Comparison of Early and Late Autologous Stem Cell Transplants for Multiple Myeloma: A Single Institution Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 928-928
Author(s):  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Suzanne R. Hayman ◽  
S. Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Plasma Cell ◽  
Complete Response ◽  
High Dose ◽  
Cell Transplant ◽  
Plateau Phase ◽  
Overall Response ◽  
Delayed Group

Background: High dose chemotherapy and autologous stem cell transplant (SCT) remains the preferred therapy for eligible patients with multiple myeloma (MM). Several studies have demonstrated an improvement in median survival with use of SCT. Patients with myeloma may undergo SCT immediately following 4–6 cycles of ‘induction’ therapy or at the time of relapse from the initial plateau phase. Available evidence does not suggest a survival difference between the two approaches. Methods: We retrospectively evaluated our experience with autologous single SCT for MM to compare the results of delayed SCT to early SCT. We identified from our transplant database, 202 patients with MM, who underwent SCT between October 1992 and November 2002. 101 patients, who responded to induction chemotherapy, had stem cells collected in plateau phase, received maintenance chemotherapy and had SCT at the time of first relapse (delayed SCT group). The remaining 101 patients, after initially achieving a response underwent upfront SCT (early SCT group). Patients refractory to initial therapy were excluded from this study. Most of the early transplants were done in the recent years and hence this group has a shorter follow up. Results: The study cohort had a median age of 55 years (range 29 – 72) at diagnosis consisting of 126 males (62%), with no significant demographic difference between the two groups. As expected measures of tumor burden (M protein, B2M and marrow plasma cell percentage) were significantly higher in the delayed group. Plasma cell labeling indices and presence of abnormal cytogenetics were higher in the delayed SCT group as well at transplant. TBI containing regimens were used more often in the delayed group reflecting a difference in the time periods of transplant. There was no difference between the groups in terms of overall response to transplant though complete response rate was higher for the early transplants. (Table). There was no difference in the time to overall response between the groups (P=0.13, Kaplan Meier estimate). Though the median progression free survival (PFS) from transplant was shorter for the delyaed SCT group, the overall survival (OS) from diagnosis of MM was comparable for the two groups (Table). The overall survival estimate at 5 year from diagnosis was 60% for both groups. Conclusions: Review of our experience demonstrates comparable overall survival for an early SCT compared to SCT at the time of relapse. Although there is an advantage for early SCT in terms of more chemosensitive disease as shown by a longer PFS from SCT, there is no benefit in OS from time of diagnosis. Patient preference and other co-morbidities should play a role in the decision regarding timing of transplant. This study has the disadvantage of being retrospective in nature and the two groups being spread over different periods in time. Early (n=101) Delayed (n=101) P Overall Response 100 (99%) 94 (94%) 0.07 Complete Response 43 (42%) 28 (27%) 0.04 Median PFS (From Transplant) 26.7 months 14.8 months <0.0001 Median OS (From diagnosis) 67 months 70 months 0.1

scholarly journals Comparison of Two Post-Transplant Predictive Indexes: Day 100 is a Better Time-Point for Response Evaluation after Autologous Stem Cell Transplantation in Multiple Myeloma: Ass Retrospective Study

2020 ◽  
Vol 7 (8) ◽  
Author(s):  
Ma’koseh M ◽  
◽  
Sa’deh S ◽  
Halahleh K ◽  
Abu-Jazar H ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Response Evaluation ◽  
Therapeutic Implications ◽  
Significant Difference

