Mary Drake

PAD combination therapy (PS‐341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma

Bortezomib (formerly PS‐341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21‐d cycles of PAD, comprising bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1–4, 8–11 and 15–18 during cycle 1 and days 1–4 during cycles 2–4. During days 1–4, patients also received 0, 4·5 or 9 mg/m2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high‐dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention‐to‐treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials.

Variation in dimethyl sulfoxide use in stem cell transplantation: a survey of EBMT centres

Summary:The cryoprotectant dimethyl sulfoxide (DMSO) is known to have toxic side effects, yet guidelines for its use in stem cell transplantation do not exist. To assess current practice in the use of DMSO and the incidence of DMSO-related complications, a single page questionnaire was mailed to 444 EBMT centres involved in autologous transplantation. The responses from 97 centres showed a wide variation in practice between transplant units regarding the concentration of DMSO used, daily DMSO dose restriction and the use of cell washing. The overall incidence of DMSO toxicity was approximately one in 70 transplants and most cases were cardiovascular and respiratory in nature. There was a trend to reduced complication rates in centres using lower concentrations of DMSO or washing cells prior to return. A large-scale prospective study of the strategies for reduction in exposure to DMSO and reduction in toxic effects is required before guidelines in the use of DMSO in stem cell cryopreservation can be promulgated.

Bortezomib, doxorubicin and dexamethasone (PAD) front‐line treatment of multiple myeloma: updated results after long‐term follow‐up

Bortezomib, doxorubicin and dexamethasone (PAD) was evaluated as induction before stem cell transplantation in newly diagnosed multiple myeloma (MM) patients, using bortezomib 1·3 mg/m2 (PAD1, N = 21) or 1·0 mg/m2 (PAD2, N = 20). Complete/very good partial response rates with PAD1/PAD2 were 62%/42% postinduction and 81%/53% post‐transplant. Progression‐free survival (29 vs. 24 months), time to re‐treatment (36 vs. 29 months) and overall survival (1 year: 100% vs. 95%; 2 years: 95% vs. 73%) were statistically similar but favoured PAD1 versus PAD2. Toxicity was lower in PAD2; bortezomib dose reduction may help manage toxicities while retaining efficacy. PAD is highly active as front‐line induction in MM.

Analysis of the effect of prior therapy on progenitor cell yield: use of a chemotherapy scoring system.

A quantitative analysis of peripheral blood stem cell (PBSC) yield, measuring absolute numbers of CD34+ cells × 106/kg and CFU‐C × 104/kg was performed in 74 consecutive patients. The interval or ‘gap’ from the end of previous chemotherapy to the date of priming was recorded in weeks.

Primary plasma cell leukemia and autologous stem cell transplantation.

Background Primary plasma cell leukemia is a rare disorder accounting for less than 5% of malignant plasma cell diseases. It has a poor prognosis compared to multiple myeloma, with a median survival of 8–12 months. The results of conventional therapy are disappointing though autologous stem cell transplantation may improve survival. Design and Methods A retrospective analysis was undertaken of the European Group for Blood and Marrow Transplantation experience of 272 patients with plasma cell leukemia and 20844 with multiple myeloma undergoing first autologous transplantation between 1980 and 2006. All patients were reported to the European Group for Blood and Marrow Transplantation registry using MED-A (limited data) or MED-B (extensive data) forms. All patients were included regardless of availability of complete data. Results There was no difference in type of graft or use of total body irradiation between patients with plasma cell leukemia and multiple myeloma, but the group with plasma cell leukemia was transplanted earlier after diagnosis (6.0 versus 7.7 months, P=0.000). Patients with plasma cell leukemia were more likely to enter complete remission after transplantation but their overall survival (25.7 months, 95% confidence interval 19.5–31.9 months) was inferior to that of patients with multiple myeloma (62.3 months, 95% confidence interval 60.4–64.3 months) (P=0.000), due to the short duration of their post-transplant response and increased non-relapse-related mortality. Conclusions This largest study ever reported on plasma cell leukemia suggests that autologous transplantation can improve outcome, although results are markedly inferior to those achieved in patients with multiple myeloma, highlighting the need for novel approaches to this aggressive disorder.

Bortezomib is effective in primary plasma cell leukemia

The ubiquitin proteasome pathway plays a critical role in regulating a number of cellular processes crucial to tumorigenesis and has recently emerged as a new molecular target for cancer therapy [1]. Sensitivity to proteasome inhibitors has been demonstrated in a number of malignancies, particularly multiple myeloma. The first proteasome inhibitor to enter clinical trials, bortezomib (Velcade) has demonstrated marked anti-myeloma activity and has been approved for the treatment of relapsed and refractory myeloma. Plasma cell leukemia (PCL) has been defined as circulating peripheral blood plasma cells exceeding 2610/l or 20% of peripheral blood cells [2]. If observed at the time of diagnosis, it is known as primary PCL and has a poor outcome from both conventional therapy and autologous or allogeneic transplantation [3,4].

Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression

Abstract:  Objective: Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgVH mutational status, gene usage and chromosomal aberrations was investigated. Methods: Ninety‐one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgVH mutational status and VH gene usage were determined using BIOMED‐2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT‐PCR) determined CD38 and Zap‐70 expression, respectively. Results: Significantly higher serum TK levels were found in IgVH unmutated, compared with IgVH mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap‐70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). Conclusion: A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgVH, good prognosis chromosomal aberrations, Zap‐70− and CD38−) who subsequently showed disease progression. Additionally, patients with VH3‐21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.

Efficacy and outcome of autologous transplantation in rare myelomas

Background As rare myelomas, i.e. the IgD, IgE, IgM and non-secretory forms, constitute only a small proportion of any study, relatively little is known about their prognosis in the era of peripheral stem cell transplantation. Design and Methods We used the European Group for Blood and Marrow Transplantation Myeloma Database to compare the outcome following autologous transplantation of over 20,000 patients with common myelomas (IgG, IgA and light chain myeloma) with the outcome of patients with rare myelomas: 379 IgD, 13 IgE, 72 IgM and 976 non-secretory cases. Results The study confirms the multiple adverse prognostic factors seen in IgD myeloma. Somewhat surprisingly, patients with IgD and non-secretory myeloma both had higher complete remission rates before and after transplantation than patients with common myelomas. However, while the overall survival of patients with non-secretory myeloma was similar to that of the patients with common myelomas, the survival of patients with IgD myeloma was significantly worse (although better than survival rates reported for non-transplanted patients); this was due to higher transplant-related mortality and relapse/progression rates. The post-transplantation survival of patients with IgE or IgM myeloma appears to be very poor. Conclusions This study provides data on the biological features of rare myelomas. The overall survival of patients with IgD, IgE or IgM myeloma is poor following autologous transplantation but substantially better than that reported for patients who were not transplanted.

ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 × 10−2). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.

Clarithromycin with low dose dexamethasone and thalidomide is effective therapy in relapsed/refractory myeloma.

A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4‐d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti‐myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects.