MM) patients in order to understand treatment outcome in clinical practice is very important. All patients diagnosed with MM and treated between Jan 2000 and Jul 2010 at Karolinska University Hospital, Huddinge and Södersjukhuset were included. Furthermore, all diagnosed patients between Jan 2005 and Jul 2010 at Karlolinska University Hopital, Solna were included. At diagnosis data regarding age, gender, type of myeloma and skeleton destruction as well as Ca, Hb, β2-microglobelin, albumin and creatinine were collected. For each treatment line, drugs given and specific start and stop dates for each drug were collected. Serum and urine M-protein was collected at baseline and each time the measurement differed from the previous. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis but not always confirmed by immunofixation since it was not required in clinical practice. Partial response (PR) was defined as a 50% reduction in M-protein. No response (NR) was defined as less than 50% reduction of M-protein. Progress was considered when M-protein increased with ≥ 25%. Novel agents were defined as bortezomib, lenalidomide and thalidomide. In the total population n=674, 89 (13%) patients were excluded due to non treatment demanding disease or plasmacytoma without MM diagnosis setting the study population to n=585. The median follow up of the study population was 815 days. The median age in the study population was 68 years and 45% were women. High dose treatment (HDT) was given to 214 (37%) patients. The median age in the HDT population was 58 years and 34% were women. The median age in the non-HDT population was 75 years and 51% was women. The median number of given treatment lines was 2. The proportion of patients receiving more treatment lines were declining rapidly with the number of received lines of therapy. The response distribution for the entire population nCR/PR/NR was 27/41/32 in 1st line, 18/34/48 in 2nd line. In the HDT population the same response distribution was 50/38/12 in 1st line and 28/38/34 in 2nd line. In the non-HDT population the response distribution was 14/43/43 in 1st line and 12/33/55 in 2nd line. The depth of the responses was significantly dependent on the line of therapy. Responses were significantly better in the HDT population vs. the non-HDT population in the first two treatment lines. There seems to be a correlation between the responses in 1st and 2nd line in the entire population. Improving the responses in 2nd line compared to 1st line seems not very likely. Statistical analysis shows that the non-HDT patients receiving novel agents in 1st line had a significantly higher probability of achieving nCR, 25% vs 9%.The same statistical difference was seen in the HDT patients with nCR rates of 65% vs 47%. The median TTP/TTNT for the study population was 309/381 days in the 1st line and 182/210 in 2nd line. In the HDT population the TTP/TTNT was 538/639 days in 1st line and 199/257 in 2nd line. In the non-HDT population the TTP/TTNT was 244/295 days in 1st line and 177/193 in 2nd line. In the HDT population both the TTP and the TTNT in the 1st line were significantly better than in the non-HDT population with no difference in the 2nd line. There was a significant trend of increasing TTP/TTNT in 1st line depending on the increased depth of the response. Statistical analysis showed that the use of novel agents in 1st line predicted a longer TTP for the non-HDT population. Median OS was 4.3 years 95% CI [3.9;5.0] with 53% censored. HDT patients had a significant longer median OS 6.3 years 95% CI [5.4;8.5] than the non-HDT patients OS 3.0 years 95% CI [2.2;3.6]. The median OS for non-HDT patients with 1st line best response nCR was 4.9 years, PR 3.3 years and NR 1.5 years. Kaplan-Mayer analysis shows that use of novel agents in the 1st line predicted a longer OS, median 5.1 years vs. 4.1 years. Patients receiving 2nd and 3rd line treatment were declining rapidly. To get a good response in 1st line increases the likelihood of having a good response in 2nd line. Receiving an nCR in 1st line seems to be very important and this study confirms the prognostic impact of achieving at least nCR. The use of novel agents improves the outcome for patients in clinical practice. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Näsman:Janssen-CIlag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Is Multiple Myeloma a Chronic Disease? A Population Based Study Comparing 1843 Patients to a Matched Swedish Population.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2970-2970 ◽  
Author(s):  
Hareth Nahi ◽  
Johan Liwing ◽  
Anders Aldrin ◽  
Johan Andreasson ◽  
Cecilie Blimark ◽  
...  
Keyword(s):  
Chronic Disease ◽  
Normal Population ◽  
M Protein ◽  
Novel Agents ◽  
High Dose ◽  
Response Distribution ◽  
Employment Equity ◽  
Swedish Population ◽  
Population Figure ◽  
Equity Ownership

