Cyclophosphamide, Thalidomide, Dexamethasone Research Articles

Adolescents and Young Adults with Multiple Myeloma, Kuwait Experience

Background Multiple myeloma MM is an incurable plasma cell malignancy with a median age of 65 years at diagnosis worldwide, a small number of publications were focused on young adult Multiple myeloma MM with special characteristics and clinical outcomes. Objectives To evaluate the incidence of MM among adolescent and young adults (AYA) in Kuwait aged 40 and below. Also, to describe the clinical characteristics, high risk features and treatment outcomes at the Kuwait Cancer Control Centre (KCCC). Materials & Methods We collected data retrospectively from the hematological malignancy registry at KCCC and looked at AYA patients (pts) with a confirmed diagnosis of Multiple myeloma at our center from 2015 till 2022, we looked at age of onset, gender, nationality, year of myeloma diagnosis, presence of extramedullary disease, International Staging System score (ISS score), cytogenetic aberrations, induction therapy, receipts of auto-transplant and maintenance therapy. Results From 2015 till 2022, 340 patients were diagnosed with MM in Kuwait, eleven patients were found 40 years old or younger, only one was female patients, the median age was 35 years old, around a third were Kuwaiti, 73% were non-Kuwaiti of middle eastern background, 4 patients were found to have extramedullary disease at diagnosis, with advanced stage ISS III found in 3/9 pts. One patient was found with 1Q gain and the rest of the 10 patients were with negative del17p, t (4,14), t(14,16), gain1q and t(11,14). Of note, interphase FISH cytogenetic is not done with CD138 selection. Six patients were treated with RVD induction (Lenalidomide, Bortizomib, Dexamethasone), two patients treated by CTD (Cyclophosphamide, Thalidomide, Dexamethasone), one pt treated by VCD (Bortizomib,Cyclophosphamide,Dexamethasone), one patient treated by Daratumumab RVD, and one patient treated by VTD. Overall response rate (ORR) was 90.9%, (10/11) responded patients proceeded to HDCT/ASCT and all these patients went on maintenance post-transplant, two patients were lost to follow up while 9 patients still under follow up, median follow up 33 months, one pt had a relapse after transplant. Conclusion MM is an uncommon disease among AYA in Kuwait (3.2%) of all myeloma patients, with favorable durable responses in this group of patients.

Autologous Peripheral Blood Stem Cell Mobilisation Techniques, Stem Cell Yields and Practice Variation-By-Country in Patients with Myeloma Undergoing First Autologous Stem Cell Transplants in EBMT Centres between 2012 and 2021

The techniques employed to mobilise autologous peripheral blood stem cells in patients with myeloma have evolved over time and vary between countries. The most common methods are (1) Cyclophosphamide and Granulocyte - Colony Stimulating Factor (G-CSF) (Cyclophosphamide), (2) G-CSF only, (3) G-CSF and Plerixafor, and (4) Other. In general, chemotherapy, usually Cyclophosphamide, is used in Europe and single agent G-CSF in North America. We performed a retrospective analysis of the EBMT database to analyse stem cell mobilisation techniques in European patients undergoing a first ASCT for myeloma over the last decade. This data was available on a select cohort of patients for whom Med B form data had been submitted. A total of 76,923 patients received a first autologous stem cell transplant for myeloma in 501 EBMT-affiliated centres between 2012 and 2021. Detailed Stem cell mobilization data including CD34 results were available on 4,710 (M 58%: F 42%) patients from 87 centers. The Median (IQR) age was 61.3 (54.7-66.1) years. MM subtypes were IgG, IgA, Light Chain and Other in 56.6%, 19.2%, 20.8% and 3.4%, respectively. The stage at first transplant was CR, VGPR/PR, SD/MR, and Rel/Prog in 17.5%, 78.4%, 2.8% and 1.3%, respectively. The frequency of use of each of the stem cell mobilization techniques were as follows: Cyclophosphamide (n=3,017, 67.1%), G-CSF only (n=1,207, 26.9%), G-CSF + Plerixafor (n=222, 4.9%) and Other (47, 1.0%). Peripheral blood stem cells were the sole stem cell source in 4,705 (99.9%) of the transplants. The comparative median annual CD34 yields (x10e6/kg) are shown below and reveal that the yields following Cyclophosphamide-based mobilization were consistently higher (6.14-7.8) than those following either G-CSF (4.46-6.1) or G-CSF and Plerixafor (2.5-5.6). When analyzed in aggregate, the median (IQR) stem cell yields (x10e6/kg) following Cyclophosphamide, G-CSF, G-CSF and Plerixafor, and Other were 7.32 (4.9-10.14), 5.25 (3.88-7.38), 4.94 (3.42-6.85) and 4.9 (3.82-7.54), respectively. When analysed by MM subtype, there was no significant difference in yield between the IgG, IgA, Light Chain and Other categories (p=0.523). We next analyzed the median annual CD34 yields (x10e6/kg) by induction regimen (no. of pts): CTD (Cyclophosphamide, Thalidomide, Dexamethasone) (n=712) 7.56, Other (n=623) 5.86, PAD (Bortezomib, Adriamycin, Dexamethasone) (n=256) 5.8, VAD (Vincristine, Adriamycin, Dexamethasone) (n=172) 5.03, VCD (Bortezomib, Cyclophosphamide, Dexamethasone) (n=1,735) 6.21, VD (Bortezomib, Dexamethasone) (n=603) 5.97, VRD (Bortezomib, Lenalidomide, Dexamethasone) (n=811) 5.42 and VTD (Bortezomib, Thalidomide, Dexamethasone) (n=3,192) 7.12 (p<0.001), the highest yields being collected following CTD and VTD (<0.001). We finally examined mobilization trends in the seven largest countries in the dataset (France, Germany, Italy, the Netherlands, Spain, Turkey, and the United Kingdom) over time. Data was available for between 9.6% and 22.8% of patients in 6 of the 7 countries; however, it was only available in 2.9% of patients from Germany. Within these clear limitations, there were wide national variations in clinical practice both over time and between countries, as shown below. Over the last decade, two-thirds of patients in EMBT centres underwent autologous stem cell collection following Cyclophosphamide and G-CSF, one quarter following single agent G-CSF and 5% following G-CSF and Plerixafor. As reported previously, yields were consistently higher following chemotherapy-based mobilization. However, we have no data on associated morbidity such as the incidence of infection, the need for hospital admission or costs. As regards the effect of prior induction regimens, the highest yields were seen in patients who had received either CTD or VTD induction, possibly reflecting less stem cell toxicity due to chemotherapy and/or deeper remissions following these regimens. Finally, limited data on trends in practice appears to show considerable variation between countries combined with significant changes in some countries over the last decade. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P-176: Effect of induction regimen in survival in newly diagnosed multiple myeloma patients receiving consolidation with autologous stem cell transplantation

