scholarly journals Duration of Therapy Is Independently Associated with Improved Progression Free and Overall Survival Following First Line Therapy for Non-Transplant Eligible Patients with Multiple Myeloma: Retrospective Analysis from a Single Centre

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5684-5684
Author(s):  
Dunnya De-Silva ◽  
Adam Bloomfield ◽  
Nicholas Counsell ◽  
Simon Cheesman ◽  
Ali Rismani ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Univariate Analysis ◽  
Total Duration ◽  
Novel Agents ◽  
First Line ◽  
Disease Response ◽  
Duration Of Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Stage 1

Abstract Background. Survival for older patients with multiple myeloma (MM) has improved with novel agents such as Proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs) . Outcomes in this heterogeneous population are also affected by pre-morbid fitness, comorbidities and tolerance of therapy. We analysed the outcomes of first line systemic therapy in this older patient group, aiming to explore the influence of patient, disease and regimen factors on outcomes. Methods. Non-transplant eligible patients undergoing first line therapy between April 2008 and April 2016 were identified retrospectively from electronic prescribing records; patient and disease features, toxicity and dose modifications were obtained from clinical records. FISH was performed on CD138+ cells using standard probes, and adverse risk was defined as per IMWG criteria. Survival was estimated using Kaplan-Meier methods and disease response by IMWG criteria. Cox Regression (univariate and multivariate) analysis was performed to identify factors influencing progression free (PFS) and overall survival (OS). Results. 84 patients were identified with median age 76 years (range 52-97); 24(28.6%) had cardiac and 12(14.3%) had pulmonary comorbidities. There was an equal spread of ISS stage and 26(31.0%) patients had extramedullary disease (EMD). Of 44 patients with FISH results at diagnosis, 18 (40.9%) had high risk features including 9(20.5%) with del(17p). Patients received a range of treatments; 51(60.7%) had PI-based regimens mainly with Bortezomib, 18(21.4%) received IMiDs (13 Thalidomide, 5 Lenalidomide) and 13(15.5%) chemotherapy. The median total duration of therapy including maintenance was 7.7months (range 0.7-24.1); this was longer (9.6months) in patients receiving IMiDs. The median PFS was 13.1 months (95% CI 10.6-15.5) and median OS was 40.5months (95% CI 30.3-50.7). The overall response rate (ORR) was 70.2%, and was higher in patients treated with novel agents (IMiD 72.2%, PI 72.0%) compared to patients treated with chemotherapy (61.6%). Younger age (70-80years vs. ≥80years), ISS stage 1, disease response ≥PR, maintenance therapy and longer total duration of therapy were associated with longer PFS in univariate analysis, and EMD was associated with shorter PFS(p's <0.1). On multivariate analysis, only total duration of therapy (HR=0.89; 0.81-0.96, p=0.005), ISS stage 1 (HR=0.28; 0.12 -0.63, p=0.002) and younger age (70-80years vs. ≥80years HR=0.50; 0.24-1.05, p=0.068) independently predicted longer PFS. Looking at factors predicting OS on univariate analysis, ISS stage 1, IMiD therapy, maintenance therapy and longer duration of therapy were associated with prolonged OS (p's <0.1). Only longer duration of therapy (HR=0.84; 0.76-0.93, p=0.001) and ISS stage 1 (HR=0.25; 0.08-0.80, p=0.020) remained significantly associated with OS on multivariate analysis. Although adverse genetic risk was associated with shorter OS on univariate analysis, the effect was not seen after adjusting for ISS stage, induction regimen and duration of therapy, where only duration of therapy remained significant (HR=0.69; 0.56-0.87, p=0.001). 18 (21.7%) patients discontinued therapy early due to toxicity; this was more frequent with PI (23.5%) and chemotherapy regimens (20.5%) compared to IMiD regimens (16.7%). 48(57%) patients required dose alterations due to toxicity, and this was commoner with IMiD (72%) compared to chemotherapy (38%) or PI (55%) based regimens. Conclusion. We report a sequential cohort of non-transplant eligible patients undergoing first line therapy in the era of novel agents. Our results indicate a consistent benefit for PFS and OS with longer duration of therapy, independent of response, regimen or adverse risk disease. ISS 1 was also an independent predictor of prolonged PFS and OS. Treatment regimen type and response did not correlate independently with PFS or OS. Despite the presence of comorbidities and discontinuations for toxicity, the PFS and OS outcomes are encouraging. This review of real-world outcomes highlights the potential benefit of continuous therapy in older patients. Improved ways of identifying patients susceptible to toxicity and use of frailty-adjusted treatment schedules would further improve outcomes in this patient group. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Outcomes of Primary Systemic Light Chain (AL) Amyloidosis in Patients Treated Upfront with Novel Agents and the Importance of Risk Adapted Treatment Strategies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1786-1786
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Magdalini Migkou ◽  
Alexandra Gkougkoutsi ◽  
...  
Keyword(s):  
Cardiac Biomarkers ◽  
Novel Agents ◽  
Al Amyloidosis ◽  
First Line ◽  
Hematologic Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Initiation Of Therapy ◽  
Intent To Treat ◽  
Stage 1

