Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 688-688 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselberg-Hacker ◽  
Sonja Zweegman ◽  
Bronno van der Holt ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Phase 2 Trial ◽  
Cell Harvest

Abstract Background A proteasome inhibitor (PI) combined with an immune-modulatory dexamethasone has significant activity in replapse and newly diagnosed Multiple Myeloma (MM). Carfilzomib is an effective 2nd generation PI. We report an update of a Phase 2 trial using Carfilzomib combined with Thalidomide and Dexamethasone in newly diagnosed MM. Introduction This investigator sponsored, dose escalation phase 2 trial was designed to investigate Carfilzomib © combined with Thalidomide (T) and Dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Fifty patients in cohort 1 received 4 cycles of Carfilzomib at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, Thalidomide 200 mg p.o. days 1 through 28 of a 28 day cycle and Dexamethasone 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 (20 patients) the dose of Carfilzomib was escalated from 27 mg/m2 to 36 mg/m2 in the same schedule. In cohort 3 (20 patients) the dose of Carfilzomib increased to 45 mg/m2 in the same schedule. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), followed by consolidation therapy: 4 cycles of Carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), Thalidomide 50 mg days 1-28 of a 28 day cycle and Dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was very good partial response (VGPR) after 4 CTD cycles: secondary endpoints were complete response (CR), stringent CR (sCR), VGPR and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results 90 patients were included as of 1st April 2013. We here report the response of cohorts 1+2 (n=70) with a median follow-up of 22 and 7 months respectively. Median age was 58 yrs and ISS stages I/II/III were 27%/40%/27%, respectively. Six (9%) patients had renal failure with serum creatinine > 2 mg/dL. Of 70 patients in cohorts 1 and 2, 8 patients stopped treatment during/after induction and 4 patients after HDM because of refusal (n=2), toxicity (n=4) non-eligibility (n=2) or progression (n=4). 39 patients completed protocol treatment with 19 still on treatment. Overall response rate on protocol treatment was 96%. After induction therapy response was 19% (CR/sCR), 60% (≥ VGPR) and 93% (≥ PR), respectively. The CR/sCR rate increased to 30% after HDM and to 49% after consolidation. CR/sCR rate was not different across ISS staged I/II/III. In addition, response was similar in poor risk FISH (gain 1q or t(4;14) or del17p: 26% of patients) and standard risk FISH (all other). Progression-free survival (PFS) f 70 patients is 74%, overall survival (OS) is 7%. Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 60/60 patients and HDM/ASCT was performed with complete hematologic recovery in 53/53 patients. This regimen was well tolerated. Safety analysis for all 3 cohorts showed non-hematological toxicity CTC Grade 3+4 in < 5%, mainly infections and skin lesions. Other toxicities were Grade 2 ≤ or less than 5% including cardiac symptoms. Purified myeloma plasma cells, obtained in 39 patients at diagnosis were used for gene expression profiling and exome sequencing. The prognostic impact of the EMC-92 gene classifier on outcome with CTd will be presented. Conclusion Carfilzomib combined with thalidomide and dexamethasone is a safe and rapidly effective regimen for newly diagnosed MM. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.

Carfilzomib Combined with Thalidomide and Dexamethasone (CTD) Is an Highly Effective Induction and Consolidation Treatment in Newly Diagnosed Patients with Multiple Myeloma (MM) Who Are Transplant Candidate

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 333-333 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselbergs ◽  
Sonja Zweegman ◽  
Bronno Van der Holt ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Research Funding ◽  
Objective Response ◽  
Hematological Toxicity ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Cell Harvest