In Multiple Myeloma (MM), response to High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT) has important prognostic and therapeutic implications. Best timing for response evaluation after ASCT is not well studied. Our study evaluated the correlation between response on day 30 and day 100 after ASCT with Progression Free Survival (PFS) and Overall Survival (OS) in 119 MM patients. Median follow-up was 39.8 months. Complete Response (CR) was achieved in 53.8% and 55.5% of patients on D 30 and D 100, respectively. On D30, there was no significant difference in PFS or OS in CR vs. no CR group (35.4 vs. 22.1 months, p: 0.058) and (92.6 months vs. not reached p: 0.96) respectively nor in responders (R) vs. Non-Responders (NR) group (97.8 vs. 47.1 months p: 0.08) and (30.2 vs. 18.9 months, p: 0.09) respectively. While on D100, PFS was significantly better in CR vs. no CR group (33.8 vs. 18.1 months, p: 0.0047) as well as in R vs. NR (30.6 vs. 16.9 months p: 0.015). However, OS was not better in either (92.6 vs. 52.1 months p: 0.46) and (92.6 months vs. not reached p: 0, 88) respectively. In conclusion, after HDC and ASCT for MM, we recommend doing response evaluation on D100 rather than D30 as it better correlates with PFS. Further studies are required to confirm this finding in the era of consolidation and maintenance treatment.

Association in Outcome of Advanced Multiple Myeloma with Polymorphisms of Inflammatory-Related Genes IL-1A, IL-1B, IL1RN, TNF-a and TNFRSF1B.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1723-1723
Author(s):  
Gabriele Buda ◽  
Alessandro Martino ◽  
Enrico Orciuolo ◽  
Antonella Lupia ◽  
Sara Galimberti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Plasma Cells ◽  
Response Rate ◽  
Interleukin 1 ◽  
High Dose ◽  
Cell Transplant ◽  
Tnf Receptor ◽  
Overall Response

Abstract Abstract 1723 Poster Board I-749 Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients (1). Interleukin-1 (IL-1) is a cytokine involved in the maturation and proliferation of B cells and plays a significant role in the development of lytic bone lesions, a major clinical feature of MM patients (pts). Previous studies demonstrated that the polymorphism of IL1b-31 significantly influenced overall survival, as reported in patients undergoing high-dose melphalan treatment followed by autologous-stem cell transplant (2). TNF-a, a potent mediator of inflammation and bone resorption, seems to be involved in the malignant transformation of plasma cells, since mononuclear cells, obtained from MM patients and exposed in vitro to TNF-a and interleukin-4, produced monoclonal plasma cells. In addition, TNF-a can stimulate plasma cell proliferation, by triggering interleukin-6 secretion, and shows proangiogenic properties in vitro. In addition, TNF-a determination was reported to be a good parameter for estimating tumor mass and for monitoring therapy outcome during treatment with different protocols. TNF-a is also able to activate NF-kB, which is the main target of bortezomib. Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism (SNP). Single nucleotide SNPs have been identified at position -308 and -238 in the gene promoter. Specifically, a G to A substitution at position -308 is associated with higher levels of TNF-a (3). TNFRSF1B is a member of the TNF-receptor superfamily. This protein through the recruitment of two anti-apoptotic proteins upgrades TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways (4). In this study, we investigated the correlation between the SNPs of IL1A -889, IL1B -511, IL1B -31, IL1RN -371 (interleukin 1 receptor antagonist), TNF-a -308 and TNFRSF1B -587 on the outcome of refractory and relapsed MM pts, receiving bortezomib containing regimen as second line therapy. From September 2005 to April 2009 we selected 98 MM pts, who received at least one cycle of chemotherapy before treatment with bortezomib and at least one cycle of high dose chemotherapy with peripheral blood stem cell transplantation in 25 pts. No associations between the SNPs at the loci regarding IL-1A, IL-1B, IL-1RN and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. TNF-a SNP at position -308 and TNFRSF1B SNP at position -587 were determined on genomic DNA extracted from blood samples. These genotypes frequencies obtained were in agreement with Hardy–Weinberg equilibrium. Patients were categorized as responders (complete + partial response = R) or non responders (stable + progression disease = NR) to treatment. The overall response in our patients was about 74.5% (73/98). In MM pts carrying the rarest A allele of TNF-a the overall response was reduced to 61% (14/23 pts), whilst GG carriers showed a better response rate of 79% (59/75pts)(OR=0.42). We obtained similar results from the analysis of TNFRSF1B SNP. Pts carrying the rarest G allele the overall response was reduced to 69% (27/39 pts), whilst TT carriers showed a better response rate of 79% (46/59pts). Our results indicate that the cytokines (IL-1A, IL-1B, IL-1RN) gene SNPs do not confer differences in the outcome of advanced MM. On the contrary TNF-a and TNFRSF1B SNPs seems to be independent factors to predict the response and the outcome in patients affected by MM and treated with bortezomib containing regimen. If these preliminary results will be confirmed, they may represent a rationale for targeting TNF-a in novel therapeutic approaches to MM. Disclosures No relevant conflicts of interest to declare.