Abstract Abstract 1786 Novel antimyeloma agents (thalidomide, lenalidomide and bortezomib) may induce high rates of hematologic responses in patients with AL amyloidosis in whom they are increasingly used. Due to the multisystemic involvement many patients with AL are frail and vulnerable to treatment related toxicity and often succumb to their disease early after initiation of therapy, mainly due to complications associated with cardiac amyloidosis. In order to investigate the outcomes of AL patients in the era of novel agents and explore strategies to reduce complications and early mortality, we analyzed 81 consecutive patients in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients were assessed and followed rigorously and received similar supportive care according to our institution's practice. Bortezomib (B) was given as first line or salvage therapy after 1/9/2005 and lenalidomide (L) was given as primary therapy or salvage after 1/1/2008. Beginning on 1/1/2011, we follow a risk-adapted strategy, in which previously untreated patients with AL received bortezomib at a dose and schedule adjusted according to performance status (PS), levels of cardiac biomarkers and age (BDa). Patients were divided in those who started therapy from 2005 to 31/12/2007 (23 patients), those who received therapy between 1/1/2008 to 31/12/2010 (36 patients) and those who started therapy after 1/1/2011 (22 patients): 54% received first line therapy with B, 40% with L and 6% received conventional therapy upfront (mostly melphalan with dexamethasone; all received novel agents at later stages of their disease). Most patients (57%) were males; the median age was 67 years (range 42–82 years); 55% had a PS ≥2; the heart was involved in 68% of patients, the kidneys in 70%, the liver in 9%, and the peripheral nerve in 25%. Median eGFR was 70 ml/min and 4% required dialysis at diagnosis. Median NTproBNP was 2318 ng/l (range 36–75000 ng/l) and according to cardiac biomarkers, 26% were Mayo stage 1, 42% stage 2 and 32% stage 3. There were no significant differences in the demographic and disease characteristics between the three groups but 80% of patients, who started therapy from 2005 to 31/12/2007, received upfront BD, 80% of patients, who started therapy from 1/1/2008 to 31/12/2010, received upfront L and 82% of patients after 1/1/2011 received upfront BDa. On intent to treat, 65% of patients achieved hematologic response to first line therapy, including 20% hemCRs. Hematologic response rates were not different between the three groups (p=0.118); however, hemCRs were more frequent in patients treated before 31/12/2007 and after 1/1/2011 (30% and 27% vs. 9% in those treated from 1/2008-12/2010). The respective hemCR rates for patients treated with B vs. L were 32% vs. 6% (p=0.025). On intent to treat, organ responses were achieved by 28% of patients. Hematologic or organ progression or death has occurred in 60.5% of patients; the median PFS was 10 months and the 1-year PFS rate was 50%, 27% and 59% for patients treated in the three consecutive time periods, respectively (p=0.011). For patients treated upfront with B- vs. L-based regimens the respective 1-year PFS rate was 51% vs. 31% (p=0.054). After progression to first line therapy, 21 (26%) patients received second line therapy: 17 received B and 4 L. The median survival of all patients was 34 months; the 1-year survival rate for patients with Mayo stage 1 disease was 94%, for stage 2 was 56% and for stage 3 was 28% (p<0.001); 18 (22%) patients died within the first 3 months from initiation of therapy (all except one had cardiac involvement). The respective early death rates were 17%, 34% and 4% for patients treated in the three time periods, respectively (p=0.024) and were 22% and 25% for B- and L-based regimens (p=0.443), indicating that the reduction of early deaths was mainly due to the risk-adapted treatment strategy after 1/2011. In conclusion, our data indicate that novel agents, and especially bortezomib, resulted in significant response rates in patients with AL amyloidosis; however, 22% of AL patients die within 3 months form initiation of therapy due cardiac amyloidosis-associated complications. A risk-adapted treatment strategy with bortezomib dose and schedule adjusted according to individual patient characteristics may reduce early mortality and allow patients to achieve a hematologic response. Updated results will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Pre-Transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for Multiple Myeloma (MM)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 597-597
