scholarly journals 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

2013 ◽  
Vol 31 (4) ◽  
pp. 448-455 ◽  
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.

Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 476-476 ◽  
Author(s):  
Jesús F San Miguel ◽  
Rudolf Schlag ◽  
Nuriet K Khuageva ◽  
Meletios Athanasios Dimopoulos ◽  
Ofer Shpilberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Second Primary ◽  
Phase 3 ◽  
Increased Risk ◽  
Equity Ownership ◽  
Second Primary Malignancies ◽  
Patient Subgroups

Abstract Abstract 476FN2 Background: Data from the initial report of the international, multicenter, phase 3 VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy. Following this report, centralized assessment of response/progression was stopped and, per protocol, patients were followed for up to 4.5 years post-last patient in date for survival and the use of subsequent anti-MM therapy only. An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant OS benefit with VMP. Here we report the final updated OS analysis of VISTA after 5 years of follow-up, including an exploratory analysis of the risk of second primary malignancies (SPMs), an important issue for MM patients receiving long-term therapy. Methods: Patients were randomized (1:1) to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, days 1, 8, 22, and 29, cycles 5–9; melphalan 9 mg/m2 days 1–4, prednisone 60 mg/m2, days 1–4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected during February 2011 by surveying all study sites to capture information for 655 (96%) patients. Results: After median follow-up of 60.1 months, with only 5% of patients lost to follow-up, median OS was 56.4 versus 43.1 months for patients randomized to VMP compared to MP (HR 0.695, p=0.0004), reflecting a 31% reduced risk of death with VMP (Figure); 5-year OS rates were 46.0% and 34.4%, respectively. This compares favorably with the 6.6-month increase in median OS in a meta-analysis of six phase 3 trials of MP-thalidomide vs MP (Fayers et al, Blood 2011). The OS benefit with VMP was seen across patient subgroups, including those aged ≥75 years (median 50.7 vs 32.9 months, HR 0.71), patients with ISS stage III MM (median 42.1 vs 30.5 months, HR 0.67), and those with creatinine clearance <60 mL/min (median 56.8 vs 36.7 months, HR 0.70), but no significant difference was observed in the small subgroup of patients with documented high-risk cytogenetics (n=46). At data cut-off (March 24, 2011), 63% of VMP and 73% of MP patients had received subsequent MM therapies; use of subsequent therapies was generally similar between arms, except for a higher proportion of MP patients receiving subsequent bortezomib (43% vs 22%). Time to next treatment (median 27.0 vs 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs 8.3 months, HR 0.573, p<0.0001) were superior with VMP vs MP. Among all patients who had received subsequent therapies, OS was superior with VMP vs MP (median 55.7 vs 46.4 months; HR 0.745, p=0.0162). A 30-month landmark OS analysis demonstrated superior survival from landmark among all VMP patients (median not reached) and among VMP patients who had received any subsequent therapy (median 28.2 months) vs MP patients who had received subsequent bortezomib (median 23.0 months). Taking into account the longer observation period due to prolonged survival on the VMP arm, analyses of SPM risk (Table) showed no difference in incidence proportions or ‘exposure'-adjusted incidence rates between arms. Rates on both arms (VMP 0.0166, MP 0.013 per patient-year) were consistent with background incidence rate in the general population aged 65–74 years (0.019, SEER database). Conclusions: VMP resulted in a substantial long-term OS benefit vs MP (13.3-month increase in median), which was seen across patient subgroups and regardless of extensive subsequent therapy. There was no increased risk of SPMs identified with VMP vs expected background rates. Disclosures: San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho Biotech: Consultancy, Honoraria. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Spicka:Janssen-Cilag: Honoraria; Celgene: Honoraria. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Janssen-Cilag: Research Funding. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy.

