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

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

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Outcomes of Newly Diagnosed Myeloma Patients Requiring Dialysis: Dialysis Independence Is Associated with Rapid Myeloma Response and Predicts for Longer Survival

Blood ◽

10.1182/blood.v128.22.4492.4492 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4492-4492

Author(s):

Meletios A. Dimopoulos ◽

Maria Roussou ◽

Maria Gavriatopoulou ◽

Despina Fotiou ◽

Dimitrios Ziogas ◽

...

Keyword(s):

Renal Failure ◽

High Risk ◽

Supportive Care ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

High Dose Dexamethasone

Abstract Renal failure (RF) is a common severe complication of symptomatic myeloma and may be severe enough to require extrarenal dialysis in approximately 1-5% of newly diagnosed patients. Severe RF is associated with high risk of early death and increased morbidity. Immediate effective anti-myeloma therapy and vigorous supportive care are the cornerstones of management. The use of high cutoff hemodialysis to rapidly reduce the load of nephrotoxic light chains seems to offer limited additional benefit in patients requiring dialysis when treated with bortezomib-based therapies (Cook M et al EHA 2016, Abs P270). However, outside clinical trials, there are limited data focusing on the management and outcomes of NDMM patients requiring dialysis. Thus, we analyzed the outcomes of consecutive newly diagnosed patients with RF requiring dialysis, who were managed and treated in a single center. Between 1995 and 2016, 50 patients (6.2% of 796 consecutive NDMM) who were treated in the Department of Clinical Therapeutics (Athens, Greece) presented with severe RF requiring dialysis. The analysis included all patients who received at least one dose of any therapy. All patients received similar supportive care and dialysis with regular filters. The median age of patients requiring dialysis was 69 years (37-88), 68% were >65 years of age. At presentation 92% had Hb <10 g/dl, 5 (10%) had platelet count <100x109/l, 12 (24%) had hypeprcalcemia (Ca ≥11.5 mg/dl) and 24 (48%) had elevated LDH (≥250 IU/l). All patients had elevated β2-microglobulin (median 21.7 mg/L, range 6-60 mg/l) and all were ISS stage 3. High risk cytogenetics (N=40) were present in 38% and per R-ISS, 75% were R-ISS-3 and 25% R-ISS-2. Myeloma was light chain only in 42%, IgA in 26%, IgG in 30% and IgD in 1 patient (2%); light chain was κ in 38 (64%) and λ in 18 (36%). Among patients who retained urine flow at presentation, median 24h Bence Jones proteinuria was 2.2 gr (range 0.1-8.8 gr). Among patients with available FLCs, median level of involved free light chain (iFLC) was 9080 mg/l (range 119-201000 mg/l). Treatment was bortezomib-based in 41 (82%) patients: 11 (22%) had bortezomib + dexamethasone (VD), 21 (42%) VD + cyclophosphamide (VCD), 8 (16%) VD + thalidomide (VTD), 1 (2%) VD + doxorubicin (PAD). Nine (18%) patients received non-bortezomib containing regimens: 5 (10%) thalidomide plus high dose dexamethasone and 4 (8%) VAD with high dose dexamethasone. Twenty-five (50%) patients became dialysis independent at a median time of 158 days from start of therapy (range 4-336 days). Age ≤65 years was associated with higher probability (75% vs 38%) and shorter time to dialysis independence (51 vs 336 days; p=0.027); no other baseline factors were associated with dialysis independence in univariate analysis. Among patients treated with bortezomib, three-drug combinations (n=30) vs VD alone (N=11) were associated with higher probability of dialysis independence (57% vs 27%; p=0.06). Among patients who became dialysis independent 12 received VCD, 4 VTD, one PAD, 3 VD, 2 MDT, 2 VAD and one T-VAD. Median follow up for all patients was 33 months and median survival was 29 months. Early mortality (within 2 months from start of therapy) was 16%, mostly due to infectious complications. On intent to treat, 64% achieved ≥PR (CR: 6%, VGPR: 32%, PR: 26%); among patients who survived >2 months, ≥PR was achieved by 76%. At 2-month landmark, patients who achieved ≥PR within the first 2 months had higher dialysis independence rates (68% vs 27%, p=0.004). Becoming dialysis independent was associated with a significant improvement in survival (median OS of 63 vs 22 months of patients who remained on dialysis; p=0.002), even after exclusion of early deaths. Notably, the survival of patients who discontinued dialysis was similar to that of the rest of patients (57 months). High dose melphalan (HDM) followed by autologous stem cell transplantation was performed in five patients while on dialysis. Four of them (80%) become dialysis independent approximately one month after HDM. In conclusion, about 6% of NDMM present with renal failure requiring dialysis but half of them can become dialysis independent after bortezomib-based therapy, without the use of special filters, especially if they achieve a rapid myeloma response. VD-based triplets increase the probability of renal response over VD alone and independence from dialysis is associated with a significant improvement in prognosis. Disclosures Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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Expected Survival in Patients with Smoldering Multiple Myeloma and Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118084 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4497-4497