Author(s):  
Ravi Vij ◽  
Xiaobo Zhong ◽  
Mei-Jie Zhang ◽  
Sagar Lonial ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Salvage Therapy ◽  
Salvage Chemotherapy ◽  
Novel Agents ◽  
Disease Stage ◽  
Karnofsky Performance Score ◽  
First Line ◽  
Immunoglobulin Isotype ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 597 Back-ground: Planned upfront AHCT after initial induction improves both overall and progression free survival (OS and PFS) for patients with MM in randomized trials. However, it is unclear whether patients with less than partial response after a finite period of initial therapy should receive AHCT immediately or undergo salvage therapy to improve the level of response pre-AHCT. Methods: We addressed this question by querying the CIBMTR (Center for International Blood and Marrow Transplant Research) database. Between 1995 and 2010, 575 patients received upfront AHCT (within 12 mo of diagnosis) for MM after failing to achieve partial or complete response (PR/CR) to initial induction therapy. The 2326 patients who achieved CR/PR pre- AHCT had superior survival and were excluded (Fig 1). The study groups included: the 324 who received additional salvage chemotherapy after non-response to first line therapy (SALVAGE) and then proceeded to AHCT; and 251 who had no additional salvage chemotherapy but proceeded to AHCT immediately (NOSALVAGE). Outcomes of non-relapse mortality (NRM), relapse, PFS, and OS were compared measuring overall survival from diagnosis. Multivariate analysis using Cox proportional hazard models incorporated the following variables: age, gender, Karnofsky performance score, immunoglobulin isotype, stage, serum creatinine at diagnosis, disease status pre-AHCT, conditioning regimen, time from diagnosis to transplant, type of transplant (single/tandem), novel agents (thalidomide/bortezomib/lenalidomide), time-period of transplant and number of lines of pre-transplant therapy (= or &gt; 1 line) on outcomes. Results: Study cohorts were well balanced with respect to age, gender, Karnofsky performance status, immunoglobulin isotype, disease stage. More pts in NOSALVAGE received VAD (60% vs. 47%, p=0.002) for first line therapy and had a base-line creatinine &gt; 1.5mg/dl (27% vs. 17%, p=0.008). In the SALVAGE cohort, 245 (75%) received one, 65 (20%) two and 14 (4%) three salvage regimens. 197/245(61%), 47/65(59%), 2/14 (14%) were sensitive to 1st, 2nd and 3rd line salvage therapies prior to transplant resulting in 55% in SALVAGE achieving CR/PR pre-AHCT. In NOSALVAGE, 93% were in a minimal response or stable disease state and 7% with progressive disease. In SALVAGE, 55% received AHCT after 2004 compared with 38% in NOSALVAGE likely reflecting additional agents available for salvage. The majority of patients in either cohort (&gt;90%) received Melphalan based AHCT and a minority (&lt;20%) planned tandem AHCT. In the SALVAGE cohort, 44% had AHCT &lt;8 months after diagnosis as compared to 74% in NOSALVAGE (P&lt;0.001). Median follow-up for survivors was 61 mo and 68 mo, respectively. Six year NRM (p=1.0), relapse (p=0.2), PFS (p=0.2) or OS (p=0.5) were no different between the two cohorts). On multivariate analysis, a higher creatinine at diagnosis (&gt; 1.5 vs &lt; 1.5) predicted for higher NRM (p=0.008) and inferior OS (p=0.003), and the use of novel agents predicted for lower risk of NRM (HR = 0.37, P=0.04). Since more time elapsed between diagnosis and transplant among patients who received additional salvage chemotherapy, a left-truncated multivariate analysis was performed to reduce this potential waiting time bias. This multivariate analysis produced similar outcomes for TRM, relapse, treatment failure and OS irrespective of whether or not salvage regimens were used (Fig 2). Conclusions: In the setting of upfront AHCT, no additional benefit could be demonstrated for salvage regimens to upgrade response prior to AHCT. Disclosures: No relevant conflicts of interest to declare.

