A Systematic Review on Efficacy and Safety of Lenalidomide Based Regimens for Treatment of Newly Diagnosed Amyloidosis

Introduction: Lenalidomide (L), a commonly used drug for the treatment of Multiple Myeloma, but currently it is not being not used as front line agent for the treatment of AL amyloidosis. It works through various mechanism, can cause direct toxicity to plasma cells, inhibits angiogenesis, and promotes tumor apoptosis. Cyclophosphamide (Cy), causes cross links between DNA which leads to cell apoptosis. For last decade, Cy is being used in combination with agents like Velcade for more than and decade, there is paucity of literature about its use in combination with L. L based regimen may be necessary in patients who have contraindications to bortezomib use, additionally targeted immunotherapy based combinations with daratumumab, through NK cell mediated cytotoxicity, may be more effective in the presence of immunomodulatory drugs. Our main objective is to analyze the published literature for the efficacy and toxicity of L based regimens for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: A systematic search of databases using (per PRISMA guidelines) PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed from January 2012 onward, with no restrictions of publication language. A total of 649 articles were identified initially and after a detailed screening, we finalized 9 studies involving 223 ND-AL patients. Results: Lenalidomide, dexamethasone, Cyclophosphamide (LCyD): In a phase II trial by Ciberia et al, (n=28) ND-AL patients (pts) were treated with LCyD. Overall hematological response (OHR) was 46% with complete response (CR) in 25%, very good partial response (VGPR) in 18% and partial response (PR) in 3% pts. Organ response (OR) was 46% with maximum pts. showing response in kidney (43%) and heart (26%). In a study by Kastritis et al., involving 24 pts, LCyD induced, OHR was observed in 55% pts with CR in 8 % (Table 1). For comparison with regimens like Cy, Bortezomib and Dexamethasone (CyBorD), in a retrospective study by Hong et al., 24 pts were given CyBorD. OHR was 89% with CR, VGPR and PR demonstrated in 55%, 33% and 10% pts respectively. 5-yr OS was 80% and 5-yr PFS was 69% (Table 1). Mikhael et al., reported 17 pts given CyBorD. OHR was 94% with CR in 71% and PR in 24% pts. Venner et al., et al. (n=43) reported 20 patients of ND-AL treated with CyBorD showed OHR of 81.4%, with CR in 41.9% and PR in 39.5%. 46% pts showed OR. Chari et al. reported 9 pts. who were given extensive combinations of Cyc and L. OHR was 88%, with CR in 22% and PR in 66% pts. 77% pts showed an OR (Table 1). Induction with L prior to High dose Melphalan (HDM) and stem cell transplant (SCT) vs front line HDM/SCT: In a study by Cowan et al., (n=45) pts in group A (n=21) received induction therapy using novel agent induction using agents like Bortezomib and Lenalidomide prior to HDM/SCT. CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. Similarly study by Scott et. al., 31 pts who received HDM consolidation were categorized in 3 groups i.e no induction, induction with V-based regimen and induction with other regimens including L. In pts with len/dex (n=2) OHR was 100%, with CR observed in 100% pts (Table 1). Melphalan (M), Lenalidomide (L) and Dexamethasone (d): In a clinical trial (NCT00890552), 25 pts who were given L, M and d, showed a CR of 8%, VGPR of 16% and PR of 33% pts. mOS was 12 mo (Table 1). Conclusion: There is paucity of literature about the use of Lenalidomide for the treatment of newly diagnosed AL patients. In ND-AL pts, CyBorD and as well as Lenalidomide/dexamethasone-based regimens has shown excellent overall hematological responses (up to 100%). Major adverse effects were anemia, thrombocytopenia, neutropenia and rash. We recommend, with adequate sample size, prospective studies need to be conducted for better understanding of efficacy and safety of L based therapies in newer combinations for the treatment of AL Amyloidosis. With good efficacy and tolerance data to support its use, Lenalidomide may have a potential role for its use as an induction agent, salvage therapy as well as post induction long term term maintenance therapy for select AL amyloidosis cases who cant achieve complete remission with induction and / or consolidation regimens. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety Profile of Bortezomib Based Regimens for Treatment of Newly Diagnosed Amyloidosis: A Systematic Review of Literature

Blood ◽

10.1182/blood-2019-127190 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5583-5583

Author(s):

Muhammad Abdullah Yousaf ◽

Muhaddis Ejaz Ahmad ◽

Maaz Ahmed Yusufi ◽

Hamza Hassan ◽

Adeela Mushtaq ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Retrospective Study ◽