Abstract Abstract 2970 Evaluating real life outcomes in Multiple Myeloma (MM) pts in order to understand treatment outcome in clinical practice is very important. The introduction of novel agents (Bortezomib, Thalidomide, Lenalidomide) has been shown to increase overall survival (OS). Can MM be regarded as a chronic disease, defined as a similar OS as a matched normal population at diagnosis, after the introduction of novel agents? All pts diagnosed with MM since earliest Jan 2000 until latest Jun 2011 from 6 university clinics, 3 regional centers and 4 local hospitals in Sweden were included. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis. Partial response (PR) was defined as a 50% reduction in M-protein, no response (NR) as less than 50% reduction and progress was considered when the increase was ≥ 25%. The Swedish population (n = 9 340 682 in 2009) was used to select a gender and 5-yrs age strata matched cohort based on 2008–2010 observed death rates. In the total MM population n=1 843, 201 (11%) pts were excluded due to non treatment demanding disease setting the study population to n=1 642. The median follow up of pts still alive was 30 months. The median age was 70 yrs and 45% women. The most common subtype was IgG (59%) followed by IgA (22%), BJ (15%) and Other (4%). High dose treatment (HDT) was given to 517 (32%) pts. The median number of given treatment lines in both the HDT and the non-HDT population was two but the number of pts receiving more treatment lines were declining rapidly. The response distribution for the HDT population nCR/PR/NR was 47/41/12% in 1st line (induction and high-dose melphalan) and 25/42/33% in 2nd line. In the non-HDT population the response distribution was 14/42/44% in 1st line and 11/31/58% in 2nd line. Non-HDT pts receiving novel agents in 1st line had significantly higher nCR rates compared to pts receiving older drugs, 22% vs. 12% as well as pts receiving novel agents in 2nd line with nCR rates of 16% vs. 6%. In the HDT population the median time to progression/time to next treatment (TTP/TTNT) was 21.0/29.7 months in 1st line and 8.1/12.7 in 2nd line. In the non-HDT population the median TTP/TTNT was 11.0/16.8 months in 1st line and 7.3/11.4 in 2nd line. There was a significantly increased TTP/TTNT in 1st and 2nd line depending on the increased depth of the response for both the HDT and non-HDT populations. The median OS for HDT pts was 6.7 yrs 95% CI[6.1;7.6] and correlated with 1st line response (nCR 7.6, PR 6.1 and NR 6.2 yrs). When comparing HDT pts to the matched normal population the 1-year survival was 97% vs. 99%, 3-year survival 86% vs. 98% and 5-year survival 66% vs. 95%. The median OS for non-HDT pts (n=1080) was 2.7 yrs 95% CI[2.5;3.0] and increased with better response in 1st line; nCR 3.4, PR 3.0 and NR 1.9 yrs. Kaplan-Mayer analysis showed that the use of novel agents in 1st line (n=316, median age 72.1 yrs) predicted a significantly longer OS compared to conventional treatment (n=764, median age 75.4), median 4.9 vs 2.3 yrs. When comparing pts that received at least two lines of treatment, pts treated with novel agents in 1st line followed by novel agents in 2nd had not reached the median survival but had a lower CI of 6.3 yrs, novel agents in 1st line followed by old agents in 2nd line had a median OS of 4.3 yrs old agents in 1st line followed by novel agents in 2nd line had a median of OS 3.3 yrs and old agents in 1st line followed by old agents in 2nd line had a median of OS 3.0 yrs. Compared to the matched normal population non-HDT pts receiving novel agents in both 1st and 2nd line the 1-year survival was 90 % vs. 96%, 3-year survival 71% vs. 86% and 5-year survival 67% vs. 77%. The number of pts receiving 2nd and 3rd line treatment declined rapidly. Non-HDT pts treated with novel agents in 1st line had a superior response and OS compared to the group treated with standard chemotherapy. Pts treated with novel agents in 2nd line as well seem to have a further improved survival compared to other alternatives. In comparison to a normal population, matched for gender and age at diagnosis, the survival is still shorter. However, if novel agents were used in an optimal treatment sequence the survival could potentially be higher. There is still a need for further development in MM treatment before one can call it a chronic disease. Figure 1: HDT treated pts compared to a matched normal population Figure 1:. HDT treated pts compared to a matched normal population Figure 2: Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Figure 2:. Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Mellqvist:Janssen, Celgene: Honoraria. Näsman:Janssen-Cilag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Is Adherence to the American College of Chest Physicians Recommended Anticoagulation Treatment Duration Associated with Different Outcomes Among Patients with Venous Thromboembolism?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1126-1126 ◽  
Author(s):  
Alex C. Spyropoulos ◽  
Ron Preblick ◽  
Jackie Kwong ◽  
Melissa Lingohr-Smith ◽  
Jay Lin
Keyword(s):  
Venous Thromboembolism ◽  
Treatment Duration ◽  
Bleeding Risk ◽  
Patient Characteristics ◽  
Baseline Period ◽  
Employment Equity ◽  
Minimum Duration ◽  
Study Population ◽  
Equity Ownership

