Increased Incidence of Extramedullary Plasmacytomas In Patients with Multiple Myeloma In the Era of Novel Therapy and Effect of Pomalidomide on Extramedullary Disease

Abstract Abstract 3047 Background: There is concern about the increased incidence of extramedullary plasmacytomas among patients with multiple myeloma (MM) in recent years (Varettoni et al Annals of Oncology 21: 325–330, 2010). There is controversy about whether novel agents increase the risk of extramedullary disease (EMD). EMD may be associated with decreased overall survival in MM. The purpose of this study was to determine the incidence of true, treatment-emergent EMD in MM among a cohort of patients who have been previously exposed to novel agent (thalidomide, lenalidomide, or bortezomib) therapy, and to evaluate the activity of pomalidomide in patients with EMD. Methods: We examined 174 consecutive patients with relapsed refractory multiple myeloma that were enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone. The study cohort was chosen since all patients had previously been exposed to novel agents, and were followed systematically. We adopted a strict definition of EMD which required that in order to be considered extramedullary, plasmacytomas must not have risen from any bone. Thus, masses arising from the bone with a soft tissue component were not considered extramedullary. Results: Of 174 patients studied, 16 patients (9.2%) had EMD prior to enrollment. In 3 of the 16 patients, EMD was present at time of diagnosis and was therefore not considered as treatment-emergent disease for this analysis. In 13 of 174 patients (7.5%) EMD developed during the course of MM, after starting therapy. All 13 patients by inclusion criteria were exposed to novel agents prior to the onset of EMD, including 100% to immunomodulatory agents (thalidomide or lenalidomide); and 78% (10 patients) were exposed to bortezomib prior to developing EMD. The median number of lines of prior therapy in these patients was 6, range 1–12). EMD occurred a median of 48 months following diagnosis (range, 16–183 months); the rate of EMD in the first 3 years following diagnosis of MM was 3%. Since all patients had prior exposure to immunomodulatory agents in this cohort, we were able to calculate the median length of time from initiation of immunomodulatory agents to onset of EMD as 24 months (range 7–119 months). The EMD sites involved included the temporal area soft tissue (3), muscle (3 [1 pt with 10 different areas of involvement, 1 pt with 5 muscles involved]), chest wall not attached to bone (3), abdominal/pelvic masses (3), kidney (2), scrotum (2), sinus (1), paraspinal (1), hilar/pleural based (1), paraesophageal (1), subcutaneous tissue (1), pancreas (1), spleen (1), mediastinum (1), pleural fluid (1), liver (1). Per protocol, all patients received pomalidomide (2-4 mg per day) and low dose dexamethasone (40 mg once a week). Of the 13 patients, there were 2 CR (with complete disappearance of EMD), 2 PR, 2 stable disease, 3 with progressive disease, and 4 patients who did not have their EMD re-evaluated. Thirty percent (n=4) of patients had a 50% or greater reduction in size of the EMD including one patient who received concomitant radiation. Overall survival from measured from trial entry was significantly shorter for patients who presented with EMD compared to those who did not have EMD, median 16 months versus not reached, p=0.002 (log-rank). Conclusion: We found that 7.5% of patients with relapsed refractory myeloma in the era of novel agents develop EMD during the course of their myeloma, including 3% within 3 years of diagnosis. The underlying reasons for the possible increased incidence of EMD may include better radiographic detection (the role of PET/CT scans and MRI), improved overall survival of patients in recent years, and the possibility that novel agents may increase the risk for strictly defined, true EMD among patients who did not have EMD at time of initial MM diagnosis. These need further study. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

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Efficacy of Novel Agents on Soft-Tissue Plasmacytomas in Patients with Relapsed Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5709.5709 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5709-5709

Author(s):

Raquel Jiménez-Segura ◽

Carlos Fernández De Larrea ◽

Maite Cibeira ◽

Natalia Tovar ◽

Esther Bladé ◽

...

Keyword(s):

