Impact of Comorbidities at Diagnosis of Acute Myeloid Leukemia on One-Year Mortality

Abstract The hematopoietic cell transplantation comorbidity index (HCT-CI) was specifically developed to assign weighted scores to comorbidities existing prior to allogeneic HCT; thus stratifying post-HCT mortality risks. The utility of comorbidities assessed prior to treatment for AML is unknown. Here, we a) investigated the impact of each comorbidity on 1-year overall mortality of patients (pts) with newly diagnosed AML, b) designed and validated a new comorbidity score (AML-CI) comparing its performance to that of the HCT-CI, and c) identified other relevant risk factors for AML outcomes. We retrospectively collected comorbidities and laboratorydata from 1079 pts with newly diagnosed AML who received therapy at 5 institutions from 2008- 2012. Pts were aged ≤49 (29%), 50-59 (25%), 60-69 (26%), and ≥70 (20%) years old. Cytogenetic-risks were favorable (21%), intermediate (36%), or unfavorable (43%). Regimen intensity was low in 18%, intermediate in 63%, and high in 19%. HCT-CI comorbidities were evaluated per HCT-CI standard comorbidity definitions with the exception that renal comorbidity was defined per serum creatinine and/or creatinine clearance. Newly evaluated comorbiditiesincluded including hyperlipidemia, hypertension, deep venous thrombosis, gastroesophageal reflux disease, hypothyroidism, hypoalbuminemia, thrombocytopenia, neutropenia, anemia, elevated lactate dehydrogenase (LDH), smoking, and alcohol intake. Pts were randomly divided into a training (n=710) and a testing set (n=369). In the training set, the unadjusted hazard ratios (HRs) for 1-year overall mortality were calculated for each comorbidity as well as all adjustment factors: gender, age, race, cytogenetic-risks, regimen intensity, WBC, blast count, and marrow blast percentages. Only factors that were associated with overall mortality at a significance level of P <.10 proceeded to the multivariate model. Each comorbidity that entered the multivariate model was then adjusted for the effect of other comorbidities as well as gender, age, cytogenetic-risks, and regimen intensity (Table 1). The adjusted HRs were employedas weights for individual comorbidities. In the validation set, the new AML-CI incorporating comorbidities had comparable power of prediction for 1-year overall mortality as the HCT-CI (c-statistic estimates of 0.6 for each). Augmenting the HCT-CI with the three new covariates: platelets, albumin, and LDH yielded c-statistic estimate of 0.61. Other than comorbidities, age (c-statistic of 0.65) and cytogenetic-risks (c-statistic of 0.62) independently predicted overall mortality (Table 2). Comorbidities at diagnosis of AML heavily influenced the survival of pts over the year following diagnosis. The new AML-CI has similar predictive power as the HCT-CI suggesting appropriateness of using the HCT-CI at diagnosis of AML given its familiarity to physicians. The augmented HCT-CI, age, and cytogenetic-risks independently stratified for risks of 1-year mortality. In the future, studying physical, cognitive, and social health might further clarify the prognostic role of increasing age. Targeting health limitations with interventions alongside specific AML-therapy might improve survival of patients. Table 1. Components of a new AML-CI based on multivariate evaluation of impact of comorbidities on 1-year mortality after diagnosis of AML Comorbidities HR Assigned score for AML-CI Arrhythmia* 1.0 ─ Coronary Artery* 1.1 ─ Valvular* 1.3 1 Cerebrovascular * 1.3 1 Hepatic* Mild 1.2 ─ Moderate/severe 1.2 ─ Renal* Mild 1.1 ─ Moderate/severe .8 ─ Pulmonary* Mild .9 ─ Moderate/severe 1.1 ─ Diabetes* 1.3 1 Tumor* 1.7 1 Peptic Ulcer* 1.3 1 Psychiatric* 1.3 1 Hyperlipidemia 1.0 ─ HTN 1.2 ─ Albumin <4 - 3.5 1.3 1 <3.5 - 3 1.2 1 <3 1.7 1 Platelets <100 - 50 1.2 ─ <50 - 20 1.4 1 <10 1.7 1 LDH >200 - 500 1.5 1 >500 - 1000 1.4 1 >1000 2.2 2 Smoking Former 1.2 ─ Current 1.1 ─ *included comorbidities within HCT-CI Table 2. Probabilities of 1-year survival per 6 different models in the validation set AML-CI HCT-CI Augmented HCT-CI* Score % OS Score % OS Score % OS 0-1 18 69 0 20 72 0-2 24 70 2 28 68 1-2 35 61 3-4 28 63 3 30 56 3-4 28 57 5-7 33 58 ≥4 23 45 ≥5 18 42 ≥8 15 34 Age Cytogenetic-risks Augmented HCTCI* + age + cyto Group % OS Group % OS Score % OS 0-49 27 81 Favorable 19 87 2-4 17 86 50-69 51 60 Intermediate 36 63 5-7 37 67 70+ 22 31 Unfavorable 45 45 8-10 27 54 ≥11 19 28 *included HCT-CI + albumin, platelet counts and LDH Disclosures Fathi: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Exelexis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Lee:Kadmon: Consultancy; Bristol-Myers Squibb: Consultancy.