Patient Outcomes with Proteosome Inhibitor Bortezomib in Multiple Myeloma at an English District General Hospital

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5745-5745
Author(s):  
Anil Vaikunth Kamat ◽  
Tariq Shafi ◽  
Raphael A. Ezekwesili
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Progression Free Survival ◽  
Second Primary ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Grade 3 ◽  
Second Primary Malignancies

Abstract Bortezomib is a targeted proteosome inhibitor licensed & approved for in multiple myeloma both as first line and in relapsed setting. This is a retrospective non experimental cross sectional quantitative comparative group study using clinical case notes, laboratory & pharmacy records for patients treated with Bortezomib in 2011 & 2012. Outcomes studied included remission status, adverse events, progression free survival and overall survival at follow up. The study also looked at the comparative responses of cohort of patients administered Bortezomib through intravenous & subcutaneous route. The cohort consisted of 33 patients, 21 male, 11 female, median age 71 years, first line 10 patients, second line 23 , median number of cycles in 2011 & 2012 – first line 3 & 8 , second line 5 & 4, respectively. In 2011, 8 received intravenous treatment, 9 were switched from intravenous to subcutaneous route whilst all patients from 2012 received subcutaneous Bortezomib. The most frequently used regimen was Bortezomib Dexamethasone ( VD). The overall response rate ( ORR >/= Minor Response) was: First line 70% (7/10) ; Second line 47.8% ( 11/23); median PFS ( Figure 1) 6 months ( First line: 7 months ; Second line : 6 months) and median overall survival ( Figure 2) at follow up: 9 months ; 39.4 % ( 13/33) First line 8.5 months, Second line 11 months. Subcutaneous Bortezomib was equivalent to intravenous Bortezomib in terms of efficacy & tolerance. Of 33 patients, there were 12 dose reductions. Adverse events reported included: peripheral Neuropathy - grade 3 - 6% ( all grades 27.3%); Diarrhoea - grade 3 - 3% (all grades 6%); Nausea / Vomiting - grade 3 - 3% ( all grades 6%) and Second Primary Malignancies - 12% ( 4 of 33). Mortality at follow up was 20 patients from cohort of 33 ; causes included disease progression in 11, second primary malignancy with disease progression in 4, COPD 2, Systemic Amyloidosis 2, Tuberculosis 1 , Multiple co morbidities 1 and Asthma with mechanical failure in single patient. Second primary malignancies ( 4/33) included Prostate carcinoma ( 1), Renal Cell Carcinoma (1), Neuroendocrine tumour ( 1 ) and Unknown Primary in single patient. Beyond second line treatment, majority (14 of 23 patients; 60.9 %) did not have further active treatment. These data indicate that patient outcomes were modest compared to published data from VISTA and APEX trials. Majority of patients did not have further active treatment beyond second line which suggests the most effective treatment strategy should be used upfront as patients may not be fit to have further lines of therapy despite availability of recently introduced novel targeted agents. A higher percentage of second primary malignancies were noticed in this cohort which should be an area of further clinical research. Figure 1: Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 1:. Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 2: Overall survival with Bortezomib as first line & second line in multiple myeloma Figure 2:. Overall survival with Bortezomib as first line & second line in multiple myeloma Disclosures No relevant conflicts of interest to declare.

scholarly journals Bortezomib (BOR)-Thalidomide-Dexamethasone (VTD) and High-Dose Melphalan (HDM) As First Line Treatment for Multiple Myeloma (MM) Is Associated with a Lower Rate of Second Primary Malignancies (SPMs) Compared to TD Plus HDM

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1182-1182 ◽  
Author(s):  
Annamaria Brioli ◽  
Annalisa Pezzi ◽  
Daniele Derudas ◽  
Maria Concetta Petti ◽  
Beatrice Anna Zannetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Alkylating Agents ◽  
Statistical Significance ◽  
Phase Iii ◽  
High Dose ◽  
Line Treatment ◽  
Increased Risk ◽  
Phase Iii Study