Abstract Abstract 333 Background: Combinations of a proteasome inhibitor (PI) with an Imid plus dexamethason such as VRD or VTD have shown significant activity in newly diagnosed Multiple Myeloma. The use of these regimens is hampered by toxicity such as polyneuropathy and costs. Carfilzomib is a second generation PI that has shown activity as single agent and in combinations. Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to investigate carfilzomib (C) combined with thalidomide (T) and dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Patients in cohort 1 received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 through 28 of a 28 day cycle and dexamethasone 40 mg on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 the dose of carfilzomib was 20 mg/m2 on days 1 & 2 followed by 36 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following single high-dose melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), thalidomide 50 mg days 1–28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was at least very good partial response (VGPR) after 4 CTD cycles, secondary endpoints were complete response (CR) according to IMWG criteria, stringent CR (sCR), VGPR and an objective response (at least PR) pre-and post HDM, progression-free (PFS) and overall survival (OS). Results: 58 patients were included as of 1stAugust 2012. We here report on the first 40 registered patients, who were included in the first cohort and who are evaluable for response and toxicity. Median age was 58 yrs and ISS stages I/II/III were 40%/35%/25%, respectively. Of 40 patients, 35 (87%) completed 4 CTD induction cycles, 31 (77) competed HDM/ASCT. So far, 17 patients completed 4 consolidation cycles. 68 % of patients achieved an objective response within 1 cycle. Cytogenetic FISH data were available in 88%. Responses were achieved across ISS (I/II/III) or FISH subgroups, i.e. gain (1q) (n=4), t(4;14) (n=4), del(17p) (n=3), del(13q) (n=10) or normal. Stem cell harvest was successfully accomplished with > 3×10*6 CD34+ yield in 34/34 patients and HDM/ASCT was performed with complete hematologic recovery in 31/31 patients. Progression-free survival was 97% at 12 months, overall survival was 100% at a median follow-up of 10.4 months. This regimen was well tolerated. Non-hematological toxicity CTC grade 3+4 included tumor lysis syndrome (5%), DVT (10%), gastro-intestinal symptoms (5%), skin rash (8%). Peripheral polyneuropathy grade 2 or 3 was observed in 6 and 1 (17%) patients. No hematological toxicity was observed. Conclusion: Carfilzomib combined with thalidomide and dexamethasone is a rapidly effective induction regimen. With the same regimen used as consolidation, a significant upgrade of responses is observed. Disclosures: Sonneveld: Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding. Lokhorst:Genmab: Consultancy.

scholarly journals A Multi-Center Phase 1b, Open-Label, Dose-Finding Pilot Study to Evaluate the Combination of Carfilzomib and Cyclophosphamide with Dexamethasone (CCyD) Prior to Autologous Stem Cell Transplant (ASCT) in Patients with Transplant Eligible Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4739-4739 ◽  
Author(s):  
William I. Bensinger ◽  
Robert Vescio ◽  
Cristina Gasparetto ◽  
Elber S. Camacho ◽  
Rajneesh Nath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Dose Finding ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Advisory Committees