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ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽

10.1182/blood.v122.21.92.92 ◽

2013 ◽

Vol 122 (21) ◽

pp. 92-92 ◽

Cited By ~ 27

Author(s):

Giuseppe Saglio ◽

Andreas Hochhaus ◽

Timothy P. Hughes ◽

Richard E. Clark ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Eligibility Criterion ◽

Molecular Response ◽

Newly Diagnosed ◽

Long Term Outcomes ◽

Vascular Events ◽

Advisory Committees ◽

The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

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Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v120.21.1676.1676 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1676-1676 ◽

Cited By ~ 13

Author(s):

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Surapol Issaragrisil ◽

Richard E Clark ◽

Josy Reiffers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

The Impact

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID; n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

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Impact of Renal Impairment (RI) on Outcomes after Treatment (Tx) with Lenalidomide and Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts): First Trial Results

Blood ◽

10.1182/blood.v124.21.2112.2112 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2112-2112

Author(s):

Meletios A. Dimopoulos ◽

Matthew C Cheung ◽

Murielle Roussel ◽

Ting Liu ◽

Barbara Gamberi ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Board Of Directors ◽

Normal Renal Function ◽

Research Funding ◽

Failure Time ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Of Death ◽

The Impact

Abstract Background: Approximately 20–40% of pts with NDMM present with RI, which is associated with a negative impact on survival (Rajkumar, 2005). In the pivotal phase 3 FIRST trial (median follow-up 37 months [mos]), continuous Rd improved progression-free survival (PFS) vs. melphalan-prednisone-thalidomide (MPT) in elderly NDMM pts by 28% (25.5 vs. 20.7 mos; HR = 0.72; P < 0.01) (Facon, Blood 2013). Although 121 pts receiving continuous Rd are still on Tx, the interim overall survival (OS) analysis showed a 22% reduction in the risk of death in favor of continuous Rd vs. MPT (HR = 0.78; P = 0.02). The present analysis was conducted to determine the impact of RI on PFS, OS, and time to 2nd antimyeloma Tx (AMT) as clinical study outcomes. Methods: Pts were randomized to 3 Tx arms: continuous Rd until progression (n = 535); Rd for 18 cycles (72 weeks) (Rd18; n = 541); or MPT for 12 cycles (72 weeks) (n = 547). Enrolled NDMM pts were categorized according to their renal function: 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (≥ 50 and < 80 mL/min), 23% had moderate RI (≥ 30 and < 50 mL/min), and 9% had severe RI (< 30 mL/min). Pts requiring dialysis were excluded. Lenalidomide starting dose was 25 mg QD for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg QOD for severe RI. Melphalan dose was reduced by 50% in pts with moderate or severe RI. The primary endpoint was PFS (continuous Rd vs. MPT); secondary endpoints were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety, and improvement in renal function from baseline. Improvement in RI was defined as shifts from baseline to most extreme post-baseline value of the calculated CrCl as a measure of renal function during the active Tx (N = 1484). Results: A PFS benefit favored continuous Rd vs. MPT irrespective of the degree of renal function (Table 1): there was a benefit in pts with normal renal function (HR = 0.72 (0.51–1.02); P = 0.06), and better in pts with mild RI (HR = 0.79 (0.62–1.00); P = 0.05) and moderate RI (HR = 0.62 (0.45–0.85); P < 0.01). A PFS benefit was also seen with continuous Rd vs. Rd18 (a secondary comparison) in pts with mild RI and moderate RI (P < 0.01 for both). An interim OS benefit with continuous Rd vs. MPT was observed in most renal subgroups. Similar results were observed between Rd18 and MPT in terms of PFS or interim OS in any of the renal subgroups. Continuous Rd, compared with Rd18 or MPT, extended time to 2nd AMT in most renal groups except severe RI (CrCl < 30mL/min) (Table 2). Improvement in RI was observed more frequently in pts treated with continuous Rd than those with Rd18 or MPT: improvement of mild RI, 48%, 43%, and 48%, respectively; of moderate RI, 67% 61%, and 62%; and of severe RI, 64%, 59%, and 56%. Overall, < 5% of pts in any Tx group experienced a worsening in renal function status during Tx (continuous Rd 2.2%; Rd18 2.8%; MPT 2.7%). The most common grade 3–4 adverse events (AEs) for these Txs were anemia, neutropenia, thrombocytopenia, deep-vein thrombosis/pulmonary embolism (DVT/PE), and peripheral sensory neuropathy (Table 3). Tx discontinuation due to AEs increased in pts with moderate and severe RI, regardless of the type of Tx (Table 3). Conclusions: PFS, OS (at interim analysis), and time to 2nd AMT outcomes generally improved continuous Rd vs. Rd18 or MPT in transplant-ineligible NDMM pts with normal renal function, and in those with mild or moderate RI. The small number of pts in the severe RI group precluded a meaningful conclusion. Continuous Rd was generally well tolerated and renal function improved in the majority of pts during Tx with continuous Rd vs. Rd18 or MPT. Disclosures Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Roussel:Celgene: Consultancy, Lecture fees Other, Research Funding. van der Jagt:Celgene Corporation: Research Funding. Jaccard:Celgene Corporation: Honoraria, Research Funding. Tosikyan:Celgene: Consultancy. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Celgene Corporation: Consultancy, Research Funding. Schots:Celgene: Research Funding. Chen:Celgene Corporation: Employment. Marek:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma – Subgroup Analysis from the GMMG-MM5 Trial