Multiple Myeloma ◽

Soft Tissue ◽

Response Rate ◽

Early Death ◽

Median Number ◽

Novel Agents ◽

Serological Response ◽

Novel Drugs ◽

Number Of Cycles ◽

Extramedullary Plasmacytomas

Abstract Introduction: the frequency of soft-tissue plasmacytomas (EMPs) is high in patients with relapsed multiple myeloma (MM). There are two types of plasmacytomas: 1) paraskeletal: originating from focal bone involvement (vertebrae, ribs, sternum, skull) and 2) extramedullary: originating from hematogenous spread (skin, liver, CNS). The reported incidence in relapsed patients is 3-34% for paraskeletal and 3-10% for extramedullary plasmacytomas. The presence of soft-tissue masses is associated with poor prognosis and the efficacy of novel agents is not well established. There are some reports about the lack of efficacy of thalidomide (Bladé et al, Br J Haematol 2001; 113: 422-24) while some efficacy has been reported with bortezomib (Rosiñol et al, Eur J Haematol 2006;76:405-08) and pomalidomide (Detweiler et al, Leukemia 2011, 25; 906-908). Aim: to analyze the effectiveness of novel drugs (thalidomide, bortezomib, lenalidomide, pomalidomide, carfilzomib) in patients with relapsed MM and EMPs. Patients and Methods: patients with EMPs (paraskeletal or extramedullary) at the time of first or subsequent relapses from our database from Hospital Clínic of Barcelona who were treated with novel agents were analyzed. Only patients receiving the novel drugs in monotherapy or in combination with corticosteroids were included in the analysis. Patients receiving combination therapy including two novel drugs (i.e. VTD, VRD) were excluded. Results: 29 patients (median age 61, M 17/F 12) with relapsed myeloma and EMPs were treated with bortezomib. The median number of previous therapies was one. 22 patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles received was 4. The serological response rate was: 4% CR, 27% PR, 7% MR, 24% SD, 17% PD, 7% early death, 14% non evaluable. The response of the plasmacytomas were: 14% CR, 17% PR, 10% SD, 41% PD, 4% early death, 14% non evaluable. The median PFS from the initiation of bortezomib was 3.9 months. Sixteen patients (median age 49 years, M 6/F 10) were treated with lenalidomide. 13 patients had paraskeletal and 3 extramedullary plasmacytomas. The median number of previous therapies was two. The median number of cycles was 5.5. Serological response was: 38% PR, 12% MR, 19% SD, 19% PD, 12% non evaluable. The plasmacytoma response was: 25% PR, 19% SD, 44% PD, 12% non evaluable. The median PFS from initiantion of lenalidomide was 8.4 months. Nine patients (median age 61 years, 3M/6F) were treated with pomalidomide at relapse. The median number of previous therapies was 4. Two patients had paraskeletal and 7 extramedullary plasmacytomas. The median number of cycles was 2. Serological response rate was: 44% PR, 11% SD, 23% PD, 11% non evaluable. However, none of the patients showed response of the plasmacytomas (11% SD, 77% PD, 11% early death). The median PFS was 1.3 months. 8 patients (median age 49 years, 6M/2F) were treated with thalidomide at relapse. The median number of previous therapies was one. Six patients had paraskeletal and 2 extramedullary plasmacytomas. The median number of cycles of thalidomide received was one. None of the patients showed serological response (25% stable disease (SD), 50% progressive disease (PD), 25% early death) or reduction in the size of the plasmacytomas (50% SD, 50% PD). The median progressive free survival (PFS) from initiation of treatment with thalidomide was 1.6 months. Four patients (median age 62, 2M, 2F) were treated with carfilzomib. The median number of previous therapies was 3. The EMPs type was paraskeletal (1) and extramedullary (3). The median number of cycles administered was one. None patient responded to carfilzomib: serological response rate: 75% SD, 25% PD; plasmacytomas response: 100% PD. The median PFS was 0.7 months. The median survival in the overall series of patients with soft tissues masses at relapse treated with novel agents was 15.2 months. Conclusions: The efficacy of novel drugs in the treatment of EMPs is limited, being the most effective bortezomib and lenalidomide. None of the patients treated with thalidomide, pomalidomide or carfilzomib showed any response of the soft-tissue involvement (paraskeletal or extramedullary). Finally, the presence of plasmacytomas at relapse is associated with poor OS even in the era of novel agents. However, the efficacy of these novel agents as part of front-line therapy is unknown. Disclosures No relevant conflicts of interest to declare.

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Analysis of 179 Patients with Newly Diagnosed Multiple Myeloma (MM) Treated with Novel Agents Followed by Autologous Stem Cell Transplantation (ASCT): a Retrospective Study

Blood ◽

10.1182/blood.v116.21.1343.1343 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1343-1343

Author(s):

Joyce Habib ◽

Neil Dunavin ◽

Gary Phillips ◽

Patrick Elder ◽

Meaghan Tranovich ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Research Funding ◽

Progression Free Survival ◽

Novel Agents ◽

Genetic Profile ◽

Newly Diagnosed ◽

Free Survival

Abstract Abstract 1343 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States with an estimated 20,580 new cases in 2009. Over the past decade, the introduction of novel agents (thalidomide, lenalidomide and bortezomib) have played a pivotal role in improving response rates, duration of response, overall survival (OS) and quality of life. In this study we describe a single center experience with novel agents used for induction followed by high dose chemotherapy (HDT) and first autologous stem cell transplant (ASCT) in patients with MM. Method: A retrospective review of the medical records of 179 newly diagnosed patients with MM seen between October 2006 and December 2009 at The Ohio State University was performed. All patients received novel therapy containing thalidomide, bortezomib or lenalidomide as part of an induction regimen followed by ASCT. All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to plot progression free survival and overall survival. Results: Of the 181 patients seen, 2 were excluded because they did not receive a novel agent as part of induction treatment. Of the 179 patients analyzed, median age was 56.8 years (29-80) with 30% of patients older than 60 years. African American represented 19%. Fifty-nine percent were male, 80% had Durie-Salmon (DS) stage III while 25%, 28%, 18% represented International prognostic score (IPS) stage I, II, and III respectively with 27% unknown. Median comorbidity index score was 2 (2-7) and median Karnofsky performance score (KPS) was 90% (70-100). Thirty percent had high risk genetic profile, and 73% received one line of treatment before ASCT. The median time from diagnosis to ASCT was 8.33 months (4-58). The overall response rate (ORR) prior to transplant was 84% (9% complete (CR), 29% very good partial (VGPR), and 46% partial (PR)). The ORR post ASCT was 89% (CR 45%, VGPR 22%, PR 21%). Non relapse mortality was 1% and 3% at 100 days and 1 year respectively. At a median follow up of 31 months (7-90), 69 patients (38%) had relapsed. Median progression free survival (PFS) was 29 months with 1 and 3 years PFS of 79.3% and 61.5% respectively (Fig. 1). The OS was not reached. One and 3 years OS were 93% and 88% respectively (Fig. 1). Univariate analysis showed that time to transplant > 12 months was associated with poor outcome and decreased overall survival (HR 3.30, p = 0.008). High risk genetic profile was also found to be associated with decreased overall survival although this was not statistically significant (HR 2.31, p = 0.070). Multivariate analysis found that only time to transplant > 12 months was an independent predictor of decreased OS. Significant predictors for disease progression were high risk genetic profile and time to transplant > 12 months in patients receiving 2 or more treatments before ASCT. Conclusion: Induction with novel agents followed by HDT and ASCT improves CR rate, in our case from 9% to 45%. Median PFS (29 months) was comparable to other published data. OS was not been reached after a median follow up of 31 months. Predictors of progression include high risk genetic profile and time to transplant > 12 months. The only significant predictor for survival was time to transplant. Our study suggests that an early transplant may improve OS and PFS. An extended analysis will be presented at the meeting. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

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Extramedullary Myeloma.

Blood ◽

10.1182/blood.v114.22.sci-5.sci-5 ◽

2009 ◽

Vol 114 (22) ◽

pp. SCI-5-SCI-5 ◽

Cited By ~ 1

Author(s):

Joan Bladé ◽

Ma Teresa Cibeira ◽

Laura Rosiñol ◽

Carlos Fernández de Larrea

Keyword(s):