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Arjun Lakshman ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

General Population ◽

Board Of Directors ◽

Research Funding ◽

Excess Mortality ◽

Advisory Committees ◽

Smoldering Multiple Myeloma ◽

Similar Survival

Abstract Background: The introduction of novel therapeutics has led to improved outcomes in patients with multiple myeloma (MM). MM and its precursor lesion smoldering multiple myeloma (SMM) have traditionally been associated with increased mortality despite treatment. We aimed to assess the impact of a diagnosis of SMM and MM compared to the general population in the context of established prognostic factors. Methods: We studied the overall survival of 1697 patients with smoldering multiple myeloma (SMM, n = 582) and multiple myeloma (MM, n = 1115) diagnosed at Mayo Clinic between 01/2005 and 12/2015. Expected survival accounting for age and sex was calculated using the United States general population (US) as the reference group. Observed and expected overall survival was expressed as the standardized mortality ratio (SMR) of observed to expected deaths. Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in subgroups. The subgroups of interest were based on the International Staging System (ISS) and the presence of fluorescence in situ hybridization (FISH) high-risk cytogenetics: t(4;14), t(14;16), t(14;20), and del(17p). Proportional hazards regression models were used to assess the associations between the aforementioned prognostic factors and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in patients with SMM and MM was 65 (32 - 92) and 63 years (24 - 90), respectively. Two hundred forty-nine patients (57%) and 663 (60%) were male. The median follow-up in patients with SMM and MM was 4.7 (0.1 - 11.0) and 2.6 years (0.2 - 9.5). The median overall survival for patients with SMM and MM was 9.0 (95% CI 8.4 - 9.7) and 7.9 years (6.4 - 8.7). With age- and sex-matched population controls as the reference, the SMRs in patients with SMM and MM were 2.6 (95% CI 2.2 - 3.0) and 4.6 (4.1 - 5.2). Among those MM patients with available data on ISS staging and FISH cytogenetics, 30% (236/780) had ISS III and 21% (188/878) had high-risk cytogenetics. Patients with MM (compared to SMM) experienced worse overall survival (HR 1.5, 95% CI 1.2 - 1.8, p < 0.001, n = 1697). Patients with ISS I/II MM (compared to SMM) experienced similar survival (HR 1.0, 95% CI 0.8 - 1.3, p = 0.698, n = 1131). Patients with ISS III MM (compared to MM with high-risk cytogenetics) experienced similar survival (HR 1.3, 95% CI 0.9 - 2.0, p = 0.128, n = 329). Conclusions: Patients with SMM and MM in this cohort experienced excess mortality compared to the general population. In the absence of universal screening the true morbidity and mortality of patients with SMM and MM remains unknown and is likely overestimated in hospital-based cohorts. Overall survival in patients diagnosed with SMM and patients with ISS I/II MM receiving contemporary anti-myeloma therapy was clinically indistinguishable. Patients treated for ISS III MM experienced overall survival similar to patients with cytogenetic high-risk disease. MM remains associated with excess mortality, the magnitude of which varies considerably based on the presence of additional tumor and host factors. The outcomes with modern therapy among the ISS I/II patients highlight the potential for improving outcomes of SMM by early intervention, especially for the higher risk patients. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:Medscape: Consultancy; Alnylam: Honoraria; janssen: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; annexon: Consultancy; celgene: Consultancy; Teva: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Abbvie: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Research to Practice: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood-2018-154 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 154-154 ◽

