Cyclophosphamide, Thalidomide And Dexamethasone Research Articles

Cyclophosphamide, Thalidomide and Dexamethasone (CTD) as First-Line Therapy in Multiple Myeloma Patients: An Experience in a Clinical Haematology Centre in Dakar, Senegal

Introduction: Induction therapy followed by high-dose chemotherapy with autologous stem cell transplantation remains the gold standard for myeloma patients who can tolerate this treatment approach. In a developing country setting, in the absence of availability of bone marrow transplantation, the CTD protocol is an accessible treatment regimen whose efficacy and lower toxicity compared to the Melphalan Prednisone protocol has been reported. This protocol has been administered since 2018 in first line. It’s against this backdrop we perform this study to assess the efficacy of this CTD protocol in first line therapy. Methods: We conducted a descriptive and analytical study including clinical, paraclinical and evolutionary data of 50 patients with MM treated during the period range from 01 September 2018 and 01 July 2022 with the CTD protocol of cyclophosphamide (500 mg at D1, D8 and D15), dexamethasone (40 mg weekly) and thalidomide (100 mg/day) in 28-day cycles. Survival outcomes were estimated by the Kaplan-Meier method. Results: The mean age was 62.3 ± 9.1 years and the sex ratio was 0.7. An advanced prognostic score at diagnosis was found in 73.5% of patients according to the Salmon and Durie score and in 32% according to the ISS. Overall remission was noted in 64%, of which 34% were in very good partial remission and partial remission in 12% of cases. Progression was noted in 4 patients. Treatment-related side effects were mainly peripheral neuropathy and anaemia in 3 patients respectively. The median survival was 38.4 months. The progression-free survival was 60%. An advanced age (≥65 years) is correlated with negative impact on survival (p = 0.04). Conclusion: Cyclophosphamide, thalidomide and dexamethasone give good outcome with less toxicity. Thus, it remains a first-line treatment alternative for newly diagnosed and low-income patients.

P-171: Multistate models provide complementary insights into outcomes for patients treated in the UK NCRI Myeloma XI randomised trial

P-171: Multistate models provide complementary insights into outcomes for patients treated in the UK NCRI Myeloma XI randomised trial

Prognostic impact of early-versus-late responses to different induction regimens in patients with myeloma undergoing autologous hematopoietic cell transplantation: Results from the CALM study by the CMWP of the EBMT.

In autologous stem cell transplant (ASCT)-eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib-based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor). The length of induction treatment required to achieve a Good response did not affect PFS (P=.65) or OS (P=.61) post-ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8months (P=.31), and median OS 81.7, 92.7, and 77.4months, respectively (P=.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR=1.21, P-value=.02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post-transplant. The kinetics of response did not affect outcomes.

A comparative study of cyclophosphamide, thalidomide and dexamethasone (CTD) versus bortezomib and dexamethasone (BDex) in light-chain amyloidosis

BackgroundCyclophosphamide, thalidomide, and dexamethasone (CTD) or bortezomib and dexamethasone (BDex) show substantial efficacy in patients with amyloid light-chain (AL) amyloidosis, especially in Chinese patients. Currently, both regimens are recommended as primary treatment options for AL amyloidosis, but no comparative study has been reported. MethodsWe retrospectively evaluated the outcomes of 81 AL patients who received CTD (n = 42) or BDex (n = 39) and used Mayo stage 2012 to match 26 pairs of patients. ResultsIn the whole cohort, the overall hematologic responses were 86% vs 91% in the CTD and BDex groups, including a complete response of 56% vs 71% based on an intention-to-treat (ITT) analysis. One- and 2-year overall survival (OS) was 90.2% and 81.7% with CTD, and 87.6% and 82.7% with BDex. After matching, BDex regimen induced a significantly deeper and more rapid hematologic response over CTD, but no statistically significant difference in OS (ITT analysis, P = 0.24; 6-month landmark analysis, P = 0.48). Cardiac response rates were similar, while there was a trend for higher renal responses in patients treated with BDex (68% vs 44%, P = 0.09). Additionally, BDex was associated with significantly improved survival in patients with advanced disease (Mayo stage III or worse; P = 0.009). Patients treated with BDex reported more episodes of severe hematologic toxicity and diarrhea. ConclusionsCTD and BDex are effective treatments for Chinese patients with AL amyloidosis, but BDex regimen appears superior to CTD in achieving a more rapid and deeper clonal response, and in improving OS in patients with advanced disease.