Blood ◽

10.1182/blood.v124.21.3475.3475 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3475-3475 ◽

Cited By ~ 1

Author(s):

Maximilian Merz ◽

Hans Salwender ◽

Mathias Hänel ◽

Uta Bertsch ◽

Christina Kunz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Group Iv ◽

Route Of Administration ◽

Prolonged Treatment ◽

Newly Diagnosed ◽

Advisory Committees ◽

The Impact

Abstract Background: In patients with relapsed multiple myeloma (MM), Moreau and colleagues (Lancet Oncol, 2011) demonstrated that subcutaneous (SC) administration of bortezomib (BTZ) significantly reduced rates of adverse events (AE) compared to the intravenous (IV) formulation without loss of efficacy. Prospective data on SC BTZ in newly diagnosed MM are limited. We investigated the impact of SC versus IV BTZ in two different induction therapies for patients with newly diagnosed MM treated within the multicenter, prospective randomized MM5 trial of the German Myeloma Multicenter Group (GMMG). Methods: From 06/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12 and 17-20) or 3 cycles VCD (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Cyclophosphamide 900 mg/m2IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9 and 11-12) for induction therapy. In the MM5 trial, induction therapy is followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. Primary end points of the ongoing study are response to treatment after induction therapy and progression-free survival. Due to improved AE profile of SC compared to IV BTZ reported by Moreau, the administration of BTZ was changed from IV to SC in 02/2012. Therefore, we were able to perform an explorative analysis of 598 patients who received at least one dose of trial medication (PAd: n=150 IV / 140 SC; VCD: n=154 IV / 140 SC). 14 patients were excluded from the analysis because administration of BTZ was changed after start of induction therapy. We analyzed whether the route of administration influenced the applied cumulative BTZ dose, toxicity and efficacy of PAd and VCD. Results: The cumulative applied BTZ dose was significantly higher in patients treated with SC BTZ (PAd: 28.9 mg; VCD: 28.8 mg) compared to IV-treated patients (PAd: 27.6 mg; VCD: 27.9 mg; p = 0.007). Analysis of reported AEs associated to induction therapy revealed a significantly higher rate in patients treated with IV BTZ (65.1%) compared to SC-treated patients (55.7%, p = 0.02). AE > °II were reported more frequently in the IV group (IV: 52.0%; SC: 43.9%, p = 0.004). In detail, abnormal laboratory findings including leucopenia and thrombocytopenia (IV: 23.0%; SC: 16.4%, p = 0.05), metabolism and nutrition disorders (IV: 12.5%; SC: 5.4%, p = 0.004) and gastrointestinal disorders (IV: 9.9%; SC: 3.9%, p = 0.006) occurred more often in IV-treated patients. Analysis of peripheral neuropathy (PN) ≥ °II revealed no significant differences between IV and SC BTZ during the first two cycles of induction therapy (cycle 1: IV: 1.6%; SC: 2.5%; cycle 2: IV: 2.3%; SC: 3.6%) but PN occurred more often in IV-treated patients during the third cycle of induction therapy compared to the SC group (IV: 7.6%; SC: 1.8%, p = 0.001). Overall response rates (partial response or better) were not influenced by the route of administration in patients treated with PAd (IV: 72.7%; SC: 70.7%; p = 0.79) or VCD (IV: 77.9%; SC: 82.1%; p = 0.39). Analysis of the VCD arm showed that rates of VGPR or better were significantly higher in patients treated with IV BTZ compared to SC-treated patients (IV: 41.6%; SC: 28.6%, p = 0.02). Rates of VGPR or better were also higher for IV-treated patients in the PAd arm but did not reach statistical significance (IV: 36.7%; SC: 31.4%, p=0.39). Patient characteristics including baseline creatinine levels > 2 mg/dl, obesity or age at inclusion > 65 years did not influence efficacy of IV or SC BTZ in both arms. Conclusion: Last year we reported on the favorable toxicity profile and equal efficacy of VCD compared to PAd. With the current analysis we demonstrate that toxicity is further reduced with SC BTZ compared to IV. We therefore recommend VCD as induction therapy. However, we show for the first time a possible loss of efficacy in SC-treated patients. Therefore it remains unclear whether the reduced toxicity justifies the general application of SC BTZ in newly diagnosed, transplant-eligible patients or whether a prolonged treatment (4 x VCD SC) may reduce toxicity while achieving similar efficacy. Further studies are warranted since our results are partially in contrast with the previously presented data in relapsed MM and the ongoing MM5 trial was initially not designed to prospectively investigate the effect of SC or IV BTZ. Disclosures Salwender: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Celgene: Honoraria; Janssen: Honoraria. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Schmidt-Wolf:Janssen: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

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A Novel Approach to Risk Stratification in Multiple Myeloma Using ISS Stage and FISH

Blood ◽

10.1182/blood-2019-130639 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1800-1800 ◽

Cited By ~ 1

Author(s):

Shaji K. Kumar ◽

Patricia Greipp ◽

Morie A Gertz ◽

Angela Dispenzieri ◽

Linda B Baughn ◽

...

Keyword(s):

Risk Assessment ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Final Model ◽

Survival Table ◽

The Impact ◽

1Q Gain

Background: A variety of risk factors have been described in multiple myeloma and current risk assessment incorporates ISS stage with specific FISH results and serum LDH (R-ISS). However, this model does not include all the current abnormalities described as prognostic for survival in multiple myeloma. Importantly, the impact of many of these high-risk abnormalities are not uniform. We examined if we can better integrate FISH results into a risk assessment tool to better predict the outcomes of newly diagnosed MM. Patients and methods: We studied a cohort of 1316 patients with FISH done within 6 months of diagnosis of MM, in whom results for commonly observed abnormalities were available. We specifically examined the individual impact of common translocations involving chromosome 14, MYC rearrangements, chromosome 1q gain (single or multiple duplication) and del13q/monosomy 13. A risk assessment system was developed, weighting each abnormality according to their Risk Ratio and integrating ISS stage and serum LDH into the final model construction. Overall survival was calculated from diagnosis, with those alive at last follow up being censored. Results: We first examined the impact of each of the above FISH abnormalities: 1) high risk translocations [t(4;14), t(14;16), or t(14,20)], 2) trisomies, 3) t(11;14), 4) MYCrearrangements, 5) del13q/monosomy 13, and 6) 1q gain . Each of the abnormalities, except for t(11;14), was prognostic for survival (Table 1 with the risk ratios). For 1q gain, the median OS was NR, 105 mos and 79 mos respectively for no abnormality, duplication of 1 copy and duplication of multiple copies, (p<0.001). On multivariate analysis, t(11;14) and trisomies were no longer prognostic for overall survival (Table 1). The cumulative impact of abnormalities demonstrated worsening survival in the presence of increasing numbers of abnormalities (Figure 1). Including ISS stage 3 and LDH > ULN as additional variables for prognostication indicated both were individually prognostic for OS. In a multivariate analysis, including these two and FISH abnormalities, 1q gain and LDH were not independently prognostic. The final model consisted of HR translocations, MYCrearrangements, del17p/monosomy 17, del13q/monosomy 13, and ISS stage 3. Each of these variables was weighted using their risk ratio and a composite score was developed using 998 patients for whom all variables were available (range: 0-7.9; median 1.8). Three patient groups were characterized: group 1 (0; 32%), group 2 (1-4; 58%) and group 3 (>4; 10%) with a median OS of 53 mos, 106 mos, and NR, respectively, p <0.001 (Figure 2). Conclusion: Using the most relevant FISH and laboratory factors, in a large cohort of patients, we refined the current system to develop a risk stratification system that predicts survival in patients with newly diagnosed MM treated with contemporary treatment regimens. This needs validation in future studies. Disclosures Kumar: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Gertz:International Waldenstrom Foundation: Research Funding; Annexon: Consultancy; Medscape: Consultancy, Speakers Bureau; Amyloidosis Foundation: Research Funding; Abbvie: Other: personal fees for Data Safety Monitoring board; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Consultancy. Dispenzieri:Akcea: Consultancy; Janssen: Consultancy; Intellia: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Cellectar: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

