SummaryInvolvement of the central nervous system (CNS) in multiple myeloma (MM) is a rare complication, with reported survival of <6 months. This report describes 37 MM patients with leptomeningeal and/or parenchymal brain involvement treated at our institution and identifies factors associated with long-term survival. From January 1999 to December 2010, 37 patients with CNS MM were evaluated at our institution. Clinical characteristics, treatment and survival were retrospectively collected. CNS disease was present at MM diagnosis in 24% and at relapse in 76%. Plasma cell leukemia (40%) and skull plasmacytomas (65%) were common, suggesting haematological and contiguous spread. Intrathecal (IT) chemotherapy was used in 81%, cranial and/or spinal irradiation in 78%, and various systemic therapies [immunomodulatory agents (IMiDs) (51%), cisplatin-based (DPACE; cisplatin, doxorubicin, cyclophosphamide, etoposide) (27%), bortezomib (19%), alkylators (11%), dexamethasone alone (8%), auto-transplant (5%)]. Median survival from CNS disease was only 4Á6 months [95% confidence interval (CI): 2Á8-6Á7]; however, nine patients had prolonged survival (median: 17Á1 months, 95% CI: 13Á2-67Á4). In general, these long-term survivors were treated with radiotherapy, multi-dosing IT chemotherapy, and IMiD-containing therapy. CNS MM is a highly aggressive disease but in our experience, long-term survival can be achieved with the combination of multi-dosing IT chemotherapy, radiation and IMiD-based therapy.
Lenalidomide in combination with dexamethasone (Len‐dex) represents a highly effective treatment in relapsed/refractory multiple myeloma (RRMM) patients. However, an increased risk of secondary primary malignancies (SPMs), including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been described in patients receiving lenalidomide. In order to assess the incidence and features of this complication, we reviewed 195 patients with RRMM treated with Len‐dex at our institution. The median follow‐up time from diagnosis of MM was 73 months (10–234 months) and from initiation of Len‐dex was 19 months (1–104 months). The median duration of Len‐dex for all patients was 7.8 months (range 1–90 months). The incidence rate (IR) for all SPMs from start of Len‐dex was 2.37 per 100 patient‐years, which reflected an IR of 1.29 for MDS/AML and 1.08 for nonhematologic malignancies (NHM). MDS was the most common SPM noted. The cumulative IR of SPM at 5 years was 1.54% from the time of MM diagnosis and 5.24% from starting Len‐dex. Multivariable cumulative incidence of SPM analysis identified older age (P = 0.005) and prior number of regimens (P = 0.026) as adverse risk factors. We found more concomitant G‐CSF use (P = 0.029) in patients with MDS/AML, however, causal association is not clear. The progression‐free survival after Len‐dex was the longest for patients in MDS/AML group, and the 5‐year overall survival did not differ among groups. Although the rate of SPM was relatively low with Len‐dex, concomitant G‐CSF should be used judiciously and patients receiving this regimen should be observed for the development of this complication.
Cyclophosphamide, bortezomib and dexamethasone (CyBorD) is a highly active three-drug induction regimen for untreated transplant-eligible multiple myeloma patients. Although CyBorD has been evaluated only in the phase 2 setting in a limited number of patients, its high efficacy and ease of administration have led to its widespread use. Given that clinical trial efficacy can overestimate real-life effectiveness, we reviewed our institutional experience with 109 newly diagnosed patients who were treated with CyBorD in a non-clinical trial setting. After a median of four cycles, overall response rate (ORR) and very good partial response rate or better (⩾ VGPR) were 95 and 66%, respectively, comparable to phase 2 studies of CyBorD and other three/four-drug induction regimens. All patients subsequently underwent successful stem cell collection and upgraded responses to ORR 98% and ⩾ VGPR 79% post transplant. At a median follow-up of 19.8 months after diagnosis, the 2-year OS probability was 95.3% (95%CI: 89-98). The presence of concurrent plasmacytoma at diagnosis was the only prognostic factor predicting poorer survival (HR = 5.56; 95%CI: 0.92-33.74; P = 0.03). CyBorD was well-tolerated, with no severe peripheral neuropathy and minimal hematologic toxicity. Therefore, CyBorD is a convenient, well-tolerated, highly effective induction regimen in preparation for autologous SCT in real-life clinical practice. INTRODUCTIONCurrently, the standard of care for induction therapy in preparation for autologous SCT (ASCT) involves incorporation of novel agents such as bortezomib and/or immunomodulatory agents (thalidomide or lenalidomide).1-11 Two-and three-drug combinations can lead to high overall response rates (ORR) of 61-100% and very good partial responses (VGPR) of 34-67%. [1][2][3][4][5][7][8][9][10][11][12][13] No combination, however, has shown clear superiority in terms of progression-free survival (PFS) or overall survival (OS). Hence, in clinical practice, a balance between efficacy, toxicity, ease of administration and cost should be considered when identifying an optimal induction regimen.CyBorD is a highly active three-drug induction regimen that has been widely adopted for use in preparation for transplant. In the original phase 2 study evaluating CyBorD using biweekly bortezomib 1.3 mg/m 2 (days 1, 4, 8 and 11), weekly cyclophosphamide (Cy) 300 mg/m 2 orally (days 1, 8, 15 and 22) and dexamethasone 40 mg orally (days 1-4, 9-12 and 17-20) on a 28-day cycle, ORR of 88% and ⩾ VGPR rates of 61% were achieved after four cycles (n = 33). 7 In an expanded cohort of the same trial (n = 30), a modified dosing schedule using a higher bortezomib dose-1.5 mg/m 2 given once weekly (days 1, 8, 15, 22) and in combination with a lower dose of dexamethasone (40 mg once weekly for cycles 3 and 4)-attained responses equivalent to the twice-weekly cohort (ORR 93% and ⩾ VGPR 60%) with less toxicity. The incidence of peripheral neuropathy was lower (57 vs 64%), with no grade 3-4 peripheral neuropathy documented, despite the hig...