Abstract Introduction: Venous thromboembolism (VTE) represents a major clinical and economic burden. The American College of Chest Physicians (ACCP) Guideline 9th Edition on the treatment of VTE recommends a minimum duration of anticoagulation (AC) therapy depending on patient risk profiles. The objectives of this study were to evaluate the clinical and economic outcomes associated with adherence to the AC treatment duration recommendation among VTE patients in the real world setting. Methods: Adult patients (≥18 years of age) with at least 1 inpatient diagnosis or 2 outpatient diagnoses on two different dates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), based on ICD-9-CM codes, were identified from the IMS Pharmetrics Plus database during 1/1/2009 through 3/31/2013. The first VTE diagnosis was defined as the index event. Study patients were required to have continuous insurance coverage during the 12 months before (baseline) and after (follow-up) the index event and no prior VTE diagnosis in the baseline period. They were also required to have received at least one outpatient anticoagulant treatment within 30 days of the initial VTE diagnosis with a minimum medication days of supply of 30 days. ACCP recommend that patients with provoked VTE or unprovoked VTE and high bleeding risks receive AC treatment for at least 3 months and that patients with unprovoked VTE and low or moderate bleeding risks or patients with cancer receive AC treatment for at least 6 months. Patient records in the database including ICD-9-CM codes and RIETE bleeding risk scores were used to group patients into 2 cohorts, one comprised of patients who received AC treatment for a duration as recommended by the ACCP (adherent group, AD) and the other comprised of patients who received AC treatment for a duration less than that recommended by the ACCP (non-adherent group, non-AD). Patient demographics and clinical characteristic were evaluated during the baseline period. Healthcare resource utilization, including hospital admissions, outpatient medical services, and prescription drug usage, were measured during the baseline and follow-up periods. VTE recurrence, defined as hospitalization or ER visit with a VTE diagnosis code, was also measured during the follow-up period. Multivariate regression analysis was utilized to compare clinical and economic outcomes of study cohorts while controlling for key patient characteristics. Results: The study population included 81,827 patients with a mean age (standard deviation) of 55.3 (13.8) years. For the index VTE event, 61% had DVT only, 26% had PE only, and 13% had DVT/PE. Of the study population, the minimum ACCP recommended AC treatment durations were 3 and 6 months for 27% (n=22,157) and 73% (n=59,670) of patients, respectively. Among all patients, 74% (n=60,550) received AC therapy for the ACCP recommended duration. The proportion of patients with VTE risks, including recent hospitalization (17% vs. 9%, p<0.001), recent surgery (9% vs. 6%, p<0.001), index diagnosis of PE only (28% vs. 20%, p<0.001), and index diagnosis of DVT/PE (15% vs. 8%, p<0.001) was greater in the AD cohort than in the non-AD cohort. Furthermore, mean Charlson Comorbidity Index score (1.67 vs. 1.59, p<0.001) and RIETE bleeding risk score (RIETE ≥1: 66% vs. 55%, p<0.001) were higher for the AD cohort compared to the non-AD cohort. The most prevalent anticoagulants used for treatment were warfarin (89% vs. 96%, p<0.001) and low molecular weight heparin (58% vs. 59%, p<0.01). After controlling for key patient characteristics, risks for all-cause hospitalization (Odds ratio (OR): 0.80, confidence interval (CI): 0.77-0.83, p<0.001) and VTE recurrence (OR=0.91, CI: 0.86-0.95, p<0.001) were lower among VTE patients in the AD cohort vs. the non-AD cohort, as were differences in all-cause total healthcare payments (-$3,416, p<0.001) and VTE-related healthcare payments (-$2,139, p<0.001) during the follow-up period. Conclusions: Approximately a quarter of the study population with VTE did not receive treatment with AC therapy for the minimum duration as recommended by the ACCP guideline. Patients who did not receive outpatient AC therapy for the recommended duration had more VTE recurrences, utilized more inpatient services, and had higher healthcare costs than patients who received AC therapy for the ACCP recommended duration. Disclosures Spyropoulos: Daiichi Sankyo, Inc.: Consultancy. Preblick:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Kwong:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Lingohr-Smith:Chimerix, Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Daiichi Sankyo, Inc: Consultancy; Novosys Health: Employment. Lin:Chimerix, Inc.: Consultancy; Daiichi Sankyo, Inc: Consultancy; Bristol-Myers Squibb: Consultancy; Novosys Health: Employment.

