A Phase III Randomized Trial of Thalidomide (THAL) Plus Zoledronic Acid (ZLD) Versus Zoledronic Acid Alone In Patients with Early Stage Multiple Myeloma (MC0289)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3053-3053 ◽  
Author(s):  
Thomas E. Witzig ◽  
Sumithra Mandrekar ◽  
Kristen Detweiler-Short ◽  
Martha Q Lacy ◽  
Kristina Laumann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Zoledronic Acid ◽  
Research Funding ◽  
Response Rate ◽  
Phase Iii ◽  
P Value ◽  
Monoclonal Protein ◽  
Duration Of Response ◽  
One Year

Abstract Abstract 3053 Background: Patients with smoldering multiple myeloma (SMM) have a higher chance of progression to active MM than patients with monoclonal gammopathy of undetermined significance (MGUS). Since active MM remains incurable and since patients with SMM can have a long time to requiring treatment, observation remains an option for these patients. Bisphosphonates can prevent the bone complications of myeloma. The immunomodulatory (IMiD) drugs are well-tolerated and have documented anti-tumor activity in active MM. We hypothesized that treatment with the IMiD THAL and a bisphosphonate (ZLD) would prolong the time to progression (TTP) over the control arm of ZLD alone. This is the first report of this phase III trial of THAL/ZLD vs ZLD alone for patients with untreated SMM. Goals: The primary goal of this trial was to compare the TTP between patients treated with THAL/ZLD versus ZLD alone in asymptomatic MM. Secondary goals were progression rate at one year, response rate, duration of response, time to next therapy, and toxicity. Methods: Patients were required to have measurable disease as defined by either a serum monoclonal protein >1.0 g by protein electrophoresis or nephelometry or >200 mg of monoclonal protein in the urine on 24 hour electrophoresis or a measurable soft tissue plasmacytoma; >10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index; absolute neutrophil count >1500/μL; platelet count >100,000/μL; creatinine <2.0 mg/dL, and a performance status of 0, 1, or 2. Patients could not have symptomatic MM that required chemotherapy. The statistical plan was to accrue 120 eligible patients (60 per arm) over 4 years and after a minimum follow-up of 12 months the study would provide >90% power at a type I error rate of 0.05 to detect an increase in the median TTP from 12 months (ZLD) to 24 months (THAL/ZLD), and >80% power to detect an increase in median TTP from 12 to 21 months). Results: The study was activated in July 2003 and closed March 2009 due to slow accrual. Sixty-eight patients (35 Thal/ZLD; 33 ZLD) with a median age 63 years (range, 47–84) were randomized. The median TTP for Thal/ZLD versus ZLD was 2.4 years versus 1.2 years, respectively, P=0.02 one-sided log-rank. After adjusting for pre-specified stratification factors, the hazard ratio for TTP was 2.2 (one-sided p value = 0.01, univariate stratified Cox PH model) for ZLD compared to Thal/ZLD. 89% of patients on the Thal/ZLD arm were progression-free survival (PFS) at one year compared to 55% on ZLD alone (one-sided p<0.001, chi-square). Similar results were obtained (Table and Figures) when the CRAB (calcium, renal, anemia, bone) criteria were applied. Confirmed response was evaluated using the first 12 months of treatment. In the Thal/ZLD arm the response rate was 31% with a median duration of response of 5.1 years (95% CI: 1.9 - NA). There were no confirmed responses in the ZLD alone arm. The median overall survival has not been reached for either arm. In regards to toxicity, no grade 5 adverse events (AEs) have been reported. Thirty patients have reported grade 3+ AEs (17 Thal/ZLD; 13 ZLD, Fisher's exact p-value 0.47). Eight patients have reported grade 4 adverse events (5 Thal/ZLD; 3 ZLD, Fisher's exact p-value 0.71). Overall, only one grade 4 event was felt to be at least possibly related to study treatment – grade 4 neutropenia in Thal/ZLD. Conclusions: While the trial did not meet its planned accrual goals, there was a significant improvement in improved in outcomes in the Thal/ZLD arm compared to control (ZLD). Thal/ZLD produces anti-tumor responses that are quite durable with the median response duration of over 5 years. ZLD alone did not produce any anti-tumor responses. This study indicates that a non-chemotherapy approach can be effective in SMM and may be a useful strategy to test in future studies. Disclosures: Off Label Use: Thalidomide for smoldering myeloma. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria.