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Quality of Life During Early Tyrosine Kinase Inhibitor Treatment As Self-Reported by Chronic Myeloid Leukemia Patients Participating in a Prospective Observational Study (SIMPLICITY)

Blood ◽

10.1182/blood.v118.21.4435.4435 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4435-4435

Author(s):

Jorge E. Cortes ◽

Michael J. Mauro ◽

Stuart L. Goldberg ◽

Ron Paquette ◽

H. Jean Khoury ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Treatment Adherence ◽

Treatment Satisfaction ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

The Impact

Abstract Abstract 4435 Background: Over the past decade, oral BCR-ABL inhibitors including imatinib, dasatinib and nilotinib have revolutionized chronic myeloid leukemia (CML) treatment. Clinical trials have provided evidence of improved outcomes with all three agents in the treatment of CML. However, limited information is available regarding the impact of disease and treatment on quality of life (QoL) in CML patients. Methods: SIMPLICITY is an ongoing 5-year USA/European prospective, observational cohort study (ClinicalTrials.gov ID: NCT01244750). Eligibility criteria include: newly diagnosed CML-CP, age ≥18 years and therapy with 1st-line imatinib, dasatinib or nilotinib at participating medical centers. The study aims to capture information on the use of these agents in clinical practice, including their impact on patient QoL. Through self-administered patient-reported outcomes (PRO) questionnaires, QoL and treatment-adherence data are being collected at 6-month intervals throughout study follow-up. Data from available initial PRO assessments of patients enrolled as of August 2011 are presented: Cancer Treatment Satisfaction Questionnaire (CTSQ), MD Anderson Symptom Inventory - CML (MDASI-CML), FACT-G (Functional Assessment of Cancer Therapy-General) and Morisky Medication Adherence Scale - 8 item (MMAS-8). Results: A total of 74 patients currently enrolled was included in this analysis of which 79.7% (n=59) received imatinib, 10.8% (n=8) received nilotinib and 9.5% (n=7) received dasatinib as 1st-line CML treatment. Median age was 57 years (range 19–94 years); a slightly higher proportion of patients were female (59.5%; n=44); and median time to completion of the PRO questionnaires from initiation of treatment was 383.5 days (range 4-1,225 days). Prior to completion of the PROs, mean treatment exposure was approximately 18 months for imatinib, 5 months for nilotinib and 4 months for dasatinib. Summary scores for the CTSQ, MDASI-CML and FACT-G are presented in Table 1. Due to small sample size, differences in scores between treatments were not statistically tested. At time of enrollment in the study, treatment satisfaction in this cohort was high (SWT score ± standard deviation [SD] =91.2 ±10.3). QoL, as measured by the FACT-G total and sub-scale scores, also indicated positive physical, social, emotional and functional well-being. Mean MDASI scores for Symptom Interference and Symptom Distress suggested the impact of symptoms was mild to moderate. From the MMAS-8, 71.8% (n=51) of patients reported medium/high adherence to their CML medication (scoring between 6–8 on an 8-point scale). Conclusions: Preliminary QoL evaluation suggests that newly diagnosed CML-CP patients are generally satisfied with treatment and report overall good health, although approximately 30% reported low adherence to their CML treatment. Initial assessment of the enrolled cohort suggests variance in treatment adherence patterns, as well as differences in the impact of symptoms by treatment; however, as these differences were not statistically tested, no firm conclusions can be drawn at this time. As patient enrollment continues, comparative effectiveness of these CML treatments and differences in QoL outcomes will be further observed. Disclosures: Cortes: Novartis: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy. Mauro:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Ariad: Research Funding. Goldberg:Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paquette:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Khoury:BMS: Membership on an entity's Board of Directors or advisory committees. Hirji:BMS: Employment. Wagner:BMS: Employment. Joo:BMS: Employment. Davis:BMS: Employment.