P0268A COMPARATIVE STUDY OF CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE (CTD) VERSUS BORTEZOMIB AND DEXAMETHASONE (BDEX) IN AL AMYLOIDOSIS: A REAL-WORD STUDY IN CHINESE PATIENTS

Abstract Background and Aims Amyloid light-chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the deposition of misfolded immunoglobulin light chains. The prognosis of AL patients is poor. About 70% of patients have renal involvement and one third of patients would progress to dialysis. Cyclophosphamide, thalidomide and dexamethasone (CTD) and bortezomib and dexamethasone (BDex) have shown great efficacy in patients with AL amyloidosis, especially in Chinese patients. But which option is more suitable for Chinese patients is unclear. Method We retrospectively evaluated 81 AL patients who received CTD (n = 42) or BDex (n = 39) and used Mayo stage 2012 to match 26 pairs of patients. Results In the whole cohort, the overall hematologic responses were 86% vs 91% in the CTD and BDex groups, including a complete response of 56% vs 71%, higher than most of the previously reported chemotherapies. One- and two-year overall survival (OS) was 90.2% and 81.7% with CTD regimen, and 87.6% and 82.7% with BDex regimen. After matching by Mayo stage 2012, BDex regimen showed the advantage in the depth and speed of hematologic response over CTD regimen, but there were no statistically significant differences in OS both based on the ITT analysis (P = 0.24) and 6-month landmark analysis (P = 0.48). Cardiac response was similar, while there was a trend for higher renal response in patients treated with BDex (68% vs 44%, P = 0.09). Additionally, we found that if the patients were limited to Mayo stage III or worse, BDex regimen was associated with improved survival (P = 0.009). Overall toxicities were manageable in both regimens. Severe hematologic toxicities and diarrhea should get more attention in patients treated with BDex. Conclusion This is the first comparison of BDex versus CTD in patients with AL amyloidosis. These results indicated that CTD and BDex regimens can be active and safe chemotherapy for Chinese patients, but BDex regimen is superior to CTD in achieving more rapidly and deeper clonal response, as well as in improving OS in selected patients.This conclusion is significant because we confirmed BDex regimen may be an optimal option in treating Chinese patients with AL amyloidosis. The definite advantages on long-term prognosis need to be verified in the further studies.

P0140RENAL PATHOLOGICAL CHANGES AFTER SUCCESSFUL TREATMENT OF LCDD USING CYCLOPHOSPHAMIDE, THALIDOMIDE AND DEXAMETHASONE: A CASE REPORT

Abstract Background and Aims The combined of cyclophosphamide, thalidomide and dexamethasone (CTD) haven’t reported in treatment of LCDD, and how the renal pathologic injury changes after treatment is still unknown. Method Here we descript a LCDD patients who undergone repeated renal biopsy after treatment. Results We report a 56-year-old woman presented with nephrotic syndrome, impaired renal function, and serum M-protein of IgG lambda. First renal biopsy showed severe nodular glomerulosclerosis with single lambda light chain linear deposit along GBM. The patient treated with 14 cycles CTD regimen, and reached the complete hematologic response and renal response. At the 29 months of follow up, the repeated biopsy showed the glomerular nodular sclerosis attenuated significantly, only trace granular electron-dense deposits along inner side of GBM.(Details in figure 1: The pathological findings of the first (A-D) and second (E-H) renal biopsy.) Conclusion This case highlights the hematologic response not only can improve the renal function, but also alleviate the renal nodular sclerosis. And the low-cost regimen, CTD, maybe a good choice.

Prognostic value of pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in multiple myeloma patients treated with thalidomide-based regimen

Neutrophils to lymphocytes ratio (NLR) and platelets to lymphocytes ratio (PLR) are considered as laboratory markers of inflammation. They can be potentially useful in predicting the course of multiple neoplasms including selected hematological cancers. The aim of the study was to assess the value of NLR and PLR in predicting the effects of therapy and prognosis in multiple myeloma patients treated with thalidomide-based regimen. The study group consisted of 100 patients treated with the first line CTD (cyclophosphamide, thalidomide, and dexamethasone) chemotherapy. The NLR and PLR were calculated before treatment. High NLR was observed in patients with higher stage of the disease, with poor performance status, hypercalcemia, and high CRP. High PLR was associated with low BMI and high CRP. In patients with high NLR, significantly shorter PFS was observed (17 vs. 26 months, p = 0.0405). In addition, high values of NLR and PLR were associated with significantly shorter OS (38 vs. 79 months, p = 0.0010; 40 vs. 78 months, p = 0.0058). Summarizing, NLR and PLR have a significant independent prognostic value for multiple myeloma patients. Furthermore, the NLR can be a predictive marker for the outcome of thalidomide-based chemotherapy.

