Lenalidomide Related Diarrhea Correlates With Survival In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5397-5397 ◽  
Author(s):  
Beth Faiman ◽  
Surbhi Sidana ◽  
Paul Elson ◽  
Kellie Bruening ◽  
Hien K. Duong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Antineoplastic Agents ◽  
Research Funding ◽  
Proportional Hazards ◽  
Late Onset ◽  
High Dose ◽  
Cell Transplant ◽  
Logrank Test ◽  
The Impact

Abstract Background We hypothesized lenalidomide (len) related diarrhea (LRD) may correlate with activation of an immune response against multiple myeloma (MM) based on colon biopsies that showed crypt apoptosis reminiscent of GVHD in 3 MM patients with severe LRD but without prior allogeneic stem cell transplantation or gastrointestinal disorder. To investigate whether survival may be influenced by the presence of LRD we performed a retrospective chart review. Methods Patients who developed symptomatic MM on or after 1/1/2005 as defined by the start of anti-MM therapy and had been on len for at least 6 consecutive months by 12/31/2010 were included in the analysis. Significant LRD was considered present if the treating physician attributed the diarrhea to len and recommended supportive therapy in at least two clinic notes.  The first time treatment for LRD was recommended was used as the date of onset of LRD. As possible confounding factors age at the start of len therapy, number of prior regimens, prior high dose chemotherapy with autologous stem cell transplant (ASCT), and use of antineoplastic agents other than corticosteroids at any time during the continuous len therapy were collected. The primary outcome was overall survival (OS), which was calculated from the start of len. Fisher’s exact test, Mann-Whitney test, and the logrank test were used to compare characteristics and duration of len between patients with and without LRD. Proportional hazards models were used to assess the impact of LRD on OS. The lag between the start of len and development of LRD was accounted for by treating LRD as a time-varying covariate in these models. Results 161 patients were identified, 47 (29%) had LRD, and 59 (37%) died during follow up. LRD and no LRD groups were balanced for gender, age, number of prior regimens, prior transplant, and use of antineoplastic agents other than corticosteroids with len, but len treatment duration differed; LRD patients had received a median of  43.4 consecutive months of len (range 5.8-82.9) compared to 14.6 (range 5.9-89) for patients without LRD (p=0.001). Onset of LRD occurred after a median of 17.7 months (range 0.3-75.4) of len therapy. In multivariable analyses, development of LRD (HR 0.46, 95% C.I. 0.21-1.00, p=0.05) was associated with improved OS as were the number of prior therapies (0-2, vs >2, HR 0.16, 95% C.I. 0.08-0.32, p<0.0001) and no use of antineoplastic therapy other than corticosteroids during len therapy (HR 0.52, 95% C.I. 0.29-0.93, p=0.03), while age and prior ASCT (p=0.52 and 0.49, respectively) were not. Conclusion Late onset of lenalidomide related diarrhea (LRD) is compatible with an immune mediated effect that may signal anti-MM immune activity since LRD requiring supportive measures correlated with survival in MM in analyses that adjusted for lag time. While more study is needed to prove this hypothesis, our findings suggest that diarrhea on len may argue for continued therapy rather than discontinuation. Disclosures: Faiman: Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Valent:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Reu:Celgene: Research Funding; Onyx: Speakers Bureau.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

scholarly journals Progressive Multifocal Leukoencephalopathy in Multiple Myeloma: A Single Institution Case Series

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4736-4736
Author(s):  
Alfredo De La Torre ◽  
Andrew Gao ◽  
Timo Krings ◽  
Donna E. Reece
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Research Funding ◽  
Jc Virus ◽  
Brain Mri ◽  
Brain Biopsy ◽  
High Dose ◽  
Cell Transplant