Bone Marrow ◽

Soft Tissue ◽

Research Funding ◽

Plasma Cells ◽

Response To Therapy ◽

Bone Lesions ◽

Serological Response ◽

Myeloma Cells ◽

Extramedullary Disease ◽

Extramedullary Plasmacytomas

Abstract Abstract SCI-5 Multiple myeloma (MM) is characterized by a proliferation of plasma cells (PC) with strong dependence on the bone marrow (BM) microenvironment. In fact, stromal cells and adhesion molecules play a crucial role in the pathogenesis of MM as well as in the homing of myeloma cells within the bone marrow, in both human myeloma and in murine plasmacytoma models. Virtually, all patients with MM will develop skeletal involvement as result of an imbalanced bone remodelling. This imbalance results in severe osteopenia and/or generalized bone lytic lesions. However, some patients develop large lytic bone lesions, as result of bone replacement by PCs, which can be considered as extramedullary tumors. Importantly, about 15% of patients with MM have soft-tissue extramedullary plasmacytomas (EMP) at diagnosis and an additional 20% develop EMP during the course of the disease. It has been suggested that patients relapsing after Allo-RIC transplantation have even a higher rate of EMP. Although the ultimate mechanisms resulting in extramedullary spread in MM remain unclear, it is likely that in patients with aggressive myeloma or at disease relapse, myeloma cells become stromal independent this favouring their proliferation and survival in the absence of the BM microenvironment. The development of extramedullary disease in MM can show different patterns. First, local soft-tissue growth from adjacent bone lesions. Second, hematogenous spread with: 1) single or multiple large subcutaneous plasmacytomas, 2) metastatic like nodules in the skin or in organs or tissues such as liver, kidney, breast or lymph nodes, and 3) CNS involvement (meningeal myelomatosis). Finally, extramedullary myeloma growth can be triggered by surgical procedures leading to the appearance of plasmacytomas at the sites of catheter insertion, laparotomy or sternotomy scars, and even local dissemination through bone surgery. In our experience, the frequency of high-risk cytogenetics –t/4;14), t(14;16) and 17pdel- by BMPC FISH analysis at diagnosis is similar in patients with or without EMP (22% vs.18%). Despite this fact, patients with extramedullary involvement usually have a more aggressive disease. In many instances, the plasma cells from EMP, particularly at relapse, show an immature or plasmablastic morphology, and highly aberrant phenotypic cell lines have been generated from extramedullary human tumors. Whether or not plasma cells from extramedullary sites have a different phenotype or cytogenetic features than the BMPC has not been reported. Soft-tissue plasmacytomas do not respond to thalidomide and cases of extramedullary progression in patients in serological response have been observed. In contrast, dramatic responses of EMP to bortezomib have been reported. In our experience, patients with extramedullary plasmacytomas show a significantly higher progressive disease rate to the induction pre-transplant regimens compared with those with no extramedullary disease (34% vs. 11%). In summary, up to one third of patients with MM will develop EMP, this being associated with a poor response to therapy and outcome. A better understanding of the mechanisms of myeloma spread and on the biology of extramedullary tumors will hopefully result in better treatment possibilities. In this regard, there is evidence suggesting that plamacytomas in mice and humans exhibit some similarities and the selection of plasmacytomas related to MM subtypes might provide an excellent opportunity for preclinical drug testing. Disclosures Bladé: Celgene: Honoraria, Research Funding; Jansen-Cilag: Honoraria, Research Funding. Cibeira:Jansen-Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Jansen-Cilag: Honoraria; Celgene: Honoraria.

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The Impact of Induction Regimen Choice on Transplant Outcome and Survival in Newly Diagnosed Multiple Myeloma in the Era of Novel Agents

Blood ◽

10.1182/blood.v126.23.3044.3044 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3044-3044

Author(s):

Rajshekhar Chakraborty ◽

Shaji Kumar ◽

Francis Buadi ◽

David Dingli ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Research Funding ◽

Novel Agents ◽

Agent Based ◽

Induction Regimen ◽

Baseline Characteristics ◽

The Impact ◽

Novel Agent

Abstract Background Induction with novel agents, including proteasome inhibitors and immunomodulators, prior to autologous stem cell transplantation (ASCT) is the standard of care frontline treatment of transplant-eligible patients with multiple myeloma (MM). Common novel agent-based induction regimens include three drug combinations with a backbone of bortezomib (V), thalidomide (T) and/or lenalidomide (R). There is limited information on the comparative efficacy of novel regimens used as part of initial therapy prior to an ASCT in terms of overall survival (OS). To address this question, we retrospectively analyzed 1096 consecutive patients undergoing ASCT for MM at Mayo Clinic. Methods Study patients included those who underwent first transplant within 12 months of diagnosis, did not receive more than one induction regimen, did not relapse prior to transplant and did not receive treatment for smoldering MM in the past. Baseline characteristics, response rates and survival data were extracted from an electronic medical record and statistical analysis was done using JMP 10.0.0 (SAS Institute Inc.). Choice of induction regimen was almost exclusively made by the referring physician. Results Median age at diagnosis was 60.3 years (Interquartile range 53.9-65.9). ISS staging at diagnosis was available for 49.7% of patients, of which, 34.2%, 39.3% and 26.5% of patients had ISS stage 1, 2 and 3 disease, respectively. Estimated median follow up was 65.6 months (95% CI 58.3-73.3). Baseline characteristics of patients by initial treatment have been summarized in table 1. Major subgroups by induction therapy included patients receiving Cy-Bor-d (n=193, 17.6%), Vd (n=64, 5.83%), Rd (n=253, 23.1%), VRd (n=126, 34.6%), Td (n=157, 14.3%) and VAD or dexamethasone alone as the non-novel agent comparator group (n=229, 20.9%). Median overall survival (OS) was significantly different between novel agent-based and conventional regimens (Log-rank test; p=0.0029), which were 102.7 months (95% CI, 95.2-112.2) and 78.8 months (95% CI, 67.8-92.6) respectively. Median OS with each regimen is shown in table 1. Among novel agent-based regimens, there was no significant difference in median OS, except Td, which was inferior to Rd (HR 1.62; 95% CI 1.17-2.24). Conclusion We cannot demonstrate with overall survival as an endpoint that the doublets of Vd and Rd are inferior to VRd or Cy-bor-d. There were insufficient patients treated with VTd to be included. Our study shows that the choice of novel induction regimen prior to ASCT does not affect survival (with the exception of Td being inferior to Rd), reflecting the wide array of effective salvage options. However, further prospective randomized clinical trials comparing these regimens are required to validate these findings. Table 1. Baseline characteristics and overall survival. Baseline characteristics and survival Cy-Bor-d (n=193) Vd (n=64) Rd (n=253) VRd (n=126) Td (n=157) VAD or Dex (n=229) p-value Median age 61.9 62.15 60.8 60.8 59.3 58.5 0.0041 Sex (percent males) 56.48 57.81 56.92 61.91 57.96 59.82 0.9271 ISS at diagnosis 1:24.82% 2:40.69% 3:34.48% 1:29.73% 2:24.32% 3:45.94% 1:40% 2:43.78% 3:16.22% 1:41.76% 2:34.06% 3:24.18% 1:28% 2:36% 3:36% 1:20% 2:60% 3:20% 0.0005 Median follow-up (95% CI) 20.3 (17.1-22.7) 49.5 (44.7-55.7) 59 (54.5-67) 26.9 (22.8-30.7) 126.7 (120.2-132.9) 143.4 (132.5-152.6) <0.0001 Median OS Not reached (Estimated 5 year OS rate 75%) 97.2 months (95% CI, 66.6-NR) 112 months (95% CI, 97.4-124.3) Not reached (Estimated 5-year OS rate 77%) 81.1 months (95% CI, 59.1-99.1) 78.8 months (95% CI, 67.8-92.6) 0.0019 Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Smith Kline: Honoraria; Novartis: Honoraria; Onyx: Honoraria; millenium: Consultancy, Honoraria; Celgene: Honoraria.