Co-Morbidity Score at the Time of Transplant Determines Prognosis in Older Patients Who Develop Acute Graft-Vs.-Host Disease (GVHD).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2244-2244
Author(s):  
Amin M Alousi ◽  
Gabriela Rondon ◽  
Grace-Julia Okoroji ◽  
Uday Popat ◽  
Leandro De Padua Silva ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Acute Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Older Age ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Morbidity Score ◽  
Co Morbidity

Abstract Abstract 2244 Poster Board II-221 Background: Older age patients are increasingly being considered for allogeneic hematopoietic cell transplants (HCT). Concerns related to early treatment related mortality (TRM), namely from acute GVHD, often limit referrals. Outcomes for older age patients who develop acute GVHD remain unknown. Methods: We performed a retrospective analysis of 83 adult patients enrolled onto two consecutive trials at MD Anderson to determine predictors for TRM at 6 months following systemic treatment of acute GVHD. These trials enrolled patients with newly diagnosed acute GVHD between 2000-2008 and included a single-center randomized trial of infliximab + methylprednisolone (MP) vs. MP alone and a multicenter trial of MP + one of 4 agents (mycophenolate, etanercept, denileukin diftitox or pentostatin). Results: Median age was 49 yrs (range, 20-70 yrs) and 63% of patients (pts) were male. 52% had acute leukemia and 31% were in remission at the time of transplant. Myeloablative condition and/ or peripheral blood HCT were performed in 52% and 54% of pts, respectively. Matched sibling, matched unrelated and mismatched transplants were 49%, 40% and 11%. GVHD prophylaxis was tacrolimus/ methotrexate in 87% of pts. Grades I/II, III/IV and visceral-organ acute GVHD represented 68%, 32% and 60% of pts occurring at a median time of onset of 25 days post-HCT. Day 28 acute GVHD response (defined as complete or partial response) was 63%. The median co-morbidity score at the time of HCT was 3 (range 0-11). Co-morbidity scores >3 were more common in pts >50 yrs (47%) than in those '50 yrs (24%), p=0.03. The proportion of responders on day 28 was comparable in pts >50 yrs (60%) and those '50 yrs (64%), p=0.7. On univariate analysis, significant predictors of higher TRM rate at 6 months following initiation of systemic therapy for acute GVHD were lack of response on day 28 post therapy (Hazard Ratio (HR) 3.6, p= 0.004), age > 50 yrs (HR 2.9, p=0.03) and co-morbidity score >3 (HR 3.1, p=0.01). There was no significant impact on the rate of TRM for donor type, cell source, intensity of conditioning regimen, donor/recipient sex mismatch, disease status at the time of transplant, GVHD grade at the time of initiation of systemic therapy or protocol assigned therapy. To adjust for potential interaction and confounding effects, multivariate analysis was performed by classifying pts into mutually exclusive groups according to day 28 response status, age, and co-morbidity score (see table). The cumulative incidence of TRM was lowest in pts who were '50 yrs of age and who responded to first line therapy with co-morbidity scores not impacting outcomes. TRM was comparably low (15%) in the absence of co-morbidity scores >3 in pts >50 yrs who responded to first line therapy. In contrast, in the presence of co-morbidity scores >3, TRM rate was high in pts >50 yrs regardless of whether pts responded (40%) or did not respond (100%) to first line therapy. Conclusion: The ability to withstand acute GVHD and/ or its therapy in pts older than 50 yrs depends on co-morbidity scores at the time of transplant. Disclosures: No relevant conflicts of interest to declare.

Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3090-3090 ◽  
Author(s):  
Evangelos Terpos ◽  
Nikolaos Kanellias ◽  
Lia A Moulopoulos ◽  
Dimitrios Christoulas ◽  
Andreas Koureas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rib Fractures ◽  
Novel Agents ◽  
First Line ◽  
Pathological Fractures ◽  
First Line Therapy ◽  
Line Therapy ◽  
Skeletal Related Events ◽  
First Relapse ◽  
Frontline Therapy

Abstract Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population. Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021). The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy. In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures: No relevant conflicts of interest to declare.

The outcome of vincristine, dactinomycin D, ifosfamide and doxorubicin (VAIA) as first-line therapy for adult-patients with metastatic ewing sarcoma; a single-center experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23501-e23501 ◽  
Author(s):  
Jean Paul Atallah ◽  
Mahmoud Abdelsatar Elshenawy ◽  
Ahmed ali Badran ◽  
Maaz Kamal Alata ◽  
Ahmed Gad ◽  
...  
Keyword(s):  
Overall Survival ◽  
Ewing Sarcoma ◽  
Primary Tumor ◽  
Univariate Analysis ◽  
Objective Response ◽  
Adult Patients ◽  
Categorical Variables ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

