A Phase II, Single-Center, Open-Label Study Of Oral Panobinostat In Combination With Lenalidomide and Weekly Dexamethasone In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5392-5392 ◽  
Author(s):  
Noa Biran ◽  
Samira Shahnaz ◽  
Sundar Jagannath ◽  
Hearn J. Cho ◽  
Keren Osman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Performance Status ◽  
Qtc Interval ◽  
Advisory Committees ◽  
Durable Response ◽  
Grade 3 ◽  
Triplet Regimen

Abstract Background Treatment options for patients with multiple myeloma (MM) refractory (ref) to lenalidomide (len) and bortezomib are urgently needed.  A promising strategy is the use of epigenetic agents such as the deacetylase inhibitor (DACi) panobinostat (pan) to modulate genes that affect drug resistance.  Pre-clinical studies with pan demonstrated synergy against MM cells when combined with dexamethasone (dex) and len, supporting this concept (Ocio EM et al. Haematologica 2010). The safety and preliminary efficacy of this triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010). The maximum tolerated doses (MTD) in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses). To investigate the hypothesis that peripheral blood plasma levels of cytokines/chemokines known to be elevated in MM patients may identify biomarkers of response to this regimen, we examined IL-6, IL-10, IL-17A, Monocyte Chemoattractant Protein (MCP)-1 and Macrophage Derived Chemokine (MDC) levels at baseline and following 4 cycles of treatment. Patients and Methods Inclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a DACI or currently receiving medications with a risk of prolonging the QTc interval were excluded. The primary objective was to evaluate the best overall response rate.   Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival.  Each drug was administered at the doses and schedule shown in Table 1. Results Overall, 5 len-refractory patients with disease progression at screening have been enrolled. Patients had a median of 2 lines of prior therapy (range 1–7). High-risk molecular findings were present in 3 patients, including 2 patients with gain of 1q21 by FISH and 1 with del p53. Very good partial response (VGPR) was achieved in 1/5, partial response (PR) in 1/5, minimal response (MR) in 1/5, and stable disease (SD) in 2/5. Two of these high-risk patients are still on study, and the patient with del p53 had PD at 4 months. Responses are durable, with 3 patients (including both patients with ≥PR) remaining on study for more than 4 months, with a median follow up of 4 months. Two patients progressed within 4 months. Grade 3 and 4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, and anemia noted in 3, 3, and 1 patient(s) respectively. There were 2 serious adverse events (SAEs) – a grade 3 pulmonary embolism and febrile neutropenia (FN) due to N. meningitidisbacteremia. The non-hematologic toxicities were all grade 1 and 2, consisting of fatigue in 5 patients and diarrhea in 2. Dose modifications were required in 2 patients for len and 2 patients for pan, 1 for FN and the other for asymptomatic T wave inversions. Cytokine profiling revealed that MDC was reduced by 48%, 7% and 72% respectively in all 3 patients having a durable response (>4 months) following therapy.  Of note, Thymus Activation-Regulated Chemokine (TARC) was identified as a biomarker of treatment response to pan in lymphoma patients (Harrison et al. Leuk Lymphoma 2013).  Both MDC and TARC bind to the chemokine receptor CCR4 and are located on chromosome 16q13. MDC promotes angiogenesis and alters T cell distribution in the bone marrow. These findings suggest a link between DACi and CCR4 receptor ligand MDC levels. Thus, MDC may be a biomarker of sustained response to pan in MM and warrants further investigation. Conclusions In rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, and that MDC may be a biomarker of this activity. This completely oral regimen is well tolerated, with primarily expected hematologic toxicities. Updated results will be presented at the annual meeting. Disclosures: Jagannath: Celgene: Honoraria; Millenium: Honoraria. Chari:Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

A Phase II, Single-Center, Open-Label Study of Oral Panobinostat in Combination with Lenalidomide and Weekly Dexamethasone in Patients with Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3486-3486 ◽  
Author(s):  
Ajai Chari ◽  
Hearn J. Cho ◽  
Samir Parekh ◽  