Partial Response ◽

Induction Therapy ◽

Cochrane Library ◽

Al Amyloidosis ◽

Cell Transplant ◽

Newly Diagnosed ◽

Efficacy And Safety

Introduction: For more than a decade, bortezomib (V) has become an integral part of initial treatment of AL amyloidosis It is cytotoxic to plasma cells. We report published literature on efficacy and safety of bortezomib based regimens in patients (pts) with newly diagnosed amyloidosis (ND-AL). Methods: Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2007 using Pubmed, Embase, Clinical Trials.gov, Cochrane Library and Web of Science. Initially, 649 articles were identified and after a thorough screening, we finalized 9 studies involving 213 ND-AL patients. Prospective (n=91) and retrospective (n=122) studies were included. MeSH terms and keywords were bortezomib and newly diagnosed AL amyloidosis. Results: Chemotherapy followed by HDCT versus frontline HDCT / ASCT: In a retrospective study involving 31 pts by Scott et al., with induction chemotherapy with V-based regimens (n=12), with non-V-based regimens (n=6) and frontline (n=13) high dose melphalan (HDM) therapy followed by autologous stem cell transplant (ASCT). Overall hematological response (OHR) and organ response (OR) rates in the entire cohort after ASCT were 77% and 58% respectively. OHR and OR were 92% & 75% in V-pretreated group and 69% & 54% in pts who received no treatment. The trend was similar for other responses (Table 1). In a clinical trial by Huang, X., et al., induction therapy with Vd (V in combination with dexamethasone) prior to HDM/SCT was compared with frontline HDM/SCT in 58 patients. The OHR, and complete response (CR) between Vd+HDM/SCT (20 evaluable pts) and frontline HDM/SCT (23 evaluable pts) groups were 85.7% versus 53.5% and 67.9% versus 35.7% respectively. All organs showed better response in Vd+HDM/SCT group (Table 1). Vd/CyBorD (Cyclophosphamide, bortezomib, dexamethasone) prior to ASCT: In a prospective clinical trial by Sanchorawala et al., 35 pts were given induction with Vd before HDM and ASCT. Among 27 evaluable pts, OHR was 100% with CR in 76.9% and very good partial response (VGPR) in 23% pts. In a study by Hong et al., 20 patients received induction with Vd or CyBorD prior to ASCT. OHR was 89% with CR in 55%, partial response (PR) in 10% and VGPR in 33%. 5-year overall survival (OS) was 80% and 5-year progression free survival (PFS) was 69%. Vd/CyBorD without ASCT: In a retrospective study by Zhao et al., 23 pts received Vd. OHR was 100% with CR in 44% and PR in 38.9% pts. Median overall survival (mOS) was 38 months and 3-year OS was 41-72%. OR was 25% with kidney being the organ showing response in maximum pts (84%). Kikukawa et al., reported 8 pts who received CyBorD, OHR was 100% with CR in 50%, PR in 25% and VGPR in 25% pts. 63% pts showed OR in heart and/or kidney. In a study by Huang, B., et al., Vd was given to 12 renal ND-AL pts and among 10 evaluable pts, OHR was 80% with CR in 50% and PR in 10%. mOS was 8.2 months and OR was 50%. Other Regimens: In a study by Lee et al., involving 19 pts, VMP (bortezomib, melphalan, prednisone) was given as induction therapy. OHR was 84% with CR in 37%, PR in 26% and VGPR in 21% pts. OS was 39% at 2 years and PFS was 8 months. OR was 53% with heart (50%) and kidney (40%). In a retrospective review by Chari et al., 9 pts were treated with a triplet regimen (V, cyclophosphamide or lenalidomide/thalidomide and d). OHR was 88% with CR in 22% and PR in 66% pts. OR was 77% with heart and kidney both at 44%. Conclusion: In ND-AL pts, V-based combination regimens are very effective and well tolerated as induction therapy, or when used as therapy prior to HDM/ASCT and this approach resulted in better outcomes when compared to frontline HDM/ASCT. Three drug combination therapy with V is effective. Kidney and heart were the major organs to show improvement with therapy. Novel combinations need to be studied in randomized prospective clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Dartumumab in Pretreated AL Amyloidosis: A Systematic Review

Blood ◽

10.1182/blood-2020-138530 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 46-47

Author(s):

Iqraa Ansar ◽

Karun Neupane ◽

Hamid Ehsan ◽

Muhammad Yasir Anwar ◽

Hassaan Imtiaz ◽

...

Keyword(s):

