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

Abstract Background Nowadays, 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 Method We 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. Results In 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 1st cycle 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. Conclusion We 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.

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Association Of Stringed Response and Immunoparesis Normalization After Bortezomib-Based Therapy Is Related To Better Outcomes In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5354.5354 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5354-5354

Author(s):

Marcio M Andrade Sr. ◽

Ilda Murillo-Florez ◽

Anel Montes-Limon ◽

Beatriz de Rueda ◽

Jose-Maria Grasa ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Retrospective Chart Review ◽

Standard Of Care ◽

Complete Response ◽

Response To Therapy ◽

First Line ◽

Female Ratio

Abstract Background Proteasoma inhibitors have proven to be one of the major advances on multiple myeloma (MM) therapy. Their principal effect in growth inhibition of MM cells is achieved not only through the inhibition of proteasomes but also by preventing the adhesion of myeloma cells to stromal cells, induction of cytokines by the microenvironment, decrease angiogenic activity and a direct apoptotic effect on MM cells. Actually it is part of the first-line standard of care therapy for patients with MM. On the other hand, multiple strategies have been developed for trying to predict response or improve the assessment of response and follow-up of MM patients. Currently, the International Myeloma Working Group (IMWG) criteria of response include immunophenotype and immunoparesis analysis. The HevyLiteTM and FreeLiteTM assays (The Binding Site Ltd. Birminghan. UK) permit a separate quantification of the amount of kappa- and lambda-bound to a given immunoglobulin (HLC) and the free light chains kappa or lambda amount quantification (FLC), both being excellent tools for immunoparesis assessment. Aims To analyze the usefulness of immunoparesis analysis by HevyLiteTM and FreeliteTM in patients who receive bortezomib-based therapy in our institution. Patients and Methods A retrospective chart review was performed including the patients diagnosed with secretor IgA or IgG MM who received therapy with bortezomib either at relapse or as first-line therapy. General clinical characteristics, therapy schedules, number of cycles, response to therapy according IMWG criteria and relapse were recorded. For the analysis, only patients with at least 4 cycles of bortezomib based regimen and HLC and/or FLC analysis performed between 4-12 weeks after complete therapy were included. Period of study: June 2004 to April 2013. Results At the end of study a total of 67 MM patients had received bortezomib-based therapy, 63 of them completed 4 or more cycles and were included in the analysis. Male/Female ratio: 31/32, mean age: 66.9 years old (46-81), therapeutic schedules were: bortezomib-prednisone: 3 (4.7%), bortezomib-dexametasone: 33 (51.6%), bortezomib-melfalan-prednisone: 18 (28.1%), bortezomib-dexametasone-lenalidomide: 8 (12.5%) and bortezomib-talidomide-dexametasone: 1 (1.6%). 55% of patients received at least 6 cycles of therapy. Immunoglobulin Myeloma subtype: IgAL: 13 (20.4%) patients, IgAK: 10 (15.6%) patients, IgGK: 32 (50.8%) patients and IgGL: 8 (14.1%) patients. A total of 46 (73%) patients showed an abnormal HLC ratio at diagnosis and 48 (76,2%) had immunoparesis before therapy; a total of 47 (74.6%) registered an abnormal FLC ratio at diagnosis. The response to therapy was: 15 (23.8%) of cases achieved a stringent complete response (SR), 3 (4.8%) a very good partial response (VGPR), 36 (57.1%) obtained a partial response (PR) and 9 (14.3%) patients had not-response/progressive-disease. At the time of post-therapy evaluation, 26 (37%) of patients had normalized FLC-ratio, 15 (23.8%) maintain the SR, 1 (1,6%) patient in VGPR and 5 (11.1%) in PR and 1 (1.6%) of non-responder patients. Normalization of HLC-ratio was only observed in patients with SR and VGPR: 13 (20.6%). Regarding the immunoparesis analysis, only 15 (23.8%) of patients with immunoparesis recovered the immune restitution (IR) at the end of therapy, of which 8 (11.7%) were SR patients, 2 VGPR and 5 PR patients. At the end of the study 47(71.4%) patients relapsed, 5 (11.11%) are on maintenance therapy and 11(17.4%) after a median follow-up of 29 months (9-94) without therapy not-relapsed; the association of SR with IR was related to a less tendency to relapse and need of therapy, 7/8 patients who achieved this status are not-relapsed. Conclusion In our cohort, patients who achieved a SR with a normalization of immunoparesis shows a clear tendency to less incidence of relapse; probably reflecting a better response with not only an undetectable monoclonal protein but also the recovery of the immune function. Even in small cohorts, the immunoparesis recovery analysis through HLC quantifications seems to be an useful tool to determine a new level of response. More investigations on this field are warranted. This work has been partially supported by a grant from Fundación para el Estudio de la Hematología y hemoterapia en Aragón (FEHHA) Disclosures: No relevant conflicts of interest to declare.