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

Blood ◽  
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.

scholarly journals Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Proteasome Inhibitor Based Therapy at First Relapse in Routine Clinical Practice in Germany

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1953-1953 ◽  
Author(s):  
H. Tilman Steinmetz ◽  
Moushmi Singh ◽  
Andrea Lebioda ◽  
Aurelien Mantonnier ◽  
Leah Fink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Treatment Duration ◽  
Employment Equity ◽  
Available N ◽  
Median Treatment ◽  
Median Treatment Duration ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership ◽  
Patient Profiles

Abstract Background: Proteasome inhibitors (PI) represent an important therapeutic advance in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). In 2017, three distinct PIs (bortezomib [BTZ], carfilzomib [CFZ] and ixazomib [IXA]) were available in Germany but real-world data describing their usage was scarce. Aim: To describe characteristics and treatment experience of PI-treated patients with RRMM in Germany. Methods: A national retrospective medical chart review included consecutive patients treated with at least one dose of PI-based regimen in participating hospitals/centers across Germany between January and June 2017. The following data were extracted until April 2018 or death of patient, whichever occurred first: patient demographics, disease characteristics and treatment history at diagnosis and at initiation of PI-based therapy. Physician assessed treatment response were also collected. Results: Physicians from 44 participating centers extracted 302 patient charts, including 219 patients in 2nd line (2L) and 83 in 3rd line treatment (3L), as shown in Figure 1. Results for 2L patients are described below (Table 1, Figure 2): BTZ-treated patients represented 42% of patients (n=92) with a PI-based therapy in 2L. BTZ was often combined with dexamethasone (dex) alone (77%). Median age was 74 years and 56.5% had an ECOG status ≥2 at 2L initiation. Most patients (86%) did not receive a prior transplant. Median treatment duration was 6 months among 40 patients who completed 2L; based on 38 narratives, 2L was ended as planned (47.4%). Where response was available (n=83), 25% of patients achieved a complete response/very good partial response [CR/VGPR]. Median time to next treatment (TTnT) was 7.5 months for 12 patients who moved to 3L. Patient profiles differed in terms of prior treatment exposure: 22% of patients had been treated with a BTZ-based therapy in both 1L and 2L and 62% switched therapies from 1L lenalidomide (len) to BTZ. None of the patients receiving len in 1L were transplanted. A CR/VGPR was achieved by 65% of prior BTZ-treated patients (13/20) and 30% of patients with prior len therapy (17/57). CFZ-treated patients: 48% (n=106) of patients received CFZ-based therapy in 2L. Of those, 56% (n=59) received CFZ in combination with len/dex (KRd) and 44% (n=47) with dex alone (Kd). Median age was 68 years, 60.4% had an ECOG status of 0-1 at 2L initiation and 49% had received a transplant. In 1L, 82% had received a BTZ-based regimen. Where response was mentioned (n=89), a CR/VGPR was reached in 53% of CFZ-treated patients. Median treatment duration was 6.5 months (24/106). Based on 21 narratives, the main reason for discontinuing CFZ in 2L was disease progression (47.6%). Median TTnT was 9.5 months for 10 patients who moved to 3L. The patient profiles by KRd or Kd combination were as follows: at KRd initiation, median age was 65 years, 10.2% of patients had an ECOG status ≥2 and 72.9% were transplanted. At Kd initiation, median age was 71 years, 76.6% of patients had an ECOG ≥2 and 19.1% were transplanted. IXA-treated patients (n=21) represented only 10% of PI-treated patients in 2L. Median age was 66 years, 71.4% had an ECOG status of 0-1 at 2L initiation, 33% were transplanted, and 72% had received a BTZ combination in 1L. Information on response was premature as it was only available for 13 patients with no CR reached (VGPR 77%). Median treatment duration was 4 months (n=9) and median TTnT was 10 months for 4 patients who moved into 3L. Limitation: The main limitation of the study was the sample size of IXA-treated patients due to open inclusion criteria to select patient charts. This analysis was not powered to compare between PIs. Hence, results are descriptive of the clinical experience with PI-based therapy to date and reflect current treatment practices in Germany in 2017. Conclusion: In Germany, distinct patient characteristics are observed in clinical practice by selected PI-based therapy. Patients treated with novel PI agents in 2L are generally younger and more transplanted than bortezomib-treated patients; these appear to be important considerations when tailoring therapy in RRMM. In addition, the choice between triplet or doublet therapy for CFZ-based combinations seems to reflect prior transplant status and patients' overall functional performance. Evidence suggests that use of novel PI agents such as CFZ can translate into deeper response in 2L. Disclosures Steinmetz: Amgen, Celgene, Novartis, Vifor: Research Funding; Amgen; BMS, Celgene, Hexal-Sandoz, Medice, Novartis; Janssen-Cilag; Pharmacosmos; Pfizer, Vifor; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, Amgen, Bayer, Celgene, Janssen-Cilag, Novartis: Other: Travel grants. Singh:Amgen: Employment, Equity Ownership. Lebioda:Amgen: Employment, Equity Ownership. Mantonnier:Kantar Health: Employment, Other: Received funding to conduct this research. Fink:Kantar Health: Employment, Other: Received funding to conduct this research. Rieth:Amgen: Employment, Equity Ownership. Suzan:Amgen: Employment, Equity Ownership. Gonzalez-McQuire:Amgen: Employment, Equity Ownership.