1867 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents, either given orally or as part of high-dose melphalan + ASCT, still remain an important component of MM therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of patients with relapsed/refractory (rel/ref) MM treated with len-based regimens (>1 cycle) to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006 and 08/2012 we identified 230 patients having received len-based therapy: len + corticosteroids 222 patients, len alone 8 patients, cyclophosphamide + len + prednisone (CPR) 32 patients. 2° MDS/AML developed in 9 patients (3.9%) at a median of 89.6 months (range 30–188) from the time of diagnosis of MM and 22.4 (2–56.6) months from the time of initiation of len regimens. The median follow-up from start of len was 1.6 years, and from the start of diagnosis 7.5 years. The median duration of len treatment was 9.4 months. The MDS/AML cytogenetic changes were variable, but four patients had deletions of all or part of chromosome 5. None of the 2° MDS/AML had translocation t(4;14), as compared to 5.9% in (−) MDS/AML subgroup. The characteristics of patients at the time of starting len, in those who later developed (+) or did not develop (−) 2° MDS/AML during therapy, are shown in Table 1. Cumulative incidence of 2° AML/MDS from time of diagnosis to time of 2° AML/MDS is 4.5% [95% CI 2.2–9.2%] at 15 years. Cumulative incidence of 2° AML/MDS from starting time of len to time of AML/MDS is 5% [95% CI 2.4–10.4%] at 5 years. The incidence of 2° MDS/AML among those who had prior oral alkylators (OA) and/or concomitant OA was 10.5% (2/19 patients), concomitant cyclophosphamide only 7.6% (1/13), prior OA only 1.9% (3/152), and 6.5% for those who did not receive prior/concomitant OA (3/46). Grade 3–4 neutropenia occurred during len in 44% versus 58% in those with and without 2° MDS/AML, respectively. G-CSF was used in 56% of pts who developed MDS compared with 53% who did not. We conclude: 1) The cumulative incidence of MDS/AML from starting len to time of 2° AML/MDS was 5% at 5 years; 2) patients who developed 2° MDS/AML while on len regimens were slightly older, had slight male predominance, higher beta-2-microglobulin, creatinine and platelet count, less often received prior ASCT, thalidomide, and bortezomib, but had longer exposure to len; 3) the relationship with OA is not entirely certain, but it appears that those with prior and concomitant exposure to OA have the highest incidence of this complication, which is most often seen in prolonged len treatment. Table 1. Patient characteristics (n=230) Feature ALL patients (+) MDS/AML (–) MDS/AML Number of patients 230 9 221 Median age, years 61 (31–80) 68 (53–76) 61 (3–80) Male 134 (58%) 6 (67%) 128 (56%) Median baseline ANC, × 109/L 2.8 (0.9–61.4) 3.0 (1.5–5.1) 2.8 (0.9–61.4) Median baseline β-2 microglobulin (nmol/L) 222 (43–1695) 300 (133–481) 222 (43–1695) Median baseline pl count, × 109/L 156 (5–479) 200 (43–277) 156 (5–479) Median baseline creatinine, μmol/L 87 (39–515) 97 (56–117) 86 (39–515) Median # prior regimens 2 (0–6) 2 (1–5) 2 (0–6) Prior alkylating agents (all) 218 (95%) 9 (100%) 209 (95%) Prior oral alkylators 167 (73%) 6 (67%) 162 (73%) Prior ASCT 187 (81%) 2 (78%) 180 (81%) Prior thalidomide 132 (57%) 3 (33%) 129 (58%) Prior bortezomib 109 (47%) 3 (33%) 106 (48%) Concomitant cyclophosphamide 32 (13.9%) 3 (33%) 29 (13%) G-CSF use 123 (53%) 5 (56%) 118 (53.39%) Median duration of Len (mo, range) 9.4 (0.1–67.2) 22.8 (6.6–56.6) 6.8 (0.1–67.2) Disclosures: Chen: Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding.
