Low-Dose 28-Day Metronomically Scheduled Therapy (METRO) for Newly Diagnosed High-Risk Multiple Myeloma: A Pilot Study

Abstract Introduction: Gene expression profiling (GEP)-defined high-risk de novo multiple myeloma (HI-MM) has a dismal prognosis with median PFS and OS stagnating at 2 and 3 years, respectively, despite the incorporation of novel agents into our Total Therapy (TT) trials. Having seen encouraging results in relapsed-refractory MM with an extended 16-day metronomic therapy (Papanikolaou, Haematologica 2014), we tested this approach in a small cohort of untreated patients with HI-MM. METRO emphasizes targeting neo-angiogenesis and other components of the bone marrow micro-environment while avoiding cytokine surges with recovering hematopoiesis following myelotoxic therapy. Patients and Methods: 10 previously untreated patients with HI-MM, who were either ineligible or unwilling for our Total Therapy protocols received a single cycle of METRO. Therapy comprised of SC bortezomib 1.0mg/m2 (0.8mg/m2 in case of grade >2 peripheral neuropathy) on days 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28 schedule, PO dexamethasone 12mg (8mg in case of prior intolerance of higher dose or diabetes mellitus) on days 1 to 4, 7 to 10, 13 to 16, 19 to 22 and 25 to 28, PO Thalidomide 100mg (50mg in case of peripheral neuropathy grade >2) and continuous IV infusions of doxorubicin and cisplatin at 1.0mg/m2 daily for 28 days. Cisplatin was dose-reduced for Cr >2mg/dL and omitted for Cr >3mg/dL. Arsenic tri-oxide was given at a fixed dose of 0.01mg/kg on the days after bortezomib. Laboratory monitoring for response and toxicities were done on a Monday-Wednesday-Friday schedule. Maximal responses, based on current IMWG definitions, were measured within 30 days of completion of cycle 1, and at least monthly thereafter. KM curves were current as of 07/31/14. The Institutional Review Board granted permission for our retrospective data review, the results of which are presented here. Results: Patient characteristics included age >=65 in 8, 5 male, 5 female with ISS III in 5 patients. Metaphase cytogenetic abnormalities (CA) were detected in 7 patients. GEP70 based high risk MM was present in all 10 patients, and GEP proliferation (PR) subgroup was dominant in 8 out of 10 patients. All 10 patients achieved at least PR, including 3 qualifying for VGPR and 4 for CR. Bone Marrow responses were equally encouraging in that 8 of 10 patients qualified for complete morphologic negativity including 4 with no minimal residual disease (MRD) by 8-color flow cytometry. Of 8 patients with FDG-avid PET-CT focal lesions, 6 achieved PET-CT CR; all patients showed decreases in SUV-max and SUV-diff (background SUV). Number and/or apparent diffusion coefficient (ADC) mapping of focal lesions and background marrow on diffusion-weighted MRI improved in all 7 evaluable patients. GEP70 risk morphed from high risk to low risk in 3/4 evaluable patients. Pre and post serologic, urinary and radiologic responses are shown in Figure 1. The median follow-up time for the population was 3.2 months (98 days). All 10 patients are alive from 1 to 7 months, and 1 suffered progression (Figure 2). Overall tolerance was good. Non-hematologic grade 3/4 SEs included fatigue, electrolyte abnormalities (20%), dyspnea, hypotension, LE edema and transaminitis (10%). Conclusion: Primary 28-day metronomic therapy is highly effective and well-tolerated in patients with previously untreated HI-MM. Further prospective studies with longer follow-up are currently being devised in an attempt to improve outcomes in this population. Figure 1: Individual responses Figure 1:. Individual responses Figure 2 Figure 2. Figure 3 Figure 3. Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

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EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

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

Blood ◽

10.1182/blood-2019-125155 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1911-1911 ◽

Cited By ~ 2

Author(s):

Meena Bansal ◽

David S. Siegel ◽

Jaeil Ahn ◽

Rena Feinman ◽

David H. Vesole ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Best Response ◽

Grade 3

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

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Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽

10.1182/blood-2019-128655 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1852-1852

Author(s):

Noemi Puig ◽

Teresa Contreras ◽

Bruno Paiva ◽

María Teresa Cedena ◽

José J Pérez ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Response Assessment ◽

Advisory Committees ◽

Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2021-149787 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2749-2749

Author(s):