Abstract Background: Carfilzomib is an epoxy ketone, second generation proteasome inhibitor approved for the treatment of relapsed and refractory multiple myeloma. It has shown very high activity when combined with lenalidomide and dexamethasone for the treatment of newly diagnosed patients with multiple myeloma. This is the first reported trial of carfilzomib, cyclophosphamide, and dexamethasone (CCyD) in newly-diagnosed, transplant eligible patients. Methods: This study was a multi-center Phase Ib, open-label, dose-finding study in newly diagnosed transplant eligible multiple myeloma patients (pts) studying the combination of CCyD as induction therapy prior to autologous stem cell transplant (ASCT). Pts could receive a minimum of 4 cycles and up to 6 cycles prior to ASCT. Pts were enrolled into a dose-escalation treatment cohort. A standard 3+3 dose escalation schedule was used with cohorts of carfilzomib 36 (initial), 45 and 56 mg/m2 (administered over 30 minutes on days 1, 2, 8, 9, 15 and 16) combined with 300 mg/m2 of oral cyclophosphamide weekly on days 1, 8, 15 and 40 mg of oral dexamethasone once weekly. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the IMWG criteria. Prior therapy was limited to up to 160 mg of dexamethasone or limited field radiation. Results: 28 patients were enrolled from 5 centers. Of 28 patients enrolled, 3 did not complete 4 cycles of therapy (1 proceeded to ASCT after Cycle 3) and are not evaluable for response (pts came off secondary to AE of pulmonary HTN unrelated, secondary to SAE of CHF possibly related, due to PI discretion related to maximum benefit achieved), 8 patients did not undergo ASCT (1 had PD after Cycle 5), 8 patients proceeded to ASCT (1 the aforementioned patient after Cycle 3), 6 patients have completed induction and are still pre-transplant and 4 patients are still on treatment. The median age was 64 years (range 44–74), 57% were male. Cytogenetic abnormalities included 13 patients with del(13), 4 with del(17p), 2 with t(14;16) and 1 with hypodiploidy for a total of 16 patients with high-risk cytogenetics. In the dose-escalation portion of the study, the maximum administered dose tested was 56 mg/m2 carfilzomib. There was one DLT in cycle 1, of Grade 3 dyspnea, at the 56 mg/m2 level. Drug-related AEs occurring in >20% of patients included fatigue (23%) and thrombocytopenia (31%). Thirty-one percent experienced at least one Grade ≥3 AE with dyspnea and nausea as the most common. There were no deaths on study with a median follow-up of 4.9m (range: 1.1 to 13.1m). One pt came off study after Cycle 5 for PD as evidenced by new plasmacytomas. Six patients received 36-45 mg/m2 carfilzomib on the dose escalation portion of this study and 22 patients received the maximum administered dose of carfilzomib at 56 mg/m2. One patient yet to be enrolled to obtain 20 efficacy evaluable pts at the maximum dose. Twenty-three patients were response evaluable. Median of 5.7 cycles of therapy with 2 CR, 9 VGPR, 10 PR, 1 MR and 1 PD for ≥ PR rate of 91%. Of the 12 response-evaluable patients with high risk cytogenetics, 92% were ≥ PR; of the 11 standard risk patients, 91% were ≥ PR. Of 9 patients who underwent stem cell mobilization, all collected adequate stem cells and median number of stem cells collected was 12.58 (5.07-25.31) x106 CD34+ cells/kg. Conclusions: The combination of CCyD given to untreated, symptomatic patients with myeloma was well tolerated and highly active with an 87% RR and a 48% ≥ VGPR after 4 to 6 cycles. This study compares favorably with other regimens used for induction prior to transplant for the management of newly diagnosed multiple myeloma. Disclosures Bensinger: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Vescio:Onyx Pharmaceuticals: Honoraria, Speakers Bureau. Gasparetto:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nath:Celgene: Consultancy. Shah:Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Durie:Onyx Pharmaceuticals: IRC Other; Millennium Pharmaceuticals: IRC, IRC Other.

Dose Escalation Phase 2 Trial of Carfilzomib Combined with Thalidomide and Low-Dose Dexamethason in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. a Trial of the European Myeloma Network

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2118-2118 ◽  
Author(s):  
Pieter Sonneveld ◽  
Emilie Asselbergs ◽  
Bronno Van der Holt ◽  
Sonja Zweegman ◽  
Marie jose Kerstens ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Phase 2 Trial ◽  
High Dose Melphalan ◽  
Dose Levels

