Extramedullary progression of multiple myeloma despite concomitant medullary response to multiple combination therapies and autologous transplant: a case report

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Introduction Extramedullary myeloma that occurs during the clinical course of multiple myeloma is rare but is an independent poor prognostic factor with mortality of 73% and median survival of 12 months despite aggressive therapies including novel agents. The clinicopathological aspects, biology and management of extramedullary myelomas are poorly understood. Our case highlights the pathobiological aspects of this important but rare entity, and the repercussions of modern therapies. Case presentation A 60-year-old Caucasian man initially presented with an anterior rib fracture. Subsequent workup revealed stage IIIB immunoglobulin G lambda multiple myeloma. A bone marrow biopsy showed sheets of plasma cells, harboring unfavorable cytogenetics including deletion of 17p and t(4;14). He achieved near complete remission and resolution of karyotypic abnormalities with three cycles of induction doxorubicin, thalidomide, and dexamethasone (clinical trial). This was followed by high-dose melphalan and autologous stem cell transplant. He relapsed 1 year later. His bone marrow at that time showed only a few scattered polyclonal plasma cells. He received three cycles of bortezomib and tanespimycin (clinical trial) and achieved very good partial response. He again relapsed 1 year later with multiple large peripheral soft tissue masses and lymph nodes. Biopsies of the peripheral lesions were consistent with extramedullary myeloma, but repeat bone marrow biopsy continued to show no evidence of intramedullary disease. Conclusions This is one of the few cases reported that illustrates the differential response of extramedullary compared to intramedullary myeloma to multiple standard combination therapies including novel therapeutics and transplant, resulting in a very short survival. Several mechanisms for intra-to-extra medullary migration and hence the differential treatment response have been hypothesized. Physicians should be aware of this problem during treatment with immunomodulatory drugs and proteasome inhibitors not only in relapsed but also in front-line setting. In such cases, there is a potential role for evolving targeted therapeutics as we continue to better understand the tumor biology

Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma

Purpose: To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20+ follicular lymphoma (FL) or marginal-zone lymphoma. Patients and Methods: Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m2 weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m2 weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment. Results: Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m2). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B. Conclusion: Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL

Undiagnosed Systemic Lupus Erythematosus Presenting as Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is rarely diagnosed in adults. Incidence is reported as one case per million persons per year. It can be triggered by conditions that affect immune homeostasis as infections, malignancies, and rheumatologic disorders. The following case demonstrates a rare instance in which undiagnosed systemic lupus erythematosus (SLE) presented as HLH. A 28-year-old male presented with progressive weakness and recurrent fevers for 2 months. Vital signs were within normal limits except for temperature of 100.3°F. His exam was unremarkable except for a left cervical scar and malar rash. His labs showed pancytopenia with neutropenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Hemophagocytosis was present on bone marrow biopsy. All workup for a source of infection was negative. A tentative diagnosis of HLH was made based on clinical presentation and laboratory data. The patient was treated with an HLH protocol. Later, it was determined that his HLH was actually secondary to a primary diagnosis of SLE. The patient was treated for SLE with an immunosuppressive regimen of cyclosporine and dexamethasone, and he improved dramatically. HLH rarely presents due to a rheumatologic condition such as SLE. Physicians should consider testing for SLE in patients diagnosed with HLH

Bortezomib plus rituximab in patients with indolent non-hodgkin\u27s lymphoma (NHL): A phase 2 study.