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Combination of Bortezomib and Dexamethasone (VD) or Bortezomib, Adriamycine and Dexamethasone (PAD) Followed by High Dose Therapy and Peripheral Blood Stem Cell Transplantation in First-Line Treatment of T(4;14) Multiple Myeloma : a Prospective Study of the MAG Group.

Blood ◽

10.1182/blood.v114.22.3408.3408 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3408-3408

Author(s):

Lionel Karlin ◽

David Ghez ◽

Marie-Olivia Chandesris ◽

Sylvain Choquet ◽

Margaret Macro ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Peripheral Blood Stem Cell ◽

Induction Treatment ◽

High Dose ◽

High Dose Therapy ◽

Free Survival ◽

Blood Stem Cell Transplantation

Abstract Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level (<10 g/dL) in 10. Four presented with renal failure and 5 with hypercalcemia. Three (16%) of 19 patients had a t(4;14) without expression of FGFR3. After induction treatment with VD or PAD, PBSC were successfully harvested with granulocyte-colony stimulating factor only (n=15) or following a cycle of high-dose cyclophosphamide (n= 7). RR after induction treatment was complete response (CR) in 6 (26%) patients, very good partial response (VGPR) in 9 (39%), partial response (PR) in 3. Five patients had refractory or progressive disease (PD), including 1 who died before stem cell mobilization. RR after HDT was CR in 11 (48%), VGPR in 4 (17%) and PR in 4 (overall RR of 82%). Three had PD. With a median follow-up of 18 months (range, 3-32), 9 (39%) patients are alive without relapse, including 4 with a 19, 27, 30 and 32 months follow-up respectively. Twelve (52%) patients relapsed. Two patients died in the first month post HDT from PD. We found a median EFS and OS from initiation of therapy of 14.7 and 30.9 months respectively. EFS was not influenced by Hb and/or serum β2m level. However, we found a significantly longer OS in patients with low β2m (median non reached) as compared to patients with high β2m (median=23.1 months, p=0.04). These preliminary results illustrate the heterogeneity of this disease and indicate that some t(4;14) MM patients seem to benefit from bortezomib containing regimen as induction treatment before HDT in term of EFS and OS. A larger series with a longer median time of follow up will be presented. Disclosures: No relevant conflicts of interest to declare.