scholarly journals Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone (Rd): The First Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 81-81 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Chaim Shustik ◽  
Andrew Belch ◽  
Maria Teresa Petrucci ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Primary Endpoint ◽  
Research Funding ◽  
Response Rate ◽  
Age Groups ◽  
P Value ◽  
Newly Diagnosed ◽  
Risk Of Death ◽  
Duration Of Response ◽  
Grade 3

Abstract Background: In the pivotal FIRST trial, a randomized, international, multicenter phase 3 study, continuous Rd compared with melphalan-prednisone-thalidomide (MPT) improved progression-free survival (PFS) which was the primary endpoint (HR = 0.72; P < 0.01). The interim overall survival (OS) analysis showed a 22% reduction in risk of death with continuous Rd vs. MPT (HR = 0.78; P = 0.02) (Facon, Blood 2013). This analysis evaluates outcomes based on age, which was a stratification parameter, and compared pts aged ≤ 75 yrs and > 75 yrs. Methods: Pts with NDMM were randomized to continuous Rd until progressive disease (PD) (N = 535); 18 cycles (72 weeks [wks]) of Rd (Rd18; N = 541); or 12 cycles (72 wks) of MPT (N = 547). Starting doses were reduced in pts aged > 75 yrs: dexamethasone (20 vs. 40 mg), melphalan (0.20 vs. 0.25 mg/kg), and thalidomide (100 vs 200 mg). The primary endpoint was PFS (continuous Rd vs. MPT) and the secondary endpoint were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety. Results: The proportion of pts aged > 75 yrs was > 34% across treatment (Tx) arms. In pts ≤ 75 yrs, 37% had ISS stage III vs. 51% in > 75 yrs. ECOG score ≥ 1 was observed in 74% and 69% of pts aged > 75 and ≤ 75 yrs, respectively. Severe renal impairment (CrCl < 30 mL/min) was observed in 14% of pts > 75 vs. 7% in ≤ 75 yrs. PFS and OS outcomes favored continuous Rd over MPT in both age groups. With a median follow-up of 37 months (mos), PFS was 27.4 mos in continuous Rd pts vs. 21.8 mos in MPT pts aged ≤ 75 yrs (HR = 0.68; P < 0.001); a trend for improved PFS was also seen for pts aged > 75 yrs (HR = 0.81; P = 0.11) (Table 1). PFS for continuous Rd vs. Rd18 pts was also increased in both age groups (HR = 0.68; P < 0.001 and HR = 0.75; P = 0.03, respectively). Response rates were consistently higher with continuous Rd vs. MPT in pts aged ≤ 75 yrs (77% vs. 66%; P < 0.001) and > 75 yrs (71% vs. 55%; P < 0.001). Duration of response with continuous Rd was longer vs. MPT in pts aged ≤ 75 yrs (40 vs. 22 mos) and pts > 75 yrs (31 vs. 24 mos). The interim analysis of OS showed an improved trend for continuous Rd vs. MPT in pts aged ≤ 75 yrs (HR = 0.77; P = 0.06) and > 75 yrs (HR = 0.80; P= 0.16). Grade 3–4 adverse events (AEs) in ≥ 10% of pts were similar across age subgroups (Table 2). Tx discontinuation due to AEs was comparable across the Tx groups and independent of age. Conclusions:Regardless of age (≤ 75 vs. > 75 yrs), continuous Rd was effective, increased PFS and interim OS, and was generally well tolerated vs. MPT in NDMM pts. Duration of response was improved with continuous Rd vs. MPT and Rd18, irrespective of age, and with a more profound benefit observed in younger pts. Continuous Rd represents a new clinical option and standard of care for these pts in the first-line setting. Abstract 81. Table 1 PFS, OS and Response Aged ≤ 75 yrs Aged > 75 yrs All pts ITT population Continuous Rd (n = 349) Rd18 (n = 348) MPT (n = 359) Continuous Rd (n = 186) Rd18 (n = 193) MPT (n = 188) Continuous Rd (n = 535) Rd18 (n = 541) MPT (n = 547) Median PFS, mos 27.4 21.3 21.8 21.2 19.4 19.2 25.5 20.7 21.2 PFS HR (95% CI); P-value Continuous Rd vs. Rd18 0.68 (0.55–0.83); P < 0.01 0.75 (0.58–0.98); P = 0.03 0.70 (0.60–0.82); P < 0.01 Continuous Rd vs. MPT 0.68 (0.56–0.83); P < 0.01 0.81 (0.62–1.05); P = 0.11 0.72 (0.61–0.85); P < 0.01 4-yr OS, % 66 61 58 47 47 39 59 56 51 OS HR (95% CI); P-value Continuous Rd vs. Rd18 0.88 (0.67–1.16); P = 0.36 0.94 (0.69–1.29); P = 0.70 0.90 (0.73–1.10); P = 0.31 Continuous Rd vs. MPT 0.77 (0.59–1.01); P = 0.06 0.80 (0.59–1.09); P = 0.16 0.78 (0.64–0.96); P = 0.02 Response rate (≥ PR), % 77 77 66 71 66 55 75 73 62 Duration of response (≥ PR), mos 40 23 22 31 20 24 35 22 22 CI, confidence interval; ITT, intent to treat; PR, partial response. Table 2 Grade 3–4 AEs Observed in ≥ 10% of Pts Aged ≤ 75 yrs Aged > 75 yrs Safety population, % Continuous Rd (n = 347) Rd18 (n = 348) MPT (n = 357) Continuous Rd (n = 185) Rd18 (n = 192) MPT (n = 184) Neutropenia 28 25 47 28 29 40 Thrombocytopenia 8 9 13 9 7 7 Anemia 18 12 20 19 23 17 Leukopenia 5 6 11 4 5 8 Infections 29 21 16 29 23 20 DVT and/or PE 10 6 8 7 8 4 Peripheral sensory neuropathy 1 1 10 1 0 8 Tx discontinuation due to AEs 28 18 28 32 25 30 DVT, deep-vein thrombosis; PE, pulmonary embolism. Disclosures Hulin: Celgene: Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Belch:Janssen, Celgene, Onyx: Honoraria. Petrucci:Celgene, Janssen-Cilag, Sanofi, Bristol-Myers Squibb: Honoraria. Dührsen:Celgene: Honoraria, Research Funding. Song:Celgene: Consultancy, Honoraria, Research Funding. Houck:Celgene: Employment. Chen:Celgene: Employment. Ervin-Haynes:Celgene: Employment.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
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.