scholarly journals Revised International Staging System (R-ISS) for Transplant-Eligible Multiple Myeloma Patients Risk Stratification

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5756-5756
Author(s):  
Telma Nascimento ◽  
Adriana Roque ◽  
Emília Cortesão ◽  
Luís Francisco Araújo ◽  
Ana Isabel Espadana ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Risk Stratification ◽  
Real Life ◽  
Staging System ◽  
Stage Ii ◽  
Novel Agents ◽  
International Staging System

Abstract BACKGROUND: In the last decades, multiple myeloma (MM) prognosis has been changing dramatically. Induction with novel agents, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (aHSCT) is the standard of care for newly diagnosed (ND) and transplant-eligible MM patients (pts). In 2015, a new score was validated [Revised International Staging System (R-ISS)], including data related to high-risk cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)] and serum lactate dehydrogenase (LDH) levels. Few recent studies have supported R-ISS as a reliable prognostic tool for estimating survival in MM pts submitted to aHSCT. AIMS: To determine whether R-ISS is a valid risk model for predicting progression free survival (PFS) and overall survival (OS) among a cohort of real-life aHSCT pts. METHODS: We conducted a single center retrospective study of ND symptomatic MM pts treated with novel agents (bortezomib, thalidomide or lenalidomide) undergoing aHSCT between Jan/2007 and Dec/2017. We excluded all pts with no available information about ISS, LDH and CA [detected by fluorescence in situ hybridization (FISH)]. Response to treatment was evaluated according to the International Myeloma Working Group consensus criteria (2016). Statistical analysis was performed using STATA v.14.2 and significant levels were set at p<0.05. RESULTS: From the total number of 186 pts submitted to aHSCT, only 81 (45%) pts presented criteria to be included in our analysis; 62% were male, with a median age at aHSCT of 60y (28-70). IgG was the most frequent subtype (59%), followed by IgA (20%). At diagnosis, 38% of pts presented anemia, 14% renal impairment (RI), 20% hypercalcemia, 63% bone disease (BD) and 32% extramedullary disease (EMD). According to ISS, 30 (37%) pts presented stage I, 30 (37%) stage II, and 21 (26%) stage III at diagnosis. There were 38% pts with high-risk CA: 24% with del17p; 19% with t(4;14), and 20% with t(14;16). High LDH levels was seen in 48% of pts. Pts were re-staged at diagnosis according to R-ISS, resulting 17% in stage I, 61% in stage II, and 22% in stage III. Thus, 16 (20%) pts previously categorized as ISS I and 3 (4%) pts as ISS III were re-classified as R-ISS II. Median time from diagnosis to aHSCT was 9.7 months. All pts received induction therapy with novel agents (a bortezomib-based therapy in 89% of pts and an IMID-based in 12%), with 81% of pts responding to first line induction; 19% were refractory. At the time of aHSCT, all pts presented at least on partial response (PR) [62% at least very good partial response (VGPR)], with an increase in the proportion of pts in complete response (CR) from 15% to 20% before and after aHSCT, respectively. Maintenance therapy was performed in 31% of pts (79% thalidomide; 21% lenalidomide). At a median follow-up of 33.4 months, median OS had not been reached. Two-years OS was 62%. Median PFS from aHSCT was 67.4%.Neither high-risk CA nor high LDH levels individually predicted lower OS and PFS (p=NS). The 2-year OS for R-ISS I, II and III was 86 %, 61% and 44%, and the 2-year PFS was 79 %, 63% and 39%, respectively. In our cohort we observed statistical significance differences between R-ISS I and III at 2 years in what concerns PFS (p=0.025) and OS (p=0.017) . No differences were seen in between other R-ISS categories. When we stratified R-ISS stage II in two subgroups based on the presence or absence of high-risk CA no differences were found. Pts classified as R-ISS III presented anemia (p<0.001) and RI (p=0.001) more frequently, but no differences concerning hypercalcemia, BD or EMD. CONCLUSIONS: In our real-life cohort, R-ISS at diagnosis was a reliable tool only to predict both OS and PFS between R-ISS I and III and not between other R-ISS subgroups. The main reasons that explain the absence of significance between all R-ISS subgroups were probably the very low number of pts with available cytogenetics compared with the total number of pts submitted to aHSCT in our center and the short follow up of our study. Larger real-life studies with a longer follow up are necessary to determine if R-ISS is a good risk stratification model to applicate to NDMM pts submitted to aHSCT in the era of novel agents. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic Molecular Stratification in Relapsed/Refractory Multiple Myeloma - Results of the Pomalidomide Mukseven (NCT02406222) Biomarker Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4327-4327
Author(s):  
James Croft ◽  
Andrew Hall ◽  
Amy L Sherborne ◽  
Katrina Walker ◽  
Sidra Ellis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
T Cell ◽  
High Risk ◽  
Real World ◽  
Research Funding ◽  
Unmet Need ◽  
Employment Equity ◽  
Equity Ownership

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

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 ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3859-3859 ◽  
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.