Bortezomib and Thalidomide, a Steroid Free Regimen in Newly Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2867-2867
Author(s):  
Nilanjan Ghosh ◽  
Anna Ferguson ◽  
Xiaobu Ye ◽  
Carol A. Huff ◽  
Ivan M. Borrello
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
Median Time ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Overall Response ◽  
Venous Thromboembolic Events ◽  
Grade 3

Abstract Abstract 2867 Poster Board II-843 Corticosteroids have historically been the backbone of most myeloma targeted therapies. However, they are often the major cause of toxicities, especially in elderly patients. In recent years, novel agents such as bortezomib and thalidomide have demonstrated significant anti-myeloma activity with increased overall response rates. We thus designed a study combining these two agents in a steroid-free regimen. Bortezomib (B) and thalidomide (T) were examined as first line treatment in 27 patients with symptomatic multiple myeloma between September 2004 and September 2006. Patients received B 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days and T 150 mg daily for a maximum of 8 cycles. The overall response rate was 81.5%, with a near CR or greater of 25.8% and a CR (immunofixation negative) of 11%. A major response identified by greater than 90% reduction in the paraprotein was seen in 33% of the patients. Responses were rapid: median time to first response was 36.5 days (range, 14-101 days) and median time to best response was 61 days (range, 16-171 days). The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%) and fatigue (7%). The only grade 3 hematologic toxicity was anemia (7%). No grade 4 toxicities were seen. 3 patients had mild peripheral neuropathy (PN) at baseline. PN was the most common reason for dose reduction with an average B dose of 1.1mg/m2 and T of 110mg daily. The major cause of discontinuation of treatment was PN. The PN completely resolved in 80% of the patients upon completion of therapy. No venous thromboembolic events (VTE) were observed even in the absence of prophylactic anticoagulation. It should be noted that upon completion of the study all patients received either B or T maintenance and no patients proceeded onto stem cell transplant immediately. The median progression free survival (PFS) was 16.8 months (95% CI 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3 year overall survival is 74%. This study demonstrates: 1) the excellent efficacy of a steroid-free regimen; 2) good PFS in the absence of stem cell transplantation; and 3) that most treatment-related PN resolves. Disclosures: Huff: Celgene: Consultancy. Borrello:Celgene: Speakers Bureau; Mellenium: Consultancy.

Collection of Stem Cell Early In the Disease Course of Multiple Myeloma Is Associated with Early Engraftment.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4518-4518
Author(s):  
Francis Buadi ◽  
Angela Dispenzieri ◽  
Shaji Kumar ◽  
Martha Lacy ◽  
David Dingli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Complete Response ◽  
Cell Transplant ◽  
Disease Course ◽  
And Storage ◽  
Stem Cell Collection