Response rates to first-line treatment in eligible patients to autologous stem transplantation in Chile

Background The treatment of choice of newly diagnosed multiple myeloma (NDMM) is an induction with proteasome inhibitors followed autologous stem cell transplantation (HSCT). Since 2013, the treatment of these patients in the public system is based on CTD (cyclophosphamide, thalidomide, and dexamethasone). Aim To evaluate the response rates achieved with CTD, and the results of HSCT in patients with NDMM in the public setting. Material and Methods Data from patients considered as candidates for HSCT from different centers of the National Adult Antineoplastic Drug Program (PANDA, for its acronym in Spanish), diagnosed between 2013 and 2017, was analyzed. The response to treatment of first and second lines of treatment was evaluated, in addition to the results of HSCT. An optimal Response was defined as the sum of strict complete remission, complete remission and very good partial response (sCR, CR and VGPR). Results One hundred and seventy-seven patients were analyzed, 54% women, and 53% with IgG multiple myeloma. Information about the international staging system was retrieved in 127 patients (71%). Seventeen percent were ISS I, 22% in ISS II and 32% ISS III. CTD was used as first treatment in 106 patients (60%), and cyclophosphamide, bortezomib and dexamethasone (CyBorD) in 13 (7%). As first line, CTD had an overall response of 50.9%, and CyBorD of 76.9%. Thirty patients were treated with bortezomib as second line treatment. Forty patients (22%) underwent HSCT. The 5-year Overall Survival (OS) in transplanted patients and non-transplanted patients was 100 and 62% respectively (p < 0.01). Conclusions The response rate achieved by CTD in these patients is suboptimal. The response to CyBorD was better.

Outcomes of Transplant-Eligible Newly Diagnosed Ultra-High Risk Myeloma Patients Treated in the NCRI Myeloma XI Trial Indicate the Need for Early Treatment Stratification and Novel Treatment Approaches

Outcomes of Transplant-Eligible Newly Diagnosed Ultra-High Risk Myeloma Patients Treated in the NCRI Myeloma XI Trial Indicate the Need for Early Treatment Stratification and Novel Treatment Approaches

PB2131 CTDA VERSUS MPT FOR MULTIPLE MYELOMA: REAL WORLD DATA FROM THE WEST OF SCOTLAND CANCER NETWORK

Background:Multiple myeloma has a median age at presentation of approximately 70 years and many patients are unsuitable for intensive induction chemotherapy and autologous stem cell transplant due to advanced age or co‐morbidity. Current West of Scotland Cancer Network, BCSH and NICE Clinical Management Guidelines supports the use of either CTDa (attenuated Cyclophosphamide, Thalidomide and Dexamethasone) or MPT (Melphalan, Prednisolone, Thalidomide) as options for first line treatment in patients ineligible for high dose therapy. Despite these recommendations there are little reported data directly comparing the efficacy of these two commonly used chemotherapy regimens.Aims:In order to determine whether the choice of either CTDa or MPT as first line therapy had any influence on survival among our patient population, we retrospectively analysed real‐world data from patients treated initially with either CTDa or MPT in the West of Scotland Cancer Network between 1/1/2013 and 1/1/2016.MethodsPatient data including demographics, details of treatment regimens, ECOG performance status, ISS and renal function at diagnosis were extracted, where available, from electronic prescribing records and electronic notes. Individual patient mortality data was collected for 6 years from initiation of their treatment. All data were analysed using “R” software (v3.5.2).Results:In total 171 patients were treated with either CTDa (n = 126) or MPT (n = 45) first line for multiple myeloma between 1/1/13 and 1/1/2016. Patients received a similar number of cycles (median 6 CTDa vs 5 MPT). Mean age for patients treated with CTDa was 74 (72.8‐75.2) and MPT 76.9 (75.4‐78.4), male to female ratio was 1:1.06 for CTDa and 1:1.8 for MPT. Kaplan Meier curves were constructed and compared using the logrank test. Median survival was 1258 days for CTDa and 785 days in the MPT group. Although the Kaplan Meier curves appeared to show some benefit to probability of survival in favour of CTDa, there was no statistically significant difference between the Kaplan Meier curves (p = 0.15). Due to the retrospective nature of our data collection we were unable to provide details of response rate or progression free survival.Summary/Conclusion:Our data show comparable survival between patients treated with CTDa or MPT in an unselected patient population. Our results are similar to those reported in the prospective UK Myeloma IX trial1. It should be noted that patients treated with both CTDa and MPT in our dataset had extensive modifications to their treatment regimen diverging from the established protocol. Most frequently patients treated with CTDa received once weekly Dexamethasone instead of four‐day steroid pulses, as reflects common clinical practice in frail or elderly patients. However, it was reassuring to note that regimen modification did not appear to adversely affect OS when compared to published data.imageAcknowledgement:The authors are grateful to Christine Crearie and colleagues in the West of Scotland Cancer Network and West of Scotland Haematology Audit Group for support and access to patient data.