Abstract Background: Carfilzomib has significant activity in newly diagnosed Multiple Myeloma (MM). We present an update of a Phase 2 trial of dose-escalated Carfilzomib combined with Thalidomide and Dexamethasone (CTd). Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to evaluate the clinical efficacy of standard dose Carfilzomib (C) (20/27 mg/m2) combined with Thalidomide (T) and Dexamethasone (D) (CTd) as induction therapy followed by high-dose Melphalan and autologous stem cell transplantation (ASCT), followed by consolidation therapy with CTd in transplant eligible patients with newly diagnosed symptomatic MM,. The second objective was to establish the maximum tolerated dose of Carfilzomib in this combination. Fifty patients were included in the first part who received 4 cycles of C at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, T 200 mg p.o. days 1 through 28 of a 28 day cycle and D 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In the second part 3 cohorts of 20 patients each were treated with escalated dose of C at 20/36 mg/m2,20/45 mg/m2 and 20/56mg/m2, respectively with T and D at the same dose. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and ASCT, followed by consolidation therapy consisting of 4 cycles CTd with C 27 mg/m2 (part1, n=50) or 36 mg/m2 or 45 mg/m2 or 56 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, respectively, combined with T 50 mg days 1-28 of a 28 day cycle and D 20 mg days 1, 8, 15, 22 of a 28 day cycle. Thrombosis prophylaxis was prescribed. The primary endpoint was very good partial response (VGPR) after 4 CTd cycles: secondary endpoints were complete response (CR), stringent CR (sCR) and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results: 111 patients were included as of 1st July 2014. We here report the response of all cohorts with a median follow-up of 34, 19, 12 and 6 months, respectively. Median age was 58 yr and ISS stages II and III were 40% and 27%, respectively. The CTd regimen was well tolerated. Fifteen patients discontinued treatment because of non-eligibility (n=3), refusal (n=2), toxicity (n=7) or progression (n=3). Safety analysis was available for all treatments in cohorts 27mg/m2 through 45mg/m2 and for induction cycles in cohort 56mg/m2. Non-hematological SAEs for the two lower dose levels were infections (n=8), polyneuropathy gr 2 (n=5), cardiac (n=3) and tumor lysis syndrome (n=2) (ASH 2013). Non-hematological SAEs for dose level 45mg/m2 (n=22) included thrombosis (n=1), reversible gastrointestinal event (n=2) and infections (n=5). At dose level 56mg/m2 SAEs were thrombosis (n=2), infections (n=3), reversible cardiac event (n=1). In 111 patients 4 cardiac events were observed (2 grade 2, 2 grade 3) 3 of which resolved completely. Two patients discontinued therapy because of thrombosis (n=1) and pneumonia (n=1). Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 85/85 patients and HDM/ASCT was performed with complete hematologic recovery in 77/78 patients. The primary endpoint ≥VGPR and CR was achieved in 94% and 56% (27mg/m2), 75% and 65% (36mg/m2), 91% and 55% (45mg/m2), 75% and 20% (56mg/m2, induction only). Of 25 CRs in dose levels 36mg/m2 and 45mg/m2, 9 (36%) were stringent CR with no clonal plasma cells in bone marrow and negative serum-free lite. VGPR + CR increased from 63% after induction to 73% after HDM/ASCT and 86% after consolidation, respectively. For CR these figures were 18%, 34% and 58%, respectively. Overall response and CR were not significantly different between dose cohorts. Responses did not differ between poor risk (gain 1q or t(4;14) or del17p) and standard risk FISH. At a median follow-up of 21 months for dose levels 27mg/m2, 36mg/m2 and 45mg/m2 ,78% of patients are alive without progression or relapse. PFS at 18 months is 88 %. Three patients died of myeloma. There were 2 second primary malignancies. Analyses for revised ISS and molecular subgroups will be presented. Conclusion: C combined with T and D is a safe and effective regimen for newly diagnosed MM. Dosing of Carfilzomib up to 56mg/m2 was well tolerated. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals, an Amgen subsidiary. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria.

Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1141-1141 ◽  
Author(s):  
Ruth Wester ◽  
Bronno van der Holt ◽  
Emelie Asselbergs ◽  
Mark van Duin ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Fixed Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

scholarly journals A Phase 2 Study with Minimal Residual Disease (MRD) Driven Adaptive Strategy in Treatment for Newly Diagnosed Multiple Myeloma with Upfront Daratumumab-Based Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3191-3191
Author(s):  
J Christine Ye ◽  
Philip S Boonstra ◽  
Daniel F. Boyer ◽  
Larry D. Anderson ◽  
Brea C. Lipe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Residual Disease ◽  
Adaptive Strategy ◽  
Response Criteria ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Trial ◽  
Patient Will ◽  
Minimal Residual

Background: Minimal Residual Disease (MRD) was clearly demonstrated as a prognostic marker for prognosis in multiple myeloma and has been integrated into IMWG clinical guidelines as one of the response criteria. There is however no consensus yet when and how to use MRD data in clinical practice throughout treatment course. Daratumumab was approved by FDA in different settings after it had been shown as a highly effective agent with a reasonable safety profile in myeloma treatment. It also showed impressive data to achieve MRD negativity. We plan to use the combination of daratumumab, lenalidomide, and dexamethasone upfront, with the addition of Velcade for consolidation if needed, in newly diagnosed multiple myeloma (NDMM) patients. We propose to use an MRD driven adaptive strategy for decision making in myeloma treatment and use daratumumab-based frontline therapy. Trial Design and Methods: We designed this prospective, single-arm, multi-center, phase 2 trial. The primary objective is to determine the rate of MRD negativity after daratumumab-based induction and consolidation therapy if necessary in both transplant eligible and ineligible NDMM patients. The secondary objective is to describe the overall survival, progression free survival, MRD conversion rate after consolidation, quality of life for patients, safety and tolerability of daratumumab-based combination regimens in both transplant eligible and ineligible patient populations, estimation of a successful stem cell mobilization after receiving daratumumab-based induction therapy. The primary endpoint will be MRD-negativity after six cycles of induction, followed by three cycles of consolidation therapy if MRD is positive after induction. We will seek to establish evidence that the true proportion of patients who can achieve MRD negativity after induction + consolidation (if still MRD+ after induction) is high, which we define as any response rate that is at least 23%. Patients with NDMM meeting IMWG diagnostic criteria are eligible for this trial, regardless of transplant candidacy. Patient will have stem cell collection after induction therapy. We will follow the patients' treatment response using IMWG response criteria including MRD status through induction, consolidation, transplant (if applied) and maintenance. Patient will come off the study if disease progression per IMWG response criteria. We plan for MRD testing by next generation sequencing and flow cytometry. This study will enroll 50 eligible patients. A two-stage design will be conducted, with an interim futility analysis after the primary endpoint is available on the first 20 enrolled patients. We will proceed to a final analysis with all 50 patients if at least 2/20 (10%) of patients achieve MRD negativity after consolidation. This trial is anticipated to be open at four academic centers. Conclusion: This multicenter phase 2 trial will apply a novel clinical trial design with an adaptive strategy to treat newly diagnosed myeloma patients based on MRD results. Therapeutic advance with Daratumumab-based combination regimen as frontline therapy may help myeloma patients to achieve higher rate of MRD negativity. Figure Disclosures Ye: AbbVie: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; MingSight: Research Funding; Portola Pharmaceuticals: Research Funding. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Lipe:amgen: Research Funding; amgen: Consultancy; Celgene: Consultancy. Talpaz:Samus Therapeutics: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

scholarly journals Phase 2 Trial of Daratumumab, Ixazomib, Lenalidomide and Modified Dose Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 864-864 ◽  
Author(s):  
Prashant Kapoor ◽  
Morie A. Gertz ◽  
Betsy Laplant ◽  
Gabriella C Malave ◽  
Eric Wolfe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Increased Risk