Characterization of Patients with Multiple Myeloma Achieving Complete Response to Bortezomib: An Interim Report From An International Electronic Observational Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4938-4938
Author(s):  
Michel Delforge ◽  
Hadewijch De Samblanx ◽  
Maria Roussou ◽  
Konstantinos Zervas ◽  
Eirini Katodritou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Clinical Practice ◽  
Observational Study ◽  
Complete Response ◽  
Practice Setting ◽  
Employment Equity ◽  
Clinical Practice Setting ◽  
Equity Ownership ◽  
Response Groups

Abstract Abstract 4938 Introduction Bortezomib (Velcade®) is effective and well tolerated in patients with multiple myeloma (MM), including those with adverse prognostic factors such as advanced age, more prior lines of therapy, and advanced-stage disease. The international, non-interventional, Electronic Velcade Observational Study (eVOBS) is an ongoing observational study that aims to assess the clinical and health economic outcomes in MM patients treated with bortezomib in the clinical-practice setting. In this study, we characterized patients achieving complete response (CR) with bortezomib in the relapsed/refractory setting, and assessed the effects of adverse prognostic factors on the rate of CR. Methods Adult patients from Belgium, France, Greece, Russia, Spain, Sweden, and Turkey scheduled to receive bortezomib for relapsed MM were eligible for inclusion in eVOBS. All bortezomib doses and concomitant treatments (except investigational therapies) were permitted; dose adjustments and cycle delays were documented. Patients are being followed for up to 3 years to document long-term outcomes; data are collected at baseline and at the end of every bortezomib cycle. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria were defined by the investigator and may have included European Group for Blood and Marrow Transplantation (EBMT), Southwest Oncology Group (SWOG), or M-protein criteria. Patients who had at least 12 weeks data or who had died by the time of data cut-off (June 30, 2009) were included in this exploratory analysis; patients were assessed after completion of four and six cycles. Results A total of 769 patients were included, 129 (16.8%) of whom achieved CR. There were no significant differences in baseline characteristics between patients who did (n=129) vs did not (n=640) achieve CR: 49.8% vs 47.3% were male, median age at baseline was 60.6 vs 62.1 years, median age at diagnosis was 57.9 vs 59.4 years, and median time since diagnosis was 2.3 vs 2.4 years. Patients with adverse prognostic factors were evenly distributed among response groups: of the patients who achieved CR, 7.8%, 55.8%, 23.3%, and 13.2% had 0, 1, 2, and 3 or more prior lines of therapy, vs 3.6%, 56.1%, 23.4%, and 15.8% of those who did not achieve CR. Similar results were seen for patients across disease stages: 14.7%, 31.0%, and 46.5% of CR patients vs 12.3%, 33.1%, and 50.2% of non-CR patients had ISS disease stage I, II, or III, respectively. Similarly, patients with comorbidities such as obesity or diabetes were evenly distributed across response groups: 6.1% and 7.1% of CR patients had obesity or diabetes, respectively, vs 4.4% and 9.6% of non-CR patients. After 4 cycles, the overall response rate (ORR) in patients who had completed 4 cycles (n=518) was 70%, including 12% complete response (CR), 16% near-CR (nCR), and 42% partial response (PR). Improved response rates were seen with prolonged therapy; after 6 cycles, the ORR in patients who had completed 6 cycles (n=321) was 82%, including 16% CR, 20% nCR, and 46% PR. As shown in the Figure, analysis of overall survival by best response at cycle 4 showed that achieving a CR/nCR is associated with significantly improved survival versus PR (p<0.0001). Conclusions Together, these results show that bortezomib, as administered in the clinical-practice setting, is highly active in relapsed/refractory MM patients, with CRs achieved among all patient subgroups. Furthermore, achievement of CR appears associated with prolonged survival and responses to bortezomib appear to improve with prolonged duration of therapy. Disclosures Delforge: Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria. Hulin:Janssen-Cilag: Honoraria; Celgene: Honoraria. Ganguly:Johnson & Johnson: Employment, Equity Ownership. Diels:Johnson & Johnson: Employment, Equity Ownership. Dhawan:Johnson and Johnson Research Pharmaceuticals: Employment. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria.

