Relative Efficacy of Treatment Options in Newly Diagnosed Multiple Myeloma: Results from a Systematic Literature Review and Network Meta-Analysis

Abstract Background: For patients with newly diagnosed multiple myeloma (NDMM), the combination of lenalidomide and dexamethasone (Rd) provides for an oral, melphalan-free approach to treatment. Although the treatment practices for these patients have been rapidly evolving, the goal to gain and maintain as deep a response as possible still remains. Autologous stem cell transplantation (ASCT) has been proven to be beneficial for NDMM patients, irrespective of age (Pawlyn C, et al. HemaSphere 2018;2:S106); however, many NDMM patients are not selected for ASCT due to poor fitness; ASCT may also be delayed due to availability of effective first-line therapy options. For these patients, current standard first-line therapeutic options include lenalidomide and bortezomib, although thalidomide is still used in some countries. Recently, many studies have aimed to assess the benefits of new therapeutic options, including triplet therapy with Rd and bortezomib (RVd) (Durie BG, et al. Lancet. 2017;389:519-27), and daratumumab in combination with bortezomib, melphalan, and prednisone (VMP+D) (Mateos MV, et al. N Engl J Med. 2018;378:518-28). The aim of this study was to estimate the relative treatment effects on progression-free survival (PFS) and overall survival (OS) in patients with NDMM not intended for ASCT and/or aged > 65 years, using a systematic literature review (SLR) and network meta-analysis (NMA) of randomized controlled trials (RCTs), including emerging therapies. Methods: According to predefined study selection criteria and literature search strategies, relevant studies were identified from MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases as well as the conference proceedings of the European Society for Medical Oncology, American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, International Multiple Myeloma Workshop, and International Society for Pharmacoeconomics and Outcomes Research. Only regimens commonly used in clinical practice were included, with a dosing schedule in line with the respective regimens' Summary of Product Characteristics (SmPC) for licensed treatments. A Bayesian fixed-effect NMA was conducted on hazard ratios (HRs) for PFS and OS to determine the comparative efficacy of treatments. NMA allows estimation of the relative treatment effects for all pairs of interventions, even for those without head-to-head comparison data from clinical trials. This is possible as long as they are included in a connected network of comparisons. Results are presented as mean HRs for PFS and OS with their credible intervals (CrIs), where an HR < 1 indicates a beneficial effect. Where HR data were unavailable, it was estimated from median or probability of survival outcomes assuming an exponential distribution. Analyses were carried out on an intention-to-treat basis. Results: The systematic literature review yielded 39 publications describing 23 RCTs. We adopted a conservative approach to constructing the evidence network and excluded trials on the basis of relevance to clinical practice and/or adherence to the SmPC. This resulted in 7 trials representing 6 regimens being included in the NMA (ALCYONE, VISTA, IFM 01/01, IFM 99-06, MM-03, FIRST, and SWOG S0777), of which 6 had data available for OS. Compared with Rd, only RVd significantly improved PFS (HR 0.72; 95% CrI 0.56, 0.9) (Figure 1A). For OS, RVd was the only therapy to show statistically significant superiority over Rd (HR 0.72, 95% CrI 0.52, 0.96) (Figure 1B). Results for PFS and OS of VMP+D versus Rd were inconclusive. A limitation of this analysis was that a small number of patients in the SWOG S0777 (Durie BG, et al. Lancet. 2017;389:519-27) trial, which examined the effect of RVd versus Rd, received ASCT, although transplantation had not been planned a priori. Future research could consider sensitivity analysis through matching adjusted indirect comparison, adjusting for this and other differences across the included studies. Conclusions: This analysis confirms Rd to be superior to other licensed treatments currently available, in terms of both PFS and OS. Of emerging treatment options, based on current published evidence, only RVd significantly extends PFS and OS. Disclosures Ramasamy: Celgene Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thom:Celgene Corp.: Consultancy. Dhanasiri:Celgene International: Employment, Equity Ownership.