Abstract Introduction Progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, is an infection that requires immunosuppression for its manifestations and is fatal disease in many cases. (1) After asymptomatic primary infection, which occurs in childhood, the virus remains quiescent. (1,4) The classical clinical presentation is that of a subacute symptomatology that develops over weeks or months and consists of diverse sensorimotor abnormalities depending on the site of brain involvement. Approximately 22 cases of PML amongst patients with multiple myeloma (MM) have been reported in the literature between 1965 and April 2020. (5) Methods We performed a retrospective chart review of all myeloma patients who were treated at the Princess Margaret Cancer Center from 2010-2020 to identify cases of PML. Patient and disease characteristics, responses, and survival outcomes were collected from Myeloma and Stem Cell Transplant databases and electronic patient records under REB approval. Results We identified 3 cases of PML in MM patients at our center over the past 10 years, all of which occurred in patients receiving therapy containing an immunomodulatory derivative (IMID), i.e., thalidomide, lenalidomide or pomalidomide. Patient 1 A 52-year-old male with kappa light chain MM presented in 2009 on hemodialysis and received upfront bortezomib and dexamethasone followed by melphalan 200mg/m 2 and autologous stem cell transplantation (ASCT) in March 2010; maintenance with thalidomide was given until July 2011 when he presented to the ER with left-sided weakness, facial droop, and decreased strength. CT scan showed right-sided hypodensity in keeping with demyelination. PML was confirmed by MRI, lumbar puncture with positive PCR for JC virus, and a brain biopsy (Fig 1 A-C). He was treated with mirtazapine, and also developed status epilepticus controlled with phenytoin and phenobarbital. His myeloma treatment was never resumed after the diagnosis of PML due to concerns about viral reactivation. Approximately 3 years after PML diagnosis, his serum free kappa protein levels started to increase; he remained on hemodialysis but experienced no new myeloma-related organ damage and no myeloma treatment was offered. His last follow-up in clinic was in March 2019. However, he succumbed to S. pneumonia septicemia in July 2019. Case 2 A 68-year-old female with IgG kappa MM diagnosed in 2004 was treated with high-dose dexamethasone induction followed by melphalan 200mg/m 2 and ASCT and relapsed 2 years later. She commenced cyclophosphamide and prednisone until July 2011 when treatment was changed to lenalidomide and prednisone; subsequent progression in February 2014 was treated with pomalidomide/bortezomib/prednisone. In November 2014, we noticed worsening vision. Brain MRI showed hyperintensity in T2 in the occipital lobe. Her myeloma treatment was stopped and she received corticosteroids with no improvement. LP in January 2015 was positive for JC virus and the diagnosis of PML was made. She was managed with supportive measures. Her last clinic follow-up was in 2015 and the patient died from progression in September 2015. Case 3 A 52-year-old male with IgA lambda MM diagnosed in 2015 was treated with CYBOR-D induction followed by melphalan 200mg/m 2 and ASCT. He initially received lenalidomide maintenance which was changed to bortezomib due to toxicity. On progression in January of 2019 he was placed on a clinical trial of the anti-BCMA antibody drug conjugate belantamab mafodotin in combination with pomalidomide and dexamethasone on which he achieved a VGPR. In October 2020, he developed confusion and memory problems, as well as involuntary twitching. A brain MRI showed possible demyelination Two LPs were negative for JC virus, but a targeted brain biopsy confirmed the diagnosis of PML (Fig 1 D-F). His myeloma treatment was discontinued, and he was started on mirtazapine. At his most recent clinic visit in May 2021 his speech, memory and functional status had improved considerably and there were no signs of myeloma progression. Conclusion Our current series of PML in MM showcases the potential contribution of IMIDs and other novel agents--such as the newer monoclonal antibodies like belantamab mafotidin-- to the reactivation of JC virus and subsequent PML. Our series also demonstrates that neurologic improvement and longer survival can be observed with earlier management. Figure 1 Figure 1. Disclosures Reece: BMS: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Mabel Rodriguez ◽  
Nelly G. Adel ◽  
Sean Devlin ◽  
Sergio A Giralt ◽  
Heather Landau
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Hospital Days ◽  
Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