Background: The current commonly used regimens in newly diagnosed multiple myeloma (NDMM) utilize steroids (dexamethasone or prednisone) in various combinations: bortezomib, lenalidomide and dexamethasone (VRd), bortezomib, thalidomide and dexamethasone (VTd), daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib, melphalan and prednisone (DVMP). However, steroid therapy may be associated with various adverse effects, including, but not limited to mood changes, insomnia, hypertension, hyperglycemia, osteoporosis, adrenal suppression, muscle weakness, and increased risk of opportunistic infections. A recent trial demonstrated improved tolerability of a regimen (Rd-R) involving an abbreviated course of dexamethasone, without compromising the efficacy in patients with intermediate-fit NDMM (Lorocca A., et al., ASH 2018). We designed a phase 2 clinical trial to examine the safety and efficacy of daratumumab, an anti-CD38 monoclonal antibody in combination with an all-oral regimen of ixazomib, a proteasome inhibitor, lenalidomide, an immunomodulatory drug, and modified dose dexamethasone (IRd). Patients and Methods: NDMM patients with measurable disease and adequate organ function were enrolled, irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response (CR) to daratumumab-IRd. Treatment consisted of daratumumab, 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks, ixazomib, 4 mg days 1, 8, 15, lenalidomide, 25 mg days 1-21, and dexamethasone upto 40 mg intravenously weekly for no more than two cycles, followed by use only as a prophylactic premedication for daratumumab-associated infusion reactions. Myeloma risk stratification was assessed by cytoplasmic immunoglobulin fluorescence in-situ hybridization (cIg FISH) analysis. Results: Overall, 40 patients were accrued, with data available on all patients for analysis at the cutoff date of July 19, 2019. The median age at enrollment was 64.5 (33-81) years; 37.5% were female. Eight (20%) patients were high risk by FISH. The median number of cycles was 6 (2-11) and the median follow up was 6.1 (2-11.7) months. Among 40 patients who had received at least 2 cycles of therapy, responses were attained rapidly; at the end of cycle 2, 88% patients achieved at least a partial response and 33% at least a very good partial response (VGPR) that improved to 52% at the end of 4 cycles among 29 patients who had completed at least 4 cycles. The overall best confirmed response rate among all 40 patients (Figure 1) was 95%, including 10% stringent CR, 5% CR and 23% near CR (13% VGPR excluding nCR). Stem cell collection was completed in 17 patients so far, all of whom required filgrastim and plerixafor. The median CD34+ cell count was 7.7 (range 2.9-11.6) million/kg . All patients were alive and 39 (97.5%) patients were progression-free at last follow up. Four (10%) patients proceeded to autologous stem cell transplantation off study, per patient and/or investigator discretion (1 in CR, 2 in PR, 1 with progressive disease). Overall, 224 cycles have been administered across the study, with dose reduction/ hold required in a subset of patients; ixazomib (10%), lenalidomide (20%), daratumumab (0%) and dexamethasone (13%); the most frequent reasons for dose adjustment were skin rash and hematologic toxicities. A grade 3 or higher adverse event, at least possibly attributed to the study drugs, was observed in 40% of patients; hematologic in 30% (lymphopenia 25%, neutropenia 15%, thrombocytopenia 5% and anemia 2.5%) and non-hematologic in 18% of patients (hyperglycemia 8%, diarrhea 5%, infections 5%, ileus 2.5%, maculopapular rash 2.5%, and fatigue 2.5%). Updated results with additional 6 months of follow up and minimal residual disease assessment related data will be presented at the meeting. Conclusion: Our early results suggest that the combination of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone is well-tolerated, with excellent activity, and does not adversely impact stem-cell mobilization in patients with NDMM. Disclosures Kapoor: Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Daratumumab in combination with Ixazomib, lenalidomide and dexamethasone for the management of newly diagnosed multiple myeloma

The Combination of the Proteasome Inhibitor Bortezomib with Doxorubicin and Dexamethasone (PAD Regimen) as Front-Line Therapy In Newly Diagnosed, High-Risk Multiple Myeloma: Results of a Phase II Prospective Multicenter Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3052-3052 ◽  
Author(s):  
Ioannis Baltathakis ◽  
Evangelos Terpos ◽  
Sosana Delimpasi ◽  
Konstantinos Liapis ◽  
Fotios Panitsas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Front Line ◽  
Grade 3 ◽  
Cell Harvest