Overall Safety and Treatment Duration in Lenalidomide (LEN)-, Thalidomide (THAL)-, and Bortezomib (BORT)-Treated Patients (Pts) within the European Post-Approval Safety Study (EU PASS) of Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4068-4068
Author(s):  
Barbara Gamberi ◽  
Charalampia Kyriakou ◽  
John Ashcroft ◽  
Miguel T. Hernandez ◽  
Jo Caers ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Disease Progression ◽  
Treatment Duration ◽  
Treatment Discontinuation ◽  
Study Entry ◽  
Current Clinical Practice ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4068 Background: The efficacy and tolerability of LEN in pts with RRMM has been demonstrated in 2 large, randomized, phase 3 studies (MM-009/010). BORT and THAL have also been shown to be effective for RRMM treatment. While many studies have described the safety of antimyeloma drugs in the clinical trial setting, few have addressed the issue of tolerability in current clinical practice. Aims: In this study, we compared the incidence of adverse events (AEs) of special interest, such as neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN) and second primary malignancies (SPM) in pts treated with LEN versus other antimyeloma therapies for RRMM in current clinical practice. Additionally, duration of treatment was assessed in the context of therapy received just prior to study entry. Methods: In this post-approval, observational, non-interventional, EU PASS study, pts with RRMM were enrolled into either the LEN cohort (LEN-based therapy) or the background cohort (all non-LEN based therapies) at the investigators' discretion. Thromboprophylaxis was per local standard practice. AEs were graded according to NCI-CTCAE v3.0. Assessments for SPM were to be conducted up to 36 months (mos) after treatment discontinuation. Results: As of May 2012, overall median follow-up was 5.7 mos (range 0.02–39.8), (6.4 mos LEN, 5.7 mos THAL, 4.9 mos BORT). There were 3107 pts across 268 institutions in 17 European countries enrolled: 2141 received LEN, 751 received BORT, 110 received THAL, and 105 received other therapies or had incomplete information on the treatment arm. 127 pts from the background cohort crossed over following the physician's decision to initiate LEN treatment as a subsequent therapy. Median age was 70 years (range, 25–95) and 54% were male. Most pts (65%) had good performance status (ECOG score 0–1); 17% had an ECOG score of 2–4. Median overall number of prior therapies was 2 (range, 0–6) and this was consistent across the cohorts: 53% had 2 prior therapies and 21% had ≥3. Baseline characteristics were similar between groups. Overall, 1397 (45.0%) had a grade 3–4 AE. Grade 3–4 neutropenia occurred in 14%, 4%, and 5% of pts in the LEN, BORT, and THAL groups, respectively. Grade 3–4 thrombocytopenia developed in 8%, 9%, and 3% of pts, respectively. In the LEN group, only 7% of pts (1% grade 3–4) reported PN (4% newly occurring) while receiving LEN (despite 36% of pts presenting with PN at baseline) compared with 28% (5% grade 3–4) with BORT (22% PN at baseline) and 16% (2% grade 3–4) with THAL (19% PN at baseline). Grade 3–4 VTE developed in 2.7% of pts in the LEN group, 0.7% in the BORT group, and 1.8% in the THAL group. Overall treatment discontinuation rates (including disease progression) were 70%, 85%, and 86% in the LEN, BORT, and THAL groups, respectively, with nearly identical discontinuation rates due to AEs (17%) in each group, and disease progression rates of 15–20%. SPM incidence was ≤1% overall and invasive SPM incidence rate per 100 patient-years (95% CI) was 1.4 (0.94 –2.09) at a median follow-up of 10 mos and was comparable across the cohorts. Incidence of death during the study was comparable with all treatments (LEN 6%, BORT 4%, and THAL 5%); the incidence of treatment-related AEs leading to death was 1.4%, 1.2% and 0.9%, respectively. The median treatment duration was 4.6 mos in the overall population; 5.4 mos in pts treated with LEN, 3.7 mos in pts treated with BORT, and 4.6 mos in pts treated with THAL. At a 5.7 mos median follow-up, 19.9%, 2.0%, and 14.5% of pts in the LEN, BORT, and THAL arms had a treatment duration of >12 mos; and 2.2%, 0.3%, and 0.9% had a treatment duration of >24 mos, respectively. In an analysis of study treatment by last therapy prior to study entry, patients receiving THAL or BORT followed by LEN had a median on-study treatment duration of 5.7 mos and 5.2 mos, respectively, independent of the line of treatment. In comparison, pts receiving THAL or BORT followed by BORT had lower median study treatment duration of 3.7 mos and 3.8 mos, respectively. Conclusions: Results of this non-interventional, observational study show that AEs were similar with all treatments except for higher rates of neutropenia and lower rates of PN with LEN, compared with BORT or THAL. Despite the current short overall follow-up, treatment duration within the LEN, BORT, or THAL groups appears to be unaffected by prior treatment received but was longer for LEN when compared with BORT or THAL. Disclosures: Küenburg: Celgene Corporation: Employment, Equity Ownership. Rosettani:Celgene Corporation: Employment, Equity Ownership. Ryder-Smith:Celgene Corporation: Employment, Equity Ownership.