Abstract Abstract 4518 Introduction: Autologous stem cell transplant (PBSCT) is an integral part of the management of Multiple Myeloma (MM). Available data suggest that the timing of PBSCT has no effect on overall outcome. Some patients currently opt to delay their transplant, especially in this era of proteosome inhibitors and iMIDs. In such patients the best time for stem cell collection is unknown. We conducted a retrospective study looking at early stem collection and storage compared to stem cell collection at the time of transplant in patients who opt to be transplanted at a later date. Method: All patients who had PBSCT performed more than one year from the time of diagnosis were reviewed. Two groups of interest were then evaluated. Early collection (ET): those who had stem cells collected within 6 months of diagnosis, and Late collection (LT): those who had stem cells collected more than 1 year from diagnosis and within 3 months of PBSCT. Results: Table 1 shows some patient characteristics. 334 patients were identified, ET (85) and LT (249). Gender distribution, Durie Salmon stage, immunoglobulin subtype and cytogenetic abnormalities were similar in both groups. The LT group was older 60 yrs compared to ET 56.6 yrs, P=0.02. More patients in the ET (77%) group were mobilized with cyclophosphamide compared to LT (51%) p<0.0001. Stem cell yield was similar in both groups 9.26 × 10(6) CD34/kg in ET and 8.19 × 10(6) in LT, P=0.16. Median number of collections was 3 in both. More patients in the LT (67%) received Melphalan 200 mg/m2 conditioning compared to ET (59%) p=0.03. Neutrophil engraftment occurred at day + 11 ET and +12 (LT) p<0.0001. ET patients achieved platelet engraftment on day + 13 compared to + 15 (LT) p=0.002. Complete response rates were similar 30% (ET) and 34% (LT). Duration of response after PBSCT was not different 12.6 months (ET) and 11.6 months (LT). Median overall survival from diagnosis was 70.5 months (ET) and 74.5 months (LT) p=0.5. Similarly there was no difference in overall survival post PBSCT 33.5 month (ET) and 32.2 months (LT). Conclusion: Stem cell collection and storage early in the disease course of multiple myeloma results in early engraftment compared to stem cell collection at the time of transplant in patients who opt for a delayed transplant. More studies looking at cost analysis will however be need to determine the cost effectiveness of early versus late stem cell collection. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Comparative Study Of The Outcome Of Isolated Chromosome 13q and Clonal Progression Detected By I-FISH Do Additional Cytogenetic Abnormalities Impact Survival In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2160-2160
Author(s):  
Edward Peres ◽  
Shatha Farhan ◽  
Philip Kuriakose ◽  
Susan Michalowski ◽  
Alexandra Sitarik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
High Dose Chemotherapy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13Q

Abstract Background Chromosomal abnormalities detected by interphase fluorescence in situ hybridization (I-FISH) are an important prognostic marker in patients with multiple myeloma (MM). Isolated chromosome 13q has been considered standard risk when identified by I-FISH and high risk by conventional cytogenetics. The impact of additional cytogenetic abnormalities with chromosome 13q identified by I-FISH in regards to prognosis has not been fully defined. In this report, we describe the outcome of patient’s with multiple myeloma with isolated chromosome 13q and 13q+ (additional cytogenetic abnormalities) identified by I-FISH at our institution between January 2003 and January 2013 and had I-FISH analysis prior to treatment. Methods The primary objective was to compare patient’s outcomes in regards to response, time to progression, and overall survival between patients who had an isolated 13q and 13q+ identified by I-FISH in the bone marrow plasma cells. Kaplan & Meier curves were generated to calculate overall survival (OS) between the two groups. Results Between January 2003 and January 2013, we identified 76 patients by I-FISH who had either an isolated 13q or 13q+ in patients with multiple myeloma (Patient characteristics Table 1). Of the patients with an isolated 13q abnormality 33% received a bortezomib-based regimen and 38% in the 13q+ group. Of the patient’s with a isolated 13q 38% went onto receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) while 20% with a 13q+ received ASCT. African American patients with 13q consisted of 65% and 60% with 13q+ in our patient population. For the 13q or 13q+ who underwent high dose chemotherapy followed by autologous stem cell transplant OS was 85% compared to the non-transplant group 45% (p=0.01) (Figure 2). On follow up at a median of 2.5 years mortality occurred in 31% of the 13q patients compared to 62% in the 13q+ group. The overall survival at 5 years was 25% in the 13q+ group compared to 65% in the patient’s with an isolated 13q, With the 13q+ group having an overall poor OS (p=0.03) Conclusion Patients who harbor the 13q and additional cytogenetic abnormalities identified by I-FISH have a significant worse outcome compared to patients with an isolated 13q. These patients should be considered high risk and consideration for treatment with novel agents and autologous stem cell transplant followed by post-transplant maintenance therapy should be considered. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcome of Adult Patients with Philadelphia Negative B Cell Acute Lymphoblastic Leukemia after Frontline Therapy Failure