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Prevalence of Oligoclonal Bands in Multiple Myeloma Patients Who Achieved Better Results Than Very Good Partial Response after Treatment with Standard or High Doses Chemotherapy-Final Analysis

Blood ◽

10.1182/blood.v126.23.4210.4210 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4210-4210

Author(s):

Luiza soares Vieira ◽

Edvan de queiroz Crusoe ◽

Manuella de S. Sampaio Almeida ◽

Lais Sousa ◽

ana Lucia Perez ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Final Analysis ◽

Complete Response ◽

High Dose Chemotherapy ◽

Oligoclonal Bands ◽

High Dose ◽

Good Partial Response

Abstract Introduction - Oligoclonal bands (OB) are monoclonal proteins distinct from those originally identified in the multiple myeloma (MM) diagnosis. Some authors consider that appearance of these bands confers a better prognosis and may be linked to immune reconstitution. There is no data of the exact prevalence of OB emergence in patients with very good partial response (VGPR) or better after different treatment schedules. Objectives - To determine the prevalence of OB in MM patients treated with or without high-dose chemotherapy that obtained at least VGPR and its prognostic value. Methods- This is a retrospective and prospective cohort study. Data were collected from records of patients that achieved at least VGPR to identify the OB emergence. Subsequently, new sample collections from the positive patients were made in order to monitor the progress and duration of the maintenance of these bands. Results-Median follow-up was 42m and 101 patients were included. Median age was 58y (29-87) and 55% were male. IgG was the most frequent component (60%). Durie-Salmon IIIA/B was identified in 92% of the population; ISS was 33% in stage I, 30% in stage II, and 31% in stage III. The prevalence of OB identified by SPE and IF was 50.5% (51 cases), with a higher prevalence in those who underwent transplantation and those who achieved complete response (p=0.00139 and p=0.0368, respectively). Progression free survival (PFS) was longer in the OB group (45.4m x 34.7m p = 0.0075). Conclusion - The OB prevalence in this population was 50.5% and oligoclonality resulted in a longer PFS. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in Czech Republic

Blood ◽

10.1182/blood-2021-153978 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4894-4894

Author(s):

Tereza Popkova ◽

Ludek Pour ◽

Ivan Spicka ◽

Jakub Radocha ◽

Alexandra Jungova ◽

...

Keyword(s):

Multiple Myeloma ◽

Survival Analysis ◽

Czech Republic ◽

Partial Response ◽

Complete Response ◽

High Dose ◽

Line Treatment ◽

Newly Diagnosed ◽

First Line ◽

First Line Treatment

Abstract Introduction: Although highly effective agents and novel therapeutic strategies are being developed, high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has not been overcome in the first-line treatment for fit patients (pts) with multiple myeloma. The objective of this work is to retrospectively analyze the use of this procedure in newly diagnosed Czech patients. Methods: Data were derived using the Czech Myeloma Group Registry of Monoclonal Gammopathies. By February 2 nd 2021, a total of 2154 newly diagnosed multiple myeloma patients who underwent HDT/ASCT were identified. Results: At the time of multiple myeloma diagnosis, the median age was 59 years; 24%/56%/14%/5%/1% pts were ECOG 0/1/2/3/4; 44%/32%/24% pts were ISS stage I/II/III; 14.5%/17.5%/68% and 84%/16% pts were Durie-Salmon stage I/II/III and subclassification A/B, respectively. The combinations of agents used in the induction regimen were proteasome inhibitor (PI), immunomodulatory drug (IMiD) and glucocorticoid (GC) in 28.5% (613/2154) pts; PI, GC and chemotherapy (CHT) in 24.8% (534/2154) pts; GC and CHT in 22,5% and IMiD, GC and CHT in 16.1% (346/2154). Other combination of drugs was used in 8.2% (177/2154) pts. It was registered that 3.7% (79/2154) induction regimens were switched to a different combination because of toxicity, patient's choice, poor peripheral venous access or other reasons. Single HDT/ASCT was performed in 77.3% (1665/2154) cases whereas tandem HDT/ASCT was given to 11.8% (254/2154) patients. In 10% (215/2154) cases, the transplantation technique was not specified. Nine percent (193/2154) patients were treated within a clinical study. The median progression free survival (mPFS) and the median overall survival (mOS) of the whole cohort was 28.9 and 92.1 months, respectively. Information about response to treatment before and after the high-dose therapy were available for 75.7% (1627/2154) and 92.2% (1987/2154) patients, respectively. Disease status at the time of HDT/ASCT was defined as stringent complete response (sCR) at 2.2% (36/1627), complete response (CR) at 11.9% (194/1627), very good partial response (VGPR) at 38.2% (621/1627), partial response (PR) at 40.9% (666/1627), minimal response (MR) at 3.6%, (58/1627), stable disease (SD) at 2.2% (36/1627), progressive disease (PD) at 1% (16/1627) patients. The overall response rate (ORR) on day 100 was 92.8% (sCR: 10.5% [209/1987], CR: 22.4% [446/1987], VGPR: 35% [696/1987], PR: 24.8% [493/1987], MR: 2.7% [54/1987], SD: 1.4% [27/1987], PD: 3.1% [62/1987]). We also performed a survival analysis of patients progressing up to 18 months after HDT/ASCT (n=1219) versus patients progressing in more than 18 months (n=935). The median OS was 41.5 versus 124.9 months, respectively. An analysis of the role of tandem HDT/ASCT in this real-world cohort will be presented at the conference. Conclusion: Globally as well as in the Czech Republic, HDT/ASCT is an important therapeutic approach in the first-line treatment of multiple myeloma. Our analysis of 2154 newly diagnosed transplant-eligible patients confirms high effectiveness - ORR of 92.8%, mPFS of 28.9 months, and long-term survival reaching mOS of 92.1 months. Disclosures Minarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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Immunophenotypic Response After Allografting In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3371.3371 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3371-3371 ◽