Cited By ~ 10

Author(s):

Chia-jen Liu ◽

Irene M. Ghobrial ◽

Mark Bustoros ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Therapeutic Intervention ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genomic Studies ◽

Equity Ownership

Abstract Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Overall and Progression Free Survival from the Mcrn-003/Myx.1 Trial: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1871-1871 ◽

Cited By ~ 1

Author(s):

Christopher P Venner ◽

Richard Leblanc ◽

Irwindeep Sandhu ◽

Darrell J White ◽

Andrew Belch ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Phase Ii ◽

Light Chain ◽

Research Funding ◽

Free Light Chain ◽

High Dose ◽

Advisory Committees

Background: Carfilzomib is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Questions remain regarding optimal dosing strategies and combinations. The MCRN-003/MYX.1 single arm phase II clinical trial of high-dose once weekly carfilzomib in combination with dexamethasone and cyclophosphamide (wCCD) in RRMM met its primary endpoint with an overall response rate (ORR) ≥ 80% after 4 treatment cycles [Venner, Blood 2018 132:1984]. This abstract focuses on previously unreported protocol specified secondary and exploratory endpoints including progression free (PFS) and overall survival (OS). Methods: This multi-centre clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had 1-3 prior lines of therapy and without proteasome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. Secondary endpoints included toxicity, depth of response, PFS and OS as defined by International Myeloma Working Group Uniform Response Criteria (2016). Exploratory endpoints included the impact of cytogenetics (CG) and prior PI or lenalidomide exposure on efficacy, and the novel endpoint of serum free light chain (sFLC) escape, defined as a > 25% change in the difference of involved to uninvolved light chain with the absolute rise > 100mg/L, in individuals with disease previously measurable by serum or urine protein electrophoresis. This analysis is based on the locked database of 19 June, 2019. Results: Of 76 patients accrued, 75 were included in the analysis. One was ineligible due to prior bortezomib refractoriness. Thirty-nine percent received 1 prior line, 44% two prior lines and 17% three prior lines of therapy. High-risk cytogenetics (t(4;14), t(14;16) and/or del P53, considered positive at any level above local accepted threshold) were identified in 32%. Twenty percent had ISS stage III disease. The majority of participants were previously exposed to PI (87%) and lenalidomide (83%). The median duration of follow-up was 25 months. The ORR at any time was 85% (1 patient achieved a response after 4 cycles) with ≥ VGPR achieved in 68% and ≥ CR in 29%. The presence of high-risk CG conferred a worse ORR (75% vs 97% respectively, p = 0.013). Thirty-one patients have died with a median OS and median PFS of 27 months and 17 months respectively (figure 1). High risk CG conferred a worse median OS (18 months vs NR, p = 0.002) and a trend toward a worse median PFS with high risk CG (14 months vs 22 months, p = 0.06; figure 1). For patients with prior PI exposure the median OS and PFS were 27 and 17 months respectively. For patients with prior lenalidomide exposure median OS and PFS were 26 and 16 months respectively. Free light chain escape events were noted in 11 patients (15%) but was the only progression event in 3 (4%). For the remaining 8 patients the sFLC rise was a harbinger of traditional relapse by electrophoresis. The median PFS when sFLC escape was included as a progression event was 17 months. With updated toxicity data the most common ≥ grade 3 non-hematologic events were infection (40%), cardiac (15%, including 5 dyspnea and 1 pulmonary edema) and vascular (17%, including 7 with hypertension and 3 with thrombotic microangiopathy). To date 57 (76%) patients have discontinued carfilzomib, including 34 due to disease progression and 14 due to toxicity. Conclusion: This phase II trial demonstrates that wCCD remains a safe and effective regimen for RRMM. The survival data presented here is comparable to current phase II and III studies examining the weekly dosing strategy. No new toxicity signals are observed but cardiovascular risks remain an important factor in the use of carfilzomib-based therapies. Using sFLC escape does not negatively affect PFS outcomes but likely better characterizes progression as a harbinger of more traditional events detected by electrophoresis. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to lenalidomide and otherwise ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: J&J: Research Funding. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; gilead: Honoraria. White:Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reece:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Louzada:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Janssen: Honoraria; Celgene: Honoraria. Hay:Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Kite: Research Funding; Takeda: Research Funding; Roche: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding. OffLabel Disclosure: While Carfilzomib is approved for use in relapsed and refractory myeloma the combination with cyclophosphamide is not approved.