<h3>Background</h3> Novel therapies improved the survival of newly diagnosed multiple myeloma patients (NDMM) during the last decades. Nevertheless, autologous stem cell transplantation (ASCT) remains a standard consolidation strategy. How induction therapy affects the outcomes in NDMM patients receiving consolidation with ASCT has not been explored in our region <h3>Objective</h3> To analyze the impact of different induction therapies in NDMM patients receiving consolidation with ASCT in overall survival (OS) and progression-free survival (PFS) <h3>Method</h3> This is a retrospective survival analysis study based on the Grupo de Estudio Latinoamericano de Mieloma Múltiple (GELAMM) registry. We included adults patients with NDMM who received ASCT as frontline consolidation therapy from 6 countries. The induction regimens compared were VCD (Bortezomib, cyclophosphamide, dexamethasone), VTD (Bortezomib, thalidomide, dexamethasone), CTD (Cyclophosphamide, thalidomide, dexamethasone), or VRD (Bortezomib, lenalidomide, dexamethasone). OS and PFS were defined as the time from MM diagnosis until the death/last control or disease progression, respectively. We used SPSSv.25 for statistical analysis. Survival was analyzed using the Kaplan-Meier model with Log-rank test. <h3>Results</h3> Five hundred eighty-five patients were included, with a median age at diagnosis of 55 years (IQR 10), 54% males, 58.6% IgG, 17.8% IgA, 17.8% Light Chain, and 5.8% other subtype. Risk stratification at diagnosis (n=534) showed 30.7% ISS-I, 34.3% ISS-II, and 35% ISS-III. Two-thirds (66.8%) received maintenance therapy. Induction regimen were 55% VCD, 25% VTD, 16.1% CTD, and 3.9% VRD. The proportion of patients by ISS group was similar among all the regimens (p=0.97). Also, the median age was equivalent among the groups included (p=0.23). At end of induction, the rate of very good partial response or better was 51.3% VCD, 56.7% VTD, 48.9% CTD, and 85% VRD. The 5-year OS for the whole group was 82.7%, and the 5-year OS per induction regimen were 82.9% VCD, 83.6% VTD, 80.1% CTD, and 89.5% VRD (Log-Rank, p=0.70). The median OS was not reached in any of the induction regimens. The 5-year PFS (n=368) for the whole group was 27%, and the 5-year PFS per induction regimen were 27.4% VCD, 20.3% VTD, 30% CTD, and 74% VRD (Log-Rank, p=0.23). The median PFS was 42 months for both VCD and VTD, 48 months for CTD, and not reached for VRD. Maintenance therapy was associated with a 5-year OS of 86.60% vs. 80.60% (p>0.05) for patients not receiving maintenance. The 5-years PFS was 30.3% for maintenance vs. 21.2% (p>0.05) in non maintenance. <h3>Conclusions</h3> in this real-world cohort, VRD as induction therapy was associated with deeper response rates and longer PFS and OS. Regardless of the frontline therapy, ASCT achieves a long PFS and OS in NDMM. There is a trend for longer PFS and OS in patients receiving maintenance. Larger number of patients may be needed to allow more robust conclusions.

Bortezomib-Thalidomide-Dexamethasone (VTD) As Salvage Treatment in Patients with Multiple Myeloma Candidates for Transplantation in the Real World

BackgroundTreatment for Multiple Myeloma (MM) has evolved greatly, ranging from corticosteroids to monoclonal antibodies. In low-resource countries, however, the first-choice treatment is still based on cyclophosphamide-thalidomide-dexamethasone (CTD) regimen, either in patients who are candidates or non-candidates for stem cell transplantation (SCT). In Peru, a few years ago, bortezomib has been introduced as salvage treatment. Bortezomib as salvage treatment has reported 6.22 months of time to progression and combined complete and partial response rates of 38% in pivotal study. 1ObjectivesTo determine the response to treatment to VTD in patients with multiple myeloma candidates to transplant. To determine progression-free survival (PFS) to VTD. To determine the percentage of transplant patients.MethodsWe retrospectively assessed the clinical efficacy and toxicity of VTD (bortezomib 1.3mg/m2 subcutaneously on days 1, 4, 8 and 11; thalidomide 100mg orally on days 1 through 21; dexamethasone 40mg orally on days 1, 2, 4, 5, 8, 9, 11, 12 for three-week cycles), as salvage treatment in patients with relapsed/refractory MM candidate to autologous stem cell transplantation treated at Instituto Nacional de Enfermedades Neoplasicas in Lima, Peru, between January 2014 and December 2016. Patients received only one prior treatment and at least 2 cycles of VTD. SPSS program was used for data analysis. Survival outcomes were estimated by Kaplan-Meier Method.ResultsSixteen patients were found to fulfill the selection criteria. The median age was 52 (39-62), fifty-six percent (n=9) were male. International Staging System III disease was present in 75%. ECOG 1-2 was present in 94%. Ig G and IgA MM were 62.5% and 12.5% respectively; lambda light chain was present in 56.3%. 37.5% of patient had renal impairment. B2µg was >3.5mg/dL in 57% of patients. CTD was the first-line in 94%, with overall response rate (ORR) of 62.5% (complete response (CR) 6.3%, very good partial response (VGPR) 12.5%, and partial response (PR) 43.8%). For VTD regimen the median number of treatment cycles delivered was three (range 2-5), totally 59 cycles. After a median of 14 months follow-up for VTD (range 4-34), the overall response rate was 75%, stringent complete response (SCR) was 18.8% (n= 3), complete response 37.5%, very good partial response 6.3%, and partial response 12.5%. Six out of 16 patients (37.5%) with VTD treatment who were candidates for transplantation finally were transplanted. Among the causes for not undergoing transplantation, infections was 40% (20% (two) of cases were pulmonary tuberculosis, one case (10%) was herpes simplex encephalitis, one case (10%) was probable pulmonary aspergillosis), relapsed disease 40%, renal failure 10%, failure of stem cell collection 10%. Median PFS was 14 months (4-33m). 2-years PFS was 37.5%. 5-years overall survival (OS) was 55%, the median was not reached (18-110m). The most common adverse events for all patients were grade 2 peripheral neuropathy and infections (four infections described above), both in 25%, deep venous thrombosis was not reported. Three deaths was reported (18.75%) all for progression disease.ConclusionVTD is an effective treatment in transplant candidates with multiple myeloma who have relapsed after one previous therapy including thalidomide. PFS is superior to Bortezomib pivotal study in relapsed disease. Infectious diseases represent 40% of cause for not undergoing transplantation.