e23501 Background: Ewing sarcoma family of tumors (ESFT) is a rare malignancy among adults. Most studies from western countries have reported improvement in outcomes following multi-agent chemotherapy. We report our experience in the management of this disease among Arab ethnicity. The aim of this study is to assess the outcome of VAIA combination as a first-line treatment in Adult-patients with metastatic Ewing sarcoma. Methods: Patients who were newly diagnosed as metastatic Ewing sarcoma between 03/1997 and 11/2016 at King Faisal Specialist Hospital and Research Center, who received VAIA as first-line therapy were eligible. The patient's characteristics were summarized using Medians with interquartile ranges (IQR) and frequencies for continuous and categorical variables, respectively. Variables including age, sex, primary tumor size, site (skeletal vs extraskeletal) and extent of metastasis in correlation with progression and overall survival were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. Results: Thirty-nine patients were identified. Male (26, 66.7%), Female (13, 33.3%). Skeletal (27, 69.2%), Extraskeletal (12, 30.8%). The median longest diameter of the primary tumor 9.75 (IQR 8-15). The most common metastatic sites were Lungs (22, 56.4%) & Bone (10, 25.6%), however, the least common sites were Bone Marrow (3, 7.7%) and liver (2, 5.1%). The median number of VAIA cycles was 10 cycles (IQR 5-14). Objective response rate (ORR) was noticed in 20 patients (51.2%) (Complete Remission (7, 17.9%), Partial Remission (13, 33.3%). One patient had stable disease and 12 (30.8%) patients had progressive disease. The assessment was not feasible in 3 (7.7%) patients. With a median follow up duration of 18 months (1-44).20 patients died (62.5%). The median PFS and OS was 10,18 months respectively with 3,5 years overall survival rate of;35.7%,26.9% respectively. Univariate analysis correlation among different variables were insignificant. Conclusions: VAIA chemotherapy combination showed poor outcomes among our patients in comparison to literature further improvement is needed in this aggressive malignancy in our region.

scholarly journals Bendamustine Adversely Affects Stem Cell Mobilization Among Patients with Mantle Cell Lymphoma (MCL): A Comparison of the BR Vs RCHOP Eras in British Columbia (BC), Canada

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4556-4556
Author(s):  
Hatem Alahwal ◽  
Parv Chapani ◽  
Diego Villa ◽  
Yasser Abou Mourad ◽  
Maryse Power ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Univariate Analysis ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Risk Of Failure ◽  
Increased Risk ◽  
Cd34 Cells ◽  
Frontline Therapy

Abstract Introduction In 2013, bendamustine/rituximab (BR) replaced RCHOP as standard first line treatment for both transplant eligible and ineligible MCL patients (pts) in BC. Retrospective cohort studies report that bendamustine has no adverse effect on peripheral blood stem cell (SC) mobilization but this is discordant with local experience. We sought to compare rates of failed SC collection in MCL pts planned for high dose chemotherapy and autologous stem cell transplant (ASCT) after BR or RCHOP and identify risk factors for failed SC mobilization and collection. Methods We identified all pts with MCL in BC treated with BR or RCHOP as first line therapy who underwent SC mobilization from Jan. 1 2003-Dec. 31 2017 using the Leukemia/Bone Marrow Transplant Program of BC and Apheresis Database Standard mobilization was with G-CSF alone (G) until difficulties with SC collection were noted after BR. Different mobilization strategies were then used, including delaying SC collection 2-3 mos after BR, G + cyclophosphamide (G+C) mobilization and/or "rescue" plerixafor if Day 1 SC collection was inadequate. Failure of SC collection was defined as yield <1 x106 CD34+ cells/kg on apheresis Day 1 (D1fail). . All variables significant in univariate analysis (P<0.1) were entered into a multivariate analysis (MVA) logistic regression model to identify factors associated with D1 fail. Results A total of 152 pts were identified. 2 were excluded as they had pre-emptive plerixafor prior to apheresis D1 on a trial. Of the remaining 150 pts, 55 (37%) received BR, 95 (63%) RCHOP for a median of 6 cycles (range 1-6). Baseline characteristics were similar between groups (Table 1). Pts receiving BR had higher remission rates compared to RCHOP (CR 58% vs 35%, P=.004) and a longer duration from their last chemotherapy to apheresis D1 (BR 89 d vs RCHOP 39 d, P<0.), reflecting an intentional change in practice. For this same reason, use of G+C mobilization was higher in BR pts (45%) compared with RCHOP pts (1%). Failure on D1 of SC collection was significantly higher after BR compared to RCHOP (45% vs. 10%, P<.001). This difference persisted when only pts mobilized with G alone were included: D1fail 60% BR vs 10% RCHOP (P<.001), Fig. 1. Among BR pts, D1fail was higher for those mobilized with G compared with G+C (60% vs. 28%, P=.03). Of the 25 BR pts with D1fail, 20 pts received rescue plerixafor (P) (1 dose: 18, 2 doses: 1, 3 doses: 1) with 17 successfully collecting > 2.0 x106 CD34+ cells/kg, 2 successfully collected after a 2nd round of SC mobilization (Pt1: G+C+P, Pt2: G+P), and 1 pt did not undergo ASCT due to collection failure. Of the 5 pts who did not receive plerixafor, 2 successfully collected with 1-2 additional apheresis days and 3 successfully collected with a 2nd round of SC mobilization (2: G+P, 1: G+C). Among the 9 RCHOP pts with D1fail, 1 had rescue plerixafor with success, 3 successfully collected after 1-2 more apheresis days and 5 had a 2nd round of SC mobilization (1: G, 4: G+P), of which 1 failed and did not proceed to ASCT. Univariate analysis identified the following associated with D1fail: frontline therapy (BR vs RCHOP, P=<.001), mobilization regimen (G+C vs G, P=.001), gender (P=.002) and D1 platelet count (P=<.001). Delaying SC mobilization in pts who received BR did not improve D1 yield (P=.31). In MVA, frontline therapy with BR had an increased risk of D1fail compared to RCHOP with an odds ratio (OR) of 7.83 (95% CI 2.7-23.1), P<.001. Using G+C significantly improved the odds of a successful collection compared to G alone (OR for D1fail 0.17 [95% CI 0.05-0.62], P=.007). Female gender and low platelet count also increased risk of D1fail in MVA (Table 2). Conclusion MCL pts who receive BR as first line therapy have an almost 8-times higher risk of failure of D1 SC collection compared to those who receive RCHOP. This failure can be overcome largely with "rescue" plerixafor and partially with planned G+C mobilization such that successful collection can be achieved in >90% of pts. However, these agents add cost and potential toxicity. Platelet count on D1 SC collection is a potential indicator of high risk of failure. Delaying SC mobilization in BR pts does not improve collection yield. The impact of bendamustine in pre-transplant chemotherapy regimens, not only for MCL but also for a broad range of lymphomas where it is being increasingly used, must be considered when planning SC mobilization strategies. Disclosures Sehn: Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