Progression Free Survival below 12 Months Following Stem Cell Transplant Is a Hallmark of High-Risk Myeloma Which Is Associated with Inferior Overall Survival — Data from the Ukmrc Myeloma XI Trial

Introduction Multi-agent induction chemotherapy followed by autologous stem cell transplant (ASCT) is a standard of care for younger patients with multiple myeloma, aimed at maximising the depth and duration of first response (PFS1). However, the duration of PFS1 is variable between patients. Improved understanding of how to identify high risk patients who relapse early and the ability to design strategies applicable to their biology represents the central aim of personalized medicine approaches for MM. This landmarked analysis of the Myeloma XI trial was designed to identify the characteristics of patients with PFS1 of less than a year after ASCT. Patients and methods In MXI patients were randomised to induction therapy with CTD (cyclophosphamide, thalidomide and dexamethasone) or RCD (lenalidomide, cyclophosphamide and dexamethasone) and +/- CVD (bortezomib, cyclophosphamide, dexamethasone) intensification in patients with Patients who completed ASCT were identified with very early relapse (PFS1 Results Of 1274 patients receiving ASCT: 178 (14%) relapsed within 12m and 1096 (86%) thereafter. There were higher rates of ≥VGPR in the PFS1≥12m group (70% vs 59%) and in both groups most patients responded at ≥PR (PFS1 Inferior outcomes continued for the PFS1 As PFS1 Discussion Nearly three quarters of those with PFS1 Disclosures Bygrave:Amgen: Honoraria; Takeda: Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding. Pawlyn:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support; Janssen: Honoraria, Other: Travel support. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity9s Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Abbvie: Consultancy. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Striha:MSD: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Hockaday:Millenium: Research Funding; MSD: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Jones:Celgene: Honoraria, Other: Travel support, Research Funding. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Garg:Amgen: Honoraria, Other: Travel Support; Takeda: Other: Travel Grant; Novartis: Other: travel support, Research Funding; Janssen: Honoraria. Williams:Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel Support, Speakers Bureau; Takeda: Honoraria, Other: Travel support; Amgen: Honoraria, Speakers Bureau. Karunanithi:Janssen: Other: Travel support, Research Funding; Celgene: Other: Travel support, Research Funding. Lindsay:Celgene: Honoraria, Other: Travel support; BMS: Consultancy, Other: Travel support; Takeda: Other: Travel support; Janssen: Consultancy; Novartis: Other: Travel support. Jenner:Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Drayson:Abingdon Health: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Gregory:Janssen: Honoraria; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Jackson:Amgen: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kaiser:Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel support; Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Cyclophosphamide, thalidomide and dexamethasone (CTD) as initial therapy for newly diagnosed multiple myeloma patients.

8051Background: Major progress has occurred in multiple myeloma (MM) treatment in recent years. . However, due to limited healthcare resources, newer agents are not readily available. In this setti...

Minimal Residual Disease (MRD) in Myeloma: Independent Outcome Prediction and Sequential Survival Benefits per Log Tumour Reduction

▪Minimal residual disease (MRD), as assessed by flow cytometry is a powerful predictor of outcome in multiple myeloma (MM). We and others have previously demonstrated that such analyses are informative in patients treated with autologous stem cell transplant (ASCT) and non-transplant regimens. It predicts outcome in patients in conventional CR and is applicable to patients with standard and adverse risk cytogenetics. As a consequence MRD assessment is under consideration as a surrogate endpoint for clinical trials. This is urgently needed in MM as >5yrs follow-up is typically required to demonstrate survival differences in trials of upfront therapy. If surrogate end points are to be used in clinical trials it is essential that a reproducible effect is demonstrable using multivariate models. Previous studies have confirmed the effect of MRD on PFS but a consistent effect on OS has been not been definitively shown. This may in part be due to the availability of effective salvage therapy but it is also possible that the traditional threshold of 10-4 for analysis and the categorization of patients as MRD-postive or negative is suboptimal. Flow cytometry does provide a quantitative assessment of residual tumour over a large range and the degree of tumour depletion may be more informative than a positive-negative analysis.397 patients from the MRC Myeloma IX trial were included in this analysis. Patients were randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) induction for 4-6 cycles followed by standard high-dose melphalan (HDM) ASCT. BM aspirates were obtained at day 100 for MRD analysis. 500,000 cells were evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. PFS and OS data analysis was landmarked from the date of the MRD assesment.Of the 397 patients with MRD data available at day 100 after ASCT, 247/397 (62.2%) achieved <0.01% MRD. The level of residual disease varied across four logs in MRD-positive patients (0.01-<0.1% in 49/397, 0.1-<1% in 72/397, 1-<10% in 26/397 and ≥10% in 3/397). The PFS and OS for individuals with ≥1% residual disease was comparable to individuals with a PR/MR/SD confirming that MRD assessment is most relevant in CR. The level of MRD correlated with outcome. The median PFS for patients with ≥10% MRD at day 100 after ASCT was 0.8 years, with 1-<10% MRD was 1.7 years, with 0.1-<1% MRD was 1.9 years, with 0.01-<0.1% MRD was 2.7 years and for patients with <0.01% MRD was 3.1 years (P<0.001). The median OS for these groups was 1 yr, 4 yrs, 5.9 yrs, 6.8 yrs and for patients with <0.01% MRD not reached with >7.5 yrs median follow-up (P<0.001, see figure).A Cox proportional hazards model was used to further evaluate factors influencing outcome. B2M and MRD were log-transformed and along with age were considered as continuous variables. ISS, haemoglobin (<115g/l), platelets (<150x10^9/l) and cytogenetics were used as stratification factors. Cytogenetic groups were classified as unfavourable for patients with gain(1q), del(1p32), t(4;14), t(14;20), t(14;16), and del(17p), or favourable for hyperdiploidy, t(11;14) and t(6;14), or unknown/inevaluable. MRD assessment (χ2 11.8, P=0.0006) and cytogenetics (χ2 35.5, P=<0.0001) were the only factors that retained significance in this multivariate model. Conventional categorical response, ISS and B2M were not predictive of OS (p=0.99, 0.16 and 0.56 respectively).We would conclude that MRD quantitation is more informative than a positive or negative categorization with a 10-4 threshold and independently predicts outcome. In this analysis we were able to demonstrate an approximate 1 year survival benefit per log tumour depletion. A lower cutpoint for predicting improved outcome was not reached and more sensitive assays will likely improve outcome prediction further. This data strongly supports the role of MRD assessment as a surrogate endpoint in clinical trials. [Display omitted] DisclosuresRawstron:Celgene: Consultancy; BD Biosciences: Consultancy, Intrasure Patents & Royalties. Gregory:Celgene: Consultancy. Davies:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Novartis: Consultancy. Cook:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Owen:Celgene: Consultancy, Honoraria, Research Funding.

