Successful Management of Transplant-Ineligible Patients with Refractory/Relapsed Multiple Myeloma By Using a Biweekly or Longer Modified Bortezomib Schedule As Interval Maintenance therapy

Abstract Background: Substantial efficacy has been demonstrated with bortezomib (Bor)-containing regimens for the treatment of refractory/relapsed (RR) patients with transplant-ineligible (TI) multiple myeloma (MM). However, the dosing schedules for induction therapy and the significance of maintenance therapy using Bor in clinical settings have yet to be standardized. Discontinuations and dose reduction of Bor owing to severe adverse events (AEs) such as peripheral neuropathy (PN) and infection are frequent causes of adjustments to the standard 9 cycles of Bor/dexamethasone (BD) therapy used for induction in clinical practice. We have previously demonstrated that a change in Bor administration to a schedule of weekly or longer intervals had similar or greater efficacy for patients with RR-MM including transplant-eligible (Tokuhira M, et al. Leuk Res. 35:591-7, 2011). To investigate the efficacy of this modified Bor dosing schedule in the treatment focusing of TI-RR-MM, we retrospectively analyzed 22 patients receiving weekly-BD induction followed by a modified schedule of biweekly or longer intervals using Bor as maintenance therapy in a single institution. Methods: Data on the 22 TI-RR-MM patients treated with BD therapy in our institution were retrospectively analyzed. The induction therapy consisted of intravenous injections of Bor (1.3 mg/m2) on days 1, 8, 15, and 22 in combination with dexamethasone (10–20 mg) on days 1 and 2 after Bor infusion, every 5 weeks. After BD induction, Bor maintenance was initiated with a schedule of biweekly or longer intervals. The dose of BD could be reduced based on AEs or other social aspects at the discretion of the treating physician. Overall survival (OS) was defined as the period between BD initiation of treatment to the last follow-up. Results: The median age of patients at the time of BD induction was 72.6 years (range, 49–84 years), and the subtypes of MM were the IgG type in 14 patients, IgA type in 6 patients, and BJP in 2 patients. Twelve patients were men and 10 were women. On the basis of the International Staging System classification, the clinical stage was I in 3 patients, II in 16 patients, and III in 3 patients. The median number of prior treatment regimens was 2.0 (range, 1–6). The median follow-up duration was 4.3 years (inter-quartile range, 3.0–7.8 years). Ten patients were alive, and 12 patients had died at the time of reporting. The median duration from the start of the first line treatment to BD initiation was 1.8 years (range, 0.1–14.8 years). The median number of BD induction cycles was 2.0 (range, 1–6), and 8 patients (36%) achieved a partial response (PR), although the other 14 patients (64%) showed stable disease or only a minimal response. Although AEs such as PN and gastrointestinal tract symptoms developed in 10 of 22 patients during BD induction, all 22 patients could move on to the maintenance phase. The median duration of Bor maintenance was 14.5 months (range, 1.8–76.5 months). Three patients were still receiving maintenance therapy at the time of reporting. Six patients (27.2%) received maintenance therapy for over 2 years, and 3 (13.6%) received it for over 4 years. The median OS was 3.6 years (range, 0.4–6.5 years), and the duration of Bor therapy from induction to the last administration was 2.5 years. The median progression free survival was 1.6 years (range, 0.3–6.5 years). During maintenance therapy, 5 patients achieved a PR. The reasons for cessation of Bor maintenance therapy were AEs in 8 patients and progressive disease in 11 patients. No patient died during Bor administration in this study. Discussion: We retrospectively analyzed 22 TI-RR-MM patients receiving modified BD therapy. Pantani L et al. reported the results of using BD therapy for 85 RR-MM patients, and demonstrated that twice-weekly Bor administration resulted in a clinical response rate of 19% and a median OS of 22 months (Ann Hematol, 2014). Although the clinical response rate in our study was inferior to that of Pantani L et al., the median OS in our study was superior (3.6 years) than those of previous reports. Because the majority of patients in this study were frail or elderly, the early decision to change to maintenance therapy before they developed severe AEs resulted in a good clinical outcome and a longer OS. Continuing BD therapy without a satisfactory molecular response might be an attractive therapeutic approach for TI-RR-MM patients. Disclosures No relevant conflicts of interest to declare.