Heart Failure ◽

Partial Response ◽

Light Chain ◽

Response Rate ◽

Renal Involvement ◽

Al Amyloidosis ◽

Cell Transplant ◽

Efficacy And Safety ◽

Mesh Terms ◽

Combination Regimens

Background: Amyloidosis is characterized by the deposition of misfolded lambda or kappa light chain (AL) proteins in tissue. It commonly affects the heart, which correlates with poor prognosis. Disease-modifying therapies aim to suppress the production of abnormal light chains. Daratumumab (Dara) use is associated with a reduction in light chain protein production. Dara is a human anti-CD38 monoclonal antibody approved for the treatment of newly diagnosed and Relapsed & Refractory Multiple Myeloma. AL amyloidosis plasma cells express CD38, and therefore, Dara is an attractive alternative in this setting. This review aims to assess the efficacy and safety of daratumumab in pre-treated AL amyloidosis patients. Methods: We conducted a comprehensive literature search in PubMed, Embase, Medline using MeSH terms and keywords "AL amyloidosis," "daratumumab", and "darzalex" to incorporate the studies published up to July 2020. We included studies assessing the efficacy and safety of daratumumab alone or in combination with other therapies in pretreated AL amyloidosis. After excluding duplicates, non-relevant, and review articles, we selected four prospective and twelve retrospective studies. RESULTS: In our review, data on 482 patients were included. The ages ranged from 35-88 years. The median number of prior therapies was 3 (ranges:2-6), and the most common therapy was bortezomib in 90% of patients followed by immunomodulators in 55% and stem cell transplant in 35%. A total of 260 (54%) patients received Dara monotherapy, 126 (26%) received Dara plus Dexamethasone (d), and 96 (20%) patients received other Dara containing two or three-drug regimens. The time from the diagnosis to the start of Dara therapy varied from 1 to 137 months. 71 % of patients had cardiac, and 62 % had renal involvement. There was a greater than 30 % reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in cardiac patients responsive to therapy. 1. Daratumumab monotherapy: Dara monotherapy achieved an overall response rate (ORR) of 76% (191/249), complete response (CR) of 30% (69/224), very good partial response (VGPR) of 41% (79/192) and partial response (PR) of 14% (19/140). The overall survival (OS) ranges from 59-100% at 10-12 months were noted. Table 1. 2. Daratumumab+ Dexamethasone: Dara plus d achieved ORR of 81% (86/106), CR of 51% (53/102), VGPR of 29% (18/62), PR of 15% (15/102), and OS of 87% at 24 months. Table 1. 3. Daratumumab with combination regimens: The use of Dara based combination regimens of Dara+pomalidomide (P)+d (36% of patients), Dara+lenalidomide (R)+d (32%) and Dara+bortezomib (V)+d (18%), reported by Abeykoon et al., showed an ORR of 88% (14/16), CR of 19 % (3/16), VGPR of 63% (10/16), PR of 6 %(1/16), OS of 89 % at 10 months and progression-free survival (PFS) of 83% at 10 months. Godara et al. reported an ORR of 100% (9/9) using a combination of Dara and birtamimab. The combination of D+cyclophosphamide (c)+V+d reported by Palladini et al. achieved an ORR of 96 % (27/28), CR of 36 % (11/28), VGPR of 29 % (8/28) and PR of 14 % (4/28).Table 1. The most reported adverse event was infusion-related reactions; grade 3-4 adverse were less than 10 % and mostly related to the heart (heart failure & atrial fibrillation). The most-reported hematological adverse effects were anemia, thrombocytopenia, neutropenia, infections, and sepsis. The most common non-hematological adverse events were heart failure, bronchitis, pneumonia, fatigue, nausea, and diarrhea. Table 2. Conclusion: Dara therapy is associated with promising efficacy with a response rate of more than 70% when used alone and more than 80% when used in combination. These regimens are well tolerated in advanced cardiac disease patients with a tolerable risk of volume overload and infusion-related complications. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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Induction with Bortezomib and Dexamethasone (BD) Followed By Risk Adapted High Dose Melphalan and Autologous Stem Cell Transplantation and BD Consolidation in Patients with AL Amyloidosis: A Phase II Feasibility Study

Blood ◽

10.1182/blood.v126.23.3178.3178 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3178-3178 ◽

Cited By ~ 1

Author(s):

Heather Landau ◽

Nicole Montanez ◽

Alexandra Cowan ◽

Hoover Elizabeth ◽

Carlos Flombaum ◽

...

Keyword(s):

Stem Cell ◽

Phase Ii ◽

Research Funding ◽

Treatment Initiation ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Weekly Schedule ◽

Newly Diagnosed ◽

Critical Determinant

Abstract Background: The depth and durability of hematologic response is a critical determinant of outcome in patients (pts) with light chain (AL) amyloidosis. Complete hematologic remissions (CR) following risk-adapted melphalan and stem cell transplant (RA-SCT) in pts with AL amyloidosis is associated with organ improvement and extended overall survival (OS). We have previously shown that using bortezomib and dexamethasone (BD) as consolidation following RA-SCT is associated with deeper hematologic responses and favorable outcomes. We have conducted a prospective phase II trial using BD as induction followed by RA-SCT and BD consolidation to determine the safety and hematologic and organ response rates of this treatment program for newly diagnosed, transplant-eligible pts with AL amyloidosis. Methods: Untreated pts with AL amyloidosis received 1-3 cycles of BD (B 1.3mg/m2, IV/SC, and D 40mg, IV/PO, days 1, 4, 8, 11). BD was discontinued before 3 cycles in patients who achieved CR. Pts were then assigned melphalan 100, 140 or 200mg/m2 based on age, renal function and cardiac involvement; Starting 3 months following RA-SCT, pts received six cycles of BD (B 1.3mg/m2, IV/SC and D 20mg, IV/PO days 1, 8, 15, 22) every 12 weeks as consolidation. Hematologic responses were assessed using International Society of Amyloidosis criteria (Palladini et al. JCO 2012) and organ responses using updated criteria (Palladini et al. Blood 2014), after induction, 3 months post RA-SCT, and at 12 and 24 months from treatment initiation. Patients with New York Heart Association Class III/IV heart failure, ECOG > 2 or > grade 2 neuropathy were ineligible. Results: Twenty pts, 70% male, with a median age of 60.1 years with renal (55%), cardiac (65%), liver/GI (15%) or nervous system (15%) involvement received BD induction and 18 patients have been transplanted. Two pts with cardiac disease died during BD induction (10% TRM); 85% of pts are alive with a median follow up of 28 mo. By intent to treat, 60% and 70% of patients achieved at least a very good partial response (>VGPR) following BD induction and RA-SCT, respectively. Overall, 95% of patients achieved hematologic responses (>PR) including 35% CR. Cardiac and renal responses were seen in 75% (N=8) and 60% (N=10) of evaluable pts at 1 year following treatment initiation. Most common grade >3 adverse events included GI (40%), Renal (30%), infectious (10%), and cardiovascular (10%); Grade 2 or higher neuropathy was seen in 40% of pts and warranted discontinuation of BD consolidation in 35% of pts. Conclusion: In newly diagnosed AL amyloidosis pts, BD induction followed by RA-SCT was safe and rapidly and effectively induced responses resulting in organ improvement. There was 10% TRM during BD induction and no deaths during transplant supporting the notion that early mortality in newly diagnosed AL pts is independent of treatment received. The high incidence of neuropathy may be related to the administration of BD on a twice weekly schedule and rendered some pts ineligible for post-transplant therapy. Whether transplant-eligible pts will ultimately derive more benefit from proteasome inhibitor induction versus consolidation is worthy of further study. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Janssen: Consultancy; Prothena: Consultancy, Honoraria; Takeda: Research Funding; Onyx: Honoraria, Research Funding. Landgren:Celgene: Honoraria; International Myeloma Foundation: Research Funding; BMJ Publishing: Consultancy; Onyx: Research Funding; Onyx: Consultancy; BMJ Publishing: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Pilot Study with Lenalidomide in Patients with POEMS Syndrome

