Response to Induction Chemotherapy with Novel Agents Does Not Predict Outcomes of Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1347-1347
Author(s):  
Salman Osman ◽  
Abraham Sebastian Kanate ◽  
Pamela Bunner ◽  
Sonia Leadmon ◽  
William Tse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
High Dose ◽  
High Dose Therapy ◽  
Advisory Committees ◽  
Remission Status ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Abstract 1347 Introduction: High dose therapy and autologous hematopoietic cell transplantation (AHCT) is a standard therapy option for at least young (<65 years) and otherwise transplant eligible multiple myeloma (MM) patients. While outcomes of AHCT in Hodgkin's and non-Hodgkin lymphoma patients showing evidence of chemo-sensitive disease pre-transplant are clearly superior, the prognostic significance of pre-AHCT remission status in MM is controversial. Failure to achieve at least a partial remission (PR) in response to induction chemotherapy before AHCT has not been shown to negatively impact transplant outcomes, at least in the pre-thalidomide (Thal)/lenalidomide (Len)/bortezomib (Bor) era (Kumar S, BMT 2004 & Singhal S, BMT 2002). Whether this paradigm holds true for novel agent-containing induction therapies is not known. Recently <50% reduction in ‘serum M-protein’ following induction with Thal or Len based induction therapy has retrospectively been shown to predict poor outcome after AHSCT (Gertz M, Blood 2010). However, data evaluating transplant outcomes relative to pre-transplant remission status assessed by strict IMWG criteria, and data in Bor-based regimens is still scant. We report here the impact pre-transplant remission status on outcomes of AHCT after chemotherapy with novel agents. Methods: The study involves 63 consecutive patients who underwent a planned, single AHCT within 1-year of starting induction chemotherapy with regimens containing Thal, Len, or Bor, between 2000–2009. All patients with normal renal function received uniform conditioning with Mel200 (MEL140 if serum creatinine was >2 mg/dl). The disease response pre- and post transplant was determined by using the IMWG criteria. SPSS version 16.0 was used for statistical analysis. Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS). Outcomes of patients achieving at least a PR (P-group; n=54) before AHCT were compared with one not achieving at least a PR (NO-P-group; n=9). As an exploratory analysis outcomes of patient achieving at least a very good partial response (VGPR) (V-group; n=40) with ones not achieving at least a VGPR (NO-V-group) was also performed (no-V group; n=23). Results: The mean age of the patients at transplant was 53yrs (range 44 –72yrs). 68 % (n=43) of patients were male. At diagnosis 42 patients (66%) had Salmon-Durie stage III disease, while 21 (34%) had stage I/II disease. Median Karnofsky performance status was 90. At the time of AHCT, the median HCT-CI score was 0. 33 % (n=21) of the patients received radiation therapy prior to transplant. At a median follow-up of 36 months, the 3 year OS of patients in P-group and NO-P-group was 58% vs. 60% (p=0.93) respectively. The 3 year PFS in similar order was 22% vs. 31% (p=0.74). The 3 year OS of patients in V-group and NO-V-group (44% vs. 62%) was also not significantly different (p=0.53). Respective figures of 3 year PFS are 22% vs. 24% (p=0.72) respectively. 3yr non relapse mortality was 5% for the whole cohort. Of the 31 patients that entered an AHCT with a PR, 15 improved to a CR post transplant, 2 improved their status to a VGPR whereas 14 remained in a PR. A total of 9 patients entered an AHCT with a stable disease (SD) of which 5 advanced to a CR, 3 a PR and one remained in SD. On the other hand of the 6 patients who entered an AHCT with a VGPR, 2 improved to a CR whereas the rest maintained their status. Finally, all the 17 patients entering an AHCT with a CR maintained their status. Conclusion: Our limited, retrospective data suggest acceptable AHCT outcomes in MM patients who do not achieve at least a PR in response to novel induction chemotherapies pre-transplantation. Failure to achieve a PR following novel induction therapies should not ‘routinely’ preclude consideration for high-dose therapy and AHCT. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamadani:celgene: Honoraria, Speakers Bureau; otsuka: Research Funding, Speakers Bureau.

scholarly journals Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3189-3189
Author(s):  
Taiga Nishihori ◽  
Rachid Baz ◽  
Leonel Ochoa ◽  
Omar Alexis Castaneda Puglianini ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Advisory Committees ◽  
Autologous Hct ◽  
Autologous Hematopoietic Cell Transplantation