Abstract The availability of novel drugs such as immunomodulatory drugs, IMiDs, and proteasome inhibitors, PI, for the front line treatment of Multiple Myeloma (MM) has dramatically changed patients’ outcomes, significantly prolonging progression free survival (PFS) and translating into an extended overall survival (OS). Despite these impressive results, concerns have been raised regarding the possibility that IMiDs (lenalidomide and thalidomide) might increase the risk of developing SPMs, especially when associated with alkylating agents such as melphalan (MEL). It has long been known that the use of MEL can result in an increased incidence of SPMs, and this risk seems to be increased by the association with IMiDs. By the opposite, the use of PI in newly diagnosed MM (NDMM) patients (pts) was not associated with an increased risk of SPMs in a phase III study aimed at comparing BOR, MEL and prednisone (MP) vs MP.[1] Despite these results, the full impact of an upfront treatment containing both a PI and an IMiD in association with high dose MEL still has to be investigated. To address this issue, we have evaluated the incidence of SPMs in pts enrolled in the GIMEMA 26866138-MMY-3006 multicentre phase III study aimed at comparing BOR, thalidomide and dexamethasone (VTD) versus TD as induction before, and consolidation after, a double course of high dose MEL. The trial, conducted in Italy from 2006 to 2008, enrolled 480 transplant eligible NDMM, of which 474 received assigned treatment. Data on the incidence of SPMs are available for 299 pts (63%, 148 VTD and 151 TD). With a median follow up of 73 months, 25/299 pts (8%) developed a SPM: 7 (2%) SPMs were hematologic and 18 (6%) were non hematologic. The median time from trial entry to development of the SPM was 36 months (range 8.4-69.0). The number of pts developing a SPM was lower in VTD arm (5%) compared to TD arm (11%, p=0.068). Among pts developing a SPM, the proportion of solid malignancies was similar between treatment arms (75% and 71% in VTD and TD, respectively). Similarly, the percentages of hematologic SPMs was 25% for VTD pts and 29% for TD. On the overall population, the incidence rate (IR) of developing a SPM was 1% at 1 year and 9.9% at 6 years (yrs). This incidence was significantly lower for patients randomised to VTD compared with patients receiving TD (6% vs 13% at 6 yrs, p=0.037). When looking at the IR of solid tumours we noticed that only 5% of VTD-treated patients developed a solid SPM, as compared to 9.6% in TD; similarly, less hematologic SPMs were observed in the BOR arm (1% vs 4% at 6 yrs for VTD and TD, respectively). When the analysis was performed according to SPMs type, no statistical significance could be demonstrated. Our data compare favourably with data previously reported on the incidence of developing SPMs in NDMM treated with BOR frontline in association with MEL. With a follow up of 6 years, we were able to confirm that treatment with PI is associated with a low risk of developing SPM. Interestingly our data suggest that treatment with PI might decrease the risk of developing a SPM compared to IMiDs based treatment. Randomised trials with PI and IMiDs treatment should prospectively evaluate this issue. References 1. San Miguel, J.F., et al., 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. J Clin Oncol, 2013. 31(4): p. 448-55. Disclosures Musto: Janssen: Honoraria; Celgene: Honoraria. Cavo:Onyx: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Millenium Pharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Changing Incidence of Major Cardiovascular Events in Multiple Myeloma Patients over Time

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3598-3598
Author(s):  
Aaron Seth Rosenberg ◽  
Qian Li ◽  
Ann M Brunson ◽  
Joseph Tuscano ◽  
Ted Wun ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Stem Cell Transplant ◽  
Incidence Rates ◽  
Cell Transplant ◽  
Risk Of Death ◽  
Increased Risk ◽  
Over Time