Blood ◽

10.1182/blood.v118.21.4612.4612 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4612-4612

Author(s):

Andrea Nozza ◽

Fabrizia Terenghi ◽

Rita Mazza ◽

Eduardo Nobile Orazio ◽

Fausto Adami ◽

...

Keyword(s):

Stem Cell ◽

Pilot Study ◽

Clinical Manifestations ◽

Poems Syndrome ◽

Bone Lesions ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Neurological Improvement

Abstract Abstract 4612 Introduction: POEMS syndrome is a rare multisystemic disease. Vascular endothelial growth factor (VEGF) correlates with the activity of the disease and it could account for clinical manifestations. Actually no controlled trials are available and there is no clear evidence for a standard therapeutic approach. Lenalidomide has anti-angiogenic activity through inhibition of VEGF and TNF alpha The aim of this study is to evaluate efficacy and safety of Lenalidomide in POEMS syndrome. Patients & method: From 10/09, we started a pilot study with Lenalidomide plus dexamethasone (RD) in pretreated or newly diagnosed POEMS patients not eligible for transplant procedure. Lenalidomide 25 mg/day was given for 21 days in association with weekly dexamethasone 40 mg until toxicity or progression occurred. After 6 cycles, pts were evaluated for response. Utonow 10pts have been enrolled, 9 men and 1 woman; median age was 51 years (range 45–76). All pts were pretreated and 2 pts had previously received high-dose melphalan with peripheral blood stem cell transplant. Monoclonal component (MC) was detected in all pts: IgAl in 3 pts, IgG l in 6 pts, l light chain in 1; all pts had sensory/motor peripheral neuropathy. Sclerotic bone lesions were detected in 5 pts, endocrinopathies in 8 pts, skin changes in 8 pts, peripheral edema in 8 pts, organomegaly in 7 pts, lymphoadenophaty in 3 pts, papilledema in 7 pts, thrombocytosis in 3 pts. VEGF serum level was elevated in all patient with a median value of 3544 pg/ml (range 1430–9788). Results: Seven pts are still on treatment with a median of 10 RD cycles (range 5–18). Six pts are evaluable for response after 6 cycles. A clinical response, with improvement of all disease manifestations, was observed in all pts. Neurological improvement was observed after 3 RD cycles, and was confirmed by nerve conduction studies after 6 cycles. One patient with tetraparesis is currently able to walk and his upper limb strength is normal with improved sensory neuropathy. MC disappeared in 2 patients. VEGF levels decreased in all pts: from a median of 3544 pg/ml (range 1430–9788) before treatment to 1539 pg/ml (467-3579) after 6 cycles. Three pts discontinued treatment: 1 withdrew consensus, 1 dropped out after 4 cycles for progression and 1 died for pulmonary infection on cycle 1. Dexamethasone dose adjustment was necessary in 5 pts and lenalidomide in 2 pts, (1 extraematological toxicity and 11 thrombocytopenia). Conclusions: This preliminary analysis,although in a limited series, highlights efficacy and safety of Lenalidomide in POEMS. Noteworthy the neurological improvement has been rapid and continuous, also in heavily pre-treated pts. At this time no patients experienced disease progression. A clear relationship between response and VEGF level was confirmed. The study accrual is ongoing. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma.

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Melphalan Based Regimens for Treatment of Newly Diagnosed Amyloidosis, Lessons from Clinical Literature: A Systematic Review

Blood ◽

10.1182/blood-2019-127192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5561-5561

Author(s):

Muhaddis Ejaz Ahmad ◽

Muhammad Abdullah Yousaf ◽

Abdul Rafae ◽

Mustafa Nadeem Malik ◽

Tariq Iqtidar Sadiq Syed ◽

...