Response Before Autologous Hematopoietic Stem Cell Transplantation Is An Important Predictor of Outcome in Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4119-4119
Author(s):  
Shatha Farhan ◽  
Heather Lin ◽  
Veerabhadran Baladandayuthapani ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Hematopoietic Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Minor Response ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Abstract 4119 Background: The outcome of multiple myeloma (MM) has improved significantly over the last 2 decades due to the availability of several novel agents and an increasing use of high-dose chemotherapy and autologous hematopoietic stem cell transplant (auto-HCT). There is considerable evidence that the response to induction therapy predicts a favorable outcome after high-dose chemotherapy and auto-HCT. In this report, we evaluated the impact of pre-transplant response to conventional agents on post auto-HCT outcomes including time to progression (TTP), progression free survival (PFS) and overall survival (OS). Methods: 1567 patients received auto-HCT at UT-MD Anderson Cancer Center between 1988 and December 2010. Pre auto-HCT disease status was divided into the following prior auto-HCT response groups: complete response (CR), very good partial response (VGPR), partial response (PR), minor response (MR), stable disease (SD) and progressive Disease (PD). The primary objective was to study the impact of prior response on the outcome. Demographics, disease-related and transplant-related variables were collected. The distributions of TTP, PFS and OS were estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups. Regression analyses of survival data was based on the univariate and multivariate Cox proportional hazards model. Results: Median age at auto-HCT was 56.8 years. Median time from diagnosis to auto-HCT was 7.9 months. Of the 1567 patients, 72 (4.6%) achieved CR before auto-HCT, 255 (16%) had VGPR, 848 (54%) had PR, 78 (5%) had MR, 189 (12%) had SD, 88 (5.6%) had PD, while the response was unknown in 37 (2%) patients. Almost 17% patients were 65 years or older at auto-HCT and approximately 7% had high-risk cytogenetic abnormalities. On univariate analysis, the response prior to auto-HCT had significant impact on TTP (p=<0.0001), PFS (p=<0.0001), and OS (p=<0.0001), In multivariate models, the response prior to auto-HCT still emerged as a significant predictor of TTP, PFS and OS (p =0.0055, p=0.0004 and p<0.0001, respectively) after adjusting for percent of plasma cells, time interval from diagnosis to transplantation and/ or creatinine level. In particular, patients who achieved CR prior to auto-HCT had significantly longer TTP, PFS and OS when compared to patients who had PR, MR, SD or PD (Figures 1–Fig 3). In contrast, TTP, PFS and OS were not significantly different between patients who achieved a CR or VGPR prior to auto-HCT. Conclusion: Patient who achieved CR or VGPR before undergoing an auto-HCT had significantly longer TTP, PFS and OS after the transplant. These results highlight the importance of effective anti-myeloma therapy to maximize the response before proceeding to auto-HCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3439-3439
Author(s):  
Brandon B. Wang ◽  
Mark A. Fiala ◽  
Mark A. Schroeder ◽  
Tanya Wildes ◽  
Armin Ghobadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
The Impact

Abstract Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear. Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results. Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID). The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1. Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months. Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT. Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance. At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed. In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002). Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

The Impact of Different Mobilization Strategies in the Setting of Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3254-3254
Author(s):  
Francesco Mazziotta ◽  
Gabriele Buda ◽  
Nadia Cecconi ◽  
Giulia Cervetti ◽  
Lorenzo Iovino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Peripheral Blood ◽  
High Dose ◽  
Roc Curve Analysis ◽  
Cd34 Cells ◽  
Significant Difference ◽  
The Impact