Cited By ~ 1

Author(s):

Luisa Giaccone ◽

Lucia Brunello ◽

Roberto Passera ◽

Moreno Festuccia ◽

Milena Gilestro ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

First Line ◽

Significant Difference ◽

The Impact

Abstract Background Minimal residual disease (MRD) by multiparameter flow-cytometry recently showed a promising role in predicting outcomes in patients with multiple myeloma. However, data on immunophenotypic response (IR) after allografting are lacking. Aim To evaluate the impact of IR and compare it to conventional complete remission (CR) following allografting in myeloma patients. Methods Sixty-six consecutive patients, median age 54 years (35-66), who underwent an allograft between January 2000 and December 2011 with a follow-up of at least 3 months were included. Disease response was evaluated by serum and urine electrophoresis, and bone marrow aspirate at baseline, 3, 6, 12, 18, 24 months after transplant and yearly thereafter. Skeletal survey or MRI were performed yearly or as clinically indicated (overt relapse or complaints of bone pain). Bone marrow aspirates had to contain at least 13000 cells/µL for flow-cytometry studies and IR was defined as absence of monoclonal plasma-cells detected by 4 or 6-colour staining with the following antibodies: CD38, CD138, CD56, CD19, CD45, cyKappa, cyLambda. CR was defined according to standard criteria (Durie et al, Leukemia 2006; 20:1467-73). Results Conditioning regimen was non-myeloablative 2Gy TBI-based in 55 patients, reduced intensity (fludarabine-melphalan-based) in 10 and myeloablative in 1 patient. Post-grafting immunosuppression consisted of cyclosporine with mycophenolate mofetil or methotrexate. Donors were HLA identical siblings in 58 patients and unrelated in 8. Only 1 patient received bone marrow as source of stem cells. Thirty-five/66 (53%) received the allograft as part of the first line treatment, whereas the remaining 31/66, (47%) were transplanted at relapse. At the time of transplant, 5/66 were both in IR and CR, 16 were only in IR and 4 patients were only in clinical CR. All 21 patients in IR at the time of transplant maintained it, while 26/45 (58%) entered IR after the allograft. Among patients surviving at least 3 months, overall treatment related mortality was 10.6% at 3 years. After a median follow-up of 69 months (range 19-147), the incidence of acute and chronic graft-versus-host disease was 45.6% and 49.3% without significant difference between responsive and non-responsive patients. At follow-up, overall, 24 patients achieved CR and IR (CR/IR group), 21 achieved IR but not CR because of persistence of urine/serum M-component (noCR/IR group), and 21 did not achieve either CR or IR (noCR/noIR group). Interestingly, none achieved CR without IR. Median overall survival (OS) and event-free survival (EFS) in patients who achieved IR were 96 and 55 months versus 36 and 7 months in those who did not (p<0.001). Median OS and EFS were not reached and 59 months in the CR/IR group, 77 and 15 months in the noCR/IR, and 30 and 5 months in the noCR/noIR respectively (p<0.001 for both EFS and OS-fig.1). In univariate analysis, being in the CR/IR group was the only significant predictor for prolonged OS and EFS (p<0.001). Of note, cumulative incidence of extra-medullary disease at first relapse after the allograft was 4% in the CR/IR, 32% in the noCR/IR and 15% in the noCR/noIR groups respectively (p<0.001). Receiving the allograft as first line therapy or later during the disease course did not significantly impact on OS and EFS. Conclusion The achievement of IR confers a favorable impact on OS and EFS after allografting. A higher incidence of extra-medullary in the noCR/IR group (some 30% of our patient cohort) may suggest that myeloma cells escape immune control outside the bone marrow. In this group, imaging studies such as positron emission tomography may clinically be indicated during follow-up to detect early relapse. Disclosures: No relevant conflicts of interest to declare.