Omar Nadeem ◽

Robert A. Redd ◽

Julia Prescott ◽

Kelsey Tague ◽

Veronica Romines ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Induction Phase ◽

Advisory Committees ◽

Study Therapy

Abstract Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the 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: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of >90% and deep remission in >40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

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Extracting Prognostic Molecular Information from PET-CT Imaging of Multiple Myeloma Using Radiomic Approaches

Blood ◽

10.1182/blood-2018-99-117103 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1906-1906

Author(s):

Christopher Wardell ◽

Terri Lynn Alpe ◽

Phil Farmer ◽

Michael W Rutherford ◽

Yan Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Ct Scans ◽

Focal Lesions ◽

Advisory Committees ◽

Pet Ct ◽

Ngs Data

Abstract Introduction: Invasive bone marrow sampling is used in multiple myeloma (MM) diagnosis to obtain biological material, which can then be used to generate prognostically important genetic features. Physically sampling the bone marrow can be uncomfortable for the patient. Also, spatial heterogeneity is a common feature in MM, with multiple focal lesions (FLs) occurring throughout the skeleton, meaning a single sample from the iliac crest may be insufficient to capture intrapatient heterogeneity. An alternative strategy is to extract data directly from diagnostic positron emission tomography-computed tomography (PET-CT) scans of patients. These radiomic features can be used as a proxy from which to infer molecular and clinical phenotypes. Compared to physical sampling, there are several advantages, including rapid analysis, minimalizing patient discomfort, reduced cost and widespread availability of the required scanning equipment in hospitals. Methods: A series of 439 newly diagnosed MM patients were selected, all of which had diagnostic PET-CT scans. A radiologist examined these data and identified focal lesions in the axial skeleton of 136/439 (31%) patients. Focal lesions were manually segmented from the PET portion of the original DICOM data using a density-based thresholding method in 3DSlicer version 4.9.0. Pyradiomics version 1.3 was used to resample the voxels in the PET data to 4x4x4 mm and extract radiomic features from each FL. A combination of 10 filters and 7 feature classes were used and a total of 1679 radiomic features were generated per lesion. Radiomic features were a mixture of first order characteristics such as maximum intensity, shape characteristics and gray level matrix features. Hierarchical clustering was applied to the radiomic features, using the Pearson correlation between features as the distance metric and Ward's method for clustering. Next generation sequencing (NGS) data was available for samples from 58/136 (43%) patients with FLs in whole genome (WGS), whole exome (WES) or targeted panel (TP) modalities. The NGS data was used to detect translocations, copy number aberrations and somatic mutations. Results: There were 789 FLs identified in 136 patients, with each patient containing an average of 5.8 FLs. The median FL volume was 4350 mm3, with a median maximum 3D diameter of 29 mm. Hierarchical clustering across all FLs and radiomic features separated the FLs into 5 discrete clusters associated with various clinical and molecular features. However, clustering appeared to be independent of other classification systems based on gene expression profiling (GEP), including the UAMS classification system and GEP70 risk score. Clustering was also independent of the International Staging System (ISS) status suggesting that it can add additional prognostic information. Clusters also appeared to be independent of somatic mutations in genes previously reported as significantly mutated in MM. Patients commonly had FLs occurring in multiple clusters, suggesting that this method takes into account the heterogeneity between lesions in the same patient. Larger FLs were grouped primarily into two clusters consistent with them having distinct features that can be recognized by this approach. Looking across the different clusters distinct differences in clinical outcome were seen between the groups, with significant differences in both PFS (p=0.007) and overall survival (p=0.005), with worse prognosis being led by a cluster of smaller lesions. Conclusions: Radiomics provides a novel method to extract potentially important data from PET-CT scans which can define individual clusters that have different clinical, molecular and prognostic features. This can provide a novel non-invasive method to assess FLs based on both their physical and radiomic characteristics. Larger study sizes will be needed to confirm the differences in outcomes seen between groups. Disclosures Boyle: Celgene: Honoraria, Other: travel grants; Janssen: Honoraria, Other: travel grants; La Fondation de Frace: Research Funding; Abbvie: Honoraria; Amgen: Honoraria, Other: travel grants; Gilead: Honoraria, Other: travel grants; Takeda: Consultancy, Honoraria. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Davies:TRM Oncology: Honoraria; MMRF: Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Amgen: Consultancy, 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; ASH: Honoraria.