Symptomatic Outcome of CTDa In Multiple Myeloma Patients

Background: Multiple Myeloma (MM) represents approximately 15% of all hematological malignancies. Despite the use of high-dose chemotherapy followed by stem cell rescue MM remains incurable at present. The goal is to control the disease as much as possible, providing the best quality of life to patients for the longest duration. Currently, CTDa (attenuated Cyclophosphamide, Thalidomide, Dexamethasone) is the best option of treatment as it is cost-effective, with no need for hospitalization with a good response.&#x0D; Objective: To find out the symptomatic responses and toxicities of CTDa in Multiple Myeloma patients.&#x0D; Materials and Methods: 25 patients of newly diagnosed MM patients were treated in the Haematology Department, Bangabandhu Sheikh Mujib Medical University (BSMMU) from July 2016 to July 2017. The mean age of the patients was 54 years, Male female ratio was 1.5:1 and most of the patients were farmers. After induction of 4 to 6 cycles of CTDa all patients were followed up at 6th and 12th weeks. At follow up we evaluated improvement of weakness, bone pain, Hb%, ESR, monoclonal protein, ß2microglobulin, bone marrow plasma cells and serum calcium and albumin level. Adverse effects, such as peripheral neuropathy, thromboembolic events, hyperglycemia, constipation, rash, and somnolence were also assessed.&#x0D; Results: Among 25 patients, complete response achieved only 13 patients (52%), where 20% and 16% of patients belonged to partial or no response respectively. The death occurred in 2 cases (12%).&#x0D; Conclusion: CTDa is a gentle approach to treat an especially frail group of patients, since virtually all patients ultimately relapse.&#x0D; KYAMC Journal Vol. 11, No.-3, October 2020, Page 124-128

Long-Term Effectiveness and Cost Effectiveness of Multiple Myeloma Treatment Strategies for Elderly Transplant-Ineligible Patients in Serbia.

IntroductionEvidence on long-term effectiveness and cost effectiveness of treatment sequences for multiple myeloma (MM) is sparse. We used published data and country-specific data to assess the cost effectiveness of four-line treatment sequences for elderly transplant-ineligible patients with MM in Serbia.MethodWe developed a Markov cohort model to compare long-term effectiveness and cost effectiveness of five sequential MM treatment alternatives from the perspective of the national healthcare provider. Effectiveness parameters on progression, mortality and adverse events were extracted from published clinical trials. Costs were based on price lists of the National Health Insurance Fund. We compared life expectancy, costs, and incremental cost-effectiveness ratios among alternative courses of action. The model was analyzed over a lifelong time horizon applying a 3% annual discount rate for effectiveness outcomes and costs. Robustness of the model was tested in multiple deterministic sensitivity analyses.ResultsThe sequences were defined by the frontline treatment: MPT (melphalan-prednisone-thalidomide), MPV (melphalanprednisone-bortezomib), CTD (cyclophosphamide-thalidomide-dexamethasone), VCD (bortezomib-cyclophosphamidedexamethasone) and BP (bendamustine-prednisone). MPV sequence resulted in the highest remaining life expectancy (4.76 life years). Cost-effectiveness analysis resulted in three non-dominated strategies: MPT, VCD, and MPV sequences, with an incremental cost-effectiveness ratio of EUR 35,300 per life-year gained (LYG) for VCD and EUR 47,200/LYG for MPV relative to MPT.ConclusionMPV sequence was the most effective in terms of life expectancy for elderly transplant-ineligible MM patients in Serbia. Bortezomib-based strategies would be recommended for the frontline treatment of patients with MM in Serbia if the willingness-to-pay threshold is around EUR 35,000-60,000/LYG.

Progression-Free Survival Analysis of Denosumab Vs Zoledronic Acid in Intent to Transplant Multiple Myeloma Patients Based on Treatment Regimen and Baseline Characteristics