Abstract Background: While multiple myeloma (MM) comprises only 2% of all cancer diagnoses, the prevalence of the disease in the US has markedly increased from 46,865 patients in 2000 to 124,733 in 2015. New therapeutic classes have led to longer survival, and allowed older patients to undergo life-prolonging therapy. Survivorship issues are now becoming relevant for this population, as ongoing therapy may have as yet unappreciated long term sequelae. MM is a disease of older patients, with a median diagnosis age of 69, and the incidence is greatest among African Americans (AA), populations at higher risk of cardiovascular disease (CVD). We therefore designed a retrospective study to quantify the incidence of new CVD in this population, as well as changes in incidence over time, hypothesizing that CVD incidence would increase due to both longer survival times, and increased utilization of potentially cardiotoxic drugs. Methods: Using the California Cancer Registry linked to the California Patient Discharge Database, we identified 15,404 patients diagnosed with MM between 1991-2012 with follow-up through 2014. CVD was defined as a hospital admission for coronary artery disease (CAD), congestive heart failure (CHF), or stroke (CVA) using ICD9 codes or if the cause of death due to CVD was the first report of CVD. Patients with prior CVD or in whom CVD was diagnosed within 60 days of MM diagnosis were excluded. All patients had a minimum of 60 days of follow up. Changes in CVD rates were assessed by era: 1991-97 (era 1), 1998-2002 (era 2), 2003-07 (era 3) and 2008-12 (era 4). The cumulative incidence of CVD was estimated from date of MM diagnosis to first CVD event, accounting for the competing risk of death. Adjusted hazard ratios (aHR) for developing CVD were estimated accounting for the competing risk of death per the methods by Fine and Grey. Results: Of the 15,404 patients, 8,056 (52%) were male, 9154 (59%) were non-Hispanic white (NHW), 1890 (12%) were African American, 2839 (18%) were Hispanic, and 1360 (9%) were Asian. Median age at diagnosis was 65, with 12% of patients <50 and11%>80. Stem cell transplant was utilized by 2989 (19%) patients. The most common insurers were private/military (42%), followed by Medicare (31%), Medicaid/other public (7%), and unknown (19%) insurance. The median age of patients who developed CVD was 68 vs 63 who were never admitted for CVD (p<0.001). The 2 and 5 year cumulative incidence of developing CVD was 15.8% (95% confidence interval (CI): 15.2% - 16.3%) and 26.3% (CI: 25.6% - 27.0%). This was significantly less in era 4 (2008-12): 12.6% (11.6% - 13.7%) and 22.3% (20.9% - 23.8%) (p<0.001) (Figure). When examining types of CVD, CVA was less common in era 1 (1991-97) compared to eras 2-4 (5 year cumulative incidence rates in eras 1-4 respectively: 3.9% [3.4% - 4.5%], 4.6% [4.0% - 5.4%], 5.0% [4.3% - 5.7%], 4.6% [3.9% - 5.4%]) (p=0.002). CAD was less common in era 4 (5 year cumulative incidence rates in ears 1-4 respectively: 10.3% [9.4% - 11.2%], 11.5% [10.5% - 12.7%], 10.8% [9.9% - 11.9%], 9.4% [8.5% - 10.5%]) (p = 0.003). CHF was less common in era 4 (5 year cumulative incidence rates in eras 1-4 respectively: 17.9% [16.7% - 19.1%], 18.6% [17.3% - 20.0%], 17.7% [16.5% - 19.0%], 13.8% [12.6% - 15.0%]. In multivariable analysis, increased age, male sex, AA race/ethnicity, increased Elixhauser comorbidity score were associated with increased risk of CVD. Surprisingly, after accounting for age Medicare insurance was associated with increased risk of CVD, while socioeconomic status was not. Use of stem cell transplant was associated with decreased risk, likely due to pre-transplant screening for CVD. Diagnosis during era 4 (2008 - 12) was associated with decreased risk of new CVD (adjusted hazard ratio 0.70 [CI: 0.63, 0.77]). Conclusion: CVD is a common complication in MM patients: within 5 years of a MM diagnosis, over 25% develop CVD requiring hospitalization. Contrary to our hypothesis, we did not find increased CVD admissions in the most recent era. Decreased admissions due to CHF and CAD in the most recent era of diagnosis may indicate a greater awareness of this issue, routine thromboprophylaxis with anti-platelet agents in patients being treated with immunomodulatory agents, or changes in secular trends in the diagnosis and treatment of CVD. CVD is an ongoing source of morbidity for MM patients requiring further study and the vigilance of clinicians. Figure. Figure. Disclosures Rosenberg: Amgen: Research Funding, Speakers Bureau.