Keyword(s):

Stem Cell ◽

Cochrane Library ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Newly Diagnosed ◽

Group A ◽

Group B ◽

High Dose Melphalan ◽

Combination Regimens

Introduction: Melphalan causes cross linkage between DNA, causes cytotoxicity in both dividing and non-dividing tumor cells. Our objective is to analyze and summarize the published literature for the efficacy of melphalan based regimen used for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after June 2006, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 649 articles were identified initially and after detailed screening, we finalized 10 studies involving 616 ND-AL patients. Results: Melphalan (M), Bortezomib (V) and dexamethasone (d)/prednisone (p): A retrospective study by Zhao et al., included 123 ND-AL patients (pts) were given M, V, and d. Overall hematological response (OHR) was 100% with complete response (CR) in 44% and partial response (PR) in 38.9% pts. Median overall survival (mOS) was 38 months (mo) and 3-yr survival ranged from 41-72%. Organ response (OR) was 25%. In a study by Lee et al., with 19 pts who received M, V, and p demonstrated OHR of 84% (Table 1). Melphalan (M) and dexamethasone (d): Sanchorawala et al. (n=70) reported patients treated with M and d showed OHR of 69%, with CR in 13% and PR in 25%. Similarly, a study by Lebovic et al. reported 40 pts who were given M, d. OHR was 58% and 13% pts showed CR (Table 1). High dose Melphalan/Stem Cell Transplant (HDM/SCT) with and without induction: In study by Cowan et al., (n=45) pts in group A (n=21) were given novel induction using agents like protease inhibitor (PI), cyclophosphamide, bortezomib and dexamethasone (CyBorD), Lenalidomide (L), dexamethasone (d) prior to high-dose melphalan (HDM). CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given frontline HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. In a study by Scott et. al., 31 pts were categorized in 3 groups who received HDCT either with no induction, induction with V-based regimen and induction with other regimens including lenalidomide/dexamethasone (len/dex), melphalan/dexamethasone (mel/dex) and thalidomide/dexamethasone (Thal/dex). OHR in mel/dex cohort (n=3) was 67% (Table 1). In a study by Huang, X. et al., 56 pts were divided in two groups of 28 pts each. Pts in group A received Vd+HDM/SCT demonstrated CR in 67.9%, VGPR in 7.1%, PR in 10 .7 % and no response (NR) in 7.1 % pts. In group B, pts received with HDM/SCT upfront demonstrated CR in 35.7%, VGPR in 10.7%, PR in 2.1 % and no response NR in 21.4 % pts (Table 1). Randomized Standard dose Melphalan (SDM) versus HDM: In a study by Jaccard et al., there were two groups. The OHR was 68% in group A pts who were given SDM and high-dose dexamethasone (HD-dex) with CR in 31% and PR in 36% pts. The OHR was 67% in group B pts who were given HDM+ASCT with CR in 40% and PR in 25% pts (Table 1). Melphalan with Total body irradiaton (TBI): Vesole et al., reported 107 pts who were given M and TBI. OHR was 32% with CR in 16% and PR in 16% pts. mOS was 47.2 mo (Table 1). Melphalan (M), dexamethasone (d), Lenalidomide (L): In a clinical trial (NCT00890552) involving 25 pts M, d, and lenalidomide were give. CR, VGPR and PR were observed in 8%, 16% and 33%. 37.5% pts showed no-response (Table 1). Conclusion: Despite heterogeneity in the AL patient population and various regimens used in published literature, melphalan based regimens are very effective for treatment. Induction regimens and supportive care have evolved over the years. Novel combination regimens used for induction followed by HD-Melphalan consolidation along with careful selection of patients for high dose chemotherapy consolidation and stem cell transplantation in routine clinical practice is the best approach for personalized therapy selection for AL amyloidosis. Cytopenias of three cell lines are the major side effects reported with Mel therapy. Just like melphalan use for treatment of multiple myeloma in novel combination regimens, future randomized prospective trials are needed to better understand the efficacy and safety profile of melphalan based newer combination regimens for AL amyloidosis treatment. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Effect of Pre and Post-Transplantation Responses on Outcome of Multiple Myeloma Patients: CR and near-CR Should Not Be Considered as Equivalent Prognostic Markers. Results of a PETHEMA/Gem Prospective Study

Blood ◽

10.1182/blood.v112.11.161.161 ◽

2008 ◽

Vol 112 (11) ◽

pp. 161-161

Author(s):

Juan José Lahuerta ◽

Maria Victoria Mateos ◽

Joaquin Martínez-López ◽

Laura Rosinol ◽

Anna Sureda ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Plasma Cells ◽

High Dose ◽

Cell Transplant ◽

Post Transplantation ◽

Post Transplant ◽

Post Induction ◽

The Impact ◽

Response Post

Abstract To achieve CR is an important goal in the treatment of most Hematological malignancies. In Multiple Myeloma (MM) although there is evidence demonstrating an association between CR and long-terms outcomes, some trials have failed to find such a correlation. In addition, it is not clear whether different responses categories, such as CR, near-CR (nCR) o Very Good Partial Response represent different prognostic subgroups or include an homogeneous group of patients with similar outcomes. Therefore, the confirmation of a possible association between different responses categories and long-term outcomes is required. We evaluated the prognostic influence on EFS and OS of pre- and post-transplant responses in newly diagnosed MM patients. Patients and Methods: We analyzed 632 patients who had been included in the prospective GEM2000 trial. All were uniformly treated with VBCMP/VBAD induction followed by high-dose therapy and autologous stem cell transplant and maintenance therapy with interpheron plus prednisone. Disease response was assessed post-induction and post-transplant using EBMT criteria, modified to include nCR. CR required at least 6 weeks of negative immunofixation (IFx) in serum and urine plus less than 5% plasma cells in BM. nCR was defined as electrophoresis-negative but IFx-positive. Partial response (PR) required greater than 50% reduction in M-protein and Stable disease (SD) included patients with minimal response and no change by EBMT criteria. Results: Probability of achieving CR post-transplant was significantly higher among patients achieving nCR versus PR (p= 0.004) versus SD or PD (p= 0.0003) pre-transplant. Patients achieving nCR or PR post-induction had similar outcomes, and both response categories showed a trend to have inferior EFS and OS as compared to patients in CR. After transplant, only borderline differences in EFS were detected upon comparing nCR with PR (nCR: median 40 months; PR median 34 months, p=0.07), by contrast the EFS of CR patients (median 61 months) was significantly longer than that of nCR or PR categories (both comparisons p<10−5). OS was longer among patients achieving CR post-transplant (median NR) compared with patients achieving nCR (median NR, p= 0.01) or PR (61 months, p < 10−5); it should be noted that nCR patients had longer OS than PR patients (p = 0.04). The multivariate analysis showed that achieving CR was associatted with significantly better EFS and OS while the EFS/OS influence of nCR was no statistically different from PR or SD. Within nCR patients, outcomes were significantly worse among those who achieved nCR post-induction and remained in nCR post-transplant compared with those who upgraded to nCR post-transplant after PR or SD post-induction. EFS and OS, and influence of response, were similar among elderly (65–70 years) and younger (<65 years) patients. (both comparisons p<10). Conclusions: Our results confirm that the degree of response is highly associated with final survival, with higher benefit for patients achieving CR by IFx, which should not be pooled with the nCR patients. Although the impact in survival is more evident for the responses measures after HDT/SCT it is also evident after induction therapy, moreover, the quality of response post-induction clearly influences response post-transplant. Finally, patients between 65 and 70 years should not be completely discouraged from HDT/SCT.

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Velcade, Thalidomide and Dexamethasone (VTD) Regimen Followed by High-Dose Chemotherapy Plus Autologous Stem Cell Transplant (HDT-ASCT) as Front-Line treatment in Newly Diagnosed Multiple Myeloma (MM) Patients: Preliminary Results of An ongoing Open Label Study

Blood ◽

10.1182/blood.v112.11.5203.5203 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5203-5203

Author(s):

Nicola Di Renzo ◽

Elsa Pennese ◽

Pasquale Forese ◽

Giovanni Reddiconto ◽

Rosella Matera ◽

...

Keyword(s):

Stem Cell ◽

Partial Response ◽

Initial Treatment ◽

Response Rate ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Who Grade ◽

Term Survival ◽

Cd34 Cells

Abstract Background and aim: In the last decade HDT-ASCT has significantly improved progression-free and overall survival of patients with MM. Achievement of CR or good partial response and the tumor reduction attained with the induction pretransplant chemotherapy have been shown to be the most relevant prognostic factors for long-term survival. In recent years, novel drugs such as thalidomide and bortezomib have been introduced in the treatment of MM. Bortezomib (B) (VelcadeÒ) as a single agent, gives a response rate ranging from 35% to 50%, including up to a 9% CR rate in relapsed/refractory patients, and of 40%, with a 10% CR rate in the up-front setting. Thalidomide (T) has been identified as the first independently active agent in MM since the introduction of melphalan and prednisone and currently represent the milestone of initial treatment in elderly patients. Since B and T target different molecular pathways, we started a phase II trial in order to assess efficacy, toxicity and rate of PBSC collection after VTD regimen delivered as induction pretransplant chemotherapy in patients with newly diagnosed MM. Patients and Methods: from June 2007 to July 2008 14 pts (M/F: 11/3) with a median age of 56 years (range: 42–71) were enrolled in the study; six pts (43%) were more than 60 yo and 7 pts had a previous history of M-GUS lasting in median 54 months. At time of treatment there were 71%, 22% and 7% having Durie and Salmon staging III, II and I respectively, while ISS was 1 in 22%, 2 in 50% and 3 in 28% of cases. One pt had renal impairment, extensive bone disease was documented in 78% of cases with 2 pts showing extramedullary disease. Sixty-five percent of pts (9/14) had IgG MM, 14% IgA, 7% light chain, and 14% non secretory myeloma. Unfavourable cytogenetic was recorded in 36% (5/14) of cases. Bortezomib was administered at 1.3 mg/m2 on days 1,4, 8, 11 as short IV infusion, thalidomide at daily dose of 100 mg PO and Dexamethasone (40 mg/die PO) the day of bortezomib infusion and the day after (640 mg for each cycle) every 4 weeks for 3–4 courses. All patients received deep venous thrombosis prophylaxis consisting of aspirin 100 mg daily (44%), low molecular weight heparin (28%) and low dose warfarin (28%). Following VTD regimen patients underwent to high-dose cyclophosphamide (4 g/m2) with G-CSF support and peripheral stem cell harvest. MEL 200 was given as conditioning regimen. All patients received standard dose of zoledronic acid monthly. Results: At present time all patients are evaluable for VTD and PBSC collection while 10 for response after transplant. After 3 courses of VTD 93% of pts achieved more than a partial response including 57% of CR and 36% of VGPR. One pt achieved a PR. VTD regimen resulted well tolerated with main toxicity consisting of WHO grade III peripheral neuropathy recorded in 37 % of pts. There were no pts with relevant hematologic toxicity or other non-hematologic toxicities and there were no chemotherapy reduction or delay because of toxicity. None of pts developed DVT. A sufficient amount of CD34+ cells (median 6.5 × 106/kg; range: 2.7–11.6) was collected in 13 of 14 evaluable pts after a median of 1.4 aphaeresis (range:1–2). One pt failed to collect after CTX and was treated with HD-Ara-C obtaining an adequate number of CD34+ cells for transplant. The median CD 34+ cells infused in the 10 transplanted pts was 3.3 ×106/kg (range: 2.0 – 4.7). Times to platelet (20×109/L) and granulocyte (500×109/L) recovery were 13 and 10 days respectively. After HDC and ASCT 7 of 10 patients presented CR (70%) and 2 (20%) a VGPR with an ORR of 90%. One pt presented progression disease after 6 months from transplant. Conclusion: these very preliminary data suggest that VTD regimen given as pretransplant chemotherapy is effective and well tolerated regimen; the capacity to give high response rate in a short time without to compromise PBSC collection makes VTD regimen a good option for initial treatment of newly diagnosed MM patients although more pts and longer follow-up are needed to assess the real impact on survival of this regimen.