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Overall Survival Patterns in Patients with Multiple Myeloma in the Era of Novel Agents and the Role of Initial Clinical Presentation and Comorbidities: A Population-Based Study

Blood ◽

10.1182/blood.v124.21.2136.2136 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2136-2136

Author(s):

Berdien Oortgiesen ◽

Eric N. van Roon ◽

Peter Joosten ◽

Robby Kibbelaar ◽

Huib Storm ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

The Netherlands ◽

Research Funding ◽

Clinical Presentation ◽

Population Based ◽

Novel Agents ◽

Bone Lesions ◽

Population Based Study ◽

Asymptomatic Patients

Abstract Introduction Clinical trials have shown improved response rates, progression-free survival and overall survival (OS) in patients with multiple myeloma (MM) when using the novel agents thalidomide, lenalidomide and bortezomib. However, outcome data provided by population-based registries, reflecting real-life, report predominantly improved OS in younger MM patients and only minimal improvement in OS in unselected MM patients older than 65 years. Population-based studies in unselected MM patients in the era of novel agents are relatively limited. Explanations for the marked variation in prognosis across patients may in part be explained by the heterogeneity in the initial clinical presentation, the pre-existing comorbidities, disease biology and response to the therapy. Specific end-organ damage caused by the disease, such as hypercalcemia, renal failure, anemia and bone lesions known as the CRAB symptoms may be associated with worse prognosis in the elderly MM patients. This descriptive prospective population-based cohort study was designed to determine the OS in patients with MM in Friesland, The Netherlands in the era of novel agents, and to analyze the influence of the CRAB symptoms and comorbidities at initial presentation on survival. Methods Since 2005 all patients diagnosed with hematological malignancies in Friesland, a province of the Netherlands, are prospectively registered and followed by their clinicians in a population-based registry, the HemoBase. For this analysis, data on clinical characteristics, comorbidities, treatment and outcome of all patients with newly diagnosed MM in Friesland during the period of January 2005 to January 2013 with a follow-up until January 2014 were retrieved from HemoBase. Supplementary information was obtained from the individual patient hospital records. Both symptomatic and asymptomatic patients were included in the study with subgroup analysis on the symptomatic patients. According to the guidelines from IMWG, each CRAB symptom was divided into two categories (11 mg/dL < serum calcium ≤ 11 mg/dL; 2 mg < creatinine ≤ 2 mg/dL; 10.2 g/d ≤ hemoglobin < 10.2 g/dL and the presence or absence of bone lesions). The patients were divided by age groups (<65, 65 – 75 and ≥75 years old) to illustrate differences in survival in the three age categories. Results From 2005 till 2013 a total of 270 patients were diagnosed with MM in Friesland. The median observation period was 29 months (range 0.26 - 104; IQR 33). Median age was 70 years (range 32 - 92; IQR 15) with a male predominance (60% male). 34, 34 and 32% of patients were < 65 years, 65 - 75 years and ≥ 75 years, respectively. The Charlson Comorbidity Index (CCI) was 0,1 or ≥2 in 60, 22, 18% of patients, respectively. Sixteen percent of patients were asymptomatic. Of symptomatic patients 63% and 27% had CRAB scores of 1-2 and 3-4, respectively. Ten percent of patients had a CRAB score of 0, but were regarded symptomatic by their treating hematologist. Among the symptomatic MM patients 80% received novel agents, 15% other chemotherapy 6% only radiotherapy. The median OS of all patients is 49.5 months, with median OS for symptomatic and asymptomatic patients of 40 and >100 months respectively. Divided into age categories < 65, 65 – 75 and ≥75 years old, the 50% OS is respectively 92, 40 and 29 months (figure 1). For all patients, implementing novel therapies improved OS compared to other therapies (43.5 vs. 21.1 months, hazard ratio (HR) = 1.8, P = 0.017. Patients with a CCI score of 0 have a higher median OS than patients with a score ≥ 2 (HR = 0.6, P = 0.036). Patients with two or more CRAB symptoms have a lower median OS than patients without any CRAB symptoms (HRadjusted = 2.2, P = 0.028). In multivariate analysis, differences in median OS were significant better for patients without hypercalcemia compared to patients with hypercalcemia (HRadj. = 0.6, P = 0.011) and for patients with a serum creatinine ≤ 2 mg/dL vs. ≥ 2 mg/dL (HRadj. = 0.4, P < 0.0001). Conclusion In this population-based study of a complete Dutch cohort of unselected MM patients over the last decade a median OS of 49.5 months was observed. Despite extensive introduction of novel agents increasing age remains an adverse prognostic factor. High comorbidity scores (CCI ≥ 2) and CRAB symptoms, such as hypercalcemia and impaired renal function at initial presentation were significantly correlated with worse median OS. Disclosures Hovenga: Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding.