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Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2019-128519 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 580-580 ◽

Cited By ~ 4

Author(s):

Mark Bustoros, MD ◽

Omar Nadeem ◽

Adam S Sperling ◽

Giada Bianchi ◽

Lily Ardente ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Advisory Board ◽

Induction Phase ◽

Advisory Committees ◽

Smoldering Multiple Myeloma

Background.This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods.Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results.In total, 53 of the planned 62 patients have been enrolled in this study from February 2017 to May 2019. The median age of the patients enrolled was 61 years (range, 41 to 84) with 22 male (41.5%). The analysis was conducted on patients who have completed at least 1 cycle of therapy (n=45). The median follow-up for the trial is 14.4 months (range: 2- 27.6). Interphase fluorescence in situ hybridization (iFISH) was successful in 37 patients (82.2%). High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 20 patients (54%). The median number of cycles completed was 14 cycles (range: 1-24). According to the study's inclusion criteria, baseline markers showed that 15, 14, and 13 patients had 3, 4, and 5 high-risk features, respectively. Moreover, 24 patients (53.3%) met the criteria of high-risk SMM, according to the Mayo 2018 model. The most common grade 3 adverse events were hypertension (6.3%), hypophosphatemia (4.2%), and rash (4.2%). Grade 4 thrombocytopenia and neutropenia were each reported in 4.4% of patients, and hyperglycemia was reported in 2.2%. Stem cells were collected in all eligible patients by the end of the induction phase. As of the abstract date, the overall response rate (partial response or better) in participants who completed at least 1 cycle of treatment was 91.1% (41/45), with 14 Complete Responses (CR, 31.1%), 9 very good partial responses (VGPR, 20%), 18 partial responses (40%), and 4 minimal Responses (MR, 10%). ORR in patients who completed the induction phase (≥9 cycles) was 97% (n= 32/33), with 14(42.4%) and 9 (27.2%) having CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. Six patients have completed the treatment protocol and are currently on follow-up. As of July 2019, none of the patients have progressed to overt MM. MRD testing by next-generation sequencing is ongoing for patients who achieved CR or VGPR and will be presented at the meeting. Conclusion.The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma with 91% ORR and 54.7% CR and VGPR to date. The high response rate, convenient schedule and manageable toxicity build on prior studies which have shown efficacy of lenalidomide and dexamethasone in high risk smoldering myeloma. Longer follow-up for disease outcome is ongoing. Disclosures Bustoros, MD: Takeda: Honoraria. Nadeem:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy. Prescott:Janssen: Equity Ownership. Munshi:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Anderson:OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Ixazomib, Lenalidomide and Dexamethasone is an investigational combination in high-risk smoldering multiple myeloma and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the use under investigation.