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3718-3718 ◽  
Author(s):  
Punit L Jain ◽  
Koji Sasaki ◽  
Hagop Kantarjian ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Response Duration ◽  
Complete Response ◽  
Cell Transplant ◽  
Overall Response ◽  
Frontline Therapy

Abstract Introduction: Intensive induction-consolidation chemotherapy achieves high rates of complete response (CR) in 90% of patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, almost a half of the patients relapse and their outcome after frontline chemotherapy failure is essentially poor. Methods: We retrospectively reviewed 463 patients with newly diagnosed Philadelphia-negative ALL from June 2002 to February 2015 at our institution. Overall survival was defined as the time interval from the date of relapse to the date of death. Kaplan-Meier method was used for survival analysis. Results: Of the 463 patients, 155 (33%) relapsed. Data on salvage therapy and long term follow-up was available in 76 patients (17%). The median time to relapse was 15 months (range, 1-111 months). The median number of salvage regimens administered was 1 (range, 1-7). Overall, 76 patients received at least 1 salvage therapy. Thirty (39%) patients received at least 2 salvage regimens and 18 (24%) received 3 or more salvage regimens. Baseline patient characteristics are summarized in the table 1. Median follow-up after frontline therapy failure was 16 months. The median survival after relapse was 8.3 months with the 1- year and 2-year survival rates being 46 % and 28% respectively. Salvage 1 included augmented HCVAD [n=13; 7/13 responses (6 CR, 1 CRp) for a median of 6 months], asparaginase based therapies [n=6; 2/6 response (2 CR) for a median of 2 months], monoclonal antibodies (MAB), blinatumomab, inotuzumab ozogamicin [n=19; 11/19 responses (6 CR, 5 CRp) for a median of 7 months], HCVAD + anti-CD20 antibody [n=11; 8/11 responses (5 CR, 3 CRp) for a median of 6 months], Miscellaneous [n=22; 2/22 responses (2 CR)] and HCVAD [n=5; 1/5 response (1 CR) for 1 month]. The overall response rate to Salvage 1 was 41% (22 CR, 9 CRp) for a median of 6 months. Nineteen (25%) patients received subsequent allogeneic stem cell transplantation (ASCT); 11 of them are alive with a median of 2 years with 7 of them in CR. Thirty patients received a second salvage regimen; the most commonly used one consisted of MAB (blinatumomab; inotuzumomab ozogamicin) [n=8; 4/8 responses (2 CR, 2 CRp) for a median of 2.5 months]. The overall response rate to salvage 2 was 30% (6 CR, 3 CRp) for a median of 3 months. At the last follow-up, overall 23 patients remained alive, 9 of them in CR. Conclusions: Outcome of patients with Philadelphia-negative ALL post frontline therapies failure is poor with a median survival of only 8.3 months. Though some salvage therapies can induce remissions, response durations are limited. Stem cell transplant after remission offers a potential of long term cure. These patients should be referred to clinical trials. Table 1. Baseline characteristics and outcome of adults with relapsed B cell ALL (Ph -) who received salvage chemotherapy: N (%)/ Median [range] N= 76 Age (years) 36 (18-86) Age ³ 60 15 (20) Male 46 (61) PS 2-3 9 (12) WBC at diagnosis (x 109/L) 7.2 [1-602] CD20 positivity at diagnosis 24 (32) Cytogenetic Abnormality Diploid 22 (29) Hypodiploid 8 (11) Hyperdiploid 12 (16) t(4;11) 5 (7) Miscellaneous 28 (37) Type of Induction chemotherapy, No. (%) Augmented BFM 28 (37) HCVAD 21 (28) HCVAD + anti-CD20 antibody 27 (35) Overall response to frontline therapy CR 73 (96) CR without platelet count recovery 2 (3) Partial response 1 (1) Median response duration, (month) 15[1-63] Response duration <12 months 35 (46) Complete response to salvage chemotherapy S1 31/76 (41) S2 9/30 (30) S3 or more 3/18 (17) Allogeneic stem cell transplant 19 (25) Figure 1. Overall survival Figure 1. Overall survival Disclosures Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Daver:ImmunoGen: Other: clinical trial, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Dendritic Cell Reconstitution Following Autologous Stem Cell Transplant for Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5212-5212
Author(s):  
Annette J. Schlueter ◽  
Judith K. Glasgow ◽  
Werner W. Wilke ◽  
Jacquie R. Marietta ◽  
Raymond J. Hohl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dendritic Cell ◽  
Stem Cell Transplant ◽  
Complete Response ◽  
High Dose ◽  
Cell Transplant ◽  
Time Points ◽  
Post Transplant ◽  
Gm Csf