Introduction: Denosumab is a monoclonal antibody targeting Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) that has been shown to reduce skeletal related events associated with bone lesions in patients with multiple myeloma and solid tumors. Results from the full primary analysis of 1718 patients with newly diagnosed multiple myeloma in an international double blind, randomized, controlled phase 3 (20090482) study that assessed the efficacy of denosumab (Dmab) vs zoledronic acid (ZA) for preventing SREs met its primary end point of non-inferiority regarding time to first SRE. The analysis of the PFS exploratory endpoint showed a clinically meaningful 10.7 months median PFS benefit (HR, 0.82; 95% CI, 0.68-0.99; descriptive P= 0.036) of Dmab vs ZA. This benefit was most pronounced in patients who were stratified into the "intent to undergo Autologous Stem Cell Transplant (ASCT)" group at randomization. Thus, we present an in-depth analysis of relevant baseline characteristics, treatment regimens and PFS outcome in patients with intent to undergo transplant receiving Dmab and ZA. Methods: Adult patients with newly diagnosed multiple myeloma (NDMM) and stratified as "intent to undergo ASCT" at randomization were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. In this subgroup, the PFS outcome was examined. Baseline characteristics and treatment regimens were compared between treatment arms. Results: 54.1% of the 1718 enrolled patients were stratified into "intent to undergo ASCT" as part of their front-line therapy, and 61.8% of "intent to undergo ASCT" did receive an ASCT. In the "intent to undergo ASCT" group, 19.6% patients had disease progression in the Dmab arm compared to 28.0% in the ZA arm (HR 0.65 (0.49-0.85)) (Figure 1). No imbalance in terms of triplet therapy use between the two study arms (TABLE 1). 55.1% in Dmab vs 52.6% in ZA arm received Triplet Therapies which included Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Bortezomib, Thalidomide, Dexamethasone (VTD), Cyclophosphamide, Thalidomide, Dexamethasone (CTD), or Bortezomib, Lenalidomide, Dexamethasone (VRD). The percentage of triplet therapies used in the "intent to undergo ASCT"patients was higher than in patients with no intent to undergo ASCT. Percentage of patients with ECOG performance status 2 was 19.4% in the Dmab group vs 18.6% in the ZA group. 26.2% of patients in the Dmab arm and 25% in the ZA arm had Multiple Myeloma ISS stage III upon diagnosis. Among intent to transplant patients there was no imbalance in terms of age, performance status, ISS stage, risk status, weight, bone marrow plasma cell % between the ZA and the Dmab arm Conclusion: Results from this post-hoc subgroup analysis suggest a more profound PFS benefit in the "intent to undergo ASCT" patient subgroup. Multiple myeloma treatment received in the intent to undergo transplant subjects was similar between the denosumab and zoledronic acid arms. No significant imbalance in demographics or baseline disease characteristics was observed between the two treatment arms. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Shimizu:Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau; Daiichi: Consultancy; Amgen: Consultancy; Fujimoto: Consultancy. Willenbacher:Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; oncotyrol: Employment, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees. Glennane:amgen: Employment, Equity Ownership. Dai:Amgen: Employment, Equity Ownership. Pasteiner:Amgen: Employment, Equity Ownership. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Clinical analysis of expression of CD47 in patients with multiple myeloma

Objective To investigate the expression of CD47 in multiple myeloma (MM) and its clinical significance. Methods From September 2016 to May 2018, all of 25 cases of MM patients who were diagnosed and treated in Hongqi Hospital Affiliated to Mudanjiang Medical University were selected as research subjects, and enrolled in study group. In study group, there were 15 males and 10 females with the age of (58.5±4.2) years. Twelve MM patients were treated with CTD (cyclophosphamide+ thalidomide+ dexamethasone) regimen and the rest 13 cases with VAD (vincristine+ pirarubicin+ dexamethasone) regimen. Six cases of individuals who received physical examination in the same period and the same hospital were included in control group. In control group, there were 3 males and 3 females with the age of (56.3±4.1) years. CD47 expression levels of mononuclear cells in bone marrow from MM patients and peripheral blood from healthy individuals were detected by flow cytometry. Relationships between CD47 expression in MM patients and complete remission (CR), recurrence in study group were analyzed. The positive expression rate of CD47 of subjects in two groups, and CR rates of MM patients with different treatment regimens and CD47 expressions in study group were compared by Fisher′s exact probability method. The procedure of this study is accordance with the requirement of the revised World Medical Association Declaration of Helsinki in 2013. Informed consent was obtained from all participants. Results ① CD47 positive expression rate of MM patients in study group was 40.0% (10/25), and was significantly higher than that of 0(0/6) in control group, and the difference was statistically significant (P=0.018). ② In study group, CR rate of MM patients with positive CD47 expression was 20.0% (2/10), and was significantly lower than that of 73.3% (11/15) in patients with negative CD47 expression, and the difference was statistically significant (P=0.013). CR rate of MM patients receiving CTD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 83.3% (5/6) in pactients with negative CD47 expression, and the difference was statistically significant (P=0.040). CR rate of MM patients receiving VAD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 85.7%(6/7) in patients with negative CD47 expression, and the difference was also statistically significant (P=0.029). ③ There was no statistically significant difference in CR rate between patients with positive CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.773). And there was no statistically significant difference in CR rate between patients with negative CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.731). ④ All 2 MM patients with positive CD47 expression who obtained CR, and 2 of 11 MM patients with negative CD47 expression had relapsed. Conclusions The expression rate of CD47 on bone marrow mononuclear cells in MM patients was significantly higher and was related to curative effect and prognosis of MM patients. CD47 may be used as a potential auxiliary evaluation indicator for efficacy and prognosis in MM. This conclusion is limited to the clinical analysis of a small sample, and it requires large sample, multi-center, randomized controlled trials for further study and verification. Key words: Multiple myeloma; Antigens, CD47; Phagocytosis; Treatment outcome; Prognosis

Cyclophosphamide + Thalidomide + Dexamethasone Versus Melphalan + Dexamethasone for the Treatment of Amyloid Light-chain Amyloidosis With Kidney Involvement: A Retrospective Study in Chinese Patients

PurposeAt present, a diverse array of treatment regimens are available for systemic amyloid light-chain (AL) amyloidosis. Both cyclophosphamide + thalidomide + dexamethasone (CTD) and melphalan + dexamethasone (MD) regimens have been recommended as first-line therapies, but no detailed comparative studies of the two have been performed. This study is the first to compare the efficacy and tolerability of the CTD and MD regimens in the treatment of AL amyloidosis. MethodsWe retrospectively reviewed data from consecutive patients with AL amyloidosis who were treated with MD or CTD as the initial regimen between June 2012 and January 2018. FindingsIn the final analysis, 38 patients received CTD, and 30 received MD. There were no significant differences in baseline characteristics, including age, sex, renal function, involved organs, level of free light chains, and Mayo Clinic amyloidosis prognostic staging. The overall hematologic response rates in the CTD and MD groups were 69.0% versus 68.0%, respectively (P = 0.94), including a complete response in 27.6% versus 8.0% (P = 0.14). Neither group reached the estimated median overall survival, and the difference between the 2 groups was not significant (P = 0.17). The median progression-free survival times were 36 versus 14 months (P = 0.24) in the CTD and MD groups, respectively. The CTD group achieved a numerically but not statistically higher prevalence of kidney response (52.9% vs 37.0%; P = 0.22). The most common adverse events in the 2 treatment groups were fatigue (48.5% vs 21.7%; P = 0.04) and constipation, anemia, nausea/vomiting, neutropenia, and syncope (all, P = NS). Deaths occurred in 6 patients in the CTD group and 9 patients in the MD group; none were considered by the investigators as related to the study treatments. There were no other serious adverse events observed in our study. ImplicationsThe CTD regimen may not be inferior to standard oral MD in terms of overall hematologic response and overall survival. Although this study was of retrospective and negative-control design with some additional limitations, it may provide a therapeutic option for use in developing countries where patients cannot afford bortezomib or melphalan.