Background: Autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy with an immunomodulatory agent or a proteasome inhibitor remains an important strategy for upfront treatment in multiple myeloma (MM) with progression-free survival (PFS) and overall survival (OS) advantage. We designed a two-arm, open-label prospective study to examine the safety and tolerability of two different dosing schedules of an oral pan-histone deacetylase inhibitor, panobinostat (pano) as an alternative maintenance therapy option in patients with MM (NCT02722941). Methods: A total of 30 MM patients who underwent autologous HCT within the preceding 90 to 180 days were enrolled at Moffitt Cancer Center using a sequential alternating allocation to starting dose of either Cohort A: 20 mg PO 3/week, q 2 weeks on a 28-day cycle, or Cohort B: 10 mg PO daily for 7 days, q 2 weeks on a 28-day cycle, for 12 cycles. Dose level -1 was cohort A: 15 mg 3/week; and cohort B: 10 mg 4/week. Patients with clinically significant cardiac diseases, bradycardia, QTc > 470 msec, bifascicular block were ineligible. EKG was performed on pre- and post-dose on day 1 & 5 of cycle 1, and pre-dose on day 1 of cycles 2-4. Relative dose intensity (RDI), a ratio of amount of drug actually delivered in mg over the amount of planned dose in mg, was calculated to evaluate the treatment feasibility as a surrogate measure. Results: The median age of the entire cohort was 60 (range, 40-73) years with a male/female = 18/12. Disease characteristics are summarized in the Table. Patients initiated pano maintenance at a median of 131 (range 91 - 178) days after autologous HCT. As of 8/1/2019, 16 patients (8 in each cohort) completed full 12 cycles of pano. The RDI for the entire cohort, cohort A, and cohort B was 94.1% (33,750mg/35,860, 98% (16,350mg/16,680mg), and 90.7% (17,400mg/19,180mg), respectively. One patient in cohort A had dose reduction, and 6 patients in cohort B had dose reductions with cytopenias (43%) and GI toxicities (43%) being the most common reasons. No patients required dose modifications due to QT prolongation thus far. There were 3 possibly treatment-associated serious adverse events (pneumonia=2; colitis=1) but all patients successfully resumed pano. Three patients progressed while on pano maintenance. No mortality has been observed thus far. Ten patients are still on pano treatment. The median follow-up is 11 (range, 1-29) months. Conclusions: RDI is 90% overall and panobinostat as a single oral maintenance agent either at 20 mg three times per week or 10 mg po daily for 7 days on alternating weeks appears to be overall well tolerated. There were more dose reductions required in the 10 mg starting dose (cohort B). Panobinostat is a safe alternative for maintenance therapy after autologous HCT. Longer follow-up is needed to confirm the utility of this approach and updated results will be presented at the meeting. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Baz:Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Panobinostat single agent maintenance therapy after autologous hematopoietic cell transplantation for multiple myeloma

scholarly journals Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 483-483
Author(s):  
Susan Bal ◽  
Saurabh Chhabra ◽  
Natalie S. Callander ◽  
Eva Medvedova ◽  
Bhagirathbhai Dholaria ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Committees ◽  
Post Induction ◽  
The Impact ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background Unprecedented depth of response is observed with quadruplet combinations in newly diagnosed multiple myeloma (NDMM). The incremental benefit of autologous hematopoietic cell transplantation (AHCT) in this setting has not be described and can be appraised with the serial assessment of minimal residual disease (MRD). Here we describe the impact of AHCT on MM burden assessed by next generation sequencing (NGS) for patients enrolled in the MASTER trial. Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for patients with high-risk chromosome abnormalities (HRCA). MRD assessment is performed by NGS (ClonoSEQ® platform) upon completion of induction therapy with 4 cycles of Dara-KRd, 60-80 days after AHCT and after each 4 cycle-block of consolidation, where applicable. Patients with confirmed MRD negativity (MRD&lt;10 -5 in two consecutive time points) enter treatment free observation and active surveillance of MRD resurgence ("MRD-SURE"). The primary endpoint of the study is negativity utilizing IMWG criteria (MRD&lt;10 −5). Achievement of MRD &lt;10 −6 is an exploratory endpoint. Patients are categorized as having 0, 1, 2+ HRCA [gain 1q, t(4;14), t(14;16), t(14;20), del(17p)]. We describe changes in MRD burden with AHCT and explore patient and disease features influencing magnitude of MRD reduction with AHCT. Results Between 3/2018 and 9/2020, 123 participants were accrued. Of those, 118 were MRD evaluable and 109 have NGS-MRD post-induction and post AHCT and are included in this analysis. The median age is 61 y (35-79) and 18% are 70 or older. Twenty-four percent of patients are non-white, 20% have ECOG 2, 19% high LDH, and 19% R-ISS3. Forty seven (43%) have 0 HRCA, 41 (38%) have 1 HRCA, and 21 (19%) with 2+ HRCA (ultra-HR MM). Forty percent achieved MRD negativity after four cycles of Dara-KRd induction, increasing to 69% after AHCT. Twenty-six percent patients were MRD&lt;10 -6 post induction, increasing to 51% post-AHCT (Table). Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT (figure). The median reduction in MRD with auto-HCT was 1.10 log 10 (range -1.26 to 3.41). Patients with HRCAs had a greater reduction in MRD burden (P=0.02). For patients with 0, 1 and 2+ HRCA, median reduction was 0.91 log 10 (range -0.75 to 2.14), 1.26 log 10 (range -0.21to 3.26) and 1.34 log 10 (range -1.28 to 3.41),respectively. More than 1 log 10 reduction in MRD was seen in 56.0% of patients, 43%, 74% and 71% of patients with 0, 1 and 2+ HRCA respectively. Greater than 2 log reductions in MRD was seen in 20% of patients, 11%, 17% and 43% of patients with 0, 1 and 2 HRCA, respectively. In multivariable analysis that included age, stage, performance status and treatment response post induction, the presence of HRCA was the only factor associated with greater than 1 log 10 reduction in MRD burden with AHCT (OR 3.6, 95% CI 1.27-10.2, P=0.016). Conclusions An ultrasensitive quantitative MRD assay using NGS demonstrates the incremental benefit of AHCT in the context of highly efficacious quadruplet induction. The greatest impact is afforded to the highest risk disease subset elucidating the biologic underpinnings of the impact of AHCT in MM. At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction. Future studies exploring AHCT deferral in NDMM should be focused on patients who are MRD negative post optimal induction. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Dholaria: Angiocrine: Research Funding; MEI: Research Funding; Pfizer: Research Funding; Jazz: Speakers Bureau; Takeda: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Celgene: Speakers Bureau. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria.

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