QT Interval Effects and M-Protein Response in a Phase 1 Study of Siltuximab (Anti-IL-6 Monoclonal Antibody) in Patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2972-2972
Author(s):  
Sheeba K. Thomas ◽  
Alexander Suvorov ◽  
Lucien Noens ◽  
Oleg Rukavitsin ◽  
Joseph Fay ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Studies ◽  
Qt Interval ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
M Protein ◽  
Qtc Interval ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS <100 ms, and PR <200 ms received siltuximab 15 mg/kg q3w as a 60 min IV infusion for 4 cycles. Patients were excluded for significant cardiac disease. ECGs and pharmacokinetics assessment were performed at Cycle 1 (pre-infusion [baseline]; end of infusion; and 1, 3, and 24 hrs post-infusion) and at Cycle 4 (pre-infusion, end of infusion, and 1 hr post-infusion). At all timepoints, triplicate 12-lead ECGs were conducted and evaluated by a central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of the least square (LS) mean 90% confidence interval (CI) for the change from baseline QTc at each time point was <20 ms. Safety data were also collected. Preliminary assessment of clinical activity was performed using M-protein measurements from local laboratories. Patients achieving a 50% reduction from baseline in M-protein after 4 cycles were eligible for extended siltuximab therapy (15 mg/kg q4w). Results Thirty patients (14 MGUS, 15 SMM, 1 IMM) with median age 59.5 (range 24, 79) yrs were enrolled. Median serum protein electrophoresis was 1.21 (range 0, 5.4) g/dL, and median urine protein electrophoresis was 0 (range 0, 267) mg/24 hrs. Twenty-eight patients completed all 4 treatment cycles, among whom 27 were evaluable for the primary endpoint of QT interval assessment. The maximum mean increase in QTc from baseline occurred 3 hrs after the Cycle 1 infusion (QTcF = 3.2 ms [LS mean 90% CI −0.01, 6.45]; QTcB = 2.7 ms [LS mean 90% CI −0.69, 6.14]). At all other time points for both QTcF and QTcB, the mean increase from baseline was ≤1.5 ms and the upper limit of LS mean 90% CI was ≤5.07 ms. An effect of siltuximab on QTc interval was therefore ruled out. Furthermore, no patient had a QTcF or QTcB increase from baseline >30 ms, and no correlation was observed between siltuximab serum concentrations and change from baseline in QTcB or QTcF. Twenty (67%) of 30 treated patients had ≥1 adverse events (AEs). AEs reported by ≥10% of patients were nausea, fatigue (20% each); thrombocytopenia, headache (each 13%); dyspnea, leukopenia, neutropenia, paraesthesia, and upper respiratory tract infection (each 10%). The majority of AEs were grade ≤2. However, 8 (27%) patients had ≥1 AE grade ≥3: neutropenia (n=3); hypertriglyceridemia, hypertension, hypotension, leukopenia, and myalgia (each n=1); and 1 patient had grade 3 ascites, cellulitis, peripheral edema, portal hypertension, and hepatic cirrhosis (diagnosis made during hospitalization). This patient discontinued treatment due to cellulitis (possibly related to siltuximab) with peripheral edema and ascites (not related to siltuximab). A second patient discontinued treatment due to grade 2 atrial fibrillation that was not related to siltuximab. No severe infusion reactions or deaths were reported. After the first 4 cycles (3 mos), 3 MGUS patients achieved an M-protein response (≥50% reduction from baseline), and 9 patients (3 MGUS, 5 SMM, 1 IMM) had minor responses (≥25% and <50% reduction from baseline). Two patients who qualified for extended treatment with siltuximab continued to receive therapy (17 and 6 cycles, respectively) at the time of database lock. Conclusion Siltuximab, given at the highest dose level used in clinical studies, did not affect the QTc interval. Overall safety was similar to what has been previously reported for other single-agent siltuximab studies. M-protein responses were seen by local laboratory assessment within the first 4 cycles. A randomized phase 2 study is ongoing to further evaluate the efficacy and safety of single-agent siltuximab in high-risk SMM. Disclosures: Thomas: Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Celgene: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Bandekar:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Uhlar:Johnson & Johnson: Employment, Equity Ownership.

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