Significant Differences in Test Availability and Access to Novel Drugs for Multiple Myeloma between Public and Private Hospitals in Latin America. Grupo De Estudio Latinoamericano De Mieloma Multiple (GELAMM)

IntroductionCompliance with Multiple Myeloma (MM) recommendations regarding diagnosis and treatment is highly variable worldwide, outside clinical trials. This survey among hematologists from Latin America (LA) aims to describe real access to diagnostic and prognostic analyses and first line treatment for newly diagnosed MM (NDMM).ObjectivesTo describe the access to diagnostic and prognostic tests and first line treatment options for MM in LA.To compare public versus private access to tests and therapies.MethodsThis is a multicenter cross-sectional study. A 16-question survey focusing on demographic characteristics of physicians, centers, and standard of care practices for NDMM was emailed to 182 hematologists from 11 LA countries. (Fig 1) The survey was open from Dec/17-Feb/18.ResultsWe received 103 completed questionnaires (56.6%) from 8 countries: Argentina (45), Uruguay (28), Chile (15), Paraguay (6), Peru (3), Costa Rica (2), Mexico (2), Venezuela (2).Most physicians (85/103) work in private and public institutions; the majority (64.7%) treat benign and malignant diseases, 30% mainly malignant diseases, and 4.9% mainly plasma cell disorders.Access to diagnostic tests is shown in Table 1. In > 20% of public hospitals there is no access to serum protein electrophoresis (SPEP), serum immunofixation (IFX) or serum immunoglobulins quantification (Igs); in 57.3% serum Free Light Chain (sFLC) assay is not done. Lack of access to Fluorescent in situ hybridization (FISH) is 67%, Computed Tomography (CT) scan 23.5%, Magnetic Resonance Imaging (MRI) 45% and Positron Emission Tomography (PET/CT) 66.5%.In private centers, lack of access to SPEP is <5%, IFX 10%, Igs 15%, sFLC 16.5%, FISH 33%, CT scan 5%; MRI 7.3% and PET/CT 20%.Thalidomide, Bortezomib and autologous stem cell transplant (ASCT) are available in all reporting countries, in public and private institutions. Lenalidomide is reported commercially available by 97.9% of physicians, Melphalan 92.7%, Daratumumab 68%, Pomalidomide 67%, Carfilzomib 60%, Ixazomib 18%. (Table 2) Nevertheless, due to reimbursement policies not all patients have access to these drugs, as reflected in treatment choices.In private institutions, 86.5% report treating ASCT-eligible patients upfront with Bortezomib-based triplets versus 51.6% in public hospitals [OR 5.72 (IC95% 2.32-14.7) p <0.001). Cyclophosphamide-Thalidomide-Dexamethasone (CTD) is used in the public setting by 40.3% (Table 3). Firstline choice for high risk MM (HRMM) is Bortezomib combinations in all private centers but in only 74.4% of public institutions (p<0.001).ASCT ineligible patients: the most used upfront regimen is Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) in private centers and CTD in public hospitals (Table 4). For HRMM, Bortezomib-based triplets is the first choice in 88.57% and 65.51% in private and public settings, respectively [OR 4.09 (CI95% 1.57-11.16) p=0.0011).Most physicians indicate maintenance treatment, mainly until progression/intolerance.(Table 5) Lenalidomide or Bortezomib are used in private centers in all countries, but for Venezuela. Only Thalidomide and Dexamethasone are available in public hospitals from 6/8 countries. Lenalidomide or Bortezomib maintenance approval require special authorization in most countries, delaying its initiation.DiscussionThis study shows real word data regarding the challenges LA faces in the care of MM patients. Access to recommended diagnostic and prognostic tests is deficient, particularly in the public setting. Diagnosis, risk assessment and response evaluation are, therefore, inaccurate. In public hospitals, >50% of patients have no access to adequate imaging evaluation, being screened by X-rays.Regardless of commercial availability, real access to novel drugs is limited, particularly in the public setting. This causes an ethical dilemma for physicians, which must treat patients depending on the health care provider and reimbursement policies rather than based on evidence.One limitation of this work is the high percentage of unanswered surveys.ConclusionLA is far from complying with international recommendations for MM approach. The most striking finding is the great difference between public and private centers in all variables. This gap is likely to translate into differences in survival, which is greatly concerning. Solving these inequities should be a priority. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Polymorphisms in the promoter region of the CRBN gene as a predictive factor for the first-line CTD therapy in multiple myeloma patients.

Cereblon is a primary molecular target for immunomodulatory drugs. The aim of this study was to evaluate the influence of selected clinical and molecular factors including single nucleotide polymorphisms (SNPs) in CRBN gene on the efficacy of first line CTD (cyclophosphamide, thalidomide, dexamethasone) chemotherapy in patients with multiple myeloma. Study group consisted of 68 patients. Analysis of CRBN gene SNPs (rs6768972, rs1672753) was performed using Real-Time PCR genotyping technique. Median progression free survival (PFS) was 15 months and overall survival (OS) 79 months. Factors associated with significantly shorter OS included ISS 3, kidney disease, weight loss, anemia, thrombocytopenia, hypoalbuminemia, elevated β2-microglobuline and CRP. The presence of t(4;14) was associated with significantly shorter PFS and OS. Both examined SNPs proved to be statistically significant, independent predictive factors of efficacy of the CTD chemotherapy. The presence of AA genotype (rs6768972) correlated with longer median PFS (18 vs 9 months; HR=0.49,95% CI: 0.26-0.91, p=0.0062). Conversely, in the carriers of CC genotype (rs1672753) significantly shorter median PFS was observed (4 vs 16 months; HR=3.93, 95% CI: 0.26-59.64, p=0.0321). In conclusion, SNPs of the CRBN gene may be useful in qualifying patients for treatment with regimens containing thalidomide.