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Efficacy and Safety Profile of Proteasome Inhibitor Based Drug Regimens for Treatment of Newly Diagnosed AL Amyloidosis: A Systematic Review

Blood ◽

10.1182/blood-2020-143106 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Saad Javed ◽

Tariq Iqtidar Sadiq Syed ◽

Hejab Fatima ◽

Syed Hashim Ali Inam ◽

Tayyab Rehan ◽

...

Keyword(s):

Systematic Review ◽

Retrospective Study ◽

Partial Response ◽

Proteasome Inhibitor ◽

Phase Iii ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Phase Iii Trial ◽

Drug Regimens

Introduction: Light chain amyloidosis (AL) is a plasma cell disorder associated with detrimental manifestations in multiple organ systems of the body. It is estimated that approximately 1275-3200 new cases occur in the United States annually. Proteasome inhibitors (PI), such as bortezomib, carfilzomib, and ixazomib used for multiple myeloma treatment are also used for the treatment of AL amyloidosis. Our aim in this review is to evaluate the efficacy and safety profile of PI-based regimens for the treatment of newly diagnosed AL Amyloidosis (ND-AL). Methods: We conducted a systematic review (following PRISMA guidelines) by completing a comprehensive literature search on PubMed, Cochrane, ClinicalTrials.gov, and Embase on June 23rd, 2020. We were able to identify 901 articles, 325 articles from PubMed, 50 from Cochrane, 23 from Clinical Trials.org, and 253 from Embase. After the screening, we selected 11 published studies (n=436) including 5 phase lll trials, 2 phase I/II trials. Results: Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD) with or without Daratumumab (Dara): In a Phase lll trial (ANDEROMADA study), Palldini et al. (2020) studied the efficacy of Dara+ CyBorD vs CyBorD in ND-AL pts (n=28). The addition of Dara to CyBorD showed an improved overall hematological response (ORR) in 96% with complete response (CR) in 54% pts at a median follow up of 17.6 months (Table 1). In a retrospective study by Lim et al. (2017), CyBorD was given to ND-AL pts (n=39) which showed an ORR in 63% with very good partial response (VGPR) in 50% pts. In a retrospective study by Diaz-Pallares et al. (2020), CyBord was given to ND-AL pts (n=34) which showed an ORR in 91% with CR, VGPR, and partial response (PR) in 26%, 26%, and 38% pts, respectively. Progression-free survival (PFS) and overall survival (OS) were reported at 26.7 months and 22 months (P=0.06) respectively (Table 1). Bortezomib, Melphalan, Dexamethasone (BMD): In a phase III trial (EMN-03 study), Kastritis et al. (2020) studied the efficacy of BMD vs MD in ND-AL pts (n=109). Addition of B to MD showed an improved ORR: 81% vs 56% (p=0.001) with CR/VGPR in 53% vs 28% pts. No significant difference in survival outcome was observed. In a phase III trial, Kastritis et al. (2015) studied the efficacy of BMD vs MD in ND-AL pts (n=69). Addition of B to MD showed an improved ORR: 75% vs 53% (p=0.075) with CR/VGPR in 56% vs 42% pts (p=0.277). OS and PFS were also improved in BMD group as compared to control group: 83% vs 72% (p= 0.295) and 61% vs 49% (p=0.079) at 2 years, respectively (Table 1). Bortezomib, Melphalan, Prednisolone (BMP): In a retrospective study by Lee et al. (2014), BMP was given to ND-AL pts (n=19) which showed an ORR in 84% pts with CR, VGPR and PR in 37%, 21% and 26% pts, respectively (Table 1). Induction with B based regimens for ASCT: In a Phase lll trial (HOVON 104), Minnema et al. (2019), studied the efficacy of BD induction prior to HDM/ASCT in pts (n=35) with ND-AL. At 6 months, BD induction prior to HDM/ASCT vs No BD Induction prior to HDM/ASCT showed an ORR: 80% vs 80% with an improved CR: 43% vs 5% and VGPR: 54% vs 51%. In a Phase I/II trial by Sanchorawala et al. (2015), BD induction followed by B-HDM conditioning for ASCT was done in pts (n=27) with ND-AL. ORR at 6 months post ASCT was observed in 100% pts with CR and VGPR in 63% and 37% pts, respectively (Table 1). Induction with B based regimen prior to ASCT vs Upfront ASCT: In a retrospective analysis by Scharman et al. (2017), 53 pts who received ASCT were categorized into 3 groups i.e. Upfront ASCT, induction with B based regimen and induction with other regimens. ND-AL Patients (n=34/53) receiving B based induction vs no induction showed an improved ORR: 94% vs 69% (p=0.04). OS also improved in B based induction as compared to no induction group: 87% vs 77% (p=0.22) at 3 years. PFS at 3 years was 61% vs 69%, respectively (Table 1). Conclusions: PI-based regimens have shown favorable outcomes in the treatment of ND-AL and are effective therapeutic options. The most promising results are observed with CyBorD+Dara. The adverse events associated with PI-based therapy are peripheral neuropathy, anemia, thrombocytopenia, and infections. Further prospective clinical trials are warranted for a broader understanding of the safety and efficacy profile of PI-based regimens and correlation with individual pts characteristics. Table Caption: Table 1: Comparative efficacy and safety of proteasome-inhibitor based drug regimens in ND-AL Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-130689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5701-5701