Background: Bortezomib (VELCADE®, Vc) a novel, first-in-class proteasome inhibitor, is being investigated in the treatment (tx) of non-Hodgkin\u27s lymphoma (NHL). Preclinical data with combined rituximab (R) and Vc suggest additive cytotoxic activity. This phase 2 study investigated the response rate to R plus Vc, weekly or twice-weekly, in patients (pts) with relapsed follicular (FL) or marginal zone (MZL) NHL. Methods: Eligibility criteria included CD20+ FL or MZL with measurable disease, and Karnofsky Performance Status (KPS) ≥50% (ECOG 0–2). Pts on any prior regimen including R had to respond and show TTP of ≥4 months. Pts were randomized (1:1) to Vc 1.3mg/m2 twice-weekly on days 1, 4, 8, and 11 of a 21-day cycle (Arm A) or Vc 1.6mg/m2 weekly on days 1, 8, 15, and 22 of a 35-day cycle (Arm B) for up to 15 weeks (5 and 3 cycles in arms A and B, respectively). Starting from day 1, R 375mg/m2 was administered weekly for 4 weeks. Response was evaluated by International Workshop Criteria. Results: 81 pts were enrolled between May 2004 and August 2005. At data reporting for this abstract, 46 (23 each arm) had received study drug, and 42 (20 Arm A, 22 Arm B) were evaluable for response. Of these 42 pts, 83% had FL and 17% had MZL; 62% were male; 55% were aged \u3e60 years (range 33–80); 93% had KPS ≥90%; 26% had lactic dehydrogenase level \u3eULN. 71% of pts received prior R (alone or in combination), and 79% of pts received prior CHOP, RCHOP, CVP or RCVP. Of 46 treated pts, 9 (39%) in Arm A and 16 (70%) in Arm B completed all planned cycles. Median Vc dose received was 15.9mg/m2 (61% of max. expected) in Arm A, and 19.0mg/m2 (99% of max. expected) in Arm B. Overall response rate was 50% (1 CR + 9 PR) in Arm A, and 45% (2 CR + 8 PR) in Arm B. 12 pts had PD (6 each arm) and 1 pt died (Arm A). Time to event analyses, including TTP and duration of response, are pending further follow-up. Tx was well tolerated in both arms; grade ≥3 AEs were seen in 10 pts in Arm A and 5 pts in Arm B. The most common grade ≥3 AEs were gastrointestinal toxicities, neutropenia, thrombocytopenia and peripheral neuropathy, but no grade ≥3 thrombocytopenia or neutropenia were observed in Arm B. SAEs were seen in 7 pts in Arm A versus 2 pts in Arm B. Conclusions: Weekly and twice weekly Vc plus R are active and well tolerated treatments for relapsed/refractory CD20+ indolent NHL. The more convenient weekly regimen appears to offer a similar response rate with less toxicity. Final efficacy and safety data for both regimens will be presented

Phase 2 study of bortezomib weekly or twice weekly plus rituximab in patients with follicular (FL) or marginal zone (MZL) lymphoma: final results.

Background: Bortezomib (btz, VELCADE®) has single-agent activity in relapsed/refractory non-Hodgkin’s lymphoma (NHL), including FL and MZL, on a twice-weekly schedule. Rituximab (R) is approved for relapsed/refractory CD20+ B-cell NHL. Preclinical studies show additive activity in lymphoma cell lines and lymphoma-bearing SCID mice. Btz and R have no overlapping toxicity. Weekly btz is active and safe in multiple myeloma trials. Methods: Patients (pts) with measurable CD20+ FL or MZL, KPS ≥50%, and a response with TTP ≥4 months to any prior R-containing regimen, were randomized to btz 1.3mg/m2 twice weekly (d 1, 4, 8, 11 of 21-d cycle, 5 cycles, Arm A) or btz 1.6mg/m2 weekly (d 1, 8, 15, 22 of 35-d cycle, 3 cycles, Arm B). R 375mg/m2 was given weekly for 4 weeks from d 1, cycle 1, in both arms. Response was evaluated by independent radiology review (IRR) and by investigators using the IWRC. Results: 81 pts (41 Arm A, 40 Arm B) were enrolled; median age: 64 yrs (63.0, 64.5); FL: 86% (80%, 93%); Stage IV: 47% (44%, 50%); KPS \u3c90%: 20% (17%, 23%); LDH \u3eULN: 27% (32%, 23%); ≥1 extranodal site: 43% (41%, 45%); FLIPI score ≥2: 69% (71%, 68%). In total, 56% (54%, 58%) had ≥2 prior lines of therapy, 81% (80%, 82%) had prior CHOP/CVP ±R, 84% (78%, 90%) had prior R (alone or combination), and 8% (7%, 8%) had prior SCT. Median % of planned cumulative btz dose received: 75% (Arm A) and 99% (Arm B); median total btz: 19.5 and 19.0mg/m2; median dosing intensities per week: 1.6 and 1.3mg/m2. Response rates and TTP in evaluable pts are shown in Table 1. TTP curves by IRR are broadly overlapping between the arms (Figure). Most common AEs were fatigue, GI events, and peripheral neuropathy. Grade ≥3 AEs were more common in Arm A (54%) vs Arm B (35%), notably thrombocytopenia (10% vs 0%) and neutropenia (10% vs 3%), as were grade ≥4 AEs and serious AEs. Conclusion: Weekly and twice weekly btz + R are active and well tolerated in relapsed/refractory CD20+ indolent NHL. The more convenient weekly regimen appears to offer similar efficacy with less toxicity. Weekly btz 1.6mg/m2 + R is being compared with R in a phase 3 stud