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Carfilzomib-Pomalidomide-Dexamethasone (KPD) in Relapsed/Refractory Multiple Myeloma Patients - an Institutional Retrospective Analysis

Blood ◽

10.1182/blood-2019-131674 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5572-5572

Author(s):

Pallavi Mehta ◽

Neha Yadav ◽

Mohan Bhaarat ◽

Sumeet Prakash Mirgh ◽

Vishvdeep Khushoo ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Progressive Disease ◽

Conflicts Of Interest ◽

Haematological Toxicity ◽

Response Assessment ◽

Median Number ◽

Entire Cohort ◽

Response Status

Introduction Multiple myeloma has relished the emergence of various novel agents in last few decades. Unfortunately,relapses are still an inevitable part and at each relapse, treatment choice becomes a complex decision making process as these patients usually have exhausted conventional therapeutic regimens.Carfilzomib is a second-in class Proteosome Inhibitor (PI) and has been approved for patientsrefractory to minimum 2 lines of prior therapies. We are, hereby, presenting our initial experience with this novel combination (KPD)in RRMM patients at our centre. Methodology Retrospective study of RRMM patients who received KPD therapy from August 2017 till October 2018. Responses were assessed as per International Myeloma Working Group. Study was approved by Institutional Review Board. Results Total 39 patients were treated with KPD regimen during study period. Median age was 56 (32-74 years) with male ratio of 51.2% (n=20). At baseline presentation, bone disease {n=32 (82%)} was the most common presenting complaint followed by anemia {n=21 (53.8%)} and renal failure {n=16 (41%)}. Most common ISS staging was ISS-3 {n=18(46.1%)} and subtype was Light chain myeloma {n=15 (38.3%)} followed by IgG {n=13 (33.3%)}.Fluorescence In Situ Hybridization (FISH) was available in {n= 10 (25%)} and it was positive for del13q (n=1/10) and del17p (n=1/10) and t(11;14) (n=1/10). (Table-1) Median number of prior lines of chemotherapy was 3(1-15). Thirty-six (91%) patients were relapsed/refractory to both bortezomib and lenalidomide whereas n=3(9%) were relapsed/refractory to bortezomib only. Eleven (30.5%) patients underwent SCT pre KPD therapy including 2/11 patients received double SCT. Pre KPD 25 (64.1%) patients had progressive disease (PD), 10 (25%) had relapse and 4 (11.1%) patients had stable disease (SD). Median number of KPD cycles were 3(1-8). Median number of KPD cycles after which response assessment was donewas 3 (2-8). Median time to treatment response was 3 (2-7) months. ORR was 51.2% {CR-n=5 (12.8%); VGPR-n=5 (12.8%), PR-n=10 (25.6%)} whereas 2 (5.1%) patient had SD and 10 (25.6%) patients had PD at 2-8 cycles. Two (5.1%) patients are yet to be assessed. (Table-1) Common hematological toxicities seen were anemia (n=8), thrombocytopenia (n=13){grade-3/4=30.7%; n=4/13} and neutropenia(n=14){grade3/4=21.4%; n=3/14}.Non haematological toxicity such as cardiac toxicity was not observed in our patients. Pre KPD 2D-ECHO was available for 13 patients and which was normal in all patients. Post 2-4 cycles of KPD, 2D-ECHO was available for 7 patients and all patients had normal ECHO. Carfilzomib induced hypertension was seen in 20 patientsand could be well controlled with antihypertensives. Peripheral neuropathy (grade1/2) was seen in 10 patients. We also observedCarfilzomib induced hyponatremia in one patient.Febrile neutropenia(bacterial =6, viral=4, possible fungal=5) was seen in 14 patients.(Table-2) Twelve (20.5%) patients proceeded to either maintenance therapy or autologous stem cell transplantation (ASCT). Eight patients opted only for maintenance (carfilzomib=5, pomalidomide-dexamethasone=2 and pomalidomide =1). Remaining n=4/12(16%) patients received SCT. Pre SCT response status was VGPR n=2; PR n=1 and SD=1. Post SCT response status was VGPR (n=3) &PR (n=1). Post SCT, 3 patients were started on maintenance therapy as Bortezomib/pomalidomide=1, Pomalidomide/dexamethasone=2. One patient has been continued on KPD as a consolidation therapy. At a median follow-up of 10 months (1-14 months), relapse rate was 12.8% (n=5). Ten (25.6%) patients had PD.Mortality rate was 8.3% (n=3), commonest cause being progressive disease. The estimated mean PFS, OS and EFS of entire cohort was 11.9 months (95% C.I. 10.8- 13 months) (figure-1 a), 13 months (95% C.I. 11.9-14 months) (figure-1 b) and 7.9 months (95% C.I. 6.5-9.3 months) (figure - 1 c) respectively. Conclusion KPD is a well-tolerated regimen for patients with RRMM who have exhausted frontline myeloma regimen, however at the cost of significant side effects like infections and hypertension. It seems to be a convincing regimen as a bridge to ASCT but warrants further studies with longer follow-up to validate our results. Disclosures No relevant conflicts of interest to declare.

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Maintenance Rituximab in Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) in the First Line Setting or at Relapse

Blood ◽

10.1182/blood-2019-125980 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5291-5291

Author(s):

Dahlia Sano ◽

Paolo Strati ◽

Pedro Alcedo ◽

V Ahalya Rao ◽

Prachee Singh ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Median Duration ◽

Induction Therapy ◽

Systemic Therapy ◽

Clinical Benefit ◽

Research Funding ◽

Median Number ◽

Second Line ◽

Line Therapy

Introduction: Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a CD20 positive subtype of Hodgkin lymphoma and can frequently present an indolent behavior. Indeed, NLPHL patients relapse more commonly than patients with classic Hodgkin Lymphoma, but relapses can usually be responsive to lower intensity therapy such as rituximab. The choice of frontline and relapse therapies depends on different factors, including staging and burden of disease, thus therapy can range from observation, to radiotherapy (XRT) alone, to systemic therapy such as R-CHOP, R-ABVD or single agent Rituximab (R) or to combined modality (systemic therapy and XRT). However, it is unclear whether maintenance rituximab (MR) would be of clinical benefit if administered after induction therapy. Methods: We retrospectively reviewed the characteristics and outcomes of 17 consecutive patients treated at our center between 12/1972 and 7/2019, with proven diagnosis of NLPHL and who received MR after having achieved complete response (CR) or partial response (PR) after any line of therapy. MR consisted of rituximab 375 mg/m2 once every 2 or 3 months for 2 years or rituximab 375 mg/m2 weekly 4 times every 6 months for 2 years, for a total maximum of 12 doses over 2 years. Progression free survival (PFS) time was calculated from start date of MR to progression date, transformation date or death date, whichever happened first. Patient with no progression, transformation or death were censored at the last follow-up date. Results: At time of initial diagnosis, median age was 37 (range, 15-50 years), 13 patients (76.5%) were male, and 4 patients (24%) had Ann Arbor stage III-IV disease. At completion of the line of induction therapy followed by MR, 75.0% of patients presented CR and 25% presented PR. However 18.7% of patients were restaged with computer tomography (CT) and 81.3% with Positron emission tomography-computed tomography (PET/CT), making the treatment response evaluation uneven. Nine patients received MR after frontline therapy, including R-CHOP in 5 patients (55.6%), rituximab monotherapy in 2 patients (22.2%), R-CVP in 1 patient (11.1%) and rituximab induction with XRT in 1 patient (11.1%). The median number of rituximab maintenance doses was 8 (range 3-12) and the median duration of MR was over 25 months (range 10-32 months). Among these patients, only one (11.1%), treated with frontline R-CHOP, progressed 97.6 months after initiation of MR. No salvage treatment was needed at time of progression, and this patient was still alive at last follow-up, 7 months after progression. No transformation and no death occurred in this patient cohort. Seven patients received MR after second line therapy, including induction R and MR (R+MR) in 5 patients (71.4%), R-CHOP in 1 patient (14.3%) and R with lenalidomide in 1 patient (14.3%). The median number of rituximab maintenance doses was 10 (range 6-12) and the median duration of MR was over 18 months (range 14-20 months). Among these patients who received MR after second line, 1 patient (14.3%) presented with transformation into diffuse large B-cell lymphoma, 7 years after start of MR. This patient received R-EPOCH chemotherapy and frontline autologous stem cell transplant (ASCT) and died of ASCT related infection 1 month after ASCT. One patient received third line R+MR with 12 doses of MR and was in complete remission at last follow-up, 93 months after start of 3rd line therapy. Globally, after a median follow-up from start of any line of MR of 54 months (range: 15-119 months), 1 patient (5.9%) progressed and did not require salvage therapy and 1 patient (5.9%) presented a transformation and died of ASCT-related infection; 5-year PFS and 5-year OS were100% (median PFS and OS were not reached). Conclusions: Patients with NLPHL receiving MR, either after frontline or subsequent lines of therapy, rarely experience relapse and have a very favorable prognosis. However, larger randomized prospective trials are essential to confirm the eventual clinical benefit of maintenance rituximab. Figure Disclosures Pinnix: Merck: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding.

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Supermobilizers with High CD34 + Cell Collection for Autologous Transplant and Impact on Survival Outcomes in Multiple Myeloma

Blood ◽

10.1182/blood-2021-151862 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1837-1837

Author(s):

Eyal Lebel ◽

Katherine Lajkosz ◽

Esther Masih-Khan ◽

Donna E. Reece ◽

Suzanne Trudel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Survival Outcomes ◽