Amishi Dhadiwal ◽  
Katarzyna Garcia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Progression Free Survival ◽  
Additional Patient ◽  
Advisory Committees ◽  
Free Survival ◽  
Grade 3 ◽  
Dose Modifications ◽  
Triplet Regimen

Abstract Background: Treatment options for patients with multiple myeloma (MM) refractory (ref) to immunomodulatory drugs and proteasome inhibitors are urgently needed. A promising strategy is the use of epigenetic agents such as the pan histone deacetylase inhibitor (HDACi) panobinostat (pan) to modulate the acetylation of histones and proteins involved in oncogenesis. Pre-clinical studies with pan demonstrate synergy against MM cells when combined with dexamethasone (dex), lenalidomide (len), and bortezomib (btz) (Ocio EM et al. Haematologica 2010). Interim data from the phase 3 PANORMA 1 study of 768 patients randomized to receive IV btz and dex with either pan or placebo revealed a 3.9 month increase in PFS with pan along with an increase in CR rates. However, this was accompanied by 25% grade 3/ 4 diarrhea versus 8% in the placebo arm. The safety and preliminary efficacy of the pan-len-dex triplet regimen was assessed in a phase 1b study of relapsed (rel) or rel/ref MM patients (Mateos et al, ASCO 2010) but was complicated by high dose dex toxicities. The maximum tolerated dose of pan and dex in that study are the doses selected for this phase 2 study. However we investigated a modified schedule (table 1) of this triplet regimen. Here, pan is given thrice weekly only every other week (instead of weekly) and dex is given weekly (instead of three 4 day pulses). Patients and Methods: Inclusion criteria were patients with rel or rel/ref MM, measurable disease, adequate performance status, organ function, and hematologic parameters. Patients previously treated with a HDACI or currently receiving medications with a risk of prolonging the QTc interval were excluded. The primary objective was to evaluate the best overall response rate (ORR). Secondary objectives were to evaluate safety, response duration, and overall and progression-free survival. Each drug was administered at the doses and schedule shown in Table 1. Results: Overall, 13 evaluable patients with progressive disease (PD) at screening have been enrolled, including 9 len-refractory (2 also pomalidomide refractory) and 4 len sensitive with a median of 4 and 3 lines of prior therapy respectively (range 1–10). High-risk molecular findings were present in 9 patients, including 6 with gain of 1q21 by FISH and 3 with del p53. Three of the patients with gain of 1q21 also had t (4;14). Of the 13 patients, there have been 3 very good partial responses (VGPR), 2 partial responses (PR), 3 minimal responses (MR), 4 stable diseases (SD), and 1 PD, for an ORR of 38% and clinical benefit rate (CBR i.e. MR or greater) of 61 %. With a median follow up of 4.5 months the median progression free survival and duration of response have not been reached. Of the 9 patients who were len refractory, there were 2 VGPR, 2 MRs, 4 SD, and 1 PD for a 22% ORR and 44% CBR. Notably, 3 len refractory patients remain on treatment for 11, 16, and 16 months including 2 with gain of 1q21 that have attained VGPRs. Grade 3/4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia, thrombocytopenia, lymphopenia, and anemia noted in 7, 4, 1, and 1 patients respectively. Grade 3/4 nonhematologic AEs included infections in 4 (with 1 one occurring while neutropenic), and 1 patient with each of the following: pulmonary embolus, neck pain, QTc prolongation, and weight loss 1. Dose modifications for neutropenia were required in 4 patients for len and in 2 patients for pan. 1 additional patient required pan dose reduction for asymptomatic T wave inversions. Nausea was noted in 2 patients and diarrhea in 3 with 2 additional patients experiencing both – however these were transient, Grade 1/2, and did not require dose modifications. Importantly, no patients discontinued therapy for toxicity. Conclusions: In rel/ref MM patients, pan in combination with len and dex demonstrates durable responses, even in len-refractory patients with high-risk molecular findings, indicating the essential role of pan in attaining a response. These results suggest that pan modulates expression of genes to restore sensitivity to len, In notable contrast to the PANORMA 1 results, this completely oral regimen is well tolerated with no Grade 3/4 GI toxicities and primarily expected hematologic toxicities. Updated results, including correlative studies, will be presented at the annual meeting. Table 1: Study Drug Doses Panobinostat Lenalidomide Dexamethasone 20 mg po Day 1, 3, 5, 15, 17,19 25 mg po Day 1-21 40 mg po Day 1, 8, 15 Disclosures Chari: Array Biopharma: Membership on an entity's Board of Directors or advisory committees; Millenium : Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

scholarly journals Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 976-976 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Ashraf Z Badros ◽  
James J. Vredenburgh ◽  
Jeffrey Matous ◽  
Aaron M. Caola ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Therapeutic Intervention ◽  
Research Funding ◽  
High Dose ◽  
Qtc Interval ◽  
Advisory Committees ◽  
High Dose Dexamethasone ◽  
Smoldering Multiple Myeloma

Abstract Purpose: This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). The overarching objective of this trial is to determine progression free survival to symptomatic myeloma (MM). Furthermore, the study examined the activity and safety of the combination therapy in patients with high-risk SMM. Patients & Methods: Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. An initial cohort of patients were randomized to a low dose dexamethasone treatment arm (Arm B) based on the following stratification factors: age >65 years and high-risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation, and +1q amplification. For cycles 3-8, patients on both treatment arms were administered elotuzumab infusions on days 1, 8, and 15. Patients on treatment Arm A received dexamethasone (40mg) on days 1, 8 and 15. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients on both treatment arms were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28 day cycle. After 11 patients were enrolled on each arm, arm B closed due to similar activity and toxicity to the high-dose dexamethasone arm based on published data demonstrating that high-dose dexamethasone, given once a week, does not have a detrimental effect on the immune system in patients with smoldering myeloma. Results: In total, 39 patients were enrolled on this study from January 2015 to date, with the participation of eight sites. The median age of patients enrolled was 62 years (range 26 to 75) with 15 males (38%) and 24 females (62%). The median number of cycles completed is 6 (range 1 to 19). Therapy related grade 3 toxicities included hypophosphatemia (23%), neutropenia (8%), infection (8%), anemia (3%), pulmonary embolism (3%), rash (3%), and diarrhea (3%). No related grade 4 or 5 toxicities have occurred thus far. Stem cell collection was successful in all patients collected to date. Unrelated toxicities include one instance of grade 4 prolonged QTc Interval. Of the 34 evaluable patients enrolled to both arms of the study, the clinical benefit rate is 97%. The overall response rate is 71%, including 9 very good partial responses (26%) and 15 partial responses (44%). The VGPR cases are currently under evaluation of possible complete responses due to the potential interference of elotuzumab with immunoelectrophoresis. Thus far, no patients have progressed to active multiple myeloma during, or after, protocol therapy. Conclusion:The combination of elotuzumab, lenalidomide, and dexamethasone is very well tolerated among patients with high-risk SMM. The high response rates among this patient population, who would otherwise remain untreated, is a promising starting point for the paradigm shift towards early therapeutic intervention in patients with high-risk SMM. Disclosures Ghobrial: Amgen: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Rosenblatt:Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding. Usmani:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Array: Research Funding; Novartis: Speakers Bureau; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Multicenter, Open Label Study of Oral Lenalidomide and Prednisone (RP) Followed by Oral Lenalidomide Melphalan and Prednisone (MPR) and Oral Lenalidomide Maintenance In Newly Diagnosed Elderly Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1940-1940 ◽  
Author(s):  
Antonio Palumbo ◽  
Patrizia Falco ◽  
Giulia Benevolo ◽  
Davide Rossi ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 1940 The combination of Melphalan-Prednisone-Lenalidomide (MPR) has shown promising results in elderly newly diagnosed myeloma patients. In the transplant setting, low-dose chemotherapy (induction) precedes high-dose chemotherapy (autologous transplantation consolidation). This approach reduces tumor mass, with few side effects, before achieving the maximum cyto-reduction with autologous transplantation. The same approach has been designed for the elderly patients. Accordingly induction with lenalidomide plus corticosteroids precedes consolidation with MPR. A two-stage phase II clinical trial was planned to evaluate the safety and efficacy of Lenalidomide-Prednisone (RP) as induction, followed by Melphalan-Prednisone-Lenalidomide (MPR) as consolidation and Lenalidomide as maintenance in elderly myeloma patients. Unfit patients with newly diagnosed symptomatic myeloma older than 65 years were enrolled. No exclusion criteria were included in the protocol, to avoid the selection of fit elderly subjects only. Patients with low blood count, abnormal performance status, hepatic, renal, cardiac or pulmonary functions were enrolled. Patients received 4 RP courses (Lenalidomide 25 mg/day for 21 days every 4 weeks, plus Prednisone 50 mg three times/week for 4 weeks) followed by 6 MPR cycles (Melphalan 2 mg and Prednisone 50 mg three times/week, for 4 weeks plus Lenalidomide 10–15 mg/day for 21 days every 4 weeks) and maintenance with Lenalidomide alone (10 mg/day for 21 days every 4 weeks). Two different dose-levels of Lenalidomide were tested in combination with MP: 15 mg (dose-level 1) and 10 mg (dose-level 2). Each cohort included 12 patients, with additional 22 patients enrolled at dose-level 2. Patients were evaluated for efficacy and toxicity after completion of at least 2 MPR cycles. Forty-six patients (median age 75, range 65–88) were enrolled. Thirty-six patients were evaluable after a median of 7 cycles and a median follow-up of 8.5 months. During RP induction, the most frequent grade 3–4 hematological adverse events were neutropenia (19%), anemia (11 %), thrombocytopenia (6%). During MPR consolidation, grade 3–4 adverse events were neutropenia (45%), and thrombocytopenia (3%). Neutropenia was increased by the addition of melphalan, but both thrombocytopenia and anemia were reduced. Non-hematological toxicities were more frequent during RP cycles and reduced during MPR cycles (cutaneous rash and infections). After RP induction, at least partial response (PR) rate was 67%, at least very good partial response (VGPR) was 17%. After 2 MPR cycles, PR rate increase to 72%, including 22% of patients who achieved at least a VGPR. Conclusions. Induction with RP followed by consolidation with MPR showed a manageable safety profile and reduced the risk of anemia, thrombocytopenia and non-hematological toxicity in unfit elderly myeloma patients. These data will be updated at the meeting. Disclosures: Palumbo: Celgene Srl: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janseen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide in combination with melphalan for multiple myeloma patients at diagnosis. Guglielmelli:Celgene: Honoraria; Janseen-Cilag: Honoraria. Gay:Celgene: Honoraria. Cavallo:Celgene: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janseen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A 28 Day Schedule for Lenalidomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2949-2949
Author(s):  
Ajai Chari ◽  
Nitin Roper ◽  
Sundar Jagannath
Keyword(s):  
Multiple Myeloma ◽  
Neuropathic Pain ◽  
Partial Response ◽  
Board Of Directors ◽  
Sensory Neuropathy ◽  
Treatment Schedule ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
D 20

Abstract Abstract 2949 Background: The treatment of patients with newly diagnosed multiple myeloma (MM) with a 3 week cycle of lenalidomide (R), bortezomib (V), and dexamethasone (D) (R 25 mg days 1–14, V 1.3 mg/m2 day 1, 4, 8, 11, and D 20 mg day 1, 2, 4, 5, 8, 9, 11, 12) is associated with unprecedented response rates (Richardson et al. Blood 2010) (see Table 1). Partial response (PR) was 100% and 74% of patients achieved a very good partial response (VGPR) or better with RVD treatment. However, these responses come at the expense of an 80% rate of sensory neuropathy (27% grade 2 and 2% grade 3) and 32% with neuropathic pain (11% grade 2, 3% grade 3). As a result, only 59% of patients received all 3 agents and at least 1 dose modification of bortezomib was required in 44% of patients including 15% for neuropathic pain, 14% for sensory neuropathy, and 8% for fatigue Recent data confirm that a decrease in the dose intensity of bortezomib (for example with weekly dosing) is associated with significantly less toxicity, but importantly (at least in the context of combination chemotherapy) without a decrease in efficacy (Bringhen et al., Blood 2010). In this retrospective study, we examine the efficacy and toxicity of a 28 day RVD treatment schedule for patients with newly diagnosed MM. Methods: All patients with newly diagnosed, symptomatic MM who received front-line RVD on a 28 day schedule where R 25 mg was given days 1–21, V 1.3 mg/m2 was given on day 1, 4, 11, 18 and D 20 or 40 mg was given on day 1, 4, 11, 18 (see Table 2) were selected for this analysis. Patients were excluded if they had received any previous systemic anti-MM therapy (except prior corticosteroids for hypercalcemia or spinal cord compression). Patients who were empirically dose reduced for comorbidities were not excluded. All patients received prophylaxis for venous thromboembolism and VZV. Results: A total of 38 patients met the inclusion criteria for analysis. The median age at start of treatment was 59.5 years. The ISS distribution was Stage I 73% of patients, Stage II 16%, and Stage III 11%. Median treatment length was 4.5 cycles (range 3–12). After four cycles of treatment with VRD, the overall response rate was 97%, which included 63% VGPR or better (24/38) and 34% PR (13/38). 1 remaining patient had an MR (49% reduction in m spike). 32% of patients (n=12/38) went on to stem cell transplantation after four cycles of treatment while the rest were placed on maintenance therapy. With a median follow up of 9 months, no patients have had disease progression. Impressively, the rate of all grades of neuropathy at four cycles was 37% (n=14/38) with 21% (n=8/38) grade 1 sensory neuropathy, 11% (n=4/38) grade 2 neuropathy with pain and 5% grade 3 (n=2/38). There were no other hematologic or non-hematologic grade 3 or 4 toxicities. Conclusion: Despite a decrease in the dose density of bortezomib and dexamethasone, the continued synergy of these agents with a full 21 day course of lenalidomide provides excellent efficacy with reduced rates of toxicity. The 28 day schedule of RVD is an efficacious, convenient, and well tolerated treatment regimen for patients with newly diagnosed symptomatic MM. The subcutaneous administration of bortezomib on this 28 day schedule may allow even further reductions in toxicity without sacrificing efficacy. Disclosures: Chari: Millenium Takeda: speakers bureau (terminated May 2010); Celgene: lecturer. Jagannath:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1911-1911 ◽  
Author(s):  
Meena Bansal ◽  
David S. Siegel ◽  
Jaeil Ahn ◽  
Rena Feinman ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Best Response ◽  
Grade 3

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

scholarly journals Treatment of Relapsed and Refractory Multiple Myeloma with Fully Oral Triplet IRD (ixazomib, lenalidomide and dexamethasone) Is Safe and with Significant Therapeutic Outcomes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jiri Minarik ◽  
Petra Krhovska ◽  
Tomas Jelinek ◽  
Alexandra Jungova ◽  
Martin Mistrik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Categorical Variables ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Extramedullary Plasmocytoma

Abstract Aims: Treatment of multiple myeloma (MM) in relapsed and refractory setting (RRMM) has been a challenge. The best outcomes have been observed in triplet combination of novel drugs. However, most combinations require weekly parenteral administration thus degrading patients´adherence to therapy, especially when treatment is scheduled "until progression". The introduction of fully oral triplet combination ixazomib, lenalidomide and dexamethasone (IRD) showed an outstanding efficacy in the Tourmaline-MM1 trial. Our aim is to determine the efficacy and safety of IRD regimen outside clinical trials. Patients and methods: A cohort of 127 RRMM patients from the Czech and Slovak Republic were treated with IRD regimen within a Named Patient Program between 2016 and 2018. The M/F ratio was 1.2:1 with median age 66 years (41-84). The representation of M-protein and light chain types as well as ISS stage was standard. The data for cytogenetics were recorded only at the time of diagnosis in 71% of patients with 15 patients having high-risk features - t(4;14), t(14;16) and del17, and 41 patients having standard risk features. In 34 patients we were not able to determine the risk status as at least one abnormality was missing and none was positive. The presence of extramedullary plasmocytoma was recorded in 15% of patients. Most patients received IRD for their 1st relapse (58.5%), followed by 2nd (23.7%) and 3rd relapse (7.6%) with significant portion of patients being treated in ≥4th relapse (10.1%). The pretreatment with individual drugs was as follows: bortezomib (BTZ) 94.5%, thalidomide (THAL) 40.9%, lenalidomide (LEN) 18.9% and carfilzomib 5.5%. 62.2% of patients underwent previous autologous stem cell transplant. Altogether 25.2% of patients were refractory to at least 1 drug with 18.9% being BTZ refractory and 7.9% LEN refractory. Data were analyzed from the Czech Registry of Monoclonal Gammopathies. Data were described by absolute and relative frequencies of categorical variables and mean (standard deviation), median (minimum-maximum) of quantitative variables. Survival measures were plotted using Kaplan-Meier methodology at 95% confidence interval, log-rank test was used to estimate the statistical significance at P<0.05. Results: The overall response rate to IRD regimen (≥ partial response, PR) was 67.1% with clinical benefit rate (≥ minimal response, MR) of 77.2%. The rate of individual responses was as follows: complete response (CR) in 11.4%, very good partial response (VGPR) in 16.5%, PR in 39.2%, MR in 10.1%, stable disease (SD) in 13.9% and progressive disease (PG) in 8.9%. The median overall survival was not reached after median follow up of 9.4 months. Median progression free survival (PFS) was 23.1 months. PFS was significantly decreasing with number of previous lines (not reached after 1 previous lines, 23.1 after 2 lines, 8.7 after 3 lines and 4.6 after ≥4 lines, p = 0,006). As expected, the best PFS increased with deeper therapeutic response (SD+PD = 4.1 months, MR = 9.0 months, PR = 15.1 months, VGPR = 13.2 months, and CR = median PFS not reached). There were limited information regarding the high risk features. Still, we confirmed adverse impact of the presence of extramedullary disease (PFS 5.5 vs 23.1 months, p = 0.001). Similarly, patients did worse when being pretreated by both proteasome inibitor and an IMiD versus solely proteasome inhibitor (PFS 10.0 vs 23.1 months, p = 0.001). The outcomes of high-risk cytogenetics were beyond statistical significance. Most toxicities were grade ≤2. Only hematological toxicity and infection reached grade 3 or higher, as follows: neutropenia in 35.1%, thrombocytopenia in 22.8%, anemia in 12.3% and infection in 19.3%. Conclusions: IRD regimen is very effective in RRMM. We confirmed its efficacy even in highly pretreated population (≥4 prior regimens) and in patients refractory to BTZ or LEN, which were exclusion criteria for the Tourmaline trial. The fully oral combination is well tolerated, with manageable side effects and easy management of dose modifications. Unlike the original trial our data show better results in patients with less pretreatment. The presence of extramedullary plasmocytoma deteriorates the prognosis of patients on IRD regimen. We thank to Takeda for enabling the Named Patient Program. With support of AZV 17-29343A, MH CZ - DRO (FNOl, 00098892) Disclosures Maisnar: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

scholarly journals Daratumumab (DARA) Plus Carfilzomib, Pomalidomide, Dexamethasone (KPd) in Lenalidomide Refractory Multiple Myeloma (MM): A Multi-Center MMRC Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-50
Author(s):  
Jagoda Jasielec ◽  
Jeff Zonder ◽  
Benjamin A Derman ◽  
Donna E. Reece ◽  
Craig E. Cole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Second Stage ◽  
Best Response ◽  
Common Grade ◽  
Grade 3

Introduction: Lenalidomide (LEN) is a cornerstone in the treatment of newly diagnosed MM both as part of induction and maintenance therapy. As a result, most patients at first or second relapse are LEN exposed/refractory creating a need for effective 2nd line and salvage therapies. While no standard of care regimen has been established in early relapse, several therapies have been evaluated combining second generation immunomodulatory agents, proteasome inhibitors, and daratumumab. We have previously reported the results from the phase I/II trial of KPd demonstrating excellent efficacy in a LEN-refractory patient population. Here, we present the first efficacy and safety results from the cohort in which DARA was added to KPd (D-KPd). Methods: This is a multi-center, open-label, Phase 1b/2 study in subjects with relapsed MM with two sequential treatment cohorts: KPd and D-KPd. Eligibility criteria and KPd doses and schedules were identical for both cohorts. Subjects with measurable disease that progressed after at least 1 prior therapy (LEN refractory disease was required for 2nd-line therapy and LEN refractory/exposed for ≥ 3rd line) were eligible. The KPd cohort has completed enrollment (n=67) and results have been previously reported. The D-KPd cohort received treatment on the following 28-day schedule: Pomalidomide 4 mg daily on days 1-21 for cycles 1-8+, Carfilzomib 20/27 mg/m2 on days 1,2,8,9,15,16 for C1-8, then 1,2,15,16 for C9+ (maintenance), dexamethasone 20 mg days 1,2,8,9,15,16,22,23 for C1-2, then 40 mg days 1,8,15,22 for C3+. DARA was administered as per standard schedule, weekly for the first 2 cycles, then every 2 weeks for cycles 3-6, and monthly thereafter. A Minimax two-stage design was employed for enrollment of subjects on this cohort. Twenty-one patients were required to accrue to the first stage, with at least 4 responders of ≥nCR at 4 cycles necessary to accrue to second stage for a total of 34 pts. Primary endpoint was rate of nCR/CR as per IMWG criteria. Minimal residual disease (MRD) was evaluated by 10-color flow cytometry with limit of detection (LOD) 10-4-10-5 and will also be assessed by next-generation sequencing (LOD 10-5-10-6). Secondary endpoints include overall response rate, depth of response, progression-free survival (PFS), and overall survival. Per study design, a nCR/CR rate of &gt;35% (over the historical 20% rate) would support further study of the D-KPd regimen. Results: As of July 29, 2020, all 22 subjects who were enrolled into the D-KPd cohort were evaluable for safety and the primary endpoint. Median age was 62 (range 37-74) with a median of 1 (range 1-3) prior lines of therapy. 81% of patients were LEN refractory, and high-risk cytogenetics per IMWG criteria were present in 12/19 (68%) evaluable patients. Subjects completed a median of 12.5 cycles (range 2-33) of therapy and 21 (95%) subjects completed at least 4 cycles; 1 subject progressed after cycle 2. In the ITT population (n=22), after 4 cycles, 86% achieved ≥PR and 46% ≥nCR, warranting further enrollment to a second stage. At best response, the ≥PR was 86% with 55% ≥nCR/CR, 45% ≥sCR, and 55% MRD negativity by flow cytometry (n=22). The most common grade 3-4 hematologic adverse events included neutropenia (64%), lymphopenia (36%), and febrile neutropenia (18%). The most common grade 3-4 non-hematologic adverse events included fatigue (27%), respiratory infections (23%), diarrhea (14%), and insomnia (14%). There was one thrombotic event (4.5%) which was grade 2. In comparison to the KPd cohort (67 patients with similar baseline characteristics), there was an improvement in efficacy as demonstrated by an increase in rate of ≥nCR at the end of 4 cycles (from 7% to 46%), as well as the best response (from 20% to 55%). High risk cytogenetics did not significantly affect response (≥nCR 46% at best response [all sCR]). With 20 months of follow-up, median PFS was not reached in the D-KPd cohort and 12-month PFS is 84% vs 63% for KPd. Rates of grade 3/4 cytopenias were higher in the D-KPd cohort. There was no treatment related mortality and 19 of 22 pts are alive. Conclusion: D-KPd demonstrates high efficacy in a population of patients with relapsed/refractory multiple myeloma enriched for high risk cytogenetics. MRD negativity by flow cytometry was achieved in 55% of subjects. The ≥nCR rate of 55% with D-KPd compares favorably to the 20% rate with KPd alone; based on the study design, this warrants further evaluation of D-KPd. Disclosures Zonder: BMS, Celgene: Research Funding; Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Berdeja:Kesios: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Prothena: Consultancy; Servier: Consultancy; Bluebird: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Phase I/II Study of Pomalidomide-Cyclophosphamide-Prednisone (PCP) in Patients with Multiple Myeloma Relapsed/Refractory to Lenalidomide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 632-632 ◽  
Author(s):  
Antonio Palumbo ◽  
Alessandra Larocca ◽  
Angelo Michele Carella ◽  
Davide Rossi ◽  