3983 Introduction: CNS involvement with MM is uncommon, estimated at 1% of patients (pts)(Fassas 2002). CNS myeloma has a reportedly dismal prognosis with median survival of only 2 months (mos) from CNS diagnosis (Nieuwenhuizen 2007). These data derive primarily from small case reports predating the use of novel agents such as the IMiDs and bortezomib. We reviewed our institutional experience with 37 CNS myeloma pts, many treated with novel agents, specifically aiming to identify longterm survivors and their disease/treatment characteristics. Methods: From 1999 to 2010, all pts with CNS MM identified by CSF plasmacytosis and/or leptomeningeal/dural disease on imaging at our institution were reviewed. Pt demographics, disease characteristics, treatments, and survival were retrospectively reviewed from charts, pharmacy records, and a myeloma database. Survival was calculated from time of CNS disease to progression (time to progression; TTP) or death (overall survival; OS). Survival analyses were performed using the Kaplan Meier method (SPSS v17.0). Results: Patient and disease characteristics:Of 758 pts diagnosed with MM at our institution over the 20 year period, 37 pts developed CNS disease (incidence 4.9%). Median age of the 37 CNS pts was 54 years (range 36–70), 51% male. A predominance of light chain subtype was noted: light chains only 32%, IgG 30%, IgA 24%, other 13%. CNS involvement was present at MM diagnosis in 9 pts (24%); at relapse in 28 pts (76%). In the relapsed pts, median number of prior therapies was 2(1–5). Median time from MM diagnosis to CNS presentation was 19.1 mos (range 4.4 weeks–11 years). Cranial nerve involvement (diplopia, facial numbness, visual blurring) was present in 24 of 37 pts (65%). Other common symptoms were headache, cognitive impairment, seizures. Fifteen pts (40%) had plasma cell leukemia (PCL) at CNS presentation. Symptomatic involvement of the orbits (11 pts; 30%) and spinal dura/epidura (17 pts; 46%) was common. Plasmacytomas of the skull adjacent to dura were seen in 65% of cases, suggesting contiguous spread. Leptomeningeal/dural enhancement or thickening on MRI was visualized in 54%, whereas parenchymal brain involvement was rare (5%). CSF plasmacytosis was reported in 24 of 34 pts tested (70%). Treatment and survival: Most pts (30/37 pts; 81%) received intrathecal (IT) chemotherapy (hydrocortisone, methotrexate, and/or cytarabine) with rapid clearance of plasma cells from CSF. Radiation was administered in 28 pts (10 craniospinal, 8 cranial only, 8 spinal only). Ten pts (30%) presented with localized CNS disease and did not require immediate systemic therapy. Various systemic therapies were used: IMiDs 16(43%), cisplatin-based (DPACE) 9(24%), bortezomib 7(19%), alkylators 5(13%), dexamethasone (DEX) alone 4(10.8%), autotransplant 1(2.7%). Consistent with the literature, median TTP from onset of CNS disease for all pts was short at 3.1 mos (95% CI 8.2–18.9). At median follow-up of 24.2 mos, median OS from CNS disease was only 4.3 mos (95% CI 3.1–5.5). However, 7 pts had prolonged survival after onset of CNS disease: 13.2, 16.1, 17.1, 34.3, 35.6, and 69.5 mos. There were no uniform laboratory or clinical features to these 7 longterm survivors. Although 2 of these pts had stable systemic disease at time of CNS onset, 3 had PCL, 5 had aggressive bone/soft tissue plasmacytomas. Three longterm survivors presented with CNS disease at time of MM diagnosis, 4 at relapse. Though all 7 underwent radiation, 6 of 7 pts received repeated IT chemotherapy (4 received maintenance IT chemotherapy every 1–2 mos), and 5 of 7 pts received thalidomide as TD (thalidomide, DEX), CTD (cyclophosphamide, thalidomide, DEX) or DTPACE (DEX, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide). Conclusion: Although CNS disease is considered an aggressive complication of MM, in our review of 37 pts, one of the largest single-institution reports of CNS myeloma in the literature, clinical presentation and outcomes are heterogeneous. The high rate of PCL and skull-based plasmacytomas suggest that both hematogenous and contiguous spread from bone can occur. With our experience, longterm survival can be achieved with cranial/spinal irradiation, multi-dosing IT chemotherapy, and oral thalidomide, previously reported to cross the blood-brain barrier. This triple modality approach, using DPACE with or without thalidomide, is being further evaluated at our institution. Disclosures: Chen: Celgene: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria.
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