Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.
Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks.
Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).
Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population. Clin Cancer Res; 16(12); 3260–9. ©2010 AACR.
This phase II trial evaluated the efficacy and safety of plitidepsin in relapsed/refractory multiple myeloma. Forty-seven patients received plitidepsin 5 mg/m2 as a 3-hour infusion every two weeks, and 19 of them added dexamethasone 20 mg/day on days 1 to 4 after showing suboptimal response to plitidepsin alone. The overall response rate was 13% with plitidepsin alone and 22% with plitidepsin and dexamethasone. Both regimens were well tolerated. These results show that plitidepsin has limited although reproducible single-agent activity in relapsed/refractory multiple myeloma, which seems to be enhanced after dexamethasone addition while remaining well tolerated. Additional studies are awaited to better define the role of plitidepsin in combination with other active agents in this indication.
Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin's lymphoma. In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. The disease primarily affects aged individuals, with a median age of 60 years at diagnosis. Despite recent advances in the treatment of multiple myeloma and the availability of novel agents, few patients, if any, can be considered cured, as the vast majority will eventually relapse (1). Thus, new active agents without known cross-resistance with other well-established anti–multiple myeloma agents are needed.
Plitidepsin is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans and is currently produced by chemical synthesis. The dose-limiting toxicities (DLT) at the phase II recommended dose of 5.0 mg/m2 over a 3-hour i.v. infusion every two weeks (2–7) included myalgia, muscular weakness, transient and reversible transaminases increase, and fatigue both in patients with solid tumors and in those treated for hematologic malignancies. Remarkably, plitidepsin lacked clinically relevant bone marrow toxicity, thus making this drug an ideal candidate to treat heavily pretreated multiple myeloma patients who usually have a poor bone marrow reserve.
Plitidepsin-induced oxidative stress leads to increased levels of cell membrane phospholipid as well as DNA oxidation (8), decreased intracellular levels of glutathione, and sustained activation of the Rac1-JNK pathway that ultimately leads to caspase-dependent apoptosis (9–11). In addition, plitidepsin has shown antiangiogenic activity in several preclinical models through inhibition of the expression of several angiogenic genes, including the vascular endothelial growth factor (VEGF) and its receptor (VEGFR-1; refs. 12–15). Plitidepsin activity has been studied in vitro and in vivo against several different models at concentrations as low as in the nanomolar range (16).
Our group recently reported the potent activity of plitidepsin, at clinically achievable concentrations, against primary multiple myeloma tumor cells and a broad spectrum of human multiple myeloma cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti–multiple myeloma agents (17). In multiple myeloma cells, Fas/CD95 translocation to lipid rafts in the cell membrane was shown after plitidepsin exposure, accounting at least partially for the rapid induction of apoptosis observed (17). Plitidepsin was also active against multiple myeloma cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells, and the results were confirmed in a mouse xenograft model. In addition, additive or even synergistic effects have been described with some of the established anti–multiple myeloma agents such as bortezomib, lenalidomide, thalidomide, and/or dexamethasone, suggesting a different mechanism of action for plitidepsin (17). In summary, these results provided a strong rationale for the clinical evaluation of plitidepsin in multiple myeloma patients.
The objective of this exploratory multicenter, open-label, single-arm, phase II clinical and pharmacokinetic trial was to assess the activity and safety profile of plitidepsin alone given at 5 mg/m2 as a 3-hour i.v. infusion every two weeks to patients with relapsed/refractory multiple myeloma. The protocol was amended after 23 patients had been treated, to allow the addition of low-dose dexamethasone (20 mg daily on days 1 to 4 of every cycle, for a total monthly dose of 160 mg) in patients with suboptimal response to single-agent plitidepsin.
Materials and Methods
This clinical trial was conducted at eight centers, seven in Spain and one in the United States. The protocol was approved by the institutional review board of each participating center, and a signed written informed consent was obtained for each patient before registration. The study is registered at ClinicalTrials.gov (website address: http://www.clinicaltrials.gov) as NCT00229203.