INTRODUCTION Multiple myeloma (MM) is considered an incurable disease. Despite the introduction of novel agents allowed deeper response, high-dose chemotherapy and autologous stem cell transplantation (ASCT) remain the standard of care for patients (pts) in good clinical conditions. The most used strategies to mobilize stem cells from bone marrow (BM) into peripheral blood are high-dose cyclophosphamide (HD-CTX) plus G-CSF and G-CSF plus plerixafor (G-CSF+P). The goal of this retrospective study is to investigate whether the two different mobilization strategies have an impact on the clearance of monoclonal PCs in the apheresis products and on pts' outcome. PATIENTS AND METHODS We analyzed 62 pts (median age 61, range 41-75, 37 males and 25 women) diagnosed with MM and treated with ASCT between Mar 2014 and Mar 2018 at our Hematology Division (Pisa, Italy). All pts received induction therapy with at least 4 cycles of bortezomib, thalidomide and dexamethasone (VTD). 9/62 pts obtained a less than partial response (PR) and received lenalidomide-based regimens. After induction, 8 (12,9%) pts achieved complete remission (CR), 26 (41,9%) were in PR, 28 (45,2%) obtained a very good partial response (VGPR). 43/62 fit pts received HD-CTX (2-3 g/sqm) on day 1 followed by G-CSF (30 MU/day) started on day 4 until day 7, increased to 60 MU/day from day 8 until the end of apheresis. In 19/62 pts, after 4 days of G-CSF (60 MU/day) administration and not sufficient mobilization, we added plerixafor (0,24 mg/kgbw) for up to 4 consecutive days. In 43/62 pts we collected apheresis samples (10μl) analyzed through flow citometry to enumerate clonal residual PCs. The panel used to asses clonality included: CD138 Per-Cp, CD38 APC, CD19 PE-Cy7, CD45 APC-Cy7, cytoplasmic immunoglobulin K chain and L chain. RESULTS At the end of the peripheral blood stem cell (PBSC) collection, pts treated with HD-CTX presented a higher CD34+ absolute count (p=0.0489) and achieved the threshold of 5x106 CD34+ cells/kgbw in a significantly (p=0.006) higher percentage. We found a nearly significant (p=0.0517) lower count of CD34+ PBSCs in pts who received lenalidomide-based regimens before the mobilization. Performing flow citometry on apheresis samples, we observed that the number of the harvested clonal PCs showed a significant correlation (p=0.0115) with the occurrence of post-ASCT relapse. ROC curve analysis investigating the predictive effect of the number of pathological PCs on disease relapse showed an area under the curve of 0,6978 (95% CI 0.5392-0.8564; p=0.0267). Neither BM residual PCs detectable on BM biopsies performed before apheresis (r=-0.1323; p=0.609) nor the type of mobilization scheme (p=0.707) had an impact on the proportion of clonal PCs in the graft. Additionally, we did not observe any statistically significant difference in progression free- (PFS) (p=0.8276) and overall survival (OS) (p=0.2475) between the HD-CTX and G-CSF+P groups. DISCUSSION PBSC mobilization has a succession rate > 85%. Despite the use of HD-CTX to increase PBSC yields and decrease tumor burden, there is not clear evidence of a superior mobilization strategy. Additionally, HD-CTX has a not negligible toxicity and approximately 10% of the pts require hospitalization. Conversely, G-CSF+P is a safe and effective approach also in poor mobilizers. In our study, we observed a significative difference in the apheresis yields (p=0.0489) and in the percentage of pts who achieved the threshold of 5x106 CD34+ cells/kgbw (p=0.006) in favor of HD-CTX. Additionally, the detection of harvested residual clonal PCs could be a promising strategy to recognise pts more likely to relapse after ASCT. Nonetheless, we failed to demonstrate a superior effect of HD-CTX in the clearance of harvested clonal PCs, in agreement with the absence of a different pts' outcome amongst the two mobilization strategies. In conclusion, the choice between the two regimens is challenging and requires careful consideration of multiple factors. Overall, young fit pts, especially in the high-risk setting, should be treated with all appropriate modalities including chemiomobilization followed by double-ASCT. Conversely, in pts candidate to a single-ASCT it is reasonable to use G-CSF+P, since HD-CTX does not improve PFS and OS and add toxicity. The absence of an in-vivo purging effect on apheresis products of chemiomobilization further strengthens a chemotherapy-free mobilization. Disclosures Galimberti: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document