Vittorio Montefusco ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Options ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Outcomes and Clinical Features of Patients with 1q+ Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3241-3241 ◽  
Author(s):  
Timothy M. Schmidt ◽  
Nisha Joseph ◽  
Levani Odikadze ◽  
Leonard Heffner ◽  
Craig C Hofmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Large Population ◽  
Chromosome 1 ◽  
Advisory Committees ◽  
Significant Difference

Abstract Introduction: Recurrent cytogenetic abnormalities have been well described in multiple myeloma and have important roles in the development and progression of myeloma, as well as prognostic implications for patient survival. Amplification of chromosome 1 (+1q) has been associated with inferior outcomes including survival. However, it is unclear whether this association is due to a primary effect of +1q on myeloma biology or secondary to its association with genomic instability and more advanced disease. Furthermore, the prognostic implication of +1q has yet to be determined in the setting of novel treatment regimens including triplet induction regimens incorporating an immunomodulatory agent and proteasome inhibitor backbone, with consideration of risk-adapted maintenance therapy. This study investigated the clinical characteristics and outcomes of a large population of multiple myeloma patients with +1q who were treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy. Methods: We collected data for 1000 patients with newly diagnosed multiple myeloma who received RVD induction and were seen at Emory University/Winship Cancer Institute between July 1, 2005 and August 31, 2016. Baseline characteristics were determined, including age, sex, race, laboratory values at diagnosis (hemoglobin, creatinine, calcium, albumin, lactate dehydrogenase, beta-2-microglobulin, isotype, paraprotein, and serum free light chains) and molecular cytogenetics by fluorescent in-situ hybridization (FISH) for +1q, t(11;14), t(4;14), t(14;16), del(17p), del(13q), and hyperdiploidy. Patients were also categorized by their ISS stage, high-risk cytogenetics (defined as t(4;14), t(14;16), or del(17p)), and whether they were treated with autologous stem cell transplantation (ASCT). The primary outcomes were response to RVD induction by IMWG criteria (complete response (CR), very good partial response (VGPR), and partial response (PR)), progression free survival (PFS), and overall survival (OS) of patients with +1q compared to patients without +1q. Hazard ratios and p-values for PFS and OS were calculated using multivariate analysis accounting for presence of ISS stage 3 disease, t(4;14), t(14;16), and del(17p). Results: Of 1000 total myeloma patients treated with RVD induction, 146 (14.6%) were noted to have +1q by FISH. Patients with +1q, compared to those without +1q, were more likely to be Caucasian (75.2% vs 60.1%, p=0.001) , have IgA isotype (29.8% vs 18.6%, p=0.049) , present with calcium > 10.5 (22.8% vs 14.3%, p=0.026) , and have concurrent high-risk abnormalities by FISH (59.6% vs 21.7%, p<0.001) . There was no significant difference in response to RVD induction, with responses of ≥CR/≥ VGPR /≥PR of 42.2%/67.2%/99.3% for patients with +1q compared with 36.1%/68.8%/97.8% for patients without +1q (p=0.693) . Median PFS was significantly shorter for patients with +1q compared with those without +1q (41.8 months vs 86.0 months , respectively, HR 2.39, p<0.001 ). OS of patients with +1q was significantly worse than patients without +1q (median not reached, HR 2.316, p=0.001 ). Conclusion: In this retrospective, single-center analysis of multiple myeloma patients treated with RVD induction, patients with 1q amplification had similar responses to induction therapy, but significantly inferior PFS and OS compared to patients without +1q. Further investigation is required to determine if the timing of 1q gain, copy number of chromosome amplification, and/or association with other high-risk cytogenetics are important contributing factors to the prognosis of patients with +1q. Disclosures Heffner: ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Hofmeister:Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Lonial:Amgen: Research Funding. Nooka:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; GSK: 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; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy.

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