scholarly journals Second Primary Malignancies Among Patients with Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1621-1621
Author(s):  
Hannah P. Cutshall ◽  
Kevin D. Arnold ◽  
Elizabeth E. Brown
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Hematologic Malignancy ◽  
Absolute Risk ◽  
Individual Treatment ◽  
Second Primary ◽  
Excess Absolute Risk ◽  
Increased Risk ◽  
Treatment Data ◽  
Second Primary Malignancies

Abstract Introduction. Treatment for multiple myeloma (MM) has undergone significant transformation in the past decade with the introduction of novel therapeutic agents, including proteasome inhibitors (PI), immunomodulatory imides (IMiD) and monoclonal antibodies (mAb), leading to significant improvements in drug tolerability, treatment response and overall survival. As overall survival improves, patients with MM are at increased risk of developing second primary malignancies. Therefore, we evaluated the incidence of second primary malignancies among patients with MM. Methods. Using data from 30,630 1-year survivors of MM reported to 13 cancer registries that constitute the Surveillance, Epidemiology, and End Results (SEER) program (1992-2015; median survival time, 4.5 years), we calculated standardized incidence ratios (SIR) for all second primary malignancies, any solid and any hematologic malignancy and cancer sites among patients with MM, stratified by calendar year of first primary diagnosis consistent with advances in treatment for MM (1992-1999, 2000-2007, 2008-2015). Individual treatment data were unavailable. Excess absolute risk (excess cancer risk per 10,000 person-years) was calculated as ([observed cancers minus expected cancers]/person-years) multiplied by 10,000. Hazard ratios were calculated using Cox proportional hazards adjusted for confounders. Analyses were conducted using SAS v.9.4. Results. Overall, among 30,630 1-year survivors of first primary MM, the standardized incidence of any second primary malignancy was significantly increased (n=1,962; SIR=1.15, 95% confidence interval [CI], 1.10-1.20; P&lt;0.0001) and SIRs were elevated in each of the three calendar periods (1992-1999, SIR=1.14; 2000-2007, SIR=1.11; 2008-2015, SIR=1.22). Of all the second primary malignancies, the incidence of any solid tumor was increased (n=1,584; SIR=1.05, 95% CI 0.99-1.10; P=0.09), albeit not significantly, with SIRs for specific solid tumor sites ranging from 0.80 to 2.23. In contrast, the incidence of any hematologic malignancy overall was significantly increased (n=317; SIR=2.28, 95% CI 2.03-2.54; P&lt;0.0001) with the largest SIRs observed for any leukemia (SIR=5.86, 95% CI 4.91-6.94; P=&lt;0.0001) and SIRs for leukemia subtypes ranging from 2.07 to 14.87. The SIR for any lymphoma was also increased but to a lesser extent (SIR=1.57, 95% CI 1.35-1.82; P&lt;0.0001). Notably, SIRs for any leukemia decreased over the three time periods (1992-1999, SIR=6.40; 2000-2007, SIR=5.77; 2008-2015, SIR=5.51) whereas SIRs for any lymphoma increased (1992-1999, SIR=1.21; 2000-2007, SIR=1.60; 2008-2015, SIR=1.81) leading to an excess absolute risk of any hematologic malignancy of 1.5 per 10,000 person-years in the latest calendar period. No differences were observed by sex or ancestry. Discussion. We confirm that MM patients are at increased risk of second primary malignancies, and particularly other blood cancers. The transposition of leukemia and lymphoma incidence over time may reflect the effect of treatment changes in recent years. Additional studies, which include individual treatment data and longer follow up time from large and diverse populations, are required to further define these relationships. Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence of Second Primary Malignancies and Peripheral Sensory Neuropathy in Patients with Multiple Myeloma Receiving Daratumumab Containing Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5550-5550 ◽  
Author(s):  
Thura Win Htut ◽  
Donald P. Quick ◽  
Myint Aung Win ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Sensory Neuropathy ◽  
Phase Iii ◽  
Control Group ◽  
Second Primary ◽  
Peripheral Sensory Neuropathy ◽  
Antitumor Effects ◽  
Refractory Multiple Myeloma ◽  
Second Primary Malignancies ◽  
Peripheral Sensory