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A Phase 2 Study of Bortezomib Plus High-Dose Melphalan (Mel/Vel) Conditioning for Autologous Hematopoietic Cell Transplantation In Multiple Myeloma,

Blood ◽

10.1182/blood.v118.21.4158.4158 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4158-4158 ◽

Cited By ~ 1

Author(s):

Taiga Nishihori ◽

Leonel Ochoa ◽

Joseph Pidala ◽

Kenneth H. Shain ◽

Rachid Baz ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Conditioning Regimen ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Autologous Hct ◽

One Year ◽

High Dose Melphalan

Abstract Abstract 4158 Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is a preferred primary treatment approach for those patients who have adequate organ function and performance status. We previously reported the use of melphalan + bortezomib conditioning regimen for tandem transplants in a different group of patients with refractory myeloma (Alekshun, et al. ASH 2007). In this study, we examine the effects of adding bortezomib to standard high-dose melphalan in patients with newly diagnosed myeloma who have chemosensitive disease. Methods: Thirty five newly diagnosed multiple myeloma patients with responsive disease (partial response (PR) or better) to induction therapy were enrolled to the study from January 2010 to June 2011. Patients received high-dose melphalan conditioning at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel). Those patients who achieved PR post induction were considered for tandem autologous transplant with Mel/Vel conditioning. Results: To date, 35 patients received autologous HCT conditioned with Mel/Vel, and 32 are evaluable for response. Median age is 56 years (range, 25 – 72) with the following disease characteristics: IgG (n=21), IgA (n=8), IgD (n=1), light chain (n=5). High-risk cytogenetics/FISH were seen in 13 patients (37%). Median beta-2 microglobulin was 3.5 (range, 1.3 – 34.8). Sixteen patients received bortezomib-based induction, 9 patients received lenalidomide-based therapy and 10 received both bortezomib and lenalidomide. Median time from initiation of induction to transplant was 221 days (range, 134 – 664). Responses to induction therapy were stringent CR (n=10), CR (n=4), very good partial response (VGPR) (n=13), and PR (n=8). Median CD34 cell dose is 4.86 × 106/kg (range, 2 – 20.08). Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 16 days (range, 11 – 19). Two patients received tandem HCT. Best responses post transplant were sCR (n=19), CR (n=3), VGPR (n=7), PR (n=1) and progressive disease (n=2). The one year progression-free survival (PFS) estimate is 77% (95% CI 0.59 – 0.95) and one year overall survival (OS) estimate is 96% (95% CI 0.88 – 1.00) with a median follow-up of 279 days (range, 47 – 515). We did not detect significant differences in OS (p=0.69) stratified by cytogenetic/FISH risk status. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses post transplant. This early result is encouraging and the regimen will be examined in expanded cohort of patients. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding.

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Quality of Life Data from a Prospective Randomised Trial of Newly Diagnosed Myeloma Patients with Renal Failure: Optimal Trial

Blood ◽

10.1182/blood-2020-140937 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Karthik Ramasamy ◽

Gulnaz Iqbal ◽

Mark T Drayson ◽

Richard Brouwer ◽

Sherin Varghese ◽

...