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First Use of Temozolomide in Primary Intra-Ocular Lymphoma (PIOL): a Very Well Tolerated and Potentially Effective Treatment.

Blood ◽

10.1182/blood.v114.22.4760.4760 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4760-4760

Author(s):

Mohamed Mesmoudi ◽

Nathalie Cassoux ◽

Veronique Leblond ◽

Helene Merle-Beral ◽

Sylvie Baudet ◽

...

Keyword(s):

Partial Response ◽

Effective Treatment ◽

Systemic Chemotherapy ◽

Conflicts Of Interest ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Enzyme Linked Immunosorbent Assay ◽

High Dose ◽

Potential Candidate ◽

First Line

Abstract Abstract 4760 Background PIOL is a rare subset of primary central nervous system lymphoma (PCNL), representing 5 to 20% of PCNL. It is usually an aggressive diffuse large B-cell lymphoma. There is no consensus on treatment procedures, classical attitudes are systemic chemotherapy (SC), radiotherapy or intraocular injection of methotrexate (IM). Relapse rate is high, with more than 10% of cases relapsing in brain. New treatments are necessary, especially with a good tolerance profile. Temozolomide (Te) has some efficiency on PCNL and seems to be a potential candidate. Methods we retrospectively analyzed PIOL treated by Te in our unit. Inclusion criteria were a diagnosis established on cytological and molecular analysis after vitrectomy or anterior chamber puncture, and the absence of brain or meningeal localization. Interleukin 10 (IL10) and 6 (IL6) dosages were made by enzyme-linked immunosorbent assay on ocular material. IL10/6 ratio >1 is a specific and sensitive test for PIOL diagnosis and IL10 kinetic a good marker of response in parallel with clinical examination. Treatment consisted in Te at 150mg/m2 orally 5 days per month, in monotherapy, without corticosteroid use. Results four patients were analyzed, 3 males and one female. All received systemic chemotherapy with at least high dose methotrexate in first line, two with addition of high dose cytarabin. First patient, aged 84 at diagnosis, relapsed 15 month after CR and received Te for three months until here death, probably by CNS lymphoma. Second patient, aged 65, progressed under SC and subsequently received IM without any success; Te was used in third line but no effect was seen. Third patient, aged 48, had a partial response after first line treatment and received SC with high dose cytarabin and stem cell transplantation; after CR he relapsed 33 months later and then received Te, partial response was clinically confirmed at 3 months and is stable at 6 months. Last patient, age 71, had a localized PIOL 3 years after the treatment of a follicular lymphoma; PIOL relapsed 6 month after the first line and Te began; clinical response was spectacular, with a vision normalization in less than one month, a clinical CR confirmed at two months, IL10 dosages were at more than 1500 pg/ml in both eyes before Te, at 22 pg/ml (left eye) after one month and 202 pg/ml (right eye) after two months, response is stable at 5 months. No toxicity appeared during treatment except for hematological grade I or II. Conclusion Temodal is a safe and effective treatment of PIOL after classical chemotherapy. Longer follow-up and larger studies are necessary to confirm these data Disclosures: No relevant conflicts of interest to declare.