Efficacy and safety of CTD and PCD regimens in treatment of patients with newly diagnosed multiple myeloma

目的分析比较CTD方案（环磷酰胺+沙利度胺+地塞米松）与PCD方案（硼替佐米+环磷酰胺+地塞米松）治疗新诊断多发性骨髓瘤（NDMM）患者的疗效、预后及安全性。方法回顾性分析2013年7月至2016年1月收治的88例NDMM患者的临床资料，其中CTD方案组49例，PCD方案组39例，比较两组患者的疗效、预后以及不良反应。结果CTD与PCD组患者治疗后的总缓解率（ORR，≥部分缓解）分别为65.3%（32/49）和84.6%（33/39），非常好的部分缓解（VGPR）及以上疗效分别为30.6%（15/49）和53.8%（21/39），差异均有统计学意义（P值分别为0.041、0.028）。中位随访11.5（3~33）个月，CTD组与PCD组患者的无进展生存（PFS）时间差异有统计学意义[（23.0±4.5）个月对未达到，P=0.050]；中位总生存（OS）时间均未达到，差异无统计学意义（P=0.257）。CTD组获得≥微小缓解（MR）与未达MR患者的中位OS时间差异有统计学意义（未达到对12.3个月，P=0.005）；PCD组获得≥VGPR与未达VGPR患者的中位OS时间差异有统计学意义（未达到对29.0个月，P=0.042）。感染是两组患者最常见的不良反应，PCD组患者周围神经病变、带状疱疹发生率明显高于CTD组，而CTD组患者血栓、心慌、皮疹等发生率偏高。结论CTD与PCD方案均为治疗NDMM患者有较好疗效的一线诱导化疗方案；PCD方案治疗强度和缓解深度优于CTD方案。

Comparative Proteomic Profiling of Sera from Patients with Refractory Multiple Myeloma Reveals Pathways and Biomarkers Predicting Response to Bortezomib-Based Therapy

Introduction: Identification of drug-resistance biomarkers in multiple myeloma (MM) is a first step to individualization of treatment. Human serum is easily collected and does not require expensive preparation to analyze, therefore it seems the most suitable material to search for biomarkers.Objective: The goal of this study was to establish serum biomarkers predicting response/resistance to PAD (bortezomib, adriamycin, dexamethasone) chemotherapy in patients with refractory MM.Material and Methods:Comparative proteome analysis was performed on pretreatment serum samples obtained from 56 proteasome inhibitor-naïve, transplant-eligible patients qualified for PAD chemotherapy due to CTD (cyclophosphamide, thalidomide, dexamethasone) refractory disease. Samples were collected after patients signed informed consent according to Declaration of Helsinki. Subjects were classified into four groups based on the response to PAD: 13 patients achieved complete response (CR group), 10 revealed very good partial response (VGPR group), 17 - partial response (PR group) and 16 - stable disease or progressive disease (SD/PD group). Serum proteins after trypsin digestion were analyzed using Q-Exactive hybrid quadrupole-Orbitrap mass spectrometer coupled to the chromatograph Dionex 3000 Ultimate nanoLC (Thermo Scientific). Obtained data were analyzed using MaxQuant/Perseus software.Results and discussion: 632 proteins were identified with a false discovery rate of 1% (FDR). A protein was considered to be differentially accumulated if the difference between experimental groups was statistically significant (p< 0.05) and the minimum fold change was ± 1.5. Proteins identified with a minimum of 2 peptides were considered significant. The proteomic signature revealed 52 proteins, which differentiated all analyzed experimental groups (ANOVA significant). The most differential proteins revealed comparison between CR/VGPR vs PD/SD groups. Eleven up-regulated and 35 down-regulated proteins were identified in sera of patients derived from PD/SD (non responders) group compared to CR/VGPR (responders) among them: sulfhydryl oxidase (fold change 2.56), kallistatin (fold change 0.32), gelsolin (fold change 0.50), thyroxine-binding globulin (fold change 0.28), PDZ and LIM domain protein 1 (fold change 2.38), corticosteroid-binding globulin (fold change 0.32), and phosphatidylinositol-glycan-specific phospholipase D (fold change 0.42). Also principal component analysis (PCA) differentiated the CR/VGPR and PD/SD patients. Proteins like thyroxine-binding globulin or corticosteroid-binding globulin seem to be nonspecifically deregulated, however sulfhydryl oxidase may have a causative relation to bad prognosis. Sulfhydryl oxidase plays an important role in growth regulation and has metastatic potential. Overexpression of this enzyme was presented in pancreatic, prostate and breast cancer. Moreover, it was showed that up-regulation of this enzyme predicts a poor prognosis in patients with breast cancer (Katchman et al. 2013).Conclusions: We identified proteins, some of which may serve as potential prognostic factors predicting response to bortezomib-based regimens in patients with refractory MM. Label-free proteomic analysis is a useful method to screen for proteins differentially expressed in the sera of multiple myeloma patients revealed different response to chemotherapy. DisclosuresDytfeld:Celgene: Research Funding; Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cost-effectiveness of bortezomib for multiple myeloma: a systematic review.

ObjectivesTo review published cost-effectiveness analyses (CEA) assessing bortezomib (BTZ) for multiple myeloma (MM) and explore possible bias affecting the cost-effectiveness of BTZ.MethodsLiterature was searched for published CEAs assessing BTZ or BTZ-containing regimens for MM from 2003 to 2015. The reported incremental cost-effectiveness ratios (ICER) were adjusted by 2014 country-specific gross domestic product per capita (GDPPC) to compare the cost-effectiveness threshold of the World Health Organization (3 GDPPC per gained quality-adjusted life year [QALY]).ResultsA total of 17 published CEAs were included in this review. When compared to non-BTZ treatments, BTZ-containing regimens were cost-effective for induction treatment prior to stem cell transplantation (SCT) in Canada, Poland, and Germany (ICER per QALY: 0.9299–2.254 GDPPC). BTZ/melphalan/prednisolone (VMP) was cost-effective for previously untreated and SCT-ineligible MM patients when compared to melphalan plus prednisolone (MP), melphalan/prednisone/lenalidomide with lenalidomide maintenance, and cyclophosphamide/thalidomide/dexamethasone (CTD) (ICER per QALY: dominant to 2.374 GDPPC) in Canada, UK, and USA. BTZ was cost-effective for relapsed/refractory MM when compared to best supportive care (ICER per life year: 0.9317–1.8210 GDPPC) in the UK and the USA, thalidomide in USA (0.5178 GDPPC/LY), and dexamethasone (DEX) in four Nordic countries (€54,451–€81,560/QALY). However, the cost-effectiveness for VMP versus MP plus thalidomide (MPT) and continuous lenalidomide (LEN) plus low-dose DEX (RD) for previously untreated and SCT-ineligible MM patients and BTZ versus LEN/DEX for relapsed/refractory MM patients could be unreliable because of the bias associated with model design and the indirect comparisons of treatment effects.ConclusionPublished CEAs suggested that BTZ or BTZ-containing regimens were cost-effective when compared to most non-BTZ treatments for MM. However, the conflicting cost-effectiveness for VMP versus MPT for previously untreated and SCT-ineligible MM and BTZ versus LEN/DEX for relapsed/refractory MM needs more robust evidence for further clarification.