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Analyses of Real World Data on Overall Survival in Multiple Myeloma Patients with at Least 3 Prior Lines of Therapy Including a PI and an IMiD, or Double Refractory to a PI and an IMiD

Blood ◽

10.1182/blood.v126.23.4498.4498 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4498-4498 ◽

Cited By ~ 2

Author(s):

Saad Usmani ◽

Tahamtan Ahmadi ◽

Yvette Ng ◽

Annette Lam ◽

Ravi Potluri ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Real World ◽

Research Funding ◽

Target Population ◽

Novel Agents ◽

Real World Data ◽

World Data ◽

Eligible Population ◽

Heavily Pretreated

Abstract Background: To fully evaluate the potential benefit of novel agents for the treatment of patients with multiple myeloma (MM) who are heavily pretreated and refractory, it is important to understand the outcomes of this patient population based on current real-world experience. An International Myeloma Working Group study determined that the median overall survival (OS) of patients refractory to bortezomib (proteasome inhibitor, PI) and at least 1 immunomodulatory drug (IMiD) was 9 months (Kumar S et al. Leukemia 2012; 26: 149). Since then, other therapies have been approved for relapsed and refractory MM in the United States (US), including pomalidomide (IMiD) and carfilzomib (PI). In this analysis, real-world data were used to define the treatment landscape and outcomes of patients with MM refractory to PIs and IMiDs or who had received ³3 prior lines of therapy (LOT; including a PI and an IMiD) and provide context to results from the single-agent daratumumab phase 2 study MMY2002 (Sirius) recently presented at ASCO 2015 (Lonial S. J Clin Oncol 33, 2015 suppl; abstr LBA8512). Methods: Two independent databases were analyzed.TheIMS LifeLink: IMS Oncology Electronic Medical Records (EMR) Database (IMS Health Incorporated, Danbury, CT) and the OPTUM Database (OPTUM, Inc., Eden Prairie, MN) both comprised US patients only. For the IMS LifeLink database, patient records from the index period of 2000-2011 were screened. For the OPTUM database, the indexing period was 2007-2014. Median OS was assessed for cohorts that met the criteria of disease that was double refractory to a PI and IMiD (Criteria 1) or had been treated with ³3 LOT including a PI and IMiD and showed disease progression within 60 days on completion of last regimen (Criteria 2). Patients who met Criteria 1 could have received ³3 prior LOT, however those who met Criteria 2 only did not meet the double refractory criteria. Subgroup analyses of the eligible population were conducted on those who were only double refractory and triple/quadruple refractory. Results: For the IMS LifeLink database, 4,030 patients with MM were screened, approximately 90% of patients were diagnosed with MM in 2006 or later, and 500 met the criteria for the target population. Of the 500 patients, 323 patients met Criteria 1 and 177 patients only met Criteria 2. For the OPTUM database, 3,837 patients with MM were screened, approximately 90% of patients were diagnosed after 2009, and 162 met the criteria for the target population, 120 of whom met Criteria 1 and 42 of whom only met Criteria 2. In the total eligible populations, median OS was 239 days in the IMS LifeLink dataset compared with 240 days in the OPTUM dataset (P = 0.5358). Among patients that were only double refractory (triple/quadruple refractory patients excluded), median OS was 228 days (n = 253) in the IMS LifeLink dataset compared with 259 days (n = 97) in the OPTUM dataset (P = 0.8052). In triple/quadruple refractory patients, median OS was 154 days (n = 70) in the IMS LifeLink dataset and 95 days (n = 23) in the OPTUM dataset (P = 0.6675). The results from both databases were consistent, hence the data were pooled for further analyses; the pooled analyses indicated that the median OS was 240 days for the eligible population (n = 662), 237 days for patients who were only double refractory (n = 350), and 154 days for patients who were triple/quadruple refractory (n = 93). A naïve comparison of the OS curves from the MMY2002 study and the pooled analysis suggests a survival benefit with daratumumab versus the real-world historical control (Figure). Conclusions: Analyses of real-world data from two independent US patient databases indicated that outcomes remain poor among patients with MM who are heavily pretreated and/or highly refractory despite the availability and use of newer PIs and IMiDs, such as carfilzomib and pomalidomide. Median OS of approximately 8 months was observed in patients with ≥3 LOT (including a PI and IMiD) or refractory to a PI and IMiD. These data not only highlight the critical need for new MM treatments for patients with advanced MM, but also provide a point of reference against which novel agents such as daratumumab could be evaluated. Disclosures Usmani: Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Celgene Corporation: Consultancy, Honoraria. Ahmadi:Janssen: Employment. Ng:Janssen: Employment. Lam:Janssen: Employment. Potluri:Smart Analyst: Employment. Mehra:Janssen: Employment.