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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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Global Expression Changes of Malignant Plasma Cells over Time Reveals the Evolutionary Development of Signatures of Aggressive Clinical Behavior

Blood ◽

10.1182/blood-2018-99-119113 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4457-4457

Author(s):

Eileen M Boyle ◽

Adam Rosenthal ◽

Yan Wang ◽

Phil Farmer ◽

Michael W Rutherford ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Adverse Outcome ◽

Patient Specific ◽

Advisory Committees ◽

Over Time

Abstract Introduction: Clustering of gene expression signatures at diagnosis has identified a number of distinct disease groups that correlate with outcome in multiple myeloma (MM). Some of these are defined by an etiologic genetic event whereas others, such as the proliferation cluster (PR) and GEP70 risk relate to acquired clinical behaviors regardless of the underlying background. The PR cluster has a number of important features, including markers of proliferation, and has been associated with an adverse outcome. This logic led us to study how gene expression patterns change over time with the aim of gaining insight into acquired features that could be targeted therapeutically or be used to predict outcome. Methods: We followed 784 newly diagnosed MM patients from the Total Therapy trials over a median of 9.5 years for whom repeated GEP of CD138+ plasma cells using Affymetrix U133 Plus 2.0 plus arrays were obtained. Raw data were MAS5 normalized and GEP70-based high-risk (HR) scores, translocation classification (TC) and molecular cluster classification were derived, as previously reported. Results: At diagnosis, 85.9% percent of patients (666/784) were identified as low-risk (LR). Among them, 23.1% (154/666) went on to develop HR status (defined by a GEP70 score > 0.66) at least once after initial diagnosis. Among the non-PR cases, 28.5% (193/677) were seen to develop a PR phenotype at some point during follow-up. Similarly, among the PR patients (n=107), we observed that 43.1% (25/58) identified as LR by GEP70 at presentation eventually develop HR status at least once during follow-up. We further analyzed 147 patients with paired diagnosis and relapse samples. Seventeen percent of patients (25/147) were PR at diagnosis. Most patients were from favorable TC prognostic groups [80% D1-D2, 8% t(11;14), 8% t(4;14) and 4% t(14;20)]. Seventy-six percent of PR patients remained PR at relapse (19/25) whereas 23% switched cluster in accordance to their translocation group. Fifteen percent of patients (22/147) became PR at relapse. They originated from four clusters and three TC groups [77% from the D1-D2, 14% t(4;14) and 9% from the t(11;14)]. Overall-survival from the time of relapse was inferior for patients categorized as PR at relapse compared to other subgroups (p< 0.0001); among PR patients at relapse, there was no difference in outcome between patients classified as PR or non-PR at diagnosis (p= 0.74). When looking at GEP70 defined risk scores, the incidence of HR status rose from 23% to 39% between diagnosis and relapse with a significant increase in mean GEP70 scores using paired t-test (p<0.0001). Patients identified as HR by GEP70 at relapse had an inferior post-relapse outcome compared to patients identified as LR (p< 0.0001); there was no difference in the outcome of patients identified as HR at relapse depending on their risk status at diagnosis (p = 0.10). Discussion: Following the introduction of therapeutic regimens aimed at maximizing response, long term survival in MM has improved. This also led to an apparent increase in the development of more aggressive disease patterns at relapse including extra-medullary disease and plasma cell leukemia. Here we show, that HR features both in terms of PR and GEP70 risk status, develop as a variable over time. At relapse, most acquired HR cases originate from standard-risk presentation cases, suggesting selective pressure for HR features. Moreover, we show that the detection of such behaviors is associated with an adverse outcome from the time of relapse. These data also suggest that repeating GEP during follow-up adds precision to better comprehend individual risk and may help identify patient specific therapeutic strategies. Indeed, understanding how these patterns develop, which genes are implicated, and their impact on the immune microenvironment should allow us to effectively utilize a wide array of treatment approaches ranging from immune-therapies to novel cell-cycle targeting agents to specifically address this type of aggressive behavior. Conclusion: The acquisition of high risk patterns captured by GEP70 risk and PR status is an ongoing process from initial diagnosis. Such high risk prognostic features have an adverse outcome from the time of development. Repeating GEP during follow-up may therefore help better predict outcome and identify patient specific therapeutic strategies. Disclosures Boyle: Janssen: Honoraria, Other: travel grants; Takeda: Consultancy, Honoraria; Gilead: Honoraria, Other: travel grants; Abbvie: Honoraria; Celgene: Honoraria, Other: travel grants; La Fondation de Frace: Research Funding; Amgen: Honoraria, Other: travel grants. Dumontet:Janssen: Honoraria; Roche: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Facon:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Barlogie:Celgene: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Other: travel stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; Dana Farber Cancer Institute: Other: travel stipend; Millenium: Consultancy, Research Funding; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend. Davies:TRM Oncology: Honoraria; Janssen: Consultancy, Honoraria; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria.

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PET-CT Defined Focal Lesions at Baseline and Day 7 Predict Outcome in GEP 70 Defined High Risk Multiple Myeloma Patients

Blood ◽

10.1182/blood.v124.21.3407.3407 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3407-3407

Author(s):

Yogesh Jethava ◽

Rachel Hunter-Merrill ◽

Gareth J Morgan ◽

Rashid Z Khan ◽

Aasiya Matin ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Focal Lesions ◽

Advisory Committees ◽

Early Therapy ◽

Time Points ◽

The Impact

Abstract Introduction: Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) scanning is an important state-of-the-art imaging tool in the initial workup of patients with multiple myeloma (MM). We evaluate the impact of PET focal lesions (FL) at baseline (BL), 7 days after starting induction therapy (D7) and prior to first autologous transplant (pre-ACST) in gene expression profiling (GEP 70) defined high risk (HR) multiple myeloma (MM) patients. Patients and methods: 48 GEP 70 HR MM patients were treated uniformly on IRB approved protocol consisting of tandem transplants with dose reduced Mel-80-VRD-PACE (melphalan, velcade, revlimid, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) and interspersed Mel-20-VTD-PACE (melphalan, velcade, thalidomide, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) consolidation and VRD (velcade, revlimid, dexamethasone) maintenance. PET examinations were performed at (BL), D7 and pre-ASCT, enumerating FDG-avid FL, their SUV max and extra-medullary disease (EMD).Of the 48 GEP 70 HR patients, 39 had BL, 28 had D7 and 42 had pre-ASCT PET examinations. 20 patients had examinations at all 3 time points. At BL, there were 24 (50%) patients with B2M >5.5mg/L and 26 (54%) with albumin <3.5g/dL. Metaphase cytogenetic abnormalities were documented in 36 (75%) patients, including deletion 13/hypodiploidy in 30 (63%). EMD was present in 3 (8%) patients, 28 (58%) had diffuse SUV <= 2 (median 2.4; range 1.4 to 9.5) and 14 (29%) had FL max SUV >3.9 (median 4.6; range 1.6 to 14.4). Results: From BL, the 3-yr PFS estimate was 46% for the group with no FL and 29% for those with FL (Figure 1a). The corresponding PFS data for the D7 was 53% for no FL at D7 as opposed to 11% for those with FL (Figure 1b), and for pre-ASCT it was 34% for no FL and 33% for those with FL (Figure 1c). Joint consideration of BL and D7 landmark revealed 3-yr PFS of 54% for those with no FL at BL, compared to 40% for those with resolution of BL FL by D7 and 18% for those whose FL did not resolve (log rank p-value=0.09), confirming the significance of FL resolution. Cox regression of PFS revealed that those with FL at BL had 2.34 times the risk of progression or death compared to those with no FL at BL (p=0.075), while those with FL at D7 had 3.27 times the risk (p=0.033). Diffuse SUV and SUV max had no impact on PFS at the three time points. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Fig 1a- PFS from baseline PET Fig 1b- PFS from D7 PET Fig 1c- PFS from pre-ASCT PET Conclusion: The prognosis of GEP 70 HR MM is dominantly affected by BL indicators of MM metabolism, as revealed by FDG uptake in FL. Our analysis in HR GEP70 MM patients confirms that early suppression of FL by D7 was key to improved PFS. MM patients who had absence of FL resolution from BL to D7 had poorer PFS and are candidates for early therapy change. Disclosures Morgan: Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

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Assessment of Total Lesion Glycolysis and Metabolic Tumor Volume Improve the Clinical Value of Focal Lesion Assessment By FDG PET/CT in Myeloma

Blood ◽

10.1182/blood.v126.23.724.724 ◽

2015 ◽

Vol 126 (23) ◽

pp. 724-724

Author(s):

James E McDonald ◽

Marcus M Kessler ◽

Michael Gardner ◽

Amy Buros ◽

Sarah Waheed ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Metabolic Tumor Volume ◽

Total Lesion Glycolysis ◽

University Of Arkansas ◽

Medical Sciences ◽

Focal Lesions ◽

Advisory Committees ◽

Pet Ct

Abstract Introduction: Focal lesions are important anatomical features seen in the bone marrow of multiple myeloma patients that contribute to drug resistance and disease relapse. Fluroine-18 fluorodexyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semi-quantitative characterization of metabolic activity by calculation of glucose uptake reported as a standardized uptake value (SUV). Lesion count and SUV are predictors of outcome. Two additional variables, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) can also be assessed and have the potential to improve the value of this approach. The purpose of this study was to determine whether TLG and MTV can predict progression free survival (PFS) and overall survival (OS), and to determine whether they are superior to traditional assessment methods. Materials and Methods: 191 patients underwent whole body PET/CT in the Total Therapy 3A trial and were evaluated using 3 dimensional region of interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal. Survival analysis was performed using Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: Baseline characteristics show that 43/191 patients (23%) had no detectable lesions by PET. 1-3 lesions were present in 55/191 (28%) of patients and over 3 lesions in 93/191 (49%) of patients. A baseline TLG >205g was seen in 18% (34/191) of patients, with a TLG >620g being seen in 7% (14/191). A baseline MTV >210cm3 was seen in 7% (14/191). The distribution of patients with high TLG scores between molecular subgroups was not even with patients in the PR, MF and HY subgroups having higher scores. The 3 year PFS and OS for patients with no PET focal lesions was 83.1% and 88.3%, for patients with 1-3 lesions was 83.9%, and 85.5%, and for patients with >3 lesions 59.6% and 63.5% (p<0.0001). The 3 year PFS and OS for patients with a baseline TLG of less than 205g was 82.8% and 86.0%, compared to patients with a baseline TLG between 205g and 620g of 75.0% and 80.0%, and to patients with a baseline TLG of greater than 620g of 14.3% and 21.4% (p<0.0001). A similar pattern was seen for complete response (CR) duration. The MTV also had prognostic importance with 3 year PFS and OS for patients with a baseline MTV of less than 210cm3 at 81.4% and 84.7%, compared to patients with a baseline MTV of greater than 210cm3 of 21.4% and 28.6% (p<0.0001). Pearson Correlation Coefficient (r) between MTV and TLG was 0.94232 (p-value <.0001). On univariate analysis baseline PET/CT with >3 focal lesions (HR 1.92, 95% CI 1.22-3.04, p=0.004), TLG >205g (HR 2.99, 95% CI 1.83-4.88, p<0.0001), baseline TLG > 620g (HR 6.90, 95% CI 3.67-12.97, p<0.0001), and MTV >210cm3 (HR 6.20, 95% CI 3.33-11.54, p<0.0001) were statistically significant in predicting OS and PFS. In multivariate analysis baseline TLG>620g retained prognostic significance for predicting PFS and OS together with high B2M, LDH and GEP based proliferation. Importantly baseline TLG >620g and baseline MTV >210cm3 were statistically more predictive of poor PFS and OS than baseline PET with >3 focal lesions in both univariate and multivariate models. Conclusion : TLG assessment is superior to counting the number of focal lesions. It is the optimum method for evaluating the extent of focal lesions and to predict clinical outcome. As this measurement can be standardized using FDA approved software, it should be utilized clinically and in trials going forward. Disclosures McDonald: University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Ntambi:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding. Heuck:Janssen: Other: Advisory Board; Millenium: Other: Advisory Board; Foundation Medicine: Honoraria; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Mitchell:Cancer Research and Biostatistics: Employment. Hoering:Cancer Research and Biostatistics: Employment. Barlogie:International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Dana Farber Cancer Institute: Other: Travel Stipend; Multiple Myeloma Research Foundation: Other: Travel Stipend. Morgan:Weisman Institute: Honoraria; CancerNet: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Outcomes of Patients with t(11;14) Multiple Myeloma: An International Myeloma Working Group Multicenter Study

Blood ◽

10.1182/blood-2019-126867 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3066-3066

Author(s):

Shaji K. Kumar ◽

Jin Lu ◽

Yang Terry Liu ◽

Max Bittrich ◽

Juan Du ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Multicenter Study ◽

Research Group ◽

Research Funding ◽

University Research ◽

Advisory Committees ◽

Entire Cohort

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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