Efficacy and Safety of Triplet Versus Doublet Salvage Therapies Among Patients with Multiple Myeloma (MM) Experiencing Early Relapse: Meta-Analysis of Phase III Randomized Controlled Trials (RCTs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5344-5344 ◽  
Author(s):  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
Madhusmita Behera ◽  
Charise Gleason ◽  
Hannah Collins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Mixed Model ◽  
Meta Analysis ◽  
Phase Iii ◽  
P Value ◽  
Serious Adverse Events ◽  
Early Relapse ◽  
The Impact ◽  
Relapsed Myeloma

Abstract Introduction: Controversy exists regarding the choice of triplet versus doublet salvage therapy among patients with multiple myeloma (MM) experiencing early relapse. Triplet therapies produce deeper responses (CR, ≥VGPR, ORR) and result in prolonged progression free survival (PFS) while doublet therapies demonstrate an improved toxicity profile. We performed a meta-analysis of the RCTs comparing triplet to doublet salvage regimens in early relapsed myeloma patients (1-3 prior lines of therapy). The objective is to test the hypothesis that triplet regimens are tolerable, improve CR, ≥VGPR, ORR rates and would translate to an improved PFS. Methods: We searched Pubmed, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 07/2015 for publications and abstracts to identify the phase III RCTs comparing triplet vs. doublet salvage therapies among patients with relapsed myeloma. A meta-analysis of 4 RCTs (PANORAMA1, MMVAR/IFM 2005-04, ASPIRE, ELOQUENT2 consisting of 2475 patients) was performed using the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the impact of triplets versus doublets (table 1) by evaluating the CR, ≥VGPR, ORR, PFS and toxicities. Mature OS data was not available for the RCTs, hence not included in meta-analysis. The consistency of results (effect sizes) among studies was investigated by means of 2 heterogeneity tests: the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P-value of the Cochran's Q test was <.1 and the I2 statistic was > 50%. Results: The pooled odds ratios of ORR, ≥VGPR and CR with triplets vs. doublets were 1.935 (P <0.000; 95% CI: 1.614-2.321); 2.185 (P <0.000; 95% CI: 1.832-2.606); 2.461 (P <0.000; 95% CI: 1.888-3.207) respectively, indicating that the odds of achieving higher quality responses are improved with triplet regimens compared to the use of a doublet regimens. The pooled hazard ratio (HR) for PFS was 0.661 (95% CI 0.596-0.734; P =0.000) in favor of triplet regimens (Figure 1). The Q-statistic for PFS (P =0.725; df =3; I2 = 0.00) suggests homogeneity across studies. Though the relative risk of selected ≥grade 3 serious adverse events (G3 SAE) was higher with triplet regimens (diarrhea, fatigue, thrombocytopenia 2.288 (95% CI 1.637-3.197; P =0.000), 1.654 (95% CI 1.263-2.166; P =0.000), 2.434 (95% CI 1.934-3.063; P =0.000), respectively), the overall G3 SAE were comparable with RR 1.498 (95% CI 1.176-1.908; P =0.001) favoring doublets. Conclusion: Our mixed model meta-analysis demonstrates that triplet regimens in early relapsed myeloma patients result in improved ORR, ≥VGPR, CR and PFS compared to doublets. G3 SAEs are higher with triplet regimens, however this appears to be influenced by the regimen-related toxicity from the PANORAMA1 trial. Appropriate dose modifications or use of selective HDAC inhibitors in future may mitigate the toxicities of the regimen. The pooled estimates ofresponse and survival strongly favor triplets in the early relapsed setting. Table 1. Triplet vs. doublet regimens in RCTs Trial Triplet regimen Doublet regimen PANORAMA1 Panobinostat, bortezomib, dexamethasone Placebo, bortezomib, dexamethasone MMVAR/IFM 2005-04 Bortezomib, thalidomide, Dexamethasone Thalidomide, Dexamethasone ASPIRE Carfilzomib, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone ELOQUENT 2 Elotuzumab, lenalidomide, Dexamethasone Lenalidomide, Dexamethasone Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Figure 1. VGPR rates and PFS with triplet vs. doublet regimens Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy; Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Onyx: Research Funding; Merck: Research Funding; Janssen: Consultancy; Spectrum: Consultancy; Novartis: Consultancy. Gleason:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