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Comparison of Outcomes and Utilization of Therapy in Multiple Myeloma Patients in the USA and Alberta, Canada

Blood ◽

10.1182/blood-2020-141088 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Andrew J. Cowan ◽

Shasank R Chennupati ◽

Yuan Xu ◽

Ang Li ◽

David A. Garcia ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Health Services ◽

Research Funding ◽

Median Overall Survival ◽

Novel Agents ◽

First Year ◽

The Us ◽

The Usa

Background: Multiple myeloma (MM) is a common global hematologic malignancy, contributing to substantial morbidity and mortality amongst diagnosed patients. Novel agents - bortezomib (Btz) and lenalidomide (Len) have changed dramatically over the past 20 years and have contributed to improvements in survival and long term outcomes for MM patients. Research has shown that there are differences in how MM is treated globally. We sought to evaluate the differences in outcomes and therapies received amongst patients treated in Alberta (AB), Canada, and in the United States (USA). Methods: Adult patients with multiple myeloma over the age of 65, diagnosed between 2007 and 2013, were identified. Data sources used for AB was the CA National Ambulatory Care Reporting System (NACRS), Discharge Abstracts Database (DAD), and CT records from AB Health Services. For the USA we used the SEER-Medicare database; MM diagnosis was extracted using a previously published algorithm. We extracted demographic data, novel agent utilization in the first year, comorbidities, and survival. Kaplan-Meier analysis was used to determine survival. Results: Patients meeting study criteria included 4,330 MM patients in the USA and 793 patients with MM in AB. The median age at diagnosis in the USA and AB was 76.6 and 75 years, respectively. Median Charlson Comorbidity index in the USA and AB was 1, and 0, respectively. With respect to frontline therapies, both AB and USA had increasing utilization of Btz and Len from 2007-2013 (Figure), with Btz use more common in AB, while Len use was more common in the US. The proportion of all patients who did not receive any therapy in the first year of diagnosis fell dramatically from 2007 to 2013 in both AB (from 86% to 25%) and the USA (from 56% to 40%). Receipt of autologous stem cell transplant was uncommon in this older cohort, in only 3.2% of MM patients in AB and 4% of patients in the US. Similar proportions of patients in the USA and AB received radiotherapy in the first year (19% US, 25% AB). Median overall survival was improved in AB at 2.8 years, (95% CI 2.6-3.2 yrs), compared with the USA, 2.2 yrs (95% CI 2.1 - 2.30, as was 5 year survival - 30% in the USA, compared with 34% in AB. Conclusions: In this cross-country comparison of MM patients in the USA and AB both treated in a single-payer health care system - AB Health Services and Medicare - novel agents are a common treatment in the first year of diagnosis. We demonstrate similar uptake of novel agents Btz and Len over 2007-2013, however, Btz utilization was higher in AB from 2011-2013, while Len was more often used in the USA from 2011-2013. Median overall survival was better in AB (2.8 years) compared with USA (2.3 years), as was long term survival at 5 years. The differences in utilization of therapy and survival are possibly related to variability in healthcare delivery systems, burden of comorbidities in these populations, and approval of anti-MM therapy over time, and require further study to better understand reasons for differential outcomes. Figure Disclosures Cowan: Sanofi: Consultancy; Cellectar: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding. Ramsey:AstraZeneca: Other: Personal Fees.