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Treatment Regimens for Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Stem Cell Transplantation: A Systematic Literature Review and Network Meta-Analysis

Blood ◽

10.1182/blood-2018-99-113668 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4741-4741 ◽

Cited By ~ 2

Author(s):

Jesus F San-Miguel ◽

Thierry Facon ◽

Meletios A Dimopoulos ◽

Maria-Victoria Mateos ◽

Michele Cavo ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Literature Review ◽

Board Of Directors ◽

Comparative Effectiveness ◽

Research Funding ◽

Meta Analysis ◽

Newly Diagnosed ◽

Advisory Committees ◽

Treatment Regimens

Abstract Background: In patients with newly diagnosed multiple myeloma (ndMM) who are ineligible for autologous stem cell transplantation (ASCT), bortezomib, melphalan, and prednisone regimen (VMP) is standard of care as a first-line treatment in most regions of the world. Daratumumab is a new monoclonal antibody aimed to improve outcomes in ndMM. The ongoing ALCYONE study demonstrated significant improvement in progression-free survival (PFS) and overall response rate (ORR) for the combination of daratumumab plus VMP (D-VMP) compared to VMP in transplant-ineligible ndMM patients (Mateos, 2018). While direct head-to-head randomized controlled trials (RCTs) are lacking, it is important to assess how D-VMP compares with other treatment regimens used in clinical practice for ndMM patients who are ineligible for ASCT. Aims: The aim of this study is to investigate the comparative effectiveness (PFS, ORR) of D-VMP with other relevant treatment regimens used in patients with ndMM who are ineligible for ASCT. Methods: We conducted a Bayesian network meta-analysis (NMA) based on RCTs identified through a systematic literature review (SLR). Both fixed effects and random effects models were tested. The results are depicted in a network of evidence, forest plots, ranking histograms and probabilities of D-VMP being better than the comparator treatment regimens. Results: The SLR revealed 25 RCTs conducted in patients with ndMM who are ineligible for ASCT. For PFS, the NMA included 20 RCTs covering 20 treatments and for ORR, the NMA included 20 RCTs covering 21 treatments. Random-effects model is preferred for PFS as well as for ORR as this model showed lower deviance information criterion (DIC), and as the homogeneity assumption was violated for PFS. The results for both PFS and ORR are summarized in Table 1. For PFS and ORR, D-VMP ranked first in the evidence of network. For PFS, D-VMP was statistically significantly more effective compared to 10 out of the 19 treatment regimens. For ORR, D-VMP was significantly more effective as compared to 12 out of the 20 treatment regimens. Conclusion: In the absence of head-to-head RCTs, NMAs allow delineation of the comparative effectiveness of different treatments. This NMA suggests that D-VMP has a higher potential of being effective in improving ORR and PFS in patients with ndMM who are ineligible for transplant compared to other available treatment options. Updated results based on a 1-year update of ALCYONE will be presented at the meeting. References: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528 Disclosures San-Miguel: Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria. Facon:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. van Beekhuizen:Ingress Health: Consultancy. Pisini:Janssen Research & Development, LLC: Employment. Nair:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment.

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Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2016-2016

Author(s):

Tomer M Mark ◽

Peter Forsberg ◽

Ihsane Ouansafi ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Maintenance with Weekly Carfilzomib in Elderly Newly Diagnosed Multiple Myeloma (IFM 2012-03)

Blood ◽

10.1182/blood-2019-131793 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3190-3190

Author(s):

Arthur Bobin ◽

Guillemette Fouquet ◽

Alain Duhamel ◽

Salomon Manier ◽

Lionel Karlin ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Treatment Options ◽