scholarly journals Characterization of Patients with Multiple Myeloma in Long- Term Remission

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4508-4508 ◽  
Author(s):  
Raphael K. Lutz ◽  
Katharina Kriegsmann ◽  
Mohamed H.S. Awwad ◽  
Carsten Müller-Tidow ◽  
Gerlinde Egerer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Research Funding ◽  
High Dose ◽  
Disease Course ◽  
Monoclonal Protein ◽  
Single Cell Rna Sequencing ◽  
Indolent Disease

Abstract INTRODUCTION: Multiple Myeloma is still considered an incurable disease despite the development of new therapy options. However, there is a small fraction of patients achieving a long- term remission (LTR) after induction therapy followed by high dose chemotherapy and autologous stem cell transplantation (ASCT). Such patients that are still in complete remission or experience an indolent disease course over many years after high dose therapy are referred to as functionally cured. To date, it is still unclear which patients experience a long term disease control. METHODS: We have screened our Myeloma register for patients that experienced a LTR over 7 years after high dose chemotherapy followed by ASCT. Characteristics of patients that fit to these criteria have been analyzed in detail. The current disease state was evaluated according to the IMWG criteria. Using the Next Generation Flow technique from Cytognos, bone marrow samples from the patients were examined for minimal residual disease (MRD, sensitivity <10-5). To further characterize the bone marrow environment of myeloma patients in LTR, we currently perform a quantitative analysis of the lymphocyte compartment in peripheral blood and bone marrow using flow cytometry. Moreover, bone marrow mononuclear cells are currently being characterized using the single cell RNA sequencing approach by 10X Genomics. RESULTS: We have identified 24 living patients with ongoing remission from 7 till 17 years after high dose therapy and autologous stem cell transplantation. Patients' characteristics are summarized in Table 1. Unexpectedly, 10 patients had a poor prognosis score at first diagnosis (6 patients with ISS score II and 4 patients with ISS score III). Furthermore, the average tumor burden, determined by plasma cell infiltration of bone marrow at initial diagnosis, was remarkably high with 49.5 %. 4 patients had high risk cytogenetics (3 patients with TP53/del17p and 1 patient with t(4;14)). Regarding the depth of response, the 24 patients were subdivided into 3 groups (Table 2). 9 of 24 patients had a detectable monoclonal protein in serum with an indolent disease course. 15 of 24 patients had no detectable monoclonal protein in serum. Of note, MRD assessment of the bone marrow by Next Generation Flow revealed MRD positivity in 4 of 15 patients. Preliminary data using flow cytometry and single cell RNA sequencing suggest a unique immunological profile of the different patient cohorts in LTR. CONCLUSION: Patients with multiple myeloma in LTR can be subdivided into 3 groups: patients with detectable monoclonal protein but indolent disease course, patients in Flow MRD negative complete remission and patients in Flow MRD positive remission. A deep analysis of patients' peripheral blood and bone marrow by flow cytometry and single cell RNA sequencing is currently being performed focusing on the immunological signature of the different patient cohorts. Preliminary results suggest a unique immunophenotype which is possibly associated to long- term disease control. Data will be presented at the meeting. Disclosures Kriegsmann: BMS: Research Funding; Celgene: Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Durie:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Goldschmidt:Takeda: Consultancy, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria.

Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 25-25 ◽  
Author(s):  
Brian Durie ◽  
Antje Hoering ◽  
S. Vincent Rajkumar ◽  
Muneer H. Abidi ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Rank Test ◽  
P Value ◽  
Advisory Committees ◽  
Significance Level ◽  
Grade 3

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; 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; Multiple Myeloma Research Foundation: Other: Travel Stipend.

Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group

2006 ◽  
Vol 24 (3) ◽  
pp. 431-436 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Philip R. Greipp
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Response Rate ◽  
Eastern Cooperative Oncology Group ◽  
Response Rates ◽  
Incidence Rates ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Monoclonal Protein ◽  
Grade 3

Purpose To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. Patients and Methods Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. Results Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). Conclusion Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

scholarly journals High-Dose Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Conditioning Prior to Autologous Transplantation for Patients with Multiple Myeloma: Results of a Prospective Phase II Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1831-1831
Author(s):  
Scott R. Solomon ◽  
Melhem Solh ◽  
Stacey Brown ◽  
Nancy Shegda ◽  
Katelin C Jackson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Genetic Risk ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Post Transplant ◽  
Grade 3 ◽  
One Year ◽  
High Dose Melphalan

Abstract Single-agent high-dose melphalan followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM). Efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed, with the exception of a sole phase III study showing improved progression-free survival (PFS) with the addition of busulfan to melphalan (Lancet Haematology 2019, 6:266-75). Bendamustine is a synthetic agent that combines the alkylating properties of a mustard-group with the antimetabolic activity of a purine analog. It can induce responses in MM resistant to other alkylators and is therefore a promising agent to test synergy in conditioning regimens. The high-dose chemotherapy combination of bendamustine, etoposide, cytarabine and melphalan (BeEAM) has been shown to be a safe and effective transplant regimen for lymphoma patients (Blood 2011, 118:3419-25). We performed a phase II study to test the safety and efficacy of BeEAM in MM patients, 18-70 years of age, with adequate organ function (EF≥40% predicted, CrCl ≥40ml/min) and within 9 months of starting induction therapy. Results were compared to a contemporaneously treated control group receiving a single high-dose melphalan 200mg/m2 transplant (Mel200) but otherwise meeting study eligibility criteria. Study patients (n=65) had a median (range) age of 59 (40, 69) years and were transplanted from 2015-2020. Other characteristics included KPS&lt;80%, HCT-CI≥3, ISS III, and high-risk FISH in 35%, 46%, 26% and 44% respectively. Pre-BMT status was (s)CR1, VGPR1, PR1 and &lt;PR1 in 26%, 43%, 26% and 5% respectively. ASCT following BeEAM was well tolerated with no non-relapse deaths through one-year post-transplant. Although at least one non-hematologic grade 3 toxicity was reported in 32 (49%) patients, there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. With a median f/u of 44 (13, 70) months, three-year OS and PFS was 92% and 57% respectively. When BeEAM patients were compared to contemporaneously treated Mel200 patients, there were no significant differences in baseline characteristics, induction regimen or use of post-transplant maintenance therapy. Neutrophil and platelet engraftment was faster following BeEAM (11 vs. 12 days, 17 vs 18 days, p&lt;0.001 and p=0.007 respectively), when compared to Mel200 patients. One-year non-relapse mortality was 0% with both BeEAM and Mel200. No significant differences were seen in quality of response, PFS or OS between BeEAM and Mel200, when analyzing either the whole cohort (see figure) or by genetic risk stratification. In multivariate analysis, controlled for genetic risk and year of transplantation, the use of BeEAM conditioning offered no benefit to Mel200 in terms of OS, PFS or risk of relapse/progression. In summary, BeEAM was shown to be a safe and effective conditioning regimen prior to up-front autologous transplant for MM. However, BeEAM conditioning appears to offer no significant advantage when compared to conventional Mel200 conditioning. Figure 1 Figure 1. Disclosures Solh: Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding; ADCT Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: Bendamustine for Multiple Myeloma