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Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

American Journal of Hematology ◽

10.1002/ajh.23223 ◽

2012 ◽

Vol 87 (7) ◽

pp. 734-736 ◽

Cited By ~ 5

Author(s):

Anna Tasidou ◽

Maria Roussou ◽

Evangelos Terpos ◽

Efstathios Kastritis ◽

Maria Gkotzamanidou ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Cyclin D1 ◽

Novel Agents ◽

Bone Marrow Biopsies

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Efficacy of Subsequent Therapies in Multiple Myeloma Patients after Progression on a BCMA Targeting Therapy: A Single-Center Experience

Blood ◽

10.1182/blood-2020-141637 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-13

Author(s):

Barry Paul ◽

Myra Robinson ◽

Kristen Cassetta ◽

Daniel Slaughter ◽

Jordan Robinson ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Overall Survival ◽

Research Funding ◽

Subsequent Treatment ◽

Single Center ◽

Targeting Therapy ◽

Single Center Experience ◽

Best Response ◽

Car T

Background: Targeting B-cell maturation antigen (BCMA) with antibody-drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor t-cells (CAR-Ts) has proven safe and effective in recent clinical trials, but relapses remain common. As most patients treated with BCMA targeting therapies are refractory to conventional anti-myeloma therapies, management of these patients poses unique challenges once they progress, with no data available to guide subsequent therapies. Methods: We performed a retrospective chart review of all relapsed refractory multiple myeloma (RRMM) patients at our institution who progressed while on or after a BCMA targeting therapy and were treated with subsequent therapies. We evaluated the best response achieved and overall survival (OS) measured from progression on BCMA targeting therapies. Kaplan Meier methods were used to estimate OS curves and landmarks between classes of BCMA targeting therapy received (ADC, bispecific antibody or CAR-T), and by type of subsequent therapy. Results: At a median follow up of 6 months, a total of 47 patients were treated with a BMCA targeting therapy. Of those, a total of 21 (44.7%) patients have progressed, with 18 (38.3%) receiving another therapy. Twelve-month overall survival of the patients who received a subsequent treatment was 51.1% (figure 1a), but varied considerably based on the class of BCMA therapy they received (figure 1b). Patients who progressed after a BCMA CAR-T had the best OS (N =2, 6 mo OS: 100%, 12 mo OS: Of the 18 patients who progressed and were treated with subsequent therapies, 7 (38.9%) received 2 lines of therapy, 5 (27.8%) received 3 lines of therapy, and 1 patient (5.6%) received 5 lines of therapy. In the first relapse, 4 (22.2%) patients received infusional chemotherapy with CAR-D PACE or CAR-DCEP, 4 (22.2%) received the combination of elotuzumab, pomalidomide, and dexamethasone (Elo-Pd; one of which was first treated with CAR-DCEP), 3 (16.7%) received selinexor based regimens. The best response seen after first-line post BCMA treatment was a partial response (PR) in 5 (27.8% of patients), whereas 8 (61.5%) patients who received second-line treatment post-BCMA therapy had a PR or better, including 3 (23.1%) who had a very good partial response (VGPR). In the third line post-BCMA, 1 (16.7%) had a VGPR, while 1 (16.7%) had stable disease as their best response. The use of Elo or Dara after anti-BCMA progression seemed to correlate with improved OS (see figure 1c below). While all these patients were Elo naïve, the majority (94.4%) were previously Dara exposed. Conclusions: Our data demonstrate that many RRMM patients who progress on BCMA targeting therapies still derive benefit from subsequent treatment. Early evidence from our experience suggests a survival advantage with monoclonal antibody-based therapies even in patients who had previously been exposed to these agents-suggesting a possible resensitization with BCMA directed therapy. Although our dataset is a single-center experience, to our knowledge it represents the first report of post-BCMA exposed management of RRMM and provides valuable insight into the treatment of this challenging and ever-expanding population. Disclosures Paul: Bristol-Myers Squibb: Other: Stock Ownership (prior employee); Amgen: Consultancy, Speakers Bureau; Regeneron: Membership on an entity's Board of Directors or advisory committees. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute. Voorhees:Adaptive Biotechnologies: Other: Personal fees; Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Usmani:Celgene: Other; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Atrash:BMS, Jansen oncology, Sanofi: Speakers Bureau; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; Amgen, GSK, Karyopharm.: Research Funding.

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