Abstract Abstract 3052 The combination of bortezomib, doxorubicin, and dexamethasone (PAD) has shown efficacy in both relapsed/refractory and untreated, symptomatic multiple myeloma (MM). The activity of this regimen is largely attributed to the recognized synergy between bortezomib and doxorubicin. Bortezomib is capable of reversing resistance to chemotherapy in MM with adverse prognostic features (high-risk myeloma), which has an unfavorable outcome with conventional chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT). In addition, disease status prior to ASCT has prognostic significance for survival, underscoring the need for highly efficient remission induction strategies. In a prospectively designed phase II trial, we focused on the efficacy and safety of the PAD combination as front-line treatment for high-risk myeloma. The study recruited patients aged ≤70 years with newly diagnosed, symptomatic MM with high-risk features (defined by at least one of the following criteria: ISS stage II/III according to serum albumin and beta2-microglobulin, and/or detection of 13q deletion by FISH or conventional karyotyping). Between 2005 and 2008, 40 patients were enrolled in the protocol. The median age of patients was 59 years (range: 41–70 years), and 27 (67.5%) were male. Each 21-day cycle of PAD included bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m2 on days 1–4, and dexamethasone 40 mg on days 1–4 and 8–11. According to protocol, patients received 4 induction cycles of PAD before proceeding to stem cell harvest and ASCT. Acyclovir and ciprofloxacin prophylaxis were routinely used. Patients were evaluated for toxicity at each cycle and for response after the end of the fourth cycle. The primary study endpoint was the response rate at the end of induction (assessed by the International Myeloma Working Group uniform response criteria, 2006). Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), ability to mobilize stem cells, and response after ASCT. ISS stage was I in 2 patients (5%), II in 18 (45%), and III in 20 (50%). Nine out of 40 patients (22.5%) presented with renal failure (creatinine >2mg/dl) due to myeloma at diagnosis. Deletion 13q was detected in 19 patients. Bone disease was present in 30 patients (75%) at diagnosis, and 19 (47.5%) had ≥3 lytic lesions on plain skeleton radiograms. Median patient follow-up time was 28.3 months (range, 1.4–49.3). All patients completed the 4 cycles of PAD, with the exception of one who died during the 2nd cycle. The overall response rate assessed after the 4th cycle of PAD was 95%. Complete remission (CR) was achieved in 12/39 (31%), very good partial remission (VGPR) in 15/39 (38.5%), and PR in 10/39 (25.5%). Thirty-one patients were considered eligible for ASCT, and an adequate stem cell harvest was achieved in all. Following ASCT, CR rate reached 52% (16/31) with a CR+VGPR rate of 84% (26/31). PFS was 67% at 2.1 years, and calculated OS was 81.4% at 4 years (Figures 1 and 2). Factors associated with shorter OS were beta2-microglobulin ≥5.5 mg/L (p=0.03), and ISS stage III (p=0.03). By assessment of the glomerular filtration rate (GFR), a significant improvement in renal function was demonstrated after induction with PAD (median GFR pre- and post-induction: 59.7 versus 82.1 ml/min, respectively; p<0.001). Improvement in kidney function was observed irrespective of the type of response. There was only one treatment-related death secondary to infection. Toxicities were manageable in general, and included grade 3–4 neutropenia in 8/40 patients (20%), grade 3–4 thrombocytopenia in 4/40 (10%), and grade 3 peripheral neuropathy in 4/40 (10%). No grade 4 peripheral neuropathy was encountered. We conclude that the PAD regimen is very effective, and produces high-quality responses in a substantial proportion of patients with newly diagnosed, high-risk MM (CR+VGPR: 69.5%). PAD is well tolerated and does not compromise stem cell mobilization and harvest. Upfront treatment with 4 cycles of PAD followed by ASCT resulted in notable PFS and OS rates in this patient group with adverse-prognosis MM. PAD was shown to be particularly beneficial in patients with renal impairment at diagnosis due to myeloma. Disclosures: Baltathakis: Janssen-Cilag: Research Funding. Terpos:Janssen-Cilag: Honoraria. Delimpasi:Janssen-Cilag: Research Funding. Dimopoulos:Janssen-Cilag: Honoraria. Harhalakis:Janssen-Cilag: Research Funding.

scholarly journals Survival Trends over 18 Years of Patients with Multiple Myeloma Harboring Del(17p) and/or t(4;14): A Retrospective Real-World Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-17
Author(s):  
Thomas Chalopin ◽  
Nicolas Vallet ◽  
Marlene Ochmann ◽  
Mourad Tiab ◽  
Pascal Godmer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Monoclonal Antibodies ◽  
Stem Cell ◽  
In Situ Hybridization ◽  
Research Funding ◽  
Newly Diagnosed ◽  
New Agents ◽  
The Past