Introduction: Proteasome inhibitors-based regimens are the mainstay of initial therapy for most patients with multiple myeloma. Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with direct antitumor effects and has an immunomodulatory component. Recent studies have demonstrated that addition of daratumumab to standard regimens enhance direct cytotoxicity on myeloma cells and have shown survival benefits. Yet, there are notable safety concerns. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of second primary malignancies (SPM) and peripheral sensory neuropathy (PSN) with newer daratumumab combination regimens. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention SPM and PSN as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 25, suggesting some heterogeneity among RCT. The SPM incidence was 76 (4.29%) in study group vs 77 (4.34%) in control group. The RR for SPM was 1.12 (95% CI: 0.74 - 1.69; P = 0.58) and RD was 0.01 (95% CI: -0.01 to 0.02; P = 0.34). The RR for SPM was noted at 2.56 (95% CI: 0.26 - 25.46; P = 0.42) in a subset of relapsed and refractory multiple myeloma. Any-grade PSN was reported in 527 (46.84%) in daratumumab arm vs 550 (48.72%) in control arm with the RR of 0.98 (95% CI: 0.80 -1.21; P = 0.88). High-grade PSN was noted in 63 (5.6%) vs 76 (6.73%) in control group with the RR of 0.73 (95% CI: 0.42 -1.27; P = 0.27). Conclusions: Our meta-analysis depicted that there was no significant increase in the risk of second primary malignancies and peripheral sensory neuropathy in patients on daratumumab combination regimen, in newly diagnosed and relapsed refractory multiple myeloma, compared to control arm. However, long-term follow-up of these patients is required to determine the actual relation with second primary malignancies. Disclosures No relevant conflicts of interest to declare.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

2009 ◽  
Vol 27 (22) ◽  
pp. 3664-3670 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

scholarly journals Safety and Efficacy of Lenalidomide in Relapsed or Refractory Multiple Myeloma

2011 ◽  
Vol 6 ◽  
pp. CMO.S7275 ◽  
Author(s):  
Adrian Alegre ◽  
Isabel Vicuña ◽  
Beatriz Aguado
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Survival Outcomes ◽  
Second Primary ◽  
Safety And Efficacy ◽  
Depth Of Response ◽  
Increased Risk ◽  
First Relapse ◽  
Immunomodulatory Drug ◽  
Second Primary Malignancies

Lenalidomide is an oral immunomodulatory drug that has helped improve outcomes in multiple myeloma (MM) patients. Combination lenalidomide and dexamethasone (Len+Dex) has been shown to increase response rates and prolong survival compared with dexamethasone alone in patients with relapsed or refractory MM (RRMM). Clinical benefit may be greatest when Len+Dex is given at first relapse, and continued treatment appears to provide greater depth of response and improved survival outcomes. The most common adverse events associated with Len+Dex are cytopenias, which are predictable and manageable. Len+Dex is associated with an increased risk of venous thromboembolism, which necessitates adequate prophylaxis. The risk of second primary malignancies does not appear to be increased in patients with RRMM treated with lenalidomide-based therapy. Here we review the safety and efficacy of Len+Dex in RRMM, and provide an overview of data from Spain on the use of Len+Dex in RRMM.

scholarly journals How I manage frontline transplant-eligible multiple myeloma in Italy