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The More Effective and the More (bio) Similar: Plerixafor and Filgrastim XM02 (tevagastrim) As First Line PBSC Mobilization Strategy in Patients with Multiple Myeloma and Lymphomas Candidate to ABMT

Blood ◽

10.1182/blood.v118.21.2994.2994 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2994-2994

Author(s):

Daniele Laszlo ◽

Giovanna Andreola ◽

Aleksandra Babic ◽

Mara Negri ◽

Cristina Rabascio ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Conflicts Of Interest ◽

Median Number ◽

High Dose Chemotherapy ◽

European Medicines Agency ◽

High Dose ◽

First Line ◽

Adequate Number ◽

Cd34 Cells

Abstract Abstract 2994 Patients affected by hematologic malignancies might benefit from high dose chemotherapy followed by peripheral stem cells (PBSC) transplant. Chemotherapy in combination with G-CSF is effective in mobilizing stem cells but often toxic, might require prolonged hospitalization and extensive supportive care. Moreover a high proportion of patients, ranging from 11 to 53%, fail to collect an adequate number of stem cells with this approach. In this setting plerixafor, a CXCR4 chemokine antagonist, has shown to increase the number of circulating CD34+ cells in cancer patients when used alone or with G-CSF and to be able to rescue patients unable to mobilize with traditional regimens. Recently, several forms of biosimilar nonglycosylated recombinant human G-CSF have been clinically developed and approved by the European Medicines Agency for the same indications as the reference filgrastim product on the basis of comparable quality, efficacy, and safety. Biosimilars also provide a more cost-effective strategy and their use in clinical setting may provide cost savings in their indicated uses. From December 2010 to July 2011, 16 patients, median age 55 (19–67), affected by Non-Hodgking Lymphoma (6), Hodgking Disease (2) and MM (8), received a combination of biosimilar version of G-CSF (Tevagrastim) and plerixafor in order to mobilize PBSC as first line strategy. Tevagrastim was self-administered (10μg/kg/die) for 3 days; on day 4 patients were admitted to the hospital, circulating CD34+ cells counted and if >20 cells/μl, plerixafor was administered (0.24mg/kg) 12 hours before the scheduled apheresis. There were 7 males and 9 females, median lines of previous chemotherapy was 1(1–4). Median number of circulating CD34+ cells on day 4 was 16 (8–42). Plerixafor was administered to all but 1 patients who had already 42 CD34+ cells/μl on day 4. On day 5, after plerixafor administration median number of circulating CD34+ cells had raised to 68/μl (18–138). All the patients underwent leukapheresis and were able to collect an adequate number of CD34+ cells necessary for the transplantation procedure with a median number of 5.2 ×106 (2.2–10.6) CD34+cells/kg in a median number of 1 procedure (1–2). For patients with Multiple Myeloma, 6/8 patients were able to collect a median of 5.8×106 CD34+/kg (4.2–10.6) in a single procedure. No major side effect was observed. So far, 7/16 patients underwent high dose chemotherapy followed by PBSC transplant. Engraftment occurred in all patients with a time to ANC>500 of 12 (9–13) and of PLT>20.000 of 13 (9–19) days. The combination of tevagrastim and plerixafor is safe and effective in mobilizing PBSC and allows a collection of a more than adequate number of cells in most of the patients in a maximum of 2 apheresis procedure, even in patients with MM who need to collect a double amount cells. Disclosures: No relevant conflicts of interest to declare.