Stem Cell Mobilization after Various Induction Regimens in Patients with Multiple Myeloma

Stem cell mobilization after various induction regimens in patients with multiple myelomaIntroduction: Rapid development of novel therapies for multiple myeloma has led to a significant improvement in response to the treatment. Stem cell mobilization before autologous stem cell transplantation is a source of considerable costs of transplant procedure. Whether modern induction regimens affect outcome of stem cell mobilization has not been extensively studied.Aim: The goal of this study was to compare efficacy of stem cell mobilization after different induction regimens in patients with multiple myeloma. The primary goal was to compare CTD (cyclophosphamide, thalidomide, dexamethasone), CVD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone) and regimens in terms of succesful stem cell collection.Methods: All patients with multiple myeloma who have been planned for stem cell collection and were treated with one of the above mentioned regimens were included in this retrospective analysis. The demographic data, amount of stem cells collected, number of days needed to reach the target collection were recorded. All patients received high dose cyclophosphamide 2,5 g/m2 prior to stem cell collection and were primed with G-CSF twice daily from day 5. The collection was started at day 10. Collection goal was 8x106/kg CD34+ cells.Results: 15 patients received CTD, 25 patients CVD and 16 patients VTD regimen before stem cell collection. Groups were comparable according to age, gender and myeloma stages. Mean collected cells at the end of collection were 9.2 (SD 2.8) for CTD, 12.3 (SD 5.6) for CVD and 10.1 (SD 2.1) for VTD (p=0.066). Mean daily harvest was 3.4, 8.0 and 7.6 x106/kg respectively (p=0.01). Mean days needed to reach desired harvest were 3, 2.25 and 1.6 days (p=0.001). No collection failure was observed.Conclusion: The best collection results were seen in patients after induction with CVD or VTD regimen. VTD regimen also required the least days for collection and seems to be most beneficial for cost of collection. CTD regimen shows the least efficacy in stem cell collection before autologous transplantation. All patients managed to harvest for at least one stem cell transplant. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Polymorphisms within beta-catenin encoding gene affect multiple myeloma development and treatment

Recent studies have suggested that cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide, and that dysregulation of Wnt/β-catenin pathway may be one of possible reasons of lenalidomide resistance. This prompted us to analyze the effect of polymorphisms within the genes coding for cereblon (CRBN (rs121918368 C>T)) and β-catenin (CTNNB1 (rs4135385 A>G; rs4533622 A>C)). MM patients (n=142) and healthy individuals (n=123) were genotyped using the Light SNiP assays.The presence of the CTNNB1 (rs4533622) A allele was more frequently detected in patients presented with stage II–III disease according to International Staging System (63/82 vs. 26/44, p=0.043) and Durie–Salmon criteria (75/99 vs. 14/26, p=0.049).The CTNNB1 (rs4135385) AA homozygosity was more frequent among patients with better response to CTD, i.e. cyclophosphamide–thalidomide–dexamethasone (18/23 vs. 32/60, p=0.047). Patients carrying the CTNNB1 (rs4533622) AA genotype were better responders to the first line therapy with thalidomide containing regimens (p<0.05). No significant association was observed between the effect of lenalidomide therapy and polymorphisms studied. However, the occurrence of neutropenia during lenalidomide therapy was more frequent among the CTNNB1 (rs4135385) AA carriers (p=0.019), while the CTNNB1 (rs4533622) AA homozygosity characterized patients with high grade (3–4) neutropenia (p=0.044).No association was found for the CRBN polymorphism.These results suggest that the CTNNB1 polymorphisms may affect the clinical course and response to chemotherapy in patients with multiple myeloma.

Venous Thromboembolism Prophylaxis with Aspirin for Multiple Myeloma Patients Receiving Thalidomide Combination As First-Line Treatment