Patients were adults previously diagnosed with multiple myeloma based on standard criteria who required treatment because of relapse following response to standard or high-dose chemotherapy, or had refractory multiple myeloma (i.e., failed to achieve at least complete response, partial response, or stable disease) to the most recent chemotherapy. Other requirements were as follows: measurable disease (defined as any quantifiable serum monoclonal protein value and/or urine light-chain excretion of ≥200 mg/24 hours for secretory multiple myeloma, and/or as the presence of soft tissue plasmacytomas as determined by clinical examination and/or radiologic assessments for oligosecretory or nonsecretory multiple myeloma), performance status (Eastern Cooperative Oncology Group) score ≤2, life expectancy ≥3 months, platelet count ≥50 × 109/L, hemoglobin ≥8.0 g/dL, absolute neutrophil count ≥1.0 × 109/L (lower values accepted if severe bone marrow involvement), corrected serum calcium <14 mg/dL, aspartate aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN), alanine aminotransferase (ALT) ≤2.5 × ULN, total bilirubin ≤1.5 × ULN, calculated creatinine clearance ≥40 mL/minute, and left ventricular ejection fraction (LVEF) within normal limits.
The study followed a two-stage design that incorporated both response and toxicity considerations (18), with α error for response (αR) of 0.10, α error for toxicity (αt) of 0.10, and β error of 0.10. At the first stage, 16 patients evaluable for efficacy received single-agent plitidepsin 5 mg/m2 as a 3-hour i.v. infusion every two weeks. Recruitment was to proceed into a second stage depending on efficacy and safety results at the first stage: (a) if at least one complete response, partial response, or minimal response occurred (>5%) and ≤4 patients had serious toxicities (<30%), up to 37 additional patients evaluable for efficacy were to be recruited at the second stage; (b) if at least one response was found but toxicity was not acceptable, a new cohort of patients was to receive plitidepsin 4 mg/m2 every two weeks; (c) if no response was found or if ≥5 patients had serious toxicities, the study was to be terminated.
Plitidepsin (Pharma Mar) was administered at a dose of 5 mg/m2 as a 3-hour i.v. infusion every two weeks (i.e., one cycle equaled two weeks). Patients with suboptimal response to plitidepsin alone (progressive disease or stable disease after three or four plitidepsin cycles) were permitted to add dexamethasone (20 mg/day orally on days 1 to 4 every two weeks). A maximum of two plitidepsin dose reductions (first to 4.25 mg/m2 and then to 3.6 mg/m2) were allowed if serious drug-related toxicity occurred in the preceding cycles. Treatment was continued until disease progression, unmanageable toxicity, investigator's decision, withdrawal of patient's consent, or treatment delay for >2 weeks (except for obvious patient's benefit). Hematopoietic growth colony stimulating factors were allowed (except during cycle 1) as well as bisphosphonates in accordance with the guidelines of the American Society of Clinical Oncology (19, 20). Antiemetic and hypersensitivity reactions prophylaxis with 5-HT3 antagonists, steroids, and anti-H1/H2 antagonists was administered at 20 to 30 minutes before each plitidepsin infusion.
Efficacy and safety assessments
All patients who received at least two plitidepsin infusions and had at least one disease assessment done at ≥8 weeks after treatment onset, experienced progression before week 8, or died due to progressive disease were evaluable for efficacy. The primary efficacy end point was the overall response rate (ORR) achieved with single-agent plitidepsin as well as after dexamethasone addition in suboptimal-responding patients, defined as the combined rate of complete response plus partial response plus minimal response evaluated according to the European Group for Blood and Marrow Transplantation (EBMT) criteria (21). Blood and 24-hour urine samples for quantification of M protein and immunoglobulins and assessment of M protein by immunofixation in serum were collected from all patients at the screening, every two weeks during the first eight weeks of treatment and every four weeks thereafter. After amendment, electrocardiograms (ECG) were done before and after each plitidepsin infusion. LVEF was regularly assessed by multiple gated acquisition scan or by echocardiography every two months while on study.
Secondary efficacy end points included time-to-event parameters, namely, time to disease progression (TTP), progression-free survival (PFS), and overall survival (OS), and overall safety. All patients who received at least one infusion (or part) of single-agent plitidepsin, and all those who received at least one infusion (or part) of plitidepsin and at least one dose of dexamethasone, were included in the assessment of toxicity of single-agent plitidepsin and of the plitidepsin plus dexamethasone combination, respectively. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0. All patients were followed until recovery from toxicity.