Keyword(s):

Renal Failure ◽

Renal Impairment ◽

Board Of Directors ◽

Research Funding ◽

Literature Search ◽

Newly Diagnosed ◽

Advisory Committees ◽

Ckd Stage ◽

The Impact

Background Renal impairment is a life threatening complication of myeloma with up to 20-25% of patients presenting with renal dysfunction. Around 28% of newly diagnosed myeloma patients with renal failure do not survive beyond 100 days compared with 10% overall. In addition to poor survival, there are no quality of life (QoL) data from published renal failure myeloma studies to guide management. OPTIMAL trial utilizes the EuroQoL (EQ-5D-3L) heath questionnaire, a validated instrument for health outcomes, to measure QoL in these patients. It is a 3 level, 5 dimensional questionnaire, assessing mobility, self-care, usual activity, pain/discomfort and anxiety/depression with either no problems, some problems or extreme problems. Participants also rate their current health on a visual analogue scale (VAS) of 0-100. We hypothesize that reported QoL in typical myeloma trials are better than the QoL for patients with renal impairment such as those recruited into the OPTIMAL trial. Methods OPTIMAL is a randomised, multi-centre phase II trial of newly diagnosed myeloma patients with renal impairment (ClinicalTrials.gov Identifier: NCT02424851). Participants were randomised to receive four 12 week cycles of Bortezomib, Bendamustine and Dexamethasone (BBD) or Thalidomide, Bendamustine and Dexamethasone (BTD); all participants received bendamustine and dexamethasone in 3 week cycles. Participants not considered suitable for autologous stem cell transplant (ASCT) could be given a further 2 cycles of treatment in their respective arms. Patient reported outcomes were measured using the validated EQ-5D-3L. Participants were asked to complete a questionnaire at baseline and on day 1 of each treatment cycle and at 1 month and 12 month follow up visits. Differences in changes of EQ-5D-3L and the VAS scores between baseline and 1 month follow up were assessed by 2 sample t-tests. To compare the EQ-5D-3L data from the OPTIMAL trial to others, a literature search was conducted to see if any data were available that provided further insight into the QoL in patient's diagnosed with myeloma and renal failure. PUBMED and MEDLINE were explored and authors emailed if EQ-5D-3L data was not identified. Results OPTIMAL recruited 31 patients between March 2015 and March 2019 from 7 centres within the UK. Of these, 17 patients completed EQ-5D-3L at baseline and at 1 month follow up; 8 on BBD and 9 on BTD. Sixty five per cent of patients were ≤70 years old, 76% male, 35% were CKD stage 4 and 65% were CKD stage 5, 59% had planned ASCT, 88% had ECOG performance status 0 or 1, 35% were on dialysis and 94% were ISS stage III. At baseline a mean of 35.2% of patients reported some or extreme problems across the 5 QoL domains compared with 36.6% at 1 month follow up (Table 1). No significant changes were detected in mean EQ-5D-3L (p=0.33) or VAS scores (p=0.72) between baseline and 1 month follow up by treatment arm (Table 2). Additionally, no differences in EQ-5D-3L scores were found between age group or dialysis status (p>0.1; Table 3). However, some improvement in anxiety and depression levels were observed overall with 59% of patients reporting none at baseline increasing to 76% at follow up. No changes were reported in self-care or the ability to perform usual activities. Mobility decreased from 71% experiencing no problems to 59%. In order to compare QoL reported by OPTIMAL with QoL reported in published myeloma trials, a literature search was undertaken and identified 48 articles of which only 11 studies reported QoL and only 4 of these reported the EQ-5D-5L. No studies assessed QoL in patients similar to the OPTIMAL trial patient population with renal impairment. However a couple of studies demonstrated improved QoL at 3 months compared to baseline across treatment arms. Conclusion It is well known that treatments used within clinical trials can significantly improve the outcomes for patients but it is important to also measure the impact on patient's QoL. The OPTIMAL trial demonstrated that this poor prognostic set of patients with renal impairment had significant reduction in anxiety and depression at 1 month follow up. It was disappointing that a literature search demonstrated a paucity of QoL data routinely collected and reported within clinical trials. Patients need to know the impact of treatments on outcomes such as survival but also need to know the impact on their QoL. Funding: NAPP Pharmaceuticals, JANSSEN-Cilag Ltd and Blood Cancers UK. Disclosures Ramasamy: Takeda: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol Myers Squibb: Research Funding; GSK: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Janssen: Research Funding; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Lindsay:Amgen: Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses.

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

Blood ◽

10.1182/blood-2021-145533 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 483-483

Author(s):

Susan Bal ◽

Saurabh Chhabra ◽

Natalie S. Callander ◽

Eva Medvedova ◽

Bhagirathbhai Dholaria ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Post Induction ◽

The Impact ◽

Autologous Hematopoietic Cell Transplantation

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

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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