Introduction: Despite the increase in overall survival in patients with multiple myeloma (MM) over the last decade as a result of the use of new chemotherapeutic agents, the immunomodulators (thalidomide and lenalidomide) are associated with a higher rate of venous thromboembolism (VTE), principally when associated with other chemotherapeutic drugs and erythropoietin (EPO). The incidence of VTE with isolated thalidomide is 3 to 4%, similar to the risk of the disease itself. The association of thalidomide with corticoids or anthracycline agents has led to an increase in the incidence of VTE to 12 and 34%, respectively. The introduction of low-dose aspirin, vitamin K inhibitors or low molecular weight heparin prophylaxis, according to the risk factors present upon diagnosis reduced the risk of thrombosis to 3 to 7%.Objectives: The objectives were to evaluate thrombotic events during the use of thalidomide as first-line treatment in symptomatic MM patients and the effectiveness of low-dose aspirin prophylaxis.Casuistic and Methods: This is a descriptive study of thrombotic events by means of a retrospective survey of patient files for MM patients who had been followed up on at the gammopathies outpatient unit at Santa Casa de Misericórdia de São Paulo from January 2009 to April 2014. The following induction therapy schedules with thalidomide for patients eligible or not for bone marrow transplantation were performed: thalidomide + dexamethasone (TD), cyclophosphamide + thalidomide + dexamethasone (CTD) and melphalan + prednisone + thalidomide (MPT). All of the patients received a dose of 100mg/day of the antiplatelet agent (aspirin) as prophylaxis.Results: In the aforementioned period, 219 patients had been diagnosed with symptomatic MM and of these, 149 patients had received thalidomide-based chemotherapy. The thalidomide group had a median age of 61 years (40 to 88). In the DS IIIA-IIIB stage, there were 131 (87.9%), 14 (9.4%) IIA-IIB, 1 (0.7%) IA and 3 (2%) had not been evaluated. According to the ISS Classification, 36 (24.2%) were ISS I, 41 (27.5%) II and 58 (38.9%) III, with 9.4% not evaluated. The most frequent isotope was IgG (56%). In relation to chemotherapy, 34 (22.8%) received TD, 98 (65.8%) CTD, 17 (11.4%) MPT. We identified 10 (6.7%) cases of thrombotic events in patients using thalidomide, thus distributed: 8 deep vein thrombosis (DVT), one case of DVT/ pulmonary embolism and one case of thrombophlebitis. Only one patient with thrombosis did not follow the prophylactic treatment at the service, which was 100mg/day of aspirin. The events occurred on average 72 days after initiating thalidomide use. Five cases were related to mobility reduction, 2 cases to obesity, 2 to smoking, 3 being ex-smokers, 3 to infection concomitant with the thrombotic event, 2 to diabetes and 1 case of previously treated breast cancer. All of the cases presented some associated risk factor.Conclusion and Discussion: The use of aspirin as prophylaxis in the group of MM patients being treated with thalidomide demonstrated efficacy in the control of risk for thrombosis. We observed 6.7% of VTE with the prophylactic use of low-dose aspirin in recently diagnosed MM patients without a history of thrombotic events, as described in the literature. Thalidomide is made available free of charge for MM treatment by the Brazilian public health system. Therefore, it is the main drug used in the MM treatment in Brazil. A better understanding of adequate thrombophylaxis according to the present risk factors is important for the optimization of the treatment of MM patients. DisclosuresNo relevant conflicts of interest to declare.

A Phase I/II Trial Of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) In Patients With Newly Diagnosed Multiple Myeloma: Final Results Of MTD Expansion Cohort

BackgroundCarfilzomib is a proteasome inhibitor that irreversibly binds its target and has been validated as both relapse and upfront therapies for multiple myeloma. To optimize pre transplant response, we combined carfilzomib with the widely accessible backbone of cyclophosphamide-thalidomide-dexamethasone (CTD). We previously reported results of the Phase I component of the trial (in which no MTD was reached); we now report results for the MTD and fully accrued expansion cohorts at the MTD of the CYCLONE trial NCT01057225. MethodsNewly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with carfilzomib IV Days 1,2,8,9,15,16 (see Table below for dosing per cohort) along with cyclophosphamide 300 mg/m2 PO Days 1,8,15, thalidomide 100 mg PO Days 1-28 and dexamethasone 40 mg PO Days 1,8,15,22. The initial phase I/ II regimen is shown below – as no DLTs were observed, we increased dosing of carfilzomib to 36 and then 45mg/m2 and have now nearly fully accrued to the Phase II dose level +1 (27mg/m2) and expansion MTD (36mg/m2). Treatment was for 4 cycles with planned SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. ResultsA total of 54 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II (CFZ 27mg/m2), and 27 at CFZ 36-45mg/m2. Median age was 63 (range 27-77) and 52% were male. ISS Stage was advanced (II-III) in 57% The overall partial response rate or better following 4 cycles of CYCLONE at dose level 0 or greater is 91%: CR 18%, VGPR 58%, PR 16%, MR 2%, SD 4%. One patient withdrew from the trial after cycle 1.At dose level 2, 3/7 patients experienced dose-limiting toxicity in cycle 1 including: grade 3 alanine aminotransferase increase (possibly related); grade 3 infusion reaction (probably related); and grade 4 heart failure with grade 3 dyspnea, atrial fibrillation, and fatigue (all possibly related). No dose-limiting toxicity was observed in 6 patients at dose level 1 and thus DL1 was deemed the MTD.Across dose levels, adverse events are fully evaluable in 48 patients. AEs of grade 3 or higher at least possibly related to CYCLONE occurred in 26 (54%) – 35% non hematological and 33% hematological. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Three cases of pneumonia required hospitalization. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included lymphopenia (23%) and neutropenia (17%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. 90% completed at least 4 cycles.With median follow-up of 16 months (range 0-64), 1-year PFS was 90% and 1-year OS was 98%. ConclusionThe 4 drug CYCLONE regimen is highly efficacious with an overall response rate after only 4 cycles of 91% (76% ≥VGPR) at the dosing level of carfilzomib IV 20/27-36 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. CYCLONE is a combination that results in rapid and deep responses with minimal neuropathy prior to stem cell transplant. Comparative studies of this regimen with longer duration of therapy (as induction or consolidation) at the defined MTD should be considered. Disclosures:Mikhael:Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Reeder:Millenium: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Costa:Otsuka: Research Funding. Stewart:Celgene: Honoraria; Millenium: Honoraria, Research Funding; Onyx: Research Funding.

Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment

Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years). At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicin-dexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics. Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01). Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) incidence and epidemiology Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of between 65 and 70 years; the mortality is 4.1/100 000/year. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) multiple myeloma (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter [1]. diagnosis Diagnosis of MM should be based on the following tests: [1] -Detection and evaluation of the monoclonal (M-) component by serum and/or urine protein electrophoresis (concentrate of 24 h urine collection); nephelometric quantification of IgG, IgA and IgM immunoglobulins; characterisation of the heavy and light chains by immunofixation; and serum-free light-chain (FLC) measurement; -Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies are the standard options to evaluate the number and characteristics. Moreover, the BM sample should be used for cytogenetic/fluorescence in situ hybridization (FISH) studies and also has the potential for immunophenotypic and molecular investigations; -Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs is necessary. A magnetic resonance imaging (MRI) or computed tomography (CT) scan may be needed to evaluate symptomatic bony sites, even if the skeletal survey is negative and the patient has symptoms suggesting bone lesions. Moreover, MRI provides greater detail and is recommended whenever spinal cord compression is suspected. Fluorodeoxyglucose positron emission tomography is currently under evaluation but should not be systematically used; -Complete blood cell count, with differential serum creatinine and calcium level.