scholarly journals Outcomes of Plasma Cell Leukemia Patients in the Era of Next-Generation Novel Agents: A Single-Center Retrospective Cohort Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Alex Ge ◽  
Chiung-Yu Huang ◽  
Thomas Martin ◽  
Jeffrey L. Wolf ◽  
Nina Shah ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Research Funding ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Next Generation ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy

Introduction Primary plasma cell leukemia (pPCL) is a rare and aggressive disease comprising 1-5% of all plasma cell dyscrasias. Although historically pPCL has been defined by circulating plasma cells (CPCs) ≥ 20% and 2.0 × 109/L, many series require only one of these two criteria for diagnosis. Over time there has been a pressing need to change the definition further in order to capture patients at an earlier stage of the disease. Recent studies have shown that multiple myeloma (MM) patients who have CPCs ≥ 5% but &lt; 20% at diagnosis have similarly poor outcomes. These thresholds for defining pPCL have not been studied in the current era of novel agents. While bortezomib-based regimens have been shown to extend pPCL patient survival, studies with next-generation agents such as carfilzomib (CFZ), pomalidomide, and daratumumab (DARA) are still scarce. Methods We performed a single-center, retrospective study of patients who at diagnosis had pPCL (defined as CPCs ≥ 20% or 2.0 × 109/L) or had MM with &lt; 20% CPCs (MM-CPC). Patients were treated at our institution between 1/1/2000-7/17/2020. Overall response rates were determined according to International Myeloma Working Group criteria. Overall survival (OS) was defined as the length of time between initiation of first line therapy and death. Progression-free survival (PFS) was defined as the length of time between initiation of first line therapy and first progression. OS and PFS were compared using log-rank tests. Results Of the 54 patients identified, 38 had pPCL and 16 had MM-CPC. The median age at diagnosis of the pPCL and MM-CPC groups were 59.2 (range 43-94) and 59.8 years (range 29-79), respectively, with a similar percentage of females, 47.4% vs. 37.5%. Both groups were similarly distributed by year of diagnosis; 76.3% and 62.5% of pPCL and MM-CPC patients were diagnosed between 2012-2020, respectively. The pPCL cohort had median CPCs of 40% (15-98) while the MM-CPC cohort had median CPCs of 4% (1-15). Median CPCs at diagnosis was 3.36 (0.44-179) × 109/L in the pPCL group compared to 0.33 (0.04-1.79) × 109/L in the MM-CPC group. Most patients for both groups were ISS stage III at diagnosis (57.9% in pPCL cohort, 56.2% in MM-CPC cohort). R-ISS assessment was not feasible due to missing data. A greater proportion of patients in the pPCL group (44.7%) had complex cytogenetics at diagnosis compared to the MM-CPC group (25.0%). All patients were exposed to at least one novel agent over the entire disease course. Of these patients, 50 (92.6%) were exposed to bortezomib, 45 (83.3%) to lenalidomide, 33 (61.1%) to CFZ, 22 (40.7%) to DARA, 13 (24.1%) to pomalidomide, and 4 (7.4%) to venetoclax. Twenty-four patients (44.4%) received an autologous stem cell transplant (ASCT). At the best response to treatment, 76.7%, 62.8% and 37.9% of patients achieved a partial response or greater to first, second and third line therapy, respectively. The median OS of the pPCL and MM-CPC groups was 34.5 and 35.5 months (p = 0.97) (Figure 1A), while the median PFS was 13.9 and 10.9 months (p = 0.52) (Figure 1B), respectively. The median follow-up was 28.1 months. No differences were observed for patients with CPCs &lt; 20% compared to patients with CPCs ≥ 20% (p = 0.98). There was trend towards a better survival for patients with CPCs &lt; 2 × 109/L compared to CPCs ≥ 2 × 109/L (p = 0.35). Since we did not observe any meaningful difference in OS or PFS between the pPCL and MM-CPC groups, we combined these groups for further survival analysis. Patients exposed to either DARA or CFZ (n = 37) had a median OS of 59.2 months, while patients exposed to neither drug (n = 17) had a median OS of 11.7 months (p = 0.02) (Figure 1C). ASCT was associated with a prolonged median OS (66.8 months vs. 17.2 months, p = 0.0001) (Figure 1D), while a complex karyotype at diagnosis was associated with a poorer median OS (17.4 months vs. 66.8 months, p = 0.01). Conclusions In the era of next-generation novel agents, overall and progression-free survival of pPCL and MM-CPC patients are similar. Patients exposed to DARA or CFZ have an improved survival compared to those who did not receive these drugs. ASCT is also associated with a superior survival over those who did not receive a transplant. Further studies are needed to evaluate the efficacy of these next-generation drugs in this patient population. Disclosures Martin: Janssen: Research Funding; Seattle Genetics: Research Funding; AMGEN: Research Funding; GSK: Consultancy; Sanofi: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Fortis: Research Funding; Roche: Research Funding; Janssen: Research Funding; Amgen: Consultancy; GSK: Research Funding; Bristol Myers Squibb: Research Funding.

