Victor H. Jimenez-Zepeda

Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents

Involvement 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 4·6 months [95% confidence interval (CI): 2·8–6·7]; however, nine patients had prolonged survival (median: 17·1 months, 95% CI: 13·2–67·4). 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.

Leukocyte cell-derived chemotaxin 2 (LECT2)–associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States

Using laser microdissection and mass spectrometry (MS)-based proteomics, we subtyped amyloid deposits from 130 cases of hepatic amyloidosis. Although we confirmed that immunoglobulin light chain amyloidosis was the most frequent cause of hepatic amyloidosis, leukocyte cell-derived chemotaxin 2 (LECT2) amyloidosis (ALect2) accounted for 25% of cases. This novel finding was associated with Hispanic ancestry, incidental discovery of amyloid in liver specimens sampled for other unrelated conditions, and a characteristic pattern of hepatic amyloid deposition. Although ALect2 patients had a common LECT2 polymorphism, pathogenic mutations were not discovered, suggesting that constitutive or compensatory LECT2 overexpression led to ALect2 deposition. These findings indicate that ALect2 is a common cause of hepatic amyloidosis in the population of the United States, and subtyping hepatic amyloid deposits by an accurate analytic method such as MS is required for optimal clinical management of hepatic amyloidosis patients and to avoid incorrect and unnecessarily toxic therapies.

Inhibiting Aberrant Signal Transducer and Activator of Transcription Protein Activation with Tetrapodal, Small Molecule Src Homology 2 Domain Binders: Promising Agents against Multiple Myeloma

The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3s SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.

Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma

This single institution, open label Phase I‐II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m2 on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28‐d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full‐dose CPR regimen produced no dose‐limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression‐free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta‐2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2‐ and 3‐ drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.

Absolute lymphocyte count as predictor of overall survival for patients with multiple myeloma treated with single autologous stem cell transplant

Post-autologous stem cell transplant (ASCT) studies have demonstrated that absolute lymphocyte count (ALC) recovery is associated with prolonged survival in some hematological malignancies. To assess whether ALC recovery has prognostic significance in patients with multiple myeloma (MM) undergoing single ASCT, we conducted a retrospective analysis of ALC at different time-points in patients with MM. In total 769 consecutive patients who underwent single ASCT from January 2000 to December 2007 were evaluated. An ALC of ≥ 1400 cells/μL at day 0, day 15 and day 90 significantly correlated with a better overall survival (OS) (median OS of 111, 90.7 and 84 months vs. 74, 70.5 and 65 months, respectively, p < 0.001 for all time-points). Multivariate analysis showed that ALC is an independent prognostic factor for OS after ASCT. In conclusion, ALC is a surrogate marker of the host immune system that correlates with better survival in patients with MM undergoing single ASCT. Immunomodulatory drugs, vaccination strategies and cellular therapies in MM should be investigated.

Efficacy of thalidomide‐based therapy following lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma

Immunomodulatory drugs (IMiDs), thalidomide and its derivative lenalidomide, have emerged as an effective treatment for relapsed/refractory multiple myeloma (MM). Clinical studies have demonstrated that thalidomide and lenalidomide each have their own distinct toxicity and efficacy [1–4] despite sharing an overlapping immunomodulatory profile [5,6]. It is evident that patients previously refractory to the less potent IMiD thalidomide can still respond when treated with lenalidomide [7,8]. However, the efficacy of thalidomide in patients refractory to lenalidomide is largely unknown. Two recent studies have looked at the use of thalidomide as a possible treatment regimen post-lenalidomide. Firstly, Guglielmelli et al. [9] followed a diverse group of 20 patients with MM that relapsed while on a reduced maintenance dosage of lenalidomide and treated these patients with a thalidomide-based salvage regimen. Their results showed a 10% overall response of equal or greater than partial response ( PR) and median response duration of 5 months. Secondly, Madan et al. [10] reported an overall response rate of 25% in a subset of four patients with lenalidomide refractory MM subsequently treated with thalidomide. We retrospectively studied 24 patients with advanced MM with relapsed disease, refractory disease, or intolerance to full dose lenalidomide and dexamethasone that were subsequently treated with a thalidomide-based regimen. In our study, the median age of subjects at the start of thalidomide therapy was 67 years (44–83) with 67% of patients being males. Monoclonal types were IgG 54% (n 5 13), IgA 33% (n 5 8), and free light chains comprising 13% (n 5 3). Seven patients (29%) had a prior thalidomide exposure pre-lenalidomide either as induction therapy pre-autologous stem cell transplant (ASCT), post-ASCT maintenance or treatment in a relapsed setting. Median time to re-exposure of thalidomide (post lenalidomide) from the end of initial exposure (pre-lenalidomide) for the described seven patients was 2.9 years (1.2–4.0 years). The same seven patients that received thalidomide prior to lenalidomide when compared to the remaining 17 patients exposed to thalidomide only post-lenalidomide had an expectedly reduced median treatment duration and overall response to thalidomide regimen given after lenalidomide (84 versus 103 days; 29 versus 35%). However, these values were not statistically significant. Table I summarizes the lenalidomideand thalidomide-based regimen and responses for all 24 patients. Nineteen of these patients tolerated and eventually progressed on lenalidomide having median treatment duration of 11.1 months, comparable with 11.3 months reported by the MM009 trial [2]. Overall, response to thalidomide-based regimen post-lenalidomide resulted in nine patients (38%) achieving a very good partial response or a partial response (VGPR 1 PR) and 13 patients (54%) achieving less than a partial response, stable disease or progressive disease (SD 1 PD). No complete responses (CR) were observed. Progression-free survival for all 24 lenalidomide-treated patients receiving thalidomide-based treatment was a median of 3.1 months (95% CI; 63–226 days) and overall survival was a median of 9.6 months (95% CI; 255–444 days). In the thalidomide containing responsive group (VGPR 1 PR), the median duration of thalidomide-based treatment was improved to 9.1 months (95% CI: 2.8–19.3) A case of leptospirosis presenting as TTP