Advisory Committees ◽

Cd34 Cells

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for selected patients with newly diagnosed multiple myeloma (MM). Studies in MM and lymphoma have suggested that ability to mobilize and collect a higher yield of CD34 + cells predicts for improved survival outcomes, perhaps reflecting better bone marrow reserve (Bolwell 2007, Raschle 2011). We aimed to validate this hypothesis by correlating high CD34 + cell collection ("supermobilizers") and survival outcomes in a large myeloma cohort with long follow-up. Methods: We retrospectively reviewed MM patients (pts) who underwent ASCT at our centre 2000-2010, correlating number of CD34 + cells collected with post-transplant progression-free survival (PFS) and overall survival (OS). Stem cells were mobilized using cyclophosphamide 2.5 g/m 2 IV (day 1), G-CSF 10 ug/kg/day SC (starting on day 4), and leukapheresis (day 11), targeting 4x10 6/kg but accepting a minimum of 2x10 6/kg to support a single transplant. Using a cut-off used in previous studies, pts were categorized as "supermobilizers" if ≥8x10 6/kg CD34+ cells were collected. Results: 621 pts were analyzed. Most pts (422/605; 70%) received high dose dexamethasone (HDD) alone or in combination with vincristine and adriamycin (VAD) for pre-transplant induction therapy (pre-dating the novel agent era) with only 18% (110/605) receiving more contemporary bortezomib-based induction (mostly cyclophosphamide, bortezomib and dexamethasone; CyBORD). The median number of CD34 + cells collected for all pts was 13.9x10 6/kg (range 2.1-61.8). The median CD34 + cells re-infused was 6.2x10 6/kg (range 2.1-25), as some cells were reserved for 2 nd ASCT, but median CD34+ cells collected correlated with CD34 + cells infused (Pearson coefficient 0.81, p<0.001). At a median follow-up of 74 months (m), we were surprised to report an inferior PFS of 24.1m for the supermobilizers collecting ≥8x10 6/kg vs 33.7m for the <8 group (p=0.038, Figure 1a), without differences in OS (p=0.612, Figure 1b). No further discrimination in PFS was observed when using a more extreme supermobilizer cut-off of 15x10 6/kg. To further understand the counterintuitive result of shorter PFS with higher mobilization capacity, we explored the continuous relationship between CD34 + cells and PFS, identifying another optimal cut-off of 4.5x10 6/kg. Pts collecting in the mid-range (4.5-8; n=129) achieved the best PFS of 34.5m, significantly improved over 24.1m in the ≥8 group (n=478) and 11.4m in the small group at the extreme lower collection range (n=14; ≤4.5x10 6/kg)(Figure 1c). A similar pattern was seen with OS (Figure 1d). Clinical and laboratory parameters that may impact both collection capacity and survival, such as age, ISS, and kidney dysfunction, were investigated as confounders but were similar between collection groups and did not predict for PFS in multivariable analyses. Treatment variables, however, differed between groups: the lower collection groups more often received bortezomib-based induction (29%, 31% and 14% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p<0.001) resulting in deeper responses pre-transplant (VGPR 50% in the ≥8 group vs 43% in the 4.5-8 group, p=0.024) (Table 1). Use of maintenance therapy post-ASCT also differed (50%, 40% and 28% in the ≤4.5, 4.5-8 and ≥8 groups, respectively, p=0.006). Discussion: In this large cohort of 621 MM patients, we report that "supermobilizers" who collected ≥8 x 10 6 CD34 + cells/kg exhibit inferior PFS from transplant than those with less robust mobilization. We suspected that this unexpected observation was due to confounding variables, and identified differences in treatment, primarily greater use of bortezomib-based induction and post-transplant maintenance therapy in the lower collection group. This group was able to achieve deeper responses (≥VGPR) even before transplant than the supermobilizer group, leading to improved PFS. Although bortezomib is routinely used as induction therapy pre-transplant currently and is not felt to be stem cell toxic, it may impair mobilization to a lesser degree, leading not to abject failure of collection but lowered capacity to achieve "supermobilizer" status. Although more research is needed to validate this hypothesis, we can at minimum conclude that high stem cell collection does not appear to predict for a long-term survival advantage. Figure 1 Figure 1. Disclosures Reece: Millennium: Research Funding; Sanofi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; BMS: Honoraria, Research Funding. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Chen: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

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The Prognostic Significance of the Stage of Reaching MRD-Negative for Patients with Multiple Myeloma Received ASCT

Blood ◽

10.1182/blood-2021-145017 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3945-3945

Author(s):

Qian Sun ◽

Juan Li

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Induction Therapy ◽

Median Overall Survival ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Hematopoietic Stem ◽

Three Stages ◽

Standard Risk

Abstract Objective: To explore the prognostic significance of the stage of reaching MRD-negative for patients with newly diagnosed multiple myeloma (NDMM) patients who received autologous hematopoietic stem cell transplantation (ASCT). Methods: A retrospective analysis of 186 NDMM patients who received "induction therapy-ASCT-maintenance therapy" in our center and reached MRD-negative, according to the stage when the patient's MRD status turned negative (induction therapy, 3 months after ASCT, maintenance therapy) is divided into three stages, A, B, and C (Figure 1). We compared the clinical characteristics and prognosis of patients in the three stages. Results: The median time to progress (TTP) of 186 patients was not reached, the median overall survival (OS) was 113.8 months, and the median follow-up time was 67.6 months; the number of cases in the three stages of A, B, and C was 73 (39.2%), 42 (22.6%), and 71 (38.2%), respectively (Figure 2). The median TTP of the patients in the three stages was not reached (P=0.013), and the median OS was not reached, not reached, and 71.2 months, respectively (P=0.026). Among the 124 standard-risk cytogenetics patients, the median TTP of the three stages of patients was not reached (P=0.121), and the median OS was not reached, not reached, and 99.6 months, respectively (P=0.091) (Figure 3). Among the 38 high-risk cytogenetics patients, the median TTP of patients in the three stages were unreached, 53.9 months, and 35.8 months (P=0.060), and the median OS was not reached, 71.2 months, and 60.2 months (P=0.625) (Figure 4). Among the 157 R-ISS Ⅰ-Ⅱ patients, the median TTP of the three stages was not reached (P=0.174), and the median OS was not reached, not reached, and 99.6 months (P=0.186) (Figure 5). Among 29 cases of R-ISS Ⅲ, the median TTP of the 3 stage patients was unreached, unreached, and 35.1 months (P<0.001), and the median OS was unreached, unreached, and 48.5 months, respectively (P=0.020) (Figure 6). Conclusion: For the same patients with MRD negative, the prognosis of patients reaching MRD-negative at different stages is different. The stage of reaching MRD-negative can predict the prognosis of patients with R-ISS stage Ⅲ, but cannot predict the prognosis of patients with R-ISS Ⅰ-Ⅱ. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A Phase II Study of Bortezomib (Velcade ®), Cyclophosphamide (Cytoxan®), Thalidomide (Thalomid®) and Dexamethasone as First-Line Therapy for Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.94.94 ◽

2008 ◽

Vol 112 (11) ◽

pp. 94-94 ◽

Cited By ~ 6

Author(s):

William Bensinger ◽

Sundar Jagannath ◽

Robert Vescio ◽

Elber S. Camacho ◽

Jeffrey Lee Wolf ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Phase Ii ◽

Induction Therapy ◽

Response Rate ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Cell Harvest

Abstract Background: This phase II trial evaluated the response rate of sequential bortezomib (VELCADE®), cyclophosphamide (Cytoxan®), and dexamethasone ([VCD]; 3 cycles) followed by bortezomib, thalidomide (Thalomid®), and dexamethasone ([VTD]; 3 cycles) as first-line therapy for patients with multiple myeloma. The primary endpoints were overall response, achievement of „d very good partial response (VGPR), as well as assessment of safety and tolerability. Methods: Patients with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of bortezomib 1.3mg/m2 days 1, 4, 8, and 11, cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg p.o. or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of bortezomib 1.0mg/m2 days 1, 4, 8, and 11; thalidomide 100 mg p.o. daily and dexamethasone same as cycles 1–3. Patients received thrombosis prophylaxis with ASA 325mg daily during cycles 4–6. Upon completion of the 6 cycles, patients proceeded to autologous stem cell harvest, transplant and/or maintenance therapy. Responses were defined as a decrease in serum and/or urine monoclonal (M) protein by 50% or greater. VGPR and other responses were as per the International Response Criteria. Results: This report provides results for all 44 eligible patients: median age 59 years; 68% male; 61% Stage III (D/S); documented ISS Stage II/III 59%; IgG 66%, IgA 17%; 17% light chain only. To date the first 30 patients are fully evaluable for response with 28-day post therapy follow up. The overall response rate (ORR; ≥PR) is 90% with 18/30 (60%) achieving CR + VGPR (CR 33%); 9/30 (30%) PR and 3/30 (10%) stable disease or not evaluable. Overall, both components of the sequential regimen were very well tolerated. One patient had a ruptured colonic diverticulum possibly related to dexamethasone, but recovered well and achieved VGPR on trial. There have been 49 therapy attributed toxicity events which have required drug/schedule adjustments. Of these, 9 events were Gd 3/4: 3 attributed to cyclophosphamide, 3 to dexamethasone, 2 attributed to bortezomib and 1 to thalidomide. DVT occurred in one patient who was at high risk because of prior bilateral hip surgery. Fourteen patients have proceeded to successful stem cell harvest and autologous transplant. Post transplant follow up as well as response information for all 44 patients will be presented. Conclusion: This bortezomib/cyclophosphamide/dexamethasone (VCD) based combination induction therapy followed by VTD is a promising addition to the treatment armamentarium for previously untreated patients. The response rates: ORR 90%; □ VGPR (60%) and CR (33%) are extremely encouraging and improve over our bortezomib/dexamethasone 2-drug experience which produced 90% □ PR and 38% □ VGPR. This very well tolerated new regimen is potentially an important step forward in induction therapy with presentation of more mature data. Supported by the Aptium Oncology Research Network and a research grant from Millennium Pharmaceuticals, Inc.

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A Phase I Study of Bortezomib During Maintenance Phase After High-Dose Melphalan and Autologous Stem Cell Transplantation In Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.2387.2387 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2387-2387 ◽

Cited By ~ 1

Author(s):

Muneer H. Abidi ◽

Zartash Gul ◽

Lawrence G. Lum ◽

Judith Abrams ◽

Simon Cronin ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Median Duration ◽

Maintenance Dose ◽

Phase 1 ◽

Novel Agents ◽

Relapsed Disease ◽

Experienced Grade

Abstract Abstract 2387 Background: Most Autologous stem cell transplant (ASCT) eligible Multiple Myeloma (MM) patients (pts) will have persistent disease after ASCT. Achieving a Complete Response (CR) after ASCT correlates with significantly longer progression free survival (PFS) and overall survival (OS). Since only 30–40% of the pts achieve a CR post ASCT there is a strong rationale for investigating post ASCT maintenance therapy with novel agents to improve PFS and OS. Maintenance therapy can have a potential role in achieving CR as well as maintaining CR post ASCT. The maintenance dose of novel agents including Bortezomib (B) was arbitrarily selected and has not been evaluated in Phase 1 trials. We designed this Phase 1 study to determine the most tolerated Maintenance dose (MtMD) of B after ASCT. To our knowledge, there are no phase 1 trials conducted to determine the maintenance dose of B post ASCT. Methods: We enrolled 15 pts from 11/28/2005 to 10/27/2009. Fourteen patients are evaluable. The primary objective was to determine the MtMD of B in 3x 3 dose de-escalation design. The secondary objectives were to evaluate CR, Overall Response (OR) and response duration. Two pts were enrolled in level (L) 1 utilizing therapeutic dose of B, 1.3 mg/m2on days (D) 1, 4,8 and 11 in a 21 day cycle. Both pts experienced dose limiting toxicities (DLT). Six pts were then enrolled in dose L 2 utilizing B, 1.3 mg2 on D 1, 4, 8 and 11 in a 28 day cycle. Seven pts were thereafter enrolled in dose L 3 utilizing B 1mg/m2 on D 1, 8 and 15 in a 28 day cycle. All pts who underwent ASCT (Day 0) were eligible and registered between D+30 to D+120 after ASCT. Conditioning regimen included melphalan at a median dose 200 mg/m2 (140-260). A maximum of 8 cycles of B were planned. B was administered at a median duration of 107 days (52-123) post ASCT. In order to properly assess dose dependent DLT, pts who received < 4 cycles for reasons other than B -related toxicity were replaced. Enrollment was moved to the next lower dose level if ≥2 DLTs were observed. The pts characteristics included a median age of 58 years old (38-68), median KPS of 90% (70-100) and 2 pts with baseline grade 1 neuropathy. The baseline disease status at the time of ASCT included 4 pts in CRu, 3 pts in VGPR, 4 pts in SD, 3 pts in PR and 1 pt with relapsed disease. Five pts had high risk features on bone marrow FISH analysis. Nine pts had received induction with immunomodulatory agents and 6 pts were treated with B based induction regimens. Results: Two pts developed DLT on L 1. One patient experienced Grade 2 neuropathy that did not resolve in two weeks and required B dose reduction. The other patient experience Grade 3 neutropenia requiring filgrastim support. In addition, 2 pts on L2 developed DLT. First pt had multiple hospital admissions due to high grade fever and dehydration. Second patient experienced Grade 2 neuropathy that did not resolve with treatment interruption and therefore B was discontinued after two cycles. No DLTs were observed in L3. Eight cycles of B were administered in L1. In L 2, 3pts received 8 cycles (1 off study), 1 pt received 3 cycles and 2 pts received 2 cycles of B. In L3, 6 of 7 pts received 8 cycles. After 1 year of post ASCT, 1 pt was in CRu, 1 pt in PR,3 pts were in SD, 2 pts had PD, 3 pts with relapsed disease and 5 pts were off-study (2 experienced DLTs, 2 withdrew consent and 1 failed to receive at least 4 cycles). All pts except 1 are alive as of 8/2/2010. The median duration of follow up for the entire cohort is 24 months (11-53).The median duration of response in L3 was 12 months (11-24). One pt enrolled on L3 died of sepsis during the course of follow up. He did not complete at least 4 cycles of B and therefore was not evaluable. Conclusion: To our knowledge, this is the first study that determines MtMD of B post ASCT. We conclude that B at a dose of 1 mg/m2 on D 1,8 and 15 in a 28 day cycle can be safely given beginning 52 d post ASCT for maintenance. A maximum of 8 cycles were administered. Phase 2 studies will determine efficacy of this regimen utilizing dose L3. IMID= Immunomodulatory drugs, VAD=Vincristine, Adriamycin, Dexamethasone, RE=Relapse, CY= Cycles. Disclosures: Abidi: Millennium: Speakers Bureau. Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Lum: Transtarget Inc: Equity Ownership.

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Smoldering Multiple Myeloma (SMM) at High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) as Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment

Blood ◽

10.1182/blood.v116.21.1935.1935 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1935-1935 ◽

Cited By ~ 3

Author(s):

María-Victoria Mateos ◽

Lucía López-Corral ◽

Miguel Hernández ◽

Pilar Giraldo ◽

Javier De La Rubia ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Maintenance Therapy ◽

Induction Therapy ◽

Plasma Cells ◽

Phase Iii ◽

Symptomatic Disease ◽

Smoldering Multiple Myeloma ◽

Risk Of Progression

Abstract Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (>50% at 2 years): >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 10 out of these 21 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developped G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. In conclusion, this second interim analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·7), with excelent tolerability; moreover, biological progressions occurring under maintenance have remained controlled over a prolonged period of time. Disclosures: Mateos: Celgene: Honoraria. Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma. De La Rubia:Celgene: Honoraria. Rosiñol:Celgene: Honoraria. Lahuerta:Celgene: Honoraria. Palomera:Celgene: Honoraria. Oriol:Celgene: Honoraria. Garcia-Laraña:Celgene: Honoraria. Hernández:Celgene: Honoraria. Leal-da-Costa:Celgene: Honoraria. Alegre:Celgene: Honoraria. Quintana:Celgene: Employment. Baquero:Celgene: Employment. García:Celgene: Honoraria. San Miguel:Celgene: Honoraria.

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The Efficacy of Salvage Autologous Stem Cell Transplant for Patients with Multiple Myeloma Who Received Maintenance Therapy Following Initial Transplant

Blood ◽

10.1182/blood.v128.22.3563.3563 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3563-3563 ◽

Cited By ~ 2

Author(s):

Justin A King ◽

Mark A Fiala ◽

Daniel R Kohnen ◽

Tanya M Wildes ◽

Keith Stockerl-Goldstein ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Complete Response Rate ◽

Complete Response ◽

Median Number ◽

Overall Response

Abstract Background: For patients relapsing after initial autologous stem cell transplantation (ASCT), a second ASCT is a potential, although infrequently used, salvage option. Until recently, the benefits of second ASCT were unclear but recent prospective studies have shown second ASCT to improve PFS and OS compared to conventional salvage therapy. However, these studies have included few patients who received maintenance therapy following initial ASCT as maintenance therapy is a relatively recent innovation and is not standard of care in many EU countries where these studies where these studies were completed. Therefore, it is not currently clear if these patients benefit similarly from second ASCT. Methods: We performed retrospective chart review of patients with multiple myeloma that received two ASCTs, one for initial treatment and one for salvage at time of relapse, between 2008 and 2016 at our institution. We identified 30 who received maintenance therapy following initial therapy; 2 patients were excluded as they experienced treatment related mortality prior to disease assessment post-ASCT, leaving 28 for the analysis. Results: The median age of the study population was 59 years (range 48-69) at second ASCT. 64% (n = 18) were males, 36% (n = 10) females. Prior to initial ASCT, the median number of induction cycles was 4 (range 2-11). 86% (n = 24) of patients received bortezomib during induction, 39% (n = 11) lenalidomide, 7% (n = 2) cyclophosphamide, and 11% (n = 3) received another agent. All patients received melphalan conditioning for initial ASCT. Maintenance therapy consisted mostly of lenalidomide (93%, n = 26); 7% (n = 2) had bortezomib maintenance due to lenalidomide intolerance. The overall response rate (ORR) was 100% (n = 28); the complete response rate was 39% (n =11). The median progression-free survival (PFS) post-ASCT was 31 months (range 9-57), the median interval between initial and salvage ASCT was 38 months (range 22-63). At relapse, 93% (n =26) received reinduction chemotherapy while 7% (n = 2) went directly to salvage ASCT. The median number of reinduction cycles was 4 (range 2-28). 54% (n = 15) of patients received carfilzomib during reinduction, 46% (n = 13) bortezomib, 32% (n = 9) cyclophosphamide, 29% (n = 8) lenalidomide, 14% (n = 4) pomalidomide, and 7% (n = 2) received another agent. Prior to second ASCT, 79% (n =22) received melphalan conditioning, while 21% (n = 6) received BEAM. 79% (n = 22) received maintenance therapy post transplantation; 39% (n = 11) received bortezomib, 21% (n = 6) pomalidomide, 11% (n = 3) lenalidomide, 7% (n =2) carfilzomib, 18% (n = 5) were observed off maintenance, and 4% (n = 1) had frank progression post-ASCT prior to starting maintenance. The overall response rate (partial response or better) was 86% (n = 24); the complete response rate was 21% (n = 6). The median estimated PFS was 12 months (95% CI 10-15). The median duration of follow-up was 16 months; the estimated 2 year overall survival was 49%. Conclusion: In patients who relapse post-ASCT with maintenance therapy, the PFS following salvage ASCT is ~40% that of the initial ASCT. Strategies to improve outcomes using novel reinduction, conditioning, and post-transplant maintenance regimens are needed for these patients. Table Table. Disclosures Wildes: Carevive Systems: Consultancy. Vij:Shire: Consultancy; Jazz: Consultancy; Karyopharma: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