Cold Agglutinin Disease Secondary to Multiple Myeloma in a Psoriatic Patient

Cold agglutinin disease (CAD) is a chronic compensated hemolytic anemia. We report a case of cold agglutinin disease secondary to multiple myeloma (MM) in a patient of erythrodermic psoriasis. The patient presented with acral cyanosis, progressive weakness and generalized desquamating scaly lesions. After confirming the diagnosis (80-90% plasma cells in bone marrow, M- spike in serum protein electrophoresis, G-ë restriction pattern in immune electrophoresis) he was given chemotherapy with CTD (cyclophosphamide, thalidomide and dexamethasone) protocol. His clinical symptoms improved and he has now completed 4 cycles of chemotherapy. The interim follow up showed achievement of PR (partial response).DOI: http://dx.doi.org/10.3329/jom.v15i2.20688 J MEDICINE 2014; 15 : 141-143

Would Be Cyclophosphamide, Thalidomide and Dexamethasone (CTD) a Possible Treatment For Multiple Myeloma Where Is Not Possible New Drugs?

BackgroundNowadays, the best evidence for symptomatic patients with Multiple Myeloma (MM) is initial induction therapy with more than two drugs that contains bortezomib. If patients are eligible it is established the use of high dose chemotherapy and autologous stem cell transplantation (ASCT). We do not have to prescribe in Brazilian public health service, due to economic reasons, new drugs such as: bortezomib and lenalidomide. On the other hand, it is known that Cyclophosphamide, thalidomide and dexamethasone (CTD) regimen is an effective primary therapy for MM and it is widely used in some countries such as United Kingdom. We have been prescribing for first line therapy CTD regimen in our clinical practice for approximately 4 years. Thus, we performed a retrospective analysis of patients with MM treated with CTD regimen in the Instituto do Câncer do Estado de São Paulo. Here we present response rate, reduction dose rate, toxicity rate and progression free survival (PFS) and overall survival (OS). Patients and MethodWe studied 71 patients that were submitted as first line treatment CTD, during 2006-2012. This regimen consists: Cyclophosphamide 500mg orally on days 1, 8, 15; Thalidomide 100mg orally on days 1 to 28 and Dexamethasone 40mg orally on days 1 to 5 and 14 to 18, every 30 days. To sensitive and eligible patients, we have submitted them for ASCT. PFS and OS were calculated by the Kaplan-Meier method. PFS was calculated from the start of treatment until progression or death or last follow-up and OS until death or last follow-up. GraphPad Prism (v5.0) software was used for statistical calculations, and P values < 0.05 were considered to be statistically significant. ResultsIn the 71 patients, 54.2% were male patients, the median age was 57.81 years old (± 7.96). Out of the 71 patients (78.7%), were classified by Durie Salmon staging as IIIA or IIIB and 30% presented stage III for the International Staging System (ISS). Fifty seven (80.2%) were considered eligible for ASCT in the beginning of treatment. Moreover, the evidences of end-organ damage felt related to the plasma cell disorder were: lytic lesions 78.6%; anemia 51.4%, renal failure 20% and hypercalcemia 11.4%. The median of CTD cycles prescribed was 6.44 (± 2.62) and 47.1% were treated in the beginning without adjustment doses. It was evidenced 5.63% deaths related to the treatment. It was observed adjustment doses after 1stcycle in 35.7% of patients due to: peripheral neuropathy 36%, tremor 16%, thrombosis 12%, bradycardia 12% and others 24%. It was observed in 71 patients: 6 (8.45%) stable disease (SD); 4 (5.63%) progressive disease (PD); 26 (36.66%) partial response (PR); 15 (21.1%) very good partial response (VGPR) and 16 (22.53%) complete response (CR), it was not possible to analyze 4 (5.63%) patients due to death. Of total eligible patients to ASCT, 57.62% were submitted for ASCT and in this moment 6.7% have been preparing for ASCT. The median of PFS was 29.2 months (CI 95% 0,22-0,66) and median of OS was not achieved. It was observed difference in OS between patients with stage III for the ISS: 28,92 months versus (vs) patients with stage I and II median not reached, p = 0.0105. PFS study demonstrated curves that patients responding to CTD at least VGPR (VGPR+CR) presented better median PFS 37.48 months than others patients (PR+PD+SD) 17.93 months, p=0.0018. Only patients that presented PD and SD response to CTD had a significantly shorter OS median 19.21 months than patients responses at least PR (PR+VGPR+RC) median was not reached, p < 0.0001. ConclusionWe conclude that CTD is a feasible regimen where is not possible to prescribe new drugs, with acceptable toxicity. Moreover, patients that presented at least VGPR and at least PR to CTD demonstrated better PFS and OS, respectively. Disclosures:No relevant conflicts of interest to declare.