Maintenance Phase ◽

Prolonged Survival ◽

Second Phase ◽

Advisory Committees ◽

Additional Information

Background. Continuous therapy, such as maintenance approach, appears to be a major therapeutic change in multiple myeloma, improving response rate and overall survival. Novel agents widen the range of treatment options, still Lenalidomide (IMiD) is widely used in this indication. Even though usually well tolerated, it remains a daily treatment, and can lead to some side effects on a long term basis. Carfilzomib, a second generation PI, allows interesting response rate and prolonged survival, with manageable adverse events. Nevertheless, only few clinical trials focused on its use in maintenance rather than in first or second line treatment. We therefore thought to study the role of 1 year Carfilzomib exposure following KMP IFM 2012-03. Methods. IFM 2012-03 is a multicenter phase I study for eNDMM (patients aged 65 years old and more) that determined the maximal tolerated dose of weekly carfilzomib, associated with melphalan and prednisone (KMP), at 70mg/m². The following results will concern the second phase of the study using intravenous Carfilzomib monotherapy in maintenance. K was administered at 36 mg/m² for 13 cycles on an every 2 weeks schedule. Results. Thirty eNDMM were recruited in IFM 2012-03. Median age is 75, with 56% R-ISS 2 or 3 and 11% high-risk cytogenetic. With K weekly from 36 to 70mg/m², ORR is reported at 93.3%, including 46.7% ≥CR ; median PFS is 35.8 months and median OS was not reached. Twenty-two (73%) patients started K maintenance and 16 (73%) completed it. Four patients progressed and 2 stopped for AEs (renal amylosis, sensory neuropahty) during the maintenance phase. At maintenance completion, 50% were ≥CR. From the start of maintenance, in landmark analysis, median PFS is 28.1 months and the estimated 36-months OS approximately 70%. Moreover, 3 patients (14%) improved their responses during maintenance. Conclusion. Carfilzomib monotherapy can be used safely in maintenance for 1 year in eNDMM, including for patients above 75 years. K maintenance may lead to deep response rate, certainly a most relevant prognostic factor for prolonged survival. Therefore, Carfilzomib maintenance, characterized with a simple administration modality, might be considered as an alternative to Lenalidomide and integrate the armamentarium of prolonged therapy in eNDMM. Further studies should still bring additional information in order to confirm our results. Disclosures Karlin: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kolb:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel and registration for my participation to international medical congres (ASH). Jaccard:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Belhadj:Celgene: Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Leleu:Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria.

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Role of High-Dose Melphalan and Autologous Stem Cell Transplantation in Multiple Myeloma Patients Presenting with t(11;14)

Blood ◽

10.1182/blood-2019-129880 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4580-4580 ◽

Cited By ~ 1

Author(s):

Eduardo Sobejano ◽

Veronica Gonzalez De La Calle ◽

Victor Higuero ◽

Fernando Escalante ◽

Ramón García-Sanz ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

University Hospital ◽

First Line ◽

Advisory Committees ◽

Baseline Characteristics ◽

Standard Risk

INTRODUCTION The t (11; 14) by fluorescent in situ hybridization (FISH) is found in 15-20% of patients with multiple myeloma (MM) . Although it was classically considered a standard risk translocation or even a good prognosis, recent studies conducted in the era of new drugs show contradictory results and it is not well established if they have to be considered intermediate or standard risk. The possibility of using targeted therapy with venetoclax for patients harboring t(11;14) makes the investigation of the outcome of newly diagnosed multiple myeloma (NDMM) with t(11;14) as relevant. METHODS We analyzed the baseline characteristics and outcome of patients with t(11;14)and receiving HDT-ASCT within the series of 647 patients with NDMM between 1988 and 2018 according to the current criteria at each moment at two academic hospitals in Spain (University Hospital of Salamanca and Hospital of Leon) . The FISH was performed on selected cells according to international regulations and centralized at the University Hospital of Salamanca. For this purpose, a descriptive cross-sectional study was first conducted comparing the characteristics of patients with t (11; 14) versus the rest. The final objective wasto evaluate the role of HDT-ASCT in NDMM with t(11;14). RESULTS The baseline characteristics of the whole series were: a median age of 71years (yrs) (range:30-96). 217 patients (33,5%) were under 65 years. 352 (56.2%) were IgG; 161 (25.7%) IgA; 87 (13.9%) Bence Jones; 19 (3%) non-secretors, and 5 and 2 cases were IgD and IgM, respectively. 320 (53.2%) received novel agents as part of the first line of therapy. Overall, 153 (27.8%) achieved complete response (CR) after first line, and 403 (73.1%) at least a partial response. After a median follow-up for living patients of 4.26 yrs (range: 0,1-27.3), the OS of the entire series was 2.74 years. T(11;14) was performed in 440 NDMM patients and was positive in 80 (18.2%). Only in 5 patients other high-risk alterations (t (14:16), t (4:14) or del17p (p53)) were detected. The baseline characteristics of patients with and without t (11:14) did not show significant differences, except for the heavy chain pattern(p <0,001). IgA was lower in patients with t(11:14) 12,8% (10 out of 78)vs 27,7% (98 out of 353). Of note, most patients with non-secretory MM (10 out of 16, 62,5%) had the t(11;14) whilst in the conventional secretory MM patients, t(11;14) was observed in 68out of 415(16,4%). In addition, the plasma cell bone marrow infiltration was significantly higher in patients with t(11;14)(> 60% Plasma Cells) 32.8% vs 13.3%(p <0.001)). HDT-ASCT was performed in 162 patients (25%)and 22 of them (13,5%) were positive for the t(11:14) and only in 2 patients, other high-risk alterations were detected.The induction therapy received in both treatments arms was homogeneous basically consisted on combinations of proteasome inhibitors plus immunomodulatory drugs. The median OS for NDMM patients undergoing ASCT was 4,33 years. (range: 0,47-26,85) and the median PFS for this patients was 2,25 yrs (range: 0,1-27,25) The median PFS for patients with t (11/14) undergoing ASCT trended to be higher than that observed in patients without t(11;14) who received also HDT-ASCT (99.1 vs 54.9 months), without obtaining significant results, (p 0.205) maybe due to the small number of patients (Figure 1).The median OS in the group of patients with and without t(11:14) undergoing ASCT was 120,8 vs 140 months (p= 0,829). In the cohort of non eligible ASCT patients both median PFS and OS for patients with t(11:14) was similar than that observed in patients without t(11:14)(median PFS of 19,9 vs 19,4 months) (p 0,438) and (median OS of 31,5 vs 44 months) (p 0,424), respectively. CONCLUSION T(11;14) seems to be a cytogenetic abnormality more frequently observed in patients with NDMM and non secretory phenotype what requires further investigation. Patients with t(11;14) benefit the most if they received HDT-ASCT and it would represent a therapeutic strategy of choice if the patient is transplant-eligible. Figure 1 Disclosures Puig: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; The Binding Site: Honoraria; Takeda, Amgen: Consultancy, Honoraria. Mateos:Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Honoraria, 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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No Increased Risk of Secondary Neoplasms in Patients Treated with Rituximab for Non-Hodgkin’s Lymphoma : A Meta-Analysis of 9 Trials

Blood ◽

10.1182/blood.v124.21.1659.1659 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1659-1659

Author(s):

Isabelle Fleury ◽

Sylvie Chevret ◽

Michael Pfreundschuh ◽

Gilles Salles ◽

Bertrand Coiffier ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Odds Ratio ◽

Research Funding ◽

Meta Analysis ◽

Advisory Committees ◽

Secondary Neoplasms ◽

Increased Risk ◽

American Society

Abstract Background. Rituximab improved outcomes of all CD20+ non-Hodgkin lymphoma (NHL) subtypes. Rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation (Stroopinsky et al., Cancer Immunol Immunother 2012) predisposing to T-cell dependent infections and to a potential impaired T-cell immunosurveillance. Secondary neoplasms (SN) is infrequent in trials including rituximab and the SN risk associated to rituximab across multiple trials has not been reported. We performed a systematic review of published trials comparing chemotherapy with or without rituximab to evaluate SN occurrence. Methods. Our primary endpoint was SN risk in patients with NHL treated with rituximab. We searched PubMed and Embase databases for randomised controlled trials on rituximab and lymphoma where rituximab constituted the only difference between treatment arms and where SN incidence or SN related death were reported. Authors were contacted for SN related rituximab exposure if not detailed. Chronic lymphocytic leukemia and HIV-related lymphomas were excluded due to increased risk of SN. Updated follow-up of eligible trials presented at annual meetings of the American Society of Clinical Oncology and American Society of Hematology were retrieved. Data were extracted independently by two authors. A random effects DerSimonian-Laird meta-analysis was performed to estimate the summary effect of rituximab on the hazard of SN. Statistical heterogeneity was tested using Woolf test. Results. We identified nine trials cumulating 4621 patients with 2312 exposed to rituximab and 2309 not exposed. These nine trials are known with the following names: PRIMA (1), GELA LNH98.5 (2), MINT (3), CORAL (4), IELSG-19 (5), EORTC20981 (6), OSHO#39 (7), SAKK 35/98 (8), RICOVER60 (9). Histology were diffuse large B cell (n=4), follicular (n=4) and marginal zone (n=1) lymphomas. Median age was 58.1 years. Sex distribution was available for seven trials with 1650 (47.6%) women and 1814 (52.4%) men. In all these trials but one (SAKK 35/98), rituximab was used associated with chemotherapy: CHOP, CHOEP, FCM, MCP, DHAP, ICE, or chlorambucil. At a median follow-up of 73 months [interquartile range: 72-84], a total of 334 SN was observed, including 169 SN in patients randomised to rituximab as compared to 165 SN in patients not randomised to rituximab (OR= 0.88; 95%CI: 0.66-1.19) (Figure 1). No evidence of significant heterogeneity was noticed across trials (p = 0.93). Notably, the proportion of females, histology subtypes, use of rituximab in first line, and use of rituximab over prolonged periods in maintenance did not influence SN risk (p = 0.94, p = 0.80, p = 0.87, p = 0.87 respectively). The SN risk was not increased in protocols administrating rituximab over periods of 8 months to 12 months (CORAL , OSHO#39) as opposed to periods of 24 months (PRIMA, EORTC20981) (p=0.86). Conclusions. This meta-analysis of nine trials randomising rituximab in NHL patients suggests no SN predisposition at a median follow-up of 6 years. SN risk associated with the combination of rituximab and new targeted therapies warrants prospective monitoring. Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Disclosures Fleury: Lundbeck: Membership on an entity's Board of Directors or advisory committees, Preceptorship Other. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding. Salles:Roche: Honoraria, Research Funding. van Oers:Roche: Consultancy. Gisselbrecht:Roche: Research Funding. Zucca:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Herold:Roche Pharma AG/Germany: Honoraria, Research Funding. Ghielmini:Roche: Research Funding, Speakers Bureau.

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Early Prediction of Treatment Response in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-111624 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3159-3159

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Treatment Cycle ◽

Validation Cohort ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Training Cohort ◽

M Spike

Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Systematic Literature Review and Network Meta-Analysis of Treatments for Relapsed/Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood.v128.22.2144.2144 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2144-2144

Author(s):

Chrissy H. Y. Van Beurden-Tan ◽

Margreet Franken ◽

Hedwig Blommestein ◽

Carin A. Uyl-De Groot ◽

Pieter Sonneveld

Keyword(s):

Multiple Myeloma ◽

Research Funding ◽

Meta Analysis ◽

Treatment Options ◽

Progression Free Survival ◽

Relative Efficacy ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Risk Of Progression

