Upfront Tandem Autologous Stem Cell Transplant Is Superior to Autologous or Allogeneic Stem Cell Transplant After Failure of a 1st Autologous Transplant,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4094-4094 ◽  
Author(s):  
Adrian Wong ◽  
Charles F. LeMaistre ◽  
Paul Shaughnessy ◽  
Carlos Bachier

Abstract Abstract 4094 Disease progression remains the main cause of treatment failure after autologous stem cell transplant (SCT) in patients with multiple myeloma (MM). It is unclear what is the best salvage therapy after failure of a 1st autologous SCT in MM. We performed a retrospective study comparing 2nd autologous (auto-auto) versus 2nd allogeneic (auto-allo) SCT in patients progressing or relapsing after their 1st autologous SCT and compare their outcomes with patients receiving sequential planned double autologous (tandem) SCT as part of their upfront therapy for MM. The data was collected from CIBMT reports and medical records at Texas Transplant Institute from 2001 to 2010. Patient's characteristics and outcomes are described in table 1. Response to 1st and 2nd SCT was determined at 100 days post transplant and classified as good (stringent complete remission [sCR], complete remission [CR], very good partial remission [VGPR]) or poor (partial remission [PR], stable disease [SD] or progressive disease [PD]). All patients in the auto-allo group received a reduced intensity regimen. 20% of the patients in the auto-auto group received maintenance therapy after their 1st transplant with either thalidomide or lenalidomide and 10% of the patients in the auto-allo group received maintenance therapy after their 1st transplant either with thalidomide. None of the patients in the tandem group received maintenance therapy. The overall survival was calculated from the date of the 2nd transplant to the known date of death in all groups. Patients in the auto-allo group (15.9 months) had a worse median survival than in the auto-auto group (39 months) with both of them having a worse survival compared to patients undergoing tandem transplants (64.3) (p value = 0.003) (FIGURE).Table:PATIENT CHARACTERISTICS AND OUTCOMESTandem (n=29)Auto-Auto (n=32)Auto-Allo (n=10)Median age, years (range)62 (41–78)62.5 (45–81)54 (43–63)Median days from diagnosis to 1st transplant224.5 (93–1344)226 (117–1074)254.5 (101–416)Median days from 1st to 2nd transplant149 (99–189)847 (210–4158)350 (88–1281)Median total CD34+ cell infused 1st transplant3.29 (2–12)5.87 (2–28)6.03 (2–14)2nd transplant3.22 (2–9)4.47 (2–19)5.25 (3–11)Median WBC engraftment11 (9–13)11 (9–47)N/AMedian Platelet engraftment16 (10–19)15 (10–23)N/ACytogenetics High Risk17%3%10%ISS at 1st transplant I31%41%40%II34%12%0III14%6%10%ISS at 2nd transplant I48%53%40%II17%9%0III10%13%10%Response to 1st transplant Good10%63%70%Poor80%25%20%Response to 2nd transplant Good52%47%30%Poor41%41%70%Median Followup (months)57.1 (3.4–76.7)24.6 (10.5–87.8)48.0 (31.9–64.0)Maintenance Therapy after 1st transplant028%10%Figure:OVERALL SURVIVALFigure:. OVERALL SURVIVAL Forward stepwise Cox regression analysis was used to measure factors affecting overall survival. Factors used for analysis included age, cytogenetics (high risk = mutated p53, t(14;16), t(4;14), del 13), International Staging System (ISS) before 1st and 2nd SCT, use of maintenance therapy after 1st SCT, days from diagnosis to 1st SCT and days from 1st to 2nd SCT, CD34+ cells infused at 1st and 2nd SCT. Age and ISS of III at 2nd transplant were identified as factors affecting survival in the auto-auto group (hazard ration of 1.081 and 5.700, respectively). In conclusion, overall survival after salvage from 2nd autologous stem cell transplant is longer than after a 2nd allogeneic transplant. Upfront, planned tandem autologous stem cell transplant is superior to both salvage strategies. Larger, randomized trials are needed to confirm these results. Disclosures: Shaughnessy: Otsuka: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2399-2399 ◽  
Author(s):  
Firoozeh Sahebi ◽  
Amrita Krishnan ◽  
Leonardo Farol ◽  
Ji-Lian Cai ◽  
George Somlo ◽  
...  