Introduction . In multiple myeloma (MM), the presence of translocation t(4;14) and/or 17p deletion, found in around 10 to 15% of the patients, is considered as high-risk feature associated with adverse survival. Despite recent advances in the treatment of MM, t(4;14) and del(17p) are still associated with poor outcome. The aim of this study was to analyze the trends of survival in patients with newly diagnosed MM harboring t(4;14) and or 17p deletion over the past two decades. Methods . Patients from five French centers with newly-diagnosed MM from 2001 to 2019 and displaying del(17p) and/or t(4;14) were retrospectively included. Cytogenetics abnormalities were detected by interphase fluorescence in situ hybridization (FISH) and del(17p) positivity cut-off was 30%. New agents were defined as: pomalidomide, carfilzomib, ixazomib and anti-CD38 monoclonal antibodies. Results . 246 patients carrying either t(4;14) (n=106 patients), del(17p) (n=121 patients) or both (n=19 patients) were included. Median age was 64 years (range, 35-91). ISS and R-ISS score were 3 in 88 patients (36%). Eighty-seven patients (35%) were diagnosed in 2001-2010 period, and 159 (65%) in 2011-2019 period. Front-line autologous stem-cell transplantation (ASCT) was performed in 121 (49%) patients. Among transplant eligible patients, 112 patients (n=93%) received triplet induction, 78 patients (64%) a consolidation regimen and 15 patients (12%) a maintenance therapy. Double-ASCT was decided in 21 patients (17%). Among transplant ineligible patients, 61 patients (49%) received melphalan-based regimen in first line, 36 (29%) a bortezomib-based and 15 patients (14%) a lenalidomide-based regimen. At any line, 92 patients (37%) received at least one of the new agents with only 12 patients (5%) in frontline therapy. Median follow-up was 41 months (IQR: 21-69). Median overall survival (OS) was 58.4 months (IQR: 50.1-66.5) for the entire cohort, 55.5 months (IQR: 46.6-78.3) for del(17p), 62.5 months (IQR: 54.2-76.1) for t(4;14) and 48.6 months (18.1-not reached) for patients with both (p=0.2). Median of first progression-free survival (PFS1) was 25.6 months (IQR: 22.2-29.8), with no difference between del(17p), t(4;14) or both (p=0.57). Importantly, no improvement of median OS was observed in patients diagnosed between 2001-2010 in comparison with patients diagnosed between 2011-2019 (63.7 versus 53.2 months, p=0.32). In univariate and multivariate analysis: age (continuous and cut-off 71 years-old) and ASCT significantly were associated with risk of death (HR: 1.03, 1.09 and 0.45, respectively). Median OS of patients eligible to ASCT was 76.1 months (IQR: 62.5-90.3) vs 42.5 months (IQR: 36.8-54.6) for patients not eligible (HR 0.45, 95%CI 0.28-0.0.71; p&lt;0.001). Double-ASCT did not improve significantly OS (75 vs 81.1 months ; p=0.41) and PFS1 (31.6 vs 47.8, p=0.30) compared with single-ASCT. Conclusion . This large multicenter real-world study confirms that patients with newly diagnosed MM carrying del(17p) and/or t(4;14) remain a therapeutic challenge with no significant overall survival improvement in the past decades despite the use of novel agents. The definition of high-risk MM patients is evolving with incorporation of new markers (i.e chromosome 1 abnormalities, PET-imaging). Minimal-residual disease achievement will also re-defined risk stratification. Nonetheless, the need for innovative approaches such as earlier strategies using new agents or immunotherapy (CAR-T cells, bispecific T-cell engager antibodies) may significantly improve outcomes. Figure captions Table 1. Clinical, biological characteristics, treatment and survival of the 246 included patients based on period of diagnosis. IQR: interquartile range; FISH: fluorescence in situ hybridization; ISS: international score system; LDH: lactate dehydrogenase; ASCT: autologous stem cell transplantation; len: lenalidomide; Poma: pomalidomide; Carfil: carfilzomib; Ixa: ixazomib; mAb: monoclonal antibodies; OS: overall survival Figure 1. Kaplan-Meier curves for overall survival for the 246 included patients based on period of diagnosis. Figure 1 Disclosures Moreau: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding.

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.

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