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PK-Directed Intravenous Busulfan In Combination With High-Dose Melphalan and Bortezomib As Conditioning Regimen For Patients With Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5513.5513 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5513-5513

Author(s):

Stefan K Barta ◽

Amitabha Mazumder ◽

Jason Carter ◽

Lawrence Almanzar ◽

Richard Elkind ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Conditioning Regimen ◽

High Dose ◽

Cell Transplant ◽

Treatment Dose ◽

Gi Symptoms ◽

High Dose Melphalan

Abstract Introduction High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2; Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. Methods Patients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov (NCT01605032). Results To date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. Conclusion PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures: Barta: Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma.

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The Outcome of Different Types of Second-Line Therapy in Multiple Myeloma Patients Relapsing After Uniform Front-Line Treatment with High-Dose Melphalan and Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.2892.2892 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2892-2892

Author(s):

Claudia Crippa ◽

Samantha Ferrari ◽

Monica Drera ◽

Marinella Calarco ◽

Antonio Regazzoli ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Dose ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Line Therapy ◽

High Dose Melphalan

Abstract Abstract 2892 Poster Board II-868 Background and aim. While multiple myeloma (MM) still remains largely incurable, therapeutic options for patients with MM are expanding. However the best way to use the different effective regimens, either in combination or in sequence, during the course of MM in the single patient is still unknown. Data from controlled studies rarely report the treatments received before and after the enrollment of patients in the clinical trial, which may significantly impact on response and survival. As an example, the best treatment for patients relapsing after first-line high-dose melphalan (HD-Mel) and autologous stem cell transplantation (ASCT) is not standardized. To this end we have retrospectively analyzed an uniform cohort of such patients treated at our Institution, comparing their outcome according to the type of second-line and further consolidation treatment received. Patients and methods. In 156 patients affected by MM and treated between 1997 and 2008 with HD-Mel and ASCT as first line therapy, relapse has occurred in 92 (59%). Females were 39 (42%), males 53 (58%), median age was 60 (range 34-75). As induction therapy before ASCT, 89 (97%) had received VAD regimen, and only 3 (3%) thalidomide/bortezomib-based regimen. Sixty-one patients (66%) had received a single ASCT and 31 a double ASCT (34%). A second-line therapy was given to 87/92 patients. They were subdivided in 3 subgroups according to the type of second-line treatment received: 1) thalidomide-based regimens (THAL) were given to 55 pts (63%) followed by a consolidation ASCT in 13 (24%) 2) bortezomib-based regimens (BORT) were used in 13 (15%) and subsequent ASCT in 3 of them (23%) 3) chemotherapy and/or steroids (CHEMO) were used in 19 (22%) followed by ASCT in 15 (79%). Median follow-up from diagnosis was 57 (13-145) in THAL, 39 (17-140) in BORT and 59 months (25-113) in CHEMO respectively. The baseline characteristics, including age, of the three subgroups were similar as well as the CR/VGPR and ORR rates obtained after first-line treatment (THAL 47% and 87%; BORT 69% and 100%; CHEMO 53% and 100%, respectively). The subgroups also did not differ in median duration of first response, which ranged from 13 to 15 months and median time to second treatment, which was 26 months in all subgroups. The proportion of patients receiving a double ASCT were significantly higher in BORT (69%) compared to THAL (34%) (P=0.03) and CHEMO (5%) (p=0.002), and in THAL (34%) compared to CHEMO (5%) (p=0.015). Results. After second line therapy the ORR (CR+VGPR+ PR) of the three subgroups was: THAL 60%, BORT 77% and CHEMO 58%. (p=NS). The second CR/VGPR rate was non significantly higher after BORT (46%) than after THAL (25%) or CHEMO (21%) (p=0.17). Moreover, when considering patients not undergoing second-line consolidation ASCT, the ORR was significantly better in THAL and BORT subgroups compared to CHEMO (50%, 70% and 0%, respectively p=0.03). After a median follow-up from second-line treatment of 28 months (range 1-99), the 2-y PFS was 38% after THAL (median 18 months), 34% after BORT (median 16 months) and 17% after CHEMO (median 12 months) (p=NS). The 2-y OS was 78% (median 49 months), 70% (median not reached), and 70% (median 33 month) after THAL, BORT and CHEMO, respectively (p=NS). However when considering patients not undergoing second-line consolidation ASCT, the 2-y OS was significantly better after THAL and BORT than after CHEMO (p=0.024). Conclusion. In spite of having frequently received a first-line double ASCT, BORT patients seemed to achieve responses of better quality. However, in patients relapsing after first-line HD-Mel and ASCT, the choice of THAL, BORT or CHEMO-based regimens as second-line therapy did not seem to impact on overall response rates and survival, provided that patients treated with CHEMO could be consolidated with a second ASCT. Hence newer drugs may be reserved for those patients not fit for ASCT, preserving them for effective third-line treatment in the other patients. Disclosures: No relevant conflicts of interest to declare.