Abstract High dose therapy followed by autologous stem cell rescue for the treatment of multiple myeloma has been shown to be associated with improved outcome including increased complete response rates and survival. It is unclear what role, if any, autologous dendritic cell (DC) reconstitution patterns play in determining outcome. DC in peripheral blood (PB) can be divided into two subsets: DC1, which favor Th1 responses and DC2, which favor Th2 responses and in some cases appear to be immunosuppressive. In this companion study to a tandem stem cell transplant research protocol, PB DC subsets were studied prior to the administration of mobilizing chemotherapy (baseline), at the time of stem cell collection, on the day of transplant and at post transplant d. 15, 30, 60, and 90 following the first transplant. GM-CSF was used as part of the mobilization regimen as well as to enhance neutrophil recovery post-transplant. DC were identified as lineage (CD3/14/16/19) negative, HLA-DR+. Of these cells, DC1 were identified as CD11c+CD123− or CD33hiCD4lo, and DC2 were identified as CD11c−CD123+ or CD33lo/−CD4+. Sixteen patients have been enrolled and 11 are at least 90 d. post transplant #1. Median followup time is 12 months (range 7–25 months). 5 patients currently are in complete remission, 3 have had partial responses, 2 have stable disease, and 1 died of recurrent disease. In most cases, DC1 counts were higher than DC2 counts at all time points examined. At baseline, this was true for 77% of patients, indicating at baseline most patients maintain the higher DC1 numbers found in healthy humans. DC numbers increased in mobilized PB, and correlated well with the patients’ baseline counts. GM-CSF was more efficient at increasing DC2 than DC1, as has been reported for G-CSF. Post-transplant, DC recovery to at or near baseline levels occurred in most patients by d. 60. There was a trend for patients who are currently disease-free and those with partial responses to have a lower DC1:DC2 ratio (i.,e., DC2 reconstitution occurred more vigorously than DC1 reconstitution). The patient who died of progressive disease had the highest DC1 counts at several time points, and among the lowest DC2 counts leading to a consistently high DC1:DC2 ratio at 30, 60, and 90 days post-transplant. This finding suggests that in autologous transplant for multiple myeloma, proportionately increased numbers of DC2 are not associated with an increased risk of relapse, as was previously reported for allogeneic bone marrow transplant, but instead are associated with an improved likelihood of complete remission. Mobilization with a growth factor that favors the DC2 subset, such as GM-CSF, may promote the post-transplant production of a DC population that is able to assist in maintaining a complete response to high dose chemotherapy. If these trends are maintained upon final analysis of the patient population, additional means of selectively increasing DC2 numbers in this transplant setting would warrant further investigation.

scholarly journals Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3

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.

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