Abstract INTRODUCTION Since the year 2000 fifteen new treatment options came to market for relapsed/refractory multiple myeloma (RRMM) after a long period in which dexamethasone has been the only treatment option. Direct comparisons are, however, lacking which makes it extremely difficult to evaluate the relative added value of each drug. Our aim was to synthesize all efficacy evidence enabling a comparison of all treatments. METHODS We performed a systematic literature review to identify all publically available phase 3 randomized controlled trials (RCTs) using EMBASE®, MEDLINE®, MEDLINE® in-process, Cochrane Central Register of Controlled Clinical Trials and the website www.clinical-trials.gov. Additionally, two abstracts from international hematology congresses (ASCO and EHA 2016) were added to our search to present the most up-to-date overview. A conventional network meta-analysis (NMA) based on progression-free survival (PFS) outcomes allowed a comparison of all available treatment options using a Bayesian fixed effect NMA programmed in WinBUGS. The oldest treatment, dexamethasone, was used as reference treatment. Additionally, results regarding bortezomib-dexamethasone versus lenalidomide-dexamethasone are presented because these were the two most commonly used comparators. RESULTS Seventeen RCTs were identified including sixteen treatment options: dexamethasone (Dex), oblimersen-dexamethasone (OblDex), thalidomide/thalidomide-dexamethasone (Thal/ThalDex), bortezomib/bortezomib-dexamethasone (Bor/BorDex), lenalidomide-dexamethasone (LenDex), pegylated doxorubicin-bortezomib (PeglDoxBor), bortezomib-thalidomide-dexamethasone (BorThalDex), vorinostat-bortezomib (VorinoBor), panobinostat-bortezomib-dexamethasone (PanoBorDex), carfilzomib-lenalidomide-dexamethasone (CarLenDex), pomalidomide-dexamethasone (PomDex), elotuzumab-lenalidomide-dexamethasone (EloLenDex), carfilzomib-dexamethasone (CarDex), ixazomib-lenalidomide-dexamethasone (IxaLenDex), daratumumab-lenalidomide-dexamethasone (DaraLenDex) and daratumumab-bortezomib-dexamethasone (DaraBorDex). To include all trials within one framework, we assumed: i) the relative efficacy of Bor versus Dex and BorDex versus Dex is the same, ii) the relative efficacy of Thal versus Dex and ThalDex versus Dex is the same, iii) time to progression (TTP) can be used as proxy for PFS in case of missing hazard ratios (HRs) and 95% confidence intervals of PFS, and iv) no difference in efficacy due to dosage scheme (100 versus 200 versus 400 mg Thal) and administration method (intravenous versus subcutaneous Bor). Figure 1 presents the NMA results. The treatments are sorted according to their rank. The figure also presents the probability of being the best treatment, HRs and 95% credible intervals (CrIs) versus Dex. Fourteen out of sixteen treatments were significantly better than Dex (HRs ranged from 0.13 to 0.76). Only OblDex ranked lower; the HR was, however, not significantly different (HR: 1.08; 95% CrI: 0.79 - 1.45). Eleven treatments reduced the risk of progression or death with more than 50%. DaraLenDex was identified as the best treatment because it was the most favorable in terms of i) HR (0.13; 95% CrI: 0.09 - 0.19), and ii) probability of being best (99% of the simulations). DaraLenDex reduced the risk of progression or death with 87% versus Dex, 80% versus Bor/BorDex and 63% versus LenDex. LenDex performed better than Bor/BorDex in ranking (7th versus 13th) as well as in HR (0.53, 95% CrI: 0.39 - 0.71). CONCLUSIONS Our NMA included all available RRMM treatments and identified DaraLenDex as being most effective. NMAs become increasingly important because they provide a complete overview of each treatment's relative efficacy in case of missing head-to-head comparisons. Figure 1. Relapsed/refractory multiple myeloma treatments' network meta-analysis results of progression-free survival outcomes Figure 1. Relapsed/refractory multiple myeloma treatments' network meta-analysis results of progression-free survival outcomes Disclosures Blommestein: BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria.