Whole blood and/or plasma samples were obtained at 12 prespecified points during the first infusion (baseline, mid-infusion, end of infusion, 15, 30 and 90 minutes, and 3, 6, 24, 48, 96, and 168 hours after the end of the infusion) in 45 of the 51 patients treated in the study. Samples were analyzed using a validated high-performance liquid chromatography system coupled with electrospray ionization tandem mass spectrometry method in ICON DS. The lower limit of quantification was 0.05 ng/mL in plasma and 0.25 ng/mL in whole blood. Individual plitidepsin plasma and whole blood concentrations were used to estimate maximum plasma concentration (Cmax), area under the concentration-time curve through infinity (AUC), terminal half-life (t1/2), clearance (Cl), and apparent steady-state volume of distribution (Vss) using WinNonlin 5.2 (Pharsight Corp.). The AUC was calculated using the log-linear trapezoidal method. Vss was estimated from the product of mean residence time and Cl.
Objective tumor response rates were calculated with binomial exact confidence intervals at 95% (95% CI) and with the quadratic loss Bayes' estimator. The Bayesian test was used to evaluate the null hypothesis (RR ≤20%) and the alternative hypothesis (RR >20%). Time-to-event end points and the estimated rate of patients alive at 12 months were calculated using Kaplan-Meier estimates and 95% CIs. Safety parameters, exposure to study drug, and reasons for study discontinuation were tabulated, and analyses were done in a descriptive fashion.
Patients and treatment
From June 17, 2004 to March 25, 2008, 53 relapsed/refractory multiple myeloma patients were enrolled. According to the study design, one partial response was achieved among the first 16 treated patients and most treatment-related adverse events (AE) were grade 1/2; thus, accrual proceeded to the second stage to complete the 53 planned patients. Fifty-one of the 53 patients enrolled were treated with single-agent plitidepsin (intent-to-treat population): 23 before the amendment and 28 after the amendment. Nineteen of these 28 patients received dexamethasone due to suboptimal response to single-agent plitidepsin; the other nine patients were withdrawn from the study due to disease progression (n = 5), adverse events (n = 3), or patient refusal (n = 1) prior to adding dexamethasone to plitidepsin (Fig. 1).
The demographic and baseline characteristics of the 51 treated patients are shown in Table 1. All patients had confirmed relapsed disease at study entry, and 41% (n = 21) of them were relapsed and refractory to last prior therapy, with a median of 4 (range, 1-8) lines of prior therapy, including 8 (42%) of the 19 patients treated with plitidepsin and dexamethasone. Particularly, bortezomib had been administered to 67% (n = 34) of patients, thalidomide to 51% (n = 26), and lenalidomide to 4% (n = 2), whereas 59% (n = 30) had previously received autologous stem cell transplantation. All patients received steroids as part of their prior therapy (median prior steroid-containing lines, 2; range, 1-6); in particular, 53% (n = 10) of the 19 patients treated with plitidepsin and dexamethasone had steroids as part of their last regimen before inclusion and only five of them had some degree of response with this regimen.
A total of 278 plitidepsin cycles were administered during the study, with a median of 4 cycles per patient (range, 1-18). Before the amendment, 23 patients received a median of 4 cycles of single-agent plitidepsin (range, 1-16). A median of 6 cycles (range, 3-18) of study treatment were given to the 19 patients in which dexamethasone was added because of suboptimal response to single-agent plitidepsin. ECG evaluations were done before and after plitidepsin infusion in 36 patients (71%) and 112 cycles (40%), respectively.
Forty-seven patients were evaluable (per protocol population) for response. According to EBMT criteria, six patients responded to single-agent plitidepsin, resulting in an ORR of 13%; two patients achieved partial response and four minimal response (Table 2). Overall, of 47 patients with available serial measurements, 34 patients (73%) had some degree of M serum protein and/or urine light chains decrease (median, -7.1%; 95% CI, -20.6% to -3.1%; P = 0.0031 according to the sign test) while on treatment with single-agent plitidepsin. Of the 28 patients enrolled after the amendment allowing dexamethasone addition in patients with suboptimal response to plitidepsin alone, 26 were evaluable for response, of which 18 effectively received dexamethasone; eight patients did not receive dexamethasone because of early progressive disease (n = 4), toxicity (n = 3) or patient refusal (n = 1). In this group of patients treated with plitidepsin plus dexamethasone (n = 18), the response status improved from minimal response to partial response in one patient and from stable disease to minimal response in one patient, thus resulting in an ORR of 22%. One additional patient achieved partial response but confirmatory test was missing; therefore, an ORR of 28% was obtained. Of note, a 63-year-old patient proceeded to transplantation as consolidation therapy after achieving a >90% M protein reduction with the plitidepsin/dexamethasone combination.