Abstract Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.


2020 ◽  
Vol 61 (8) ◽  
pp. 1877-1884 ◽  
Author(s):  
Dipenkumar Modi ◽  
Jie Chi ◽  
Seongho Kim ◽  
Lois Ayash ◽  
Asif Alavi ◽  
...  

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2872-2872
Author(s):  
Madhusmita Behera ◽  
Ambuj Kumar ◽  
Mohamed A. Kharfan-Dabaja ◽  
Benjamin Djulbegovic

Abstract Background: Primary systemic amyloidosis (AL) is a rare plasma cell clonal disorder(8/million) characterized by extracellular deposits of material composed mainly of fragments of light chain immunoglobulin throughout a body. Standard chemotherapy (e.g. melphalan and prednisone) is associated with poor outcomes (typical median survival is between 12–18 months with less than 5% survive 10 years). Autologous stem cell transplant (ASCT) has been increasingly advocated for treatment of AL. However, it is uncertain whether ASCT is better than standard chemotherapy. To address this uncertainty, we undertook a systematic review/meta-analysis to evaluate the efficacy of high-dose chemotherapy and autologous stem-cell transplant (HSCT) versus conventional chemotherapy in patients with AL. Methods: Data search of published studies included Medline [all randomized controlled trials (RCTs)], Cochrane library and hand search of references. Studies were included if they were comparison trials of HSCT versus conventional chemotherapy, regardless if they were RCTs, prospective studies with historical control, or single arm studies. The studies were eligible if patients had biopsy proven AL with at least one major organ involved. Data were extracted on benefits as well as harms (overall survival, event-free survival, response, treatment related mortality, treatment-related morbidity). Results: Out of 34 identified studies only 13 met the inclusion criteria for the current systematic review (2 RCTs, 2 prospective non-randomized trials involving historical control, and 9 single arm trials). Altogether these trials enrolled 1056 patients. Pooled data from 4 trials with controls (RCT and non-RCT) found similar overall survival for ASCT and conventional therapy arms [hazard ratio (HR) of 1.10 (95% CI 0.88, 1.36, p=0.4); p= 0.6]. Analysis of data according to trial design also did not find any difference in survival [HR for RCTs was 1.10 (95% CI 0.88, 1.37) and for non RCTs HR was 0.98 (95% CI 0.29, 3.35)]. The complete hematological response was also similar in both arms in RCTs (Odds ratio [OR]=1.38, 95%CI 0.67, 2.85; p=0.4) and non RCTs (OR=1.78, 95%CI 0.22, 14.65; p=0.32). The pooled proportion of treatment-related deaths in the single arm studies for AHCT was 0.119 (95% CI = 0.09 to 0.14)]. Conclusion: The results from the meta-analysis indicate that there is no statistically significant difference between the treatment effects from high-dose chemotherapy with ASCT and conventional chemotherapy. Hence, the efficacy of ASCT in improving overall survival and complete hematological response remains to be proven.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1222-1222 ◽  
Author(s):  
Patrick B Johnston ◽  
Ivana N Micallef ◽  
Stephen M Ansell ◽  
David J Inwards ◽  
Luis F. Porrata ◽  
...  