Lenalidomide Combined With Cyclophosphamide and Dexamethasone Is Effective and Well Tolerated Induction Treatment For Newly Diagnosed Myeloma Patients Of All Ages

Lenalidomide Combined With Cyclophosphamide and Dexamethasone Is Effective and Well Tolerated Induction Treatment For Newly Diagnosed Myeloma Patients Of All Ages

Clonal Evolution In Two Multiple Myeloma Patients and a Biclonal MGUS Patient

BackgroundMultiple myeloma (MM) and its benign precursor monoclonal gammopathy of undetermined significance (MGUS) are diseases characterised by the production of monoclonal immunoglobulins. Clonal heterogeneity in MM has become a well-accepted phenomenon; however dogma would suggest the proteins produced by these clones remain consistent. Free light chain (FLC) escape is one exception to this rule, but is comparatively poorly documented and to our knowledge has not been identified in MGUS patients. Here we report 2 cases of MM patients with intact immunoglobulin and FLC producing clones that have different sensitivities to treatment leading to escape. In addition we report an MGUS patient whose routine corticosteroid treatment for polymyalgia rheumatica (PMR) impacted on the intact immunoglobulin but not the FLC producing clones and led to an escaping FLC clone which was subsequently diagnosed as myelomic. MethodsSerum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) were performed using Hydrasys 2 apparatus (SEBIA). Serum free light chain (FLC) levels were measured nephelometrically on a Siemens BNTM II using polyclonal antisera assays, Freelite®(The Binding Site Group Limited, Birmingham, UK). ResultsTwo intact immunoglobulin MM patients (Patient 1 IgAκ: 14.4g/L, κ FLC: 1320 mg/L, age: 65, sex: male; Patient 2 IgAλ: 8g/L, λ FLC: 9510 mg/L, age: 48, sex: male) were monitored through the course of their disease for 762 and 1330 days respectively. Following cyclophosphamide, thalidomide and dexamethasone (CTD) treatment Patient 1 achieved a VGPR (∼90% reduction in IgAk and 65% reduction in FLC) which was stable for 270 days. Subsequently whilst only a trace of IgAκ was present, dFLC levels increased from 460mg/L to 15194mg/L. Patient 2 achieved a CR following treatment with vincristine, doxorubicin and dexamethasone (VAD) and autologous stem cell transplant (ASCT) which was stable for 330 days. As with Patient 1 relapse was characterised by a substantial increase in dFLC from 8.61mg/L to 3168mg/L. In both patients the velocity of change and sensitivity to treatment of the intact immunoglobulin and FLC suggested the presence of heterogeneous clones.A rare biclonal MGUS patient, IgGκ (3.9g/L) and λ FLC (316mg/L), was identified during routine laboratory investigations (age: 71, sex: female) and followed annually in accordance with local guidelines (low/moderate risk MGUS). 16 months following MGUS diagnosis the patient was started on oral methylprednisolone for PMR. The treatment resolved the PMR and coincidently caused a reduction in the IgGκ serum concentration (trace quantities) and a normalisation of the FLC κ/λ ratio. A year post steroidal treatment whilst the IgGκ monoclonal protein concentration remained stable, dFLC levels increased from 9.6 mg/L to 1052 mg/L (κ/λ ratio: 0.008), indicating the emergence of a λ FLC clone although the patient remained asymptomatic. 4 months later and almost 4 years following diagnosis, the patient progressed to symptomatic disease with severe renal impairment (creatinine 6.19 mg/dL; eGFR 7.03 ml/min/1.73m2) anemia (Hb 9.0g/dL) and 70% clonal plasma cells present in the bone marrow. The dFLC concentration had further increased to 9726 mg/L however the IgGκ monoclonal protein was no longer detectable by IFE indicating the biclonal MGUS had progressed to a λ light chain multiple myeloma. DiscussionRoutine monitoring of MM patients to detect FLC escape is recommended by international guidelines, in light of the MGUS patient FLC escape leading to MM, we suggest routine evaluation of FLC levels in MGUS may also be beneficial. Disclosures:Endean:The Binding Site Group Ltd: Employment. Harding:The Binding Site: Employment.