High-Dose Carfilzomib and Dexamethasone As First-Line Treatment in Symptomatic Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4258-4258 ◽  
Author(s):  
Tomer M Mark ◽  
Sujitha Yadlapati ◽  
Lyubov Neglyad ◽  
Jennifer Bourke ◽  
David Jayabalan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Research Funding ◽  
Maximum Response ◽  
First Line ◽  
Disease Response ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3 ◽  
Stem Cell Collection

Abstract Background: Carfilzomib (Cfz) is approved for use in relapsed and refractory multiple myeloma (RRMM) at a dose of 27mg/m2 after escalation from 20mg/m2. The response rate for Cfz and dexamethasone (dex) as first-line therapy in multiple myeloma (MM) is unknown. Higher doses of Cfz have been shown to enhance overall response in RRMM (Lendvai 2014); the presence of a dose-response relationship of Cfz for first-line therapy in untreated MM has not been evaluated. A protocol of Cfz-Dex induction at two dosing levels, followed by BiRd (Clarithromycin 500mg PO BID, Lenalidomide (Len) 25mg for 21/28 days, Dex 40mg weekly) consolidation, and thereafter Len (10mg 12/28 days) maintenance, evaluated response and safety by Cfz dose level in patients (pts) with newly diagnosed symptomatic MM. The ORR and safety data for Cfz-Dex induction stratified by Cfz dose is reported. Methods: 70 patients with untreated MM were enrolled in a phase 2 study of Cfz-dex. Cfz-dex is: Cfz IV on D1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of cycle 1 and 45mg/m2 thereafter and Dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Screening echocardiogram and pulmonary function testing were performed. Brain natriuretic peptide (BNP) was measured with each cycle. Cfz-dex was continued until plateau in disease response (unchanged M-protein for 2 cycles). Elective stem cell collection was then performed in transplant eligible pts. This was followed by BiRd until 2nd response plateau, and then by LEN maintenance. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Results: 25 pts received Cfz-Dex at 45 mg/m2 and 44 (out of 45 enrolled) pts at 56 mg/m2 for at least 1 cycle and were evaluable for response. 56% of pts were ISS II/III and 64% had high-risk cytogenetics as per IMWG definition. Pts received a median of 5 cycles of Cfz-dex in both the 45 mg/m2 (range 1-10) and 56 mg/m2 groups (range 1-14). Maximum response to Cfz-dex is shown in Table 1. There was no difference in response between the 45 and 56mg/m2 groups (P = 0.20). Median time to PR and maximum response for the 45 and 56 mg/m2 cohorts were both 2 and 3 cycles, respectively. 42 pts had stem cell harvest. All collected stem cells to support at least two transplants (> 5 x 10^6 CD34/kg) in one mobilization attempt using G-CSF, with mean yield of 13.74x10^6 CD34/kg (range 5.94-32.14). 79% collected in 1 apheresis session. Adverse events (AEs) were notable for renal failure in 3 pts (2 Grade 2, 1 grade 3) and congestive heart failure in 1 pt (grade 3). Two of the 3 cases of renal failure occurred in the 56 mg/m2 cohort, all other AEs occurred in the 45mg/m2 cohort. All AEs resolved after stopping Cfz. There was no correlation with TTE, PFTs or serial BNPs and development of cardiac or pulmonary toxicity. Discussion: This is the first prospective study evaluating induction responses to Cfz-dex in MM. Cfz-dex is safe and active in induction at both 45 and 56 mg/m2, with an ORR of 93% and rate of >= VGPR of 68% despite a primarily high risk