The overall median TTP and PFS for single-agent plitidepsin was 2.3 months, and these values increased to 4.2 and 3.8 months, respectively, for the plitidepsin plus dexamethasone group (P = 0.0045, according to the log-rank test; Fig. 2). The median follow-up of all patients was 8.0 months (range, 0.3-31.8 months). Median OS was 16.7 months with single-agent plitidepsin prior to the amendment, and was not reached in the group of patients included after the amendment. For all patients, the 1-year OS was 55% (95% CI, 37.5-73.0%). Duration of response ranged from 1.8 to 6.2 months with single-agent plitidepsin and from 2.8 to 5.7 months with plitidepsin plus dexamethasone.
All 51 treated patients were included in the safety analysis. Table 3 presents the grade 3/4 related AEs reported in ≥10% of patients treated with single-agent plitidepsin and plitidepsin plus dexamethasone.
Concerning hematologic toxicity, in the group of patients receiving single-agent plitidepsin, the most common grade 3/4 AE was anemia (29%) whereas grade 3/4 thrombocytopenia and neutropenia occurred in only 18% and 12% of patients, respectively. Similar frequencies were found in the cohort of patients receiving plitidepsin plus dexamethasone. It should be noted that 92% (n = 47), 43% (n = 22), and 47% (n = 24) of the patients already had some grade of anemia, neutropenia, or thrombocytopenia, respectively, at baseline.
Concerning nonhematologic toxicity, the most frequent grade 3/4 related AEs in the group of patients receiving single-agent plitidepsin were fatigue (16%) and muscular toxicity (6%); when dexamethasone was added, the frequency of grade 3/4 fatigue increased to 21% and that of muscular toxicity to 16% (grade 4 in one patient only); two patients developed renal failure (Table 3).
The most common grade 3/4 biochemical abnormality was transient, noncumulative increase in transaminase levels in single-agent plitidepsin, and grade 3/4 creatine phosphokinase (CPK) increase in plitidepsin plus dexamethasone (Table 3). Grade 3 ALT increases were more common with single-agent plitidepsin (28% versus 5% of patients). Grade 3/4 CPK increases were slightly more frequent (22% versus 14%) with plitidepsin and dexamethasone than with plitidepsin alone.
Atrial fibrillation occurred in three patients (6%), and four patients (8%) had asymptomatic decreased LVEF to <50% while on treatment. Confounding factors among these patients included ongoing infection, age, and/or presence of pre-existing cardiac conditions.
Overall, eight patients (16%) died during or within 30 days of last study treatment dose. Death was due to progressive disease (n = 3), cardiopulmonary arrest (n = 2), and bilateral pneumonia, pulmonary embolism, and multiorganic failure secondary to septic shock (n = 1 each). None of these deaths were considered related to treatment.
Pharmacokinetic parameters are summarized in Table 4. On average, Cmax was 1.93 times higher and AUC was 3.4 times higher in whole blood than in plasma. Both plitidepsin Cl (3-4 times higher) and Vss (4 times higher) were higher in plasma than in whole blood. Half-life values were similar (44 hours in whole blood versus 50 hours in plasma). Plitidepsin Cl and Vss in whole blood were 49% and 55% higher than the values found in patients treated at the same dose and schedule with several types of solid tumors who participated in a previous phase I study.
Patients showing partial response and minimal response had a statistically significant prolongation of plasma half-life with respect to those patients without response (median plasma half-life in responders and nonresponders, 79 and 48 hours respectively; P = 0.0097, as per binomial logistic regression). Consequently, the last time point (168 hours after the infusion) was 35% higher in responders than in nonresponders (median, 0.175 and 0.130 ng/mL, respectively). No differences in Cmax and AUC were seen between responders and nonresponders. None of the pharmacokinetics (PK) parameters evaluated were significantly related to any of the toxicities reported in this study. Importantly, the four patients with decreased LVEF <50% did not have more plitidepsin exposure in terms of PK than patients without LVEF decrease.
Plitidepsin is a new compound of marine origin currently in clinical development with preliminary clinical activity against both solid tumors and hematologic malignancies. In the present study, single-agent plitidepsin given at 5 mg/m2 as a 3-hour i.v. infusion every two weeks showed clinical activity in a population of 51 heavily pretreated patients with relapsed or refractory multiple myeloma. According to EBMT criteria, 6 of 47 evaluable patients (13%) achieved partial response or minimal response; in addition, some degree of serum M protein and/or urine light chains decrease was observed in most (