scholarly journals Time to Next Treatment Is Response Dependent and Treatment Independent Based on Evidence from RCTs in Stem Cell Transplantation Eligible Multiple Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2122-2122
Author(s):  
Chrissy H. Y. Van Beurden-Tan ◽  
Philippe Moreau ◽  
Laura Rosiñol ◽  
Walter Gregory ◽  
Michel van Agthoven ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clin Oncol ◽  
Research Funding ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Rank Test ◽  
P Value ◽  
Pivotal Phase ◽  
Data Set ◽  
Treatment Sequences

Abstract INTRODUCTION Multiple Myeloma (MM) is an incurable disease and its treatment is characterized by treatment sequences (treatment lines). We questioned whether a health economic (HE) model could be developed that analyses treatment sequences (TS) rather than a particular line of treatment in transplant eligible patients with MM. In this model we hypothesized that the time to next treatment (TTNT) is response dependent (i.e. complete, partial or no response; CR, PR or NR) rather than primarily dependent on the choice of specific regimens. METHODS We have analyzed the patient level data of the following major phase III RCTs in newly diagnosed SCT eligible MM patients: HOVON-50 (N=536): TAD vs VAD, HDM/ASCT, Thalidomide vs Interferon maintenance (Lokhorst et al Blood 2010), HOVON-65/GMMG-HD4 (N=827): PAD vs VAD, HDM/ASCT, Bortezomib vs Thalidomide maintenance (Sonneveld et al J Clin Oncol 2012) and IFM 2005-01 (N=478): Bortezomib/Dexamethasone vs VAD induction (Harousseau et al J Clin Oncol 2010). The following data were included: treatment arm, best response, TTNT and survival status. Patients were censored after last date of contact. Patients who did not have any information on TTNT were excluded from our analyses. Kaplan-Meier curves and Cox proportional hazards models were fitted on this data to investigate whether the TTNT is mainly response dependent and whether the quality of response is predictive for TTNT. Data from PETHEMA/GEM05 (Rosiñol et al Blood 2012) and MRC Myeloma IX (Morgan et al Haematologica 2012) are currently being prepared to be included in our analyses. RESULTS The hazard ratio (HR) of CR patients (pts) in the experimental treatment arm versus CR pts in the comparator arm is 0.664 (95% Confidence Interval: 0.418-1.055, p-value = 0.083) for HOVON-50 (N=134 pts), 0.922 (95% CI: 0.688-1.235, p-value = 0.586) for HOVON-65 (N=329 pts), and 2.512 (95% CI: 0.522-12.094, p-value = 0.251) for IFM 2005-01 (N=202 pts). The HR of PR pts in the active arm versus PR pts in the comparator arm is 0.777 (95% CI: 0.596-1.014, p-value = 0.063) for HOVON-50 (N=254 pts), 0.860 (95% CI: 0.674-1.098, p-value = 0.226) for HOVON-65 (N=337 pts), and 0.393 (95% CI: 0.128-1.207, p-value = 0.103) for IFM 2005-01 (N=175 pts). The HR of NR pts in the active arm versus NR pts in the comparator arm is 1.303 (95% CI: 0.754-2.250, p-value = 0.343) for HOVON-50 (N=62 pts) and 0.760 (95% CI: 0.402-1.436, p-value = 0.398) for HOVON-65 (N=67 pts). The number of NR patients in the IFM study was too low (N=15) to show any sensible results on the HR. The HR of CR pts versus PR pts is 3.012 (95% CI: 2.300-3.945, p-value = 0.000) in HOVON-50, 1.935 (95% CI: 1.600-2.341, p-value = 0.000) in HOVON-65, and 2.269 (95% CI: 1.012-5.091, p-value = 0.047) in IFM 2005-01. The comparator arms’ TTNT (i.e. VAD) of the HOVON trials were tested similar given the result of the log rank test (p-value = 0.5165 for CR pts, and p-value = 0.0579 for PR pts). For the median TTNT and corresponding confidence intervals data of the comparator arms from both HOVON studies were used. The median TTNT for CR pts is 58 months (95% CI: 51 – 70 months), for PR pts is 29 months (95% CI: 27 – 32 months), and for NR pts is 8 months (95% CI: 6 – 13 months). Even though the comparator arm of the IFM 2005-01 study was similar to the comparator arms of the HOVON studies, we did not include this data in the calculation of the median TTNT mainly because the median was not reached in the IFM trial. The number of excluded pts was low (86, 94 and 86 pts in HOVON-50, HOVON-65 and IFM 2005-01 respectively) and scattered evenly across the response categories and treatment arms, implying no bias was introduced when excluding these patients from our data set. CONCLUSIONS In our analyses we have discovered that in the pivotal phase III RCTs with Thalidomide and/or Bortezomib in SCT eligible MM patients, TTNT is response dependent and not treatment dependent. Furthermore, patients achieving CR were observed to have a significantly longer TTNT compared to those achieving PR at best. Disclosures Rosiñol: Janssen: Honoraria; Celgene: Honoraria. van Agthoven:Janssen-Cilag BV: Employment. Sonneveld:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding.

Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5028-5028
Author(s):  
Victor H Jimenez-Zepeda ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Ahmed M. Rabea ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Response Rate ◽  
Treated Patient ◽  
Median Number ◽  
Disease Stage ◽  
Vein Thrombosis ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Previously Treated

Abstract Abstract 5028 Lenalidomide (len) and bortezomib (btz) are active in multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone (Mitsiades N, et al). The combination of lenalidomide (Revlimid), bortezomib (velcade), and dexamethasone (RVD) has shown excellent efficacy in relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts), with an overall response rate (ORR) of 84% and a partial response (PR) rate of 68%, including 21% complete/near complete responses (CR/nCR), median duration of response was 24 weeks in responding patients and median number of cycles was 6 (Anderson KC, et al. ASCO 2009: abstract 8536). The aim of this study is to assess the efficacy and toxicity profile when len is used in combination with btz and dexamethasone (dex) for pts with relapsed/refractory (rel/ref) disease outside the setting of clinical trials. Patients and Methods We retrospectively reviewed the records of all pts with rel/ref MM who were treated with RVD at Princess Margaret Hospital between March 2009 and March 2010. Eighteen pts were treated with at least 1 full cycle of RVD therapy given as len 10 mg/d on days 1–14, btz 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles and dex (20 mg or 40 mg on days of and after btz). Pts routinely received concomitant antithrombotic and antiviral prophylaxis. Primary endpoints were response rate, time to progression (TTP) and toxicity. Responses were assessed according to modified EBMT and Uniform criteria. Toxicity was assessed using NCI-CTC, version 3.0. Results Clinical characteristics are seen in Table 1. Median age was 57 (37-71) years; 55% were female. The median number of prior therapies was 3 (2-6), and the majority of pts had already been treated with len (83%) and btz (78%) separately, and 77% had received both drugs previously but not in combination. In many instances, pts previously treated with len had len added to btz + dex at progression (n=5), or pts previously treated with btz had btz added to len + dex, at progression (n=4). After a median of 4.9 cycles (range 1–14), PR was observed in 7 (39%) and stable disease (SD) in 2 (11%) pts, for an ORR of 39%. Disease progression was seen in 14 pts at a median TTP of 4 months (1-13.6 months). Currently, 6 pts (33%) remain alive at a median F/U of 6.83 months (1.4-18.6 months). Median overall survival was 6.88 months (1-18.6 months) and six patients had a greater than 6 month response. Six pts have experienced grade 3/4 adverse events, including anemia, neutropenia, muscle weakness, hyperglycemia, and pneumonia. No deep vein thrombosis was observed. The side effect profile was manageable; importantly no patient experienced worsening of peripheral neuropathy. Conclusions The ORR for our heavily treated patient population was 39% which is lower than that reported by Anderson et al (ASCO, 2009). The median TTP was also short at 4 months. These differences can be partly explained by the fact the majority of our pts had previously received all the agents in RVD, while only 8% of the pts in the Anderson series had prior len exposure. These data suggest that the RVD combination can be effective in rel/ref MM, but responses/duration are affected by very advanced disease stage at relapse and the extent of prior treatment. Disclosures: Reece: Celgene: Honoraria, Research Funding. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Presence of PD-1 Expressing T Cells Predicts for Inferior Overall Survival in Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1785-1785 ◽  
Author(s):  
Gasmi Billel ◽  
Eric L Smith ◽  
Ahmet Dogan ◽  
Meier Hsu ◽  
Sean Devlin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
P Value ◽  
Newly Diagnosed ◽  
Cell Infiltrate ◽  
Cell Exhaustion