Efficacy of stem cell mobilization in patients with newly diagnosed multiple myeloma after a CTD (cyclophosphamide, thalidomide, and dexamethasone) regimen

The CTD (cyclophosphamide, thalidomide, and dexamethasone) regimen is known to be an effective primary therapy in patients with newly diagnosed multiple myeloma (MM). However, stem cell yields after CTD remain inconsistent. The aim of the present study is to identify the influence of the CTD regimen on the outcome of peripheral blood stem cell (PBSC) collection. Fifty-four patients received four cycles of CTD, and PBSCs were mobilized with cyclophosphamide and G-CSF or with G-CSF alone. Each patient from whom ≤4.0×10(6) CD34(+) cells/kg were collected received a second mobilization course. The median duration from the start of a CTD regimen to the first collection was 4.3months. Forty-eight patients were mobilized with cyclophosphamide followed by G-CSF, and six patients were mobilized with G-CSF alone. The median day of apheresis was day 3 (range day 2-day 5). The overall response rate at mobilization was 96.3%, including 11.1% complete response, 22.2% very good partial response, and 63.0% partial response. The median number of harvested CD34(+) cells was 12.8×10(6) cells/kg. At the second mobilization, 88.9% of patients reached the minimal stem cell collection target of ≥2.0×10(6) cells/kg, and 75.9% of patients achieved the collection target of ≥4.0×10(6) cells/kg. CTD within four cycles is an effective primary therapy in patients with newly diagnosed MM and only minimally affects subsequent PBSC collection.

A Matched Comparison of Cyclophosphamide, Bortezomib and Dexamethasone (CVD) Versus Cyclophosphamide, Thalidomide and Dexamethasone (CTD) in the Treatment of Mayo Cardiac Stage III Patients with AL Amyloidosis.

AbstractAbstract 2966 Introduction:Poor survival in AL amyloidosis is largely driven by outcomes in patients with advanced cardiac disease. To date, the Mayo cardiac staging system is the most widely used tool to identify these high risk patients. For stage III patients few treatment options exist to modify the natural history of this disease with up to 50% dying within the first 6 months. Moreover, there are currently no studies comparing different regimens in the novel agent era specifically addressing this group. Here we present a matched comparison examining response and survival endpoints after upfront treatment in Mayo stage III patients using either Cyclophosphamide, Bortezomib and Dexamethasone (CVD) or Cyclophosphamide, Thalidomide and Dexamethasone (CTD), the current standard of care for this disease in the United Kingdom. Patients and Methods:The primary cohort comprises 78 patients (39 in each arm) referred to the National Amyloidosis Centre in London between 2008–2012. All patients had cardiac involvement by the 2005 consensus criteria and all were Mayo stage III. The CVD cohort reflects all patients seen at the NAC with Mayo stage III disease treated with this regimen upfront. Based on baseline NT-proBNP (>8000ng/L) and dFLC (>180mg/L) the patients were then matched with a recent cohort treated with CTD as first line therapy. The CVD and CTD regimens were recommended as previously described (1,2). Dose modifications were at the discretion of the treating haematologist. Both conventional haematologic responses and dFLC responses were examined (3,4). Overall survival (OS) was calculated by the Kaplan-Meier method and calculated from the start of treatment until death or last follow-up. To correct for the influence of early deaths on response rates a landmark analysis was performed in patients surviving at least 3 months from treatment (n=21 (CVD) and n=30 (CTD)). Results:In the intention-to-treat (ITT) cohort response rates are comparable although there was a trend to higher CR rates with the CVD regimen (table 1). On an ITT basis, there was no statistically significant difference in the 1-year OS (59.4% vs 46.2% for CVD and CTD respectively, p = 0.9, figure 1a). A high rate of early deaths is noted. 23.7% of CVD and 13.1% of CTD patients died within 6 weeks (p = 0.24). 36.8% of CVD and 23.7% of CTD patients died within 3 months (p = 0.22). In the landmark analysis upfront therapy with CVD correlated with an improved 1-year OS (94% vs 62.1%, p = 0.01, figure 1 b). This may be partly driven by the increased CR rate in the CVD cohort compared to those receiving CTD (47% vs 24% respectively, p = 0.03, table 1). Conclusion:Compared with CTD, treatment with CVD was not associated with a reduction in the high rate of early deaths often seen in patients with Mayo cardiac stage III disease. However, these data suggest that survival of patients treated with CVD upfront may be superior among those who remain alive after the first 3 months, consistent with the higher CR rates achieved. While it did not reach statistical significance the high rate of early deaths indicates that further optimisation and better supportive care strategies are required during the early stages of treatment especially with CVD. Ongoing phase III trials are currently underway to address these issues in a prospective manner. [Display omitted] The ITT cohort is shown in (A) and the landmark cohort is shown in (B). Solid and dashed lines reflect CVD and CTD treated patients respectively. [Display omitted] Disclosures:Wechalekar:Janssen-Cilag: Honoraria.

Sequential Immunomodulatory Drug (IMiD) and Proteosome Inhibitor Therapy Improves Response Rates in Newly Diagnosed Multiple Myeloma: Preliminary Results From the Myeloma XI Trial

AbstractAbstract 335 BackgroundInduction treatment for myeloma has focused on improving response rates and many centres have evaluated and used triplets of therapy based on either IMiD or proteosome inhibitor drugs. Other strategies rely on combining the two classes of novel agents and excellent response rates have been obtained. An alternative approach to this, which moves some way towards personalised therapy, is to use sequential combinations of the two classes of novel agents dependent on the response achieved. The aim of this approach is to maximise responses and, by so doing, improve survival. MethodsIn order to test this concept, we have carried out a trial, Myeloma XI, which compared responses to cyclophosphamide, thalidomide and dexamethasone (CTD) with cyclophosphamide, lenalidomide and dexamethasone (CRD). Following the randomised use of either of these triplets, given to maximum response, patients achieving no response (NC or PD) received further therapy with a triplet composed of cyclophosphamide, bortezomib and dexamethasone (CVD). In order to test if a bortezomib combination could improve the response of maximally treated patients, those with a suboptimal response (MR or PR) were randomised to either no further therapy or to CVD. For patients achieving ≥ VGPR no further induction was given. Younger fitter patients went on to receive HDM plus ASCT whereas older less fit patients did not. All patients were eligible for a maintenance randomisation to no maintenance, lenalidomide or lenalidomide/vorinostat maintenance. For patients receiving CVD, treatment was continued to a maximum of 8 cycles, with response being assessed using IMWG criteria after each cycle and therapy continued to maximum response or intolerance. Here we present the response rates for patients who have received CVD. ResultsAt the time of this initial analysis 1424 patients have been randomised overall; 790 in the intensive pathway and 634 in the non-intensive pathway. Across both pathways, of the refractory patients with no response to induction treatment, an upgrade in response from NC or PD to ≥MR was seen after CVD treatment in 58% of patients, with 31% going on to achieve a VGPR or CR. In the other group of patients, those with a suboptimal response to induction treatment and randomised to receive CVD, 45% went on to achieve VGPR or CR. These patients reduced their paraprotein value by a mean of 74% from the start of CVD suggesting that the improvement in response is significant and not the result of patients marginally crossing the boundaries of response criteria. It seems that even in a group of maximally treated patients that response rates can be increased further by the use of a proteosome inhibitor drug.In the MRC Myeloma IX study the response rates at a similar time point for those treated with similar thalidomide based induction were PD/NC 7.1%, MR/PR 41.8%, VGPR/CR 37.5%. Assuming at least the same response rates in the current study then we calculate that it would be possible to get approximately 45% extra patients from MR/PR and 31% from PD/NC to ≥VGPR, equating to an approximate 21% increase in the ≥VGPR rate to 59% of the total patients. ConclusionsWe have demonstrated an improvement in response with the addition of a bortezomib based regimen in the group of patients who had a suboptimal response following induction chemotherapy with an IMiD based regimen. Particularly encouraging is the excellent rate of achievement of CR/VGPR in patients with no initial response to treatment. We anticipate that together this will significantly improve the percentage of patients achieving ≥VGPR, approximating 60% of all patients following induction, a response rate that should improve further following ASCT. Further follow up is required to know whether or not this will translate into an improvement in OS or PFS, however from previous studies we would expect this to be the case. Disclosures:Pawlyn:Celgene: Unrestricted educational grant Other. Off Label Use: Lenalidomide and vorinostat as maintenence therapy. Davies:Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other; Ortho Biotech: Honoraria, Speakers Bureau. Gregory:Celgene: Unrestricted educational grant Other. Szubert:Celgene: Unrestricted educational grant Other. Bell:Celgene: Unrestricted educational grant Other. Ouzman:Celgene: Unrestricted educational grant Other. Drayson:Celgene: Unrestricted educational grant Other. Owen:Celgene: Unrestricted educational grant Other. Jackson:Celgene: Honoraria, Unrestricted educational grant Other. Russell:Celgene: Unrestricted educational grant Other. Morgan:Ortho Biotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other.