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Thalidomide Based Regimens for Treatment of Unfit Patients with Relapsed and Refractory Multiple Myeloma: a Monocentric Experience

Blood ◽

10.1182/blood.v116.21.5048.5048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5048-5048

Author(s):

Alessandro Moscetti ◽

Francesca Saltarelli ◽

Maria Paola Bianchi ◽

Bruno Monarca ◽

Giacinto La Verde

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Response Rate ◽

Conflicts Of Interest ◽

Therapeutic Option ◽

Alkylating Agents ◽

High Dose ◽

Refractory Multiple Myeloma ◽

Unfit Patients

Abstract Abstract 5048 Thalidomide, an immunomodulating drug with antiangiogenic activity, is an efficacious therapeutic option for unfit patients with multiple myeloma. Its efficacy may be increased by the addiction of steroids or other cytotoxic drugs such melphalan or cyclophosphamide. In this study we assessed the efficacy and toxicity of thalidomide based regimens as savage therapy in a series of elderly patients with relapsed/refractory multiple myeloma. Previous treatments included at least one therapy (range 1–4), such as high dose dexamethasone, alkylating agents, anthracyclines, IFN-α and autologous graft. Thalidomide 50–200 mg/die was administered orally in a total of 16 patients (median age 73.8 years, range 59–84) with relapsed/refractory multiple myeloma observed in our Hematology Department between May 2004 and January 2010. Oral dexamethasone or prednisone was added to the treatment. All patients continued therapy until relapse or progression and were prospectively followed-up including accurate monitoring of side effects. Response to thalidomide was assessed according to the European Group for Blood and Marrow Transplantation criteria. The median follow-up time was 25.6 months (range 8 – 68). Overall response rate was 81.2% (13/16 patients) with a median duration of response of 26.7 months (range 7 – 67): 3 patients showed a very good partial remission, 10 partial response, 1 stable disease and 2 progression of disease. During follow-up, 6 patients died (3 due to progression, 2 due to other neoplasm, 1 due to heart failure), 10 patients are still alive (2 VGPR and 7 PR in continuous therapy, 1 PD in third line therapy). No response was observed in 3/16 patients (18.7%). Despite the following side effects, mild to moderate bradycardia (25%, 1 needed PMK positioning and 1 dose reduction), peripheral sensitive polyneuropathy (18.7%) and constipation (6%), no patient discontinued therapy. This study shows that thalidomide based regimens are an effective therapy with a high response rate and manageable side effects when used in patient with multiple myeloma with relapsed/refractory disease. Disclosures: No relevant conflicts of interest to declare.

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