Abstract Background: Programmed cell death 1 (PD-1) protein downregulates T cell activation and is related to immune tolerance. PDL1 up regulation, T cell infiltration, and T cell exhaustion are features, which suggest susceptibility to PD-1 blockade antibodies. Blockade of PD-1 or its ligand PD-L1 has shown promising responses in several malignancies. Although little clinical activity has been seen in patients with relapsed multiple myeloma (MM), the role of the PD-1 pathway and T cell exhaustion in newly diagnosed MM has not been explored. Objective: To determine whether T-cell infiltrate or expression of PD-1 correlates with clinical features and prognosis among patients with newly diagnosed multiple myeloma. Methods: We screened a clinically annotated database of 341 patients seen at MSKCC between 1998 and 2012 that had Multiple Myeloma, received a bone marrow transplant and were consented to a biospecimen research protocol for availability of pre-treatment bone marrow specimens. A total of 64 bone marrow biopsy specimens were identified. Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded specimens using an anti human CD3 monoclonal antibody (mAb) (Dako, Clone F7.2.38) and an anti human PD-1 mAb (Cell Marque, catalog #315M-95). CD3 and PD1 IHC staining were graded as negative (<5% for CD3, < 1% for PD1), or positive (≥5% for CD3, ≥1% for PD1). Correlative analyses were performed between CD3/PD1 expression and clinical outcome using the following parameters: International Staging System (ISS), cytogenetic risk, progression free survival (PFS), overall survival (OS), and response to treatment. Groups were compared by Fisher's exact test. OS and PFS were assessed by Cox regression and estimated by Kaplan-Meier methods. Results: 23 specimens (36%) were CD3 positive and 10 specimens (16%) were PD-1 positive. All PD-1 positive specimens were CD3 positive. 41 specimens (64%) were CD3 negative (<5%) and PD1 negative (<1%). Based on these results, specimens were divided into three groups: Exhausted T-cell infiltrate (CD3+/PD1+), non exhausted T-cell infiltrate (CD3+/PD1-) and no T-Cell infiltrate (CD3-/PD1-). In the exhausted T-cell infiltrate group 30% of patients had ISS stage 3 and 40% had high risk cytogenetics. In the non-exhausted T-cell group 15% of patients had ISS stage 3 and 15% high cytogenetic risk. In the no T-cell infiltrate group 10% had ISS stage 3 disease and 22% high cytogenetic risk. These proportions were not significantly different across the 3 groups. Median OS from 1st auto infusion was 7 years while median PFS was 2.3 years. On univariate analysis, there was no significant difference in PFS between the 3 groups. The presence of CD3 and PD1 T-cells were significantly associated with OS (p-value = 0.04). Median OS from 1st auto infusion was 43 months for the exhausted T-Cell infiltrate group followed by 83 months for the no T-Cell infiltrate group. The non exhausted T-cell group had the highest OS, median not reached; OS by 7-years was 75%. Cytogenetic risk at diagnosis was significantly associated with OS (p-value = 0.03). In a multivariable model, CD3/PD1 staining continued to trend toward an association with OS (p-value = 0.08) and cytogenetic risk remained significant (p-value = 0.05). Conclusions: The presence of T-cells with PD-1 expression was not associated with higher risk disease at MM diagnosis based on cytogenetics and ISS stage. The presence of PD-1 expressing CD3+ T cells trends toward an association with poorer overall survival in newly diagnosed MM, especially compared to non exhausted T-cell infiltrate, suggesting the possibility that T cell exhaustion represents a novel high risk disease characteristic. Further investigation is necessary to assess if the presence of CD3+PD-1+ T cells is an independent prognostic feature in newly diagnosed MM. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Landgren:International Myeloma Foundation: Research Funding; Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Consultancy; BMJ Publishing: Consultancy; Celgene: Honoraria; Onyx: Honoraria; BMJ Publishing: Honoraria; Onyx: Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Efranat: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document