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Melphalan-Based Autologous Transplantation in the Octogenarian Multiple Myeloma Patient Population

Blood ◽

10.1182/blood-2018-99-110241 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4608-4608 ◽

Cited By ~ 2

Author(s):

Neeraj Y Saini ◽

Romil Patel ◽

Ankur Varma ◽

Qaiser Bashir ◽

Ruby Delgado ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Hematopoietic Stem

Abstract Abstract: Background: Upfront autologous hematopoietic stem cell transplantation (auto-HCT) combined with novel anti-myeloma drugs is considered the standard of care for transplant-eligible patients with multiple myeloma (MM). However, this treatment is generally avoided in older patients due to concerns about toxicity. MM is primarily a disease of the elderly, with >35% patients being older than 70 years of age at diagnosis. We have previously reported on the role of auto-HCT in MM patients >70 years1. In this study, we evaluate the safety and feasibility of auto-HCT in patients ≥80 years who received auto-HCT at our institution. Methods: We retrospectively reviewed the outcomes of MM patients with age ≥80 years who underwent auto-HCT between January, 2007, and June, 2018. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of auto-HCT to the last follow up or the censored date. Kaplan-Meier method was used to estimate PFS and OS. Results: Between January, 2013, and December, 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥80 years. Also, between January, 2016, and June, 2018, a total of 210 MM patients with age ≥80 years were treated at our institution, and only 3(0.14%) underwent auto-HCT. Overall among 1740 patients with MM who received an auto-HCT at our institution between the beginning of 2007 to June, 2018, 9(0.5%) patients were ≥ 80 years of age (range 80-83). Table 1 summarizes the patient characteristics of these nine patients. All patients had an ECOG performance status of either 0 or 1. The median hematopoietic stem cell transplant - comorbidity index for the cohort was 3 (range, 0-5). Eight (89%) patients were in first remission, and 1 (11%) patient had relapsed disease at auto-HCT. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. Eight patients (89%) received maintenance therapy with lenalidomide. The median follow-up from auto-HCT was 18 months (range 0.5 - 50 months). No (0%) patient died within 100 days of auto-HCT. Out of 8 evaluable patients, 4 (50%) achieved a complete response, 2 (25%) very-good partial, and 2 (25%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. Median PFS was 31.5 months, while the median OS has not been reached (Fig1). 2-yr PFS and OS were 62.5% and 75% respectively. One patient died 22 months post-transplant due to non-transplant related cause. Conclusions: In selected MM patients ≥80 years old, auto-HCT was feasible, with 0% TRM, 100% response rate, and 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy. References: Qazilbash, M. H. et al. Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma. Bone Marrow Transplantation39, 279-283 (2007). Disclosures Shpall: Affirmed GmbH: Research Funding. Thomas:Celgene: Research Funding; Array Pharma: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Orlowski:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

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Efficacy and Safety of Aidi Injection Combined with Transcatheter Arterial Chemoembolization on Primary Hepatic Carcinoma: A Systematic Review and Meta-Analysis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6376429 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14

Author(s):

Weihao Chen ◽

Yurong Wang ◽

Qiuer Liang ◽

Yunfei Cai ◽

Xudong Chen ◽

...

Keyword(s):

Clinical Response ◽

Transcatheter Arterial Chemoembolization ◽

Response Rate ◽

Clinical Response Rate ◽

Efficacy And Safety ◽

Hepatic Carcinoma ◽

Primary Hepatic Carcinoma ◽

Significant Difference ◽

Aidi Injection ◽

Arterial Chemoembolization

Objectives. To evaluate the efficacy and safety of Aidi injection (ADI) combined with transcatheter arterial chemoembolization (TACE) for primary hepatic carcinoma (PHCC). Methods. We conducted a literature search in EMBASE, PubMed, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases from the earliest possible year to April 2018. Randomized controlled trials (RCTs) involving ADI combined with TACE versus TACE alone for patients with PHCC were included. The Cochrane Risk of Bias tool was applied for quality assessment. Results. 22 studies involving 1611 participants were included. The clinical response rate (RR = 1.28, 95% CI: 1.17-1.40; P < 0.00001), KPS score (RR = 1.78, 95% CI: 1.59-2.00; P < 0.00001), survival rate (RR = 1.27, 95% CI: 1.16-1.39; P < 0.00001), immune function (MD = 1.24, 95% CI: 0.98-1.51; P < 0.00001), and adverse effects (RR = 0.62, 95% CI: 0.57-0.68; P < 0.00001) of ADI plus TACE showed significant difference when compared with TACE alone. Conclusions. ADI combined with TACE in the treatment of PHCC improved the clinical response rate and safety compared to TACE alone. However, due to poor methodological quality of many of the included RCTs, more rigorously designed and large-scale RCTs are warranted to examine this beneficial effect in the future.

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