2020 ◽  
Vol 12 (s1) ◽  
Author(s):  
Vittorio Montefusco ◽  
Giovanni Martinelli ◽  
Claudio Cerchione
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Second Primary ◽  
Induction Phase ◽  
Free Survival ◽  
Second Primary Malignancies

The treatment of transplant-eligible multiple myeloma patients in Italy consists in an induction phase based on bortezomib plus thalidomide plus dexamethasone (VTd), followed by a single or tandem autologous stem cell transplantation (ASCT), followed by lenalidomide maintenance. This approach offers an overall response rate of 93% and a CR rate of 58% with acceptable toxicity. Lenalidomide maintenance adds a significant increase in disease control, with a progression free survival after ASCT of 53 months, and an overall survival of 86 months. Second primary malignancies represent the most concerning toxicity of lenalidomide maintenance with a 6.9% incidence. However, the benefit in terms of increased myeloma control largely outweigh this complication. The incorporation of daratumumab in this treatment schema will further improve these clinical results.

Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3500-3500
Author(s):  
Thierry Andre ◽  
Kai-Keen Shiu ◽  
Tae Won Kim ◽  
Benny Vittrup Jensen ◽  
Lars Henrik Jensen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Failure Time ◽  
Statistical Significance ◽  
Final Analysis ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Crossover Effect ◽  
End Points ◽  
Risk Of Death ◽  
Crossover Rate

3500 Background: In the phase III, randomized open-label KEYNOTE-177 (NCT02563002) study 1L pembrolizumab (pembro) versus chemotherapy (chemo) provided superior progression-free survival (PFS) at second interim analysis (IA2) in patients (pts) with MSI-H/dMMR mCRC. The study continued to final analysis of overall survival (OS), planned after 190 OS events or 12 months after IA2, whichever occurred first. We present results of the final analysis of OS, 12 months after IA2. Methods: A total of 307 pts with MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to 1L pembro 200 mg Q3W for up to 2y or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab. Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Pts receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were OS and PFS (RECIST v1.1, central review). Secondary end points included ORR, duration of response (DOR) (RECIST v1.1, central review), and safety. For OS significance, the p-value had to meet a prespecified α of 0.0246 (one-sided). Sensitivity analyses to adjust for crossover effect were performed. Data cut-off for final analysis was Feb 19, 2021. Results: Median (range) study follow-up was 44.5 mo (36.0-60.3) with pembro vs 44.4 mo (36.2-58.6) with chemo. 56 (36%) pts crossed over from chemo to pembro, with 37 more receiving anti-PD-1/PD-L1 therapies off study (60% effective crossover rate in the ITT). The HR for OS favored pembro vs chemo with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359; median not reached [NR] vs 36.7 mo); this difference did not reach statistical significance. Sensitivity analysis by the rank-preserving structure failure time model and inverse probability of censoring weighting showed OS HRs of 0.66 (95% CI 0.42-1.04) and 0.77 (95% CI 0.44-1.38), respectively. Pembro vs chemo met the prespecified criteria for PFS superiority at IA2. At final analysis, median PFS was 16.5 mo vs 8.2 mo (HR 0.59; 95% CI, 0.45-0.79), but was not formally tested per analysis plan. Confirmed ORR was 45.1% (20 CR, 49 PR) vs 33.1% (6 CR, 45 PR). Median (range) DOR was NR (2.3+ to 53.5+) vs 10.6 mo (2.8 to 48.3+), respectively. Treatment-related adverse events (TRAEs) occurred in 79.7% vs 98.6% of pts; 21.6% vs 66.4%, respectively, had grade ≥3 TRAEs. Conclusions: As 1L therapy for pts with MSI-H/dMMR mCRC, pembro vs chemo provides statistically superior PFS with fewer TRAEs, and is associated with a trend toward reduced mortality that did not meet statistical significance likely due to the high crossover rate from chemo to anti-PD1/PD-L1 therapies. Together these data confirm pembro as a new standard-of-care in the 1L for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002.

Sign in / Sign up

Export Citation Format

Share Document