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A Phase I/II Study of Pomalidomide-Cyclophosphamide-Prednisone (PCP) in Patients with Multiple Myeloma Relapsed/Refractory to Lenalidomide

Blood ◽

10.1182/blood.v118.21.632.632 ◽

2011 ◽

Vol 118 (21) ◽

pp. 632-632 ◽

Cited By ~ 1

Author(s):

Antonio Palumbo ◽

Alessandra Larocca ◽

Angelo Michele Carella ◽

Davide Rossi ◽

Vittorio Montefusco ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Treatment Options ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; 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. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors Associated with Development of Extramedullary Disease in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-114854 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5596-5596

Author(s):

Martin Stork ◽

Sabina Sevcikova ◽

Marta Krejci ◽

Zdenek Adam ◽

Viera Sandecka ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Abstract Background Multiple myeloma (MM) is the second most common hematological malignancy characterized by plasma cell (PC) infiltration of the bone marrow. Unfortunately, better imaging techniques convey multiple reports about increased incidence of the so-called extramedullary disease of MM (EM), an aggressive, mostly resistant entity with poor prognosis for patients. EM probably develops because of 'bone marrow escape' of PC subclone that migrates out of the BM infiltrating soft tissues losing dependence on the BM microenvironment, either partially or completely. There are two types of EM - primary, found at the time of MM diagnosis, and secondary, found at the time of MM relapse. However, there are very few reports about EM. Aims This study aims to analyze risk factors connected to EM development. Methods Data from the Registry of Monoclonal Gammopathies (RMG) were analyzed. The RMG represents a database for collection of clinical data concerning diagnosis, treatment and follow-up of Czech MM and other monoclonal gammopathies patients. In total, data of 4985 MM patients were collected into the RMG database between 2007 and June 2017. Our analysis compared patients who developed EM at initiation of first or higher line of therapy with patients without EM during at least 5-year-long follow-up (patients who died earlier included). Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with EM occurrence at first line and relapse, respectively. Results In total, 4985 MM patients data were collected into the RMG database between 2007 and 2017. Patients were treated with bortezomib, lenalidomide, thalidomide, pomalidomide, ixazomib and daratumumab. Regardless of treatment, EM patients responded worse than MM patients did to any form of treatment. While primary EM patients had similar PFS as MM patients, OS was significantly worse (48.7 vs 60.6 months, resp.). Secondary EM patients did even worse, with PFS 8.7 months and OS 23.8 months only. We found 543 MM patients (10.9%) who developed EM during the entire follow-up. Out of these EM patients, we found 309 patients who were diagnosed with primary EM at initiation of first line of therapy. At initiation of 2nd line of treatment, we found 111 secondary EM patients. At 3rd, 4th and 5th, we found 61, 39 and 23 EM patients, resp. Finally, 309 patients who developed EM at initiation of 1st line and 234 patients who developed EM at initiation of further treatments were compared to 2092 patients who did not develop EM during the entire course of the disease. Overall, occurrence of EM at 1st or higher lines of treatment was associated with younger age, male sex, low ISS, D-S substage A, low B2 microglobulin, low creatinine, high hemoglobin, elevated thrombocytes, other types of M-Ig than IgG and presence of bone lesions. For EM cases found only at initiation of 1st line (primary EM), we found association with high ECOG status, low LDH, low M-protein quantity and low % of plasma cells infiltration in the bone marrow. For EM cases found at MM relapse (secondary EM), we found association with high D-S stage, high LDH, high CRP, high Ca, del13q and gain1q. Conclusion EM remains an aggressive disease with poor prognosis regardless of use of novel drugs. Surprisingly, in our group of patients, most EM disease developed early in the course of the disease - more than 60% at first relapse. We analyzed risk factors connected to development of EM and found that LDH, hemoglobin, thrombocytes and M-Ig status were associated with EM development. We suggest that in such patients, PET/CT or whole body MRI should be performed regularly to ensure early detection of EM. Grant support: AZV 17-29343A. Disclosures Maisnar: BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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