Author(s):

Justin King ◽

Mark A. Fiala ◽

Scott R. Goldsmith ◽

Keith E. Stockerl-Goldstein ◽

Mark A. Schroeder ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Older Patients ◽

Research Funding ◽

Small Sample ◽

Poor Performance Status ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Equity Ownership

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

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Efficacy of Modified Vrd-Lite for Transplant Ineligible Multiple Myeloma

Blood ◽

10.1182/blood-2020-143459 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Mizuki Ogura ◽

Tadao Ishida ◽

Moe Nomura ◽

Hirofumi Irita ◽

Junichiro Nashimoto ◽

...

Keyword(s):

Adverse Effect ◽

Multiple Myeloma ◽

Cardiac Amyloidosis ◽

Staging System ◽

Treatment Interruption ◽

Cardiac Complications ◽

High Dose ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

The Impact

BACKGROUND: High dose chemotherapy followed by autologous peripheral blood stem cell transplantation is an effective treatment for multiple myeloma. However, many patients with newly diagnosed multiple myeloma are transplant-ineligible because of their age and complications, result in a poorer prognosis than transplant-eligible patients. Furthermore, many of them cannot complete normal chemotherapy because of low tolerability. Here, we investigated the efficacy and safety of modified bortezomib with lenalidomide and dexamethasone (mVRD-lite) for transplant-ineligible patients with newly diagnosed multiple myeloma. STUDY DESIGN: A retrospective observational analysis was performed on patients who received mVRd-lite for the first line chemotherapy between Jan. 2016 and Mar. 2020 in our hospital. Patients who received high dose dexamethasone to reduce tumor burden, and patients who received bortezomib with dexamethasone or lenalidomide with dexamethasone as a reduction regimen of mVRd-lite were also included. We evaluated ORR, OS, PFS and adverse effect. mVRD-lite at first was administered over a 28-day cycle. Bortezomib 1.3 mg/m2 weekly was administered subcutaneously on days 1, 8, 15 and 22. Lenalidomide 15 mg was given orally 18 days, omitted on days 1, 8, 15, which are the days of bortezomib administration. Dexamethasone 20 mg was given orally on days 1, 2, 8, 9, 15, 16, 22, which are the day of and day after bortezomib. We also reviewed patients background, especially complication of light-chain amyloidosis and considered the impact of cardiac amyloidosis on patient prognosis. This study was conducted with the permission of the Ethics Review Board in our hospital. RESULTS: The subjects analyzed totaled 40 transplant-ineligible patients. 11(27.5%) patients were AL amyloidosis associated with multiple myeloma and 8(20%) patients had cardiac amyloidosis. Median age at diagnosis was 73 (range 48-86) and Male:Female=1:1. Most of them were judged inadequate to transplantation due to their age, general condition, or complication. One patient was ruled unfit to transplantation, because of his refusion. The Revised International Staging System (R-ISS) were I in 5 (12.5%), II in 25 (62.5%) and III in 8 (20%). 5(25%) patients switched to maintenance therapy. 17(42.5%) patients discontinued treatment, because of adverse effect (cardiac failure 4 ; two of them combined with cardiac amyloidosis, rash 4, peripheral neuropathy 3, infection 3, etc). 2(5%) patients died during treatment by mVRd-lite, because of Grade 4 adverse effect, such as pneumonia. 11(27.5%) patients died during observation period and causes of death were primary disease and TRM. 1(2.5%) patient was died of heart failure associated with cardiac amyloidosis. The overall response rate(ORR) during treatment period of mVRd-lite was obtained in 34(85%), including sCR in 5 (12.5%), VGPR in 13 (32.5%) and PR in 14(30%). 2(5%) patients achieved MRD negative. SD were observed in 3(7.5%) patients. 3(7.5%) patients were not evaluated efficacy because of treatment interruption by adverse effect. Overall survival rate at two year is 64.3%, median OS was not reached, at a median follow-up of 20 months. CONCLUSIONS: Transplant-ineligible multiple myeloma patients are associated with poor prognosis. Modified RVD-lite is one of the appropriate therapeutic options, in the transplant-ineligible multiple myeloma patients. Twenty-five percent of patients with cardiac amyloidosis had treatment discontinued due to cardiac complications. Further study is needed for treatment of patients with multiple myeloma complicated with cardiac amyloidosis. Disclosures Ishida: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Ono pharmaceutical co: Speakers Bureau; Takeda pharmaceutical co: Speakers Bureau. Nashimoto:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Tsukada:Takeda pharmaceutical co: Speakers Bureau. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding.

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