population. Specific dose did not correlate with response. Higher dose of Cfz did not lead to more toxicity. Cfz-dex induction led to successful stem cell collection in all attempts. Cfz-dex is a highly active and well-tolerated induction regimen. Transitioning to IMiD-based therapy after maximum response led to deeper responses with a remarkable 97% rate of VGPR or better. Table 1. Maximum Response with Cfz-Dex, followed by BiRD consolidation and lenalidomide maintenance: Response Category Cfz-Dex 45 mg/m2 Cfz-Dex 56 mg/m2 Overall Cfz-Dex phase BiRD phase Lenalidomide maintenance phase N = 25 (%) N = 44 (%) N = 69 (%) N = 44 (%) N = 33 (%) >= PR 22 (88) 42 (95) 65 (93) 44 (100) 33 (100) >= VGPR 16 (72) 31 (70) 45 (68) 42 (95) 32 (97) >= CR 3 (12) 2 (5) 5 (7) 12 (27) 15 (45) SCR 3 (12) 2 (5) 5 (7) 9 (20) 13 (39) CR 0 (0) 0 (0) 0 (0) 3 (7) 2 (6) VGPR 13 (52) 29 (66) 42 (61) 30 (68) 17 (52) PR 6 (24) 11 (25) 17 (25) 2 (5) 1 (3) SD 3 (12) 2 (5) 5 (7) 0 0 Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib as first line therapy in myeloma.. Rossi:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pearse:Celegen: Consultancy. Perry:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.

scholarly journals Natural History of Skeletal Related Events in Patients with Multiple Myeloma Who Received First- and Second- Line Therapy with Novel Agents: Results from a Single Center Analysis in 620 Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4326-4326
Author(s):  
Evangelos Terpos ◽  
Nikolaos Kanellias ◽  
Eftathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Vassilis Koutoulidis ◽  
...  
Keyword(s):  
Research Funding ◽  
Novel Agents ◽  
Long Bone ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Skeletal Related Events ◽  
First Relapse

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p<0.0001) or abnormal MRI pattern (49% vs. 11.3%, p<0.0001) at diagnosis. No correlation was found between the presence of SREs at diagnosis and a specific SNP of those studied. Frontline therapy with IMiD-based regimens was given in 38% of patients; 27% patients received bortezomib-based regimens and 28% both IMiD and bortezomib-based therapies (VTD or VRD); 7% received only conventional chemo. Bisphosphonates (BPs) were given to 465 patients (75%) at diagnosis; the vast majority (91%) received zoledronic acid. The remaining 155 patients did not receive upfront BPs, mainly due to renal insufficiency. During first line treatment, 39 (6.3%) patients developed a SRE: 25/341 (7.3%) on bortezomib- (including combos with an IMiD) and 14/235 (6%) on IMiD-based regimens. At the time of first relapse, 4.5% of patients presented with new fractures and 12% required local radiotherapy to bone (SRE rate: 16.5%). The rate of SREs at first progression was much higher in patients who did not receive upfront BPs (92.3% vs. 7.7%). There was no difference in the incidence of SREs at first relapse between patients who received PI- vs. non-PI-based regimens as first line therapy (54.2% vs. 45.8%, p=0.544). During second line therapy, 12.2% of patients developed a SRE, with no difference regarding the second line therapy (PI- or IMiD-based regimens). In total, 126 (20.3%) patients developed at least one SRE, during the course of the first and second line of therapy; this was more common in those who presented with an SRE at diagnosis (33% vs 12%; p<0.03). Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

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