Abstract Abstract 1222 Poster Board I-244 Background Survival for patients with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now update on outcomes of patients who have had at least 100 day follow up post ASCT. Baseline characteristics Between June, 2000 and January, 2009, 22 patients underwent ASCT for PCNSL. Median age at transplant was 50 years old (range 26-67). Median number of prior treatments 1 (range 1-3). Median time from diagnosis to transplant was 7.2 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0-3). Disease status at transplant: First CR 10 patients, later CR or PR 12 patients. Results Twenty-two patients underwent ASCT for PCNSL and have a minimum of 100 days follow-up. All patients received BEAM conditioning. Median follow up post-transplant was 30 months (range 3-107 months). Eight patients have relapsed at a median of 217 days (range 40-1349). Of the patients who relapsed, four have died of disease progression and the remaining four are alive after additional therapy. Median overall survival from diagnosis or transplant has not been reached. Median progression free survival from transplant was 70 months. Conclusions Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2-3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline secondary to radiation therapy in patients who are appropriate candidates. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4554-4554
Author(s):  
Catherine Garnett ◽  
Chrissy Giles ◽  
Osman Ahmed ◽  
Maialen Lasa ◽  
Holger W. Auner ◽  
...  

Abstract Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4524-4524
Author(s):  
Prashanth Kumar ◽  
Nisha Joseph ◽  
Dhwani Almaula ◽  
Lawrence H Boise ◽  
Jonathan L. Kaufman ◽  
...  

Abstract Introduction: In younger patients that are transplant-eligible, autologous stem cell transplant (ASCT) prolongs overall survival based on several prospective randomized control trials. Nevertheless, ASCT is not a curative approach and majority of the patient's relapse, requiring further salvage therapeutic options. However, in the face of an ongoing paradigm shift in myeloma therapeutics, there is a significant knowledge gap regarding how patients relapse following ASCT. We analyzed the patterns of relapse among myeloma patients after ASCT. Methodology: We have evaluated a total of 975 patients that underwent ASCT during the period January 2008 through June 2014 from our myeloma database. 273 patients had documented evidence of first relapse post-ASCT on the laboratory parameters, radiologic or pathologic findings based on IMWG criteria for relapse. We categorized the relapses as biochemical vs symptomatic, and described their frequencies and characteristics. Median time of follow up from diagnosis is 68 months and from ASCT is 54 months. We used IBM SPSS version 23.0 to generate the survival statistics. Results: Median time from ASCT to relapse is 20 months. A total of 182 (66.7%) patients (105M, 77F) experienced biochemical relapse, while 91 (33.3%) patients (50M, 41F) had symptomatic relapse. More IgA patients (30.8% vs 23.1%, p=0.06) relapsed as symptomatic myeloma. While characterizing relapses, we did not find any differences in symptomatic relapses by the risk group [high risk (31.3%) vs standard risk (31.9%), p=0.193, ISS stage I (29.3%) vs II (32.9%) vs III (32.8%), p=0.807] or by maintenance [yes (30.7%) vs no (38.1%), p=0.211]. Among the patients that had a symptomatic relapse, presence of new bone lesions (52%) and anemia (42%) are the most common forms of relapse seen. Only 4% presented as hypercalcemia and 1% presented as renal failure illustrating the benefits of closer follow up. Overall survival is similar among patients that relapsed as biochemical or symptomatic relapse (log rank, p=0.105). More importantly, impressive median OS of 145 months from the ASCT among this entire cohort (at median follow up 54 months, figure 1). Conclusions: Two-thirds of the patients relapse as a biochemical relapse post-ASCT. The patterns of biochemical vs symptomatic relapses were similar among patients by maintenance, by risk status and also by the ISS stage. The significant improvement in OS among the entire cohort emphasizes the power of the new therapeutic salvage strategies aimed at gaining the survival advantage even among this selected group of patients undergoing early relapses. Disclosures Kaufman: Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Pharmacyclics: Consultancy. Lonial:Novartis: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Onyx: Consultancy; Merck: Consultancy; Janssen: Consultancy; BMS: Consultancy; BMS: Consultancy; Millenium: Consultancy; Celgene: Consultancy. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy.


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