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Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 Years: Results of a Randomized Phase III Study

Blood ◽

10.1182/blood.v118.21.3069.3069 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3069-3069 ◽

Cited By ~ 7

Author(s):

Antonio Palumbo ◽

Federica Cavallo ◽

Izhar Hardan ◽

Barbara Lupo ◽

Valter Redoglia ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Patients ◽

High Dose Melphalan

Abstract Abstract 3069FN2 Background: High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims: In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods: All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results: Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions: PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting. Disclosures: Palumbo: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Genomic and Transcriptomic Landscape of Double-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-122197 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3056-3056 ◽

Cited By ~ 1

Author(s):

Bachisio Ziccheddu ◽

Giulia Biancon ◽

Chiara De Philippis ◽

Filippo Bagnoli ◽

Francesco Maura ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

High Dose ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Oncology Research

In Multiple myeloma (MM) no treatment has a curative potential and even complete response to novel agents such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) are followed by relapse over time. Next generation sequencing (NGS) has showed how MM at diagnosis is defined by several somatic mutations, but only few drivers, even fewer "druggable" mutations, and many found at a subclonal level. At relapse, targeted studies have shown occasional mutations in drug target genes but the genomic and transcriptomic determinants of chemoresistance in MM remains elusive. We selected 42 MM patients refractory to both lenalidomide and PIs. Whole exome sequencing was performed in 40 of them, and RNAseq in 27. Clinical annotation was available for all patients. Standard analysis pipelines where applied to analyze mutations, copy number alterations (CNAs), mutational signatures, gene expression and expressed mutations. Patients received a median of 3 lines of treatment, with median overall survival of 14.6 months from sampling. We found a median of 77.5 mutations per patient, which is more than what reported at diagnosis (Bolli et al, Nature Communications 2014;5:2997). 100% of samples showed evidence of subclonality, and 37% of them exhibited a higher number of subclonal than clonal variants. Therefore, even at this advanced stage the MM genome is evolving and is composed of different subclones that may display different chemosensitivity. The mutational landscape was also different. TP53 mutations were the second most common after KRAS (20% and 17.5%, respectively). Interestingly TP53 mutations all clustered in patients receiving bortezomib as the last line of treatment. Only 2 patients showed a CRBN mutation, both subclonal. Combining mutations and CNA analysis, the TP53 pathway was the most frequently inactivated (45% of patients). Altogether, mutations or deletions of genes in the CRBN E3 ubiquitin ligase complex were found in 32.5% of patients, while proteasomal subunit genes were infrequently hit. Refractory cases were also uniquely characterized by a novel signature linked to exposure to alkylating agents, whose activity was more pronounced after high-dose melphalan suggesting a mutagenic effect of the drug on residual cells at the time of transplant. Whether this has any pathogenetic role on the disease course remains to be elucidated. RNAseq analysis did not show any influence of treatment or mutational data on the clustering of samples, which was mainly influenced by karyotypic events. The main cluster was composed by non-hyperdiploid patients with both amp(1q) and del(13): these showed CCND2 and MCL1 upregulation, the latter representing a marker of venetoclax resistance and novel target of experimental treatments. Only 26.3% of mutations were expressed, and this correlated with the clonality level of the mutation. However, most mutations in driver genes were expressed, with the notable exception of those causing nonsense mediated decay. Overall, classical high-risk features or CRBN pathway mutations were found in 65% of the cohort. However, only amp(1q) predicted survival in our cohort. The lack of prognostic value of high-risk lesions is likely explained by a higher prevalence of such features in double-refractory stages. Our data suggest that gene mutation is not a preferred mode of evolution of drug resistance in MM. Chemoresistance of the bulk tumor population is likely attained though differential, yet converging evolution of different subclones that are overall highly variable from patient to patient and within the same patient. Disclosures Kastritis: Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Corradini:Janssen: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Kite: Honoraria; BMS: Other: Travel Costs; Sanofi: Honoraria; Servier: Honoraria; Roche: Honoraria; Novartis: Honoraria, Other: Travel Costs. Bolli:Celgene: Honoraria; Novartis: Honoraria; Gilead: Other: travel expenses.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117871 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 804-804 ◽

Cited By ~ 7

Author(s):

Mark Bustoros ◽

Chia-jen Liu ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

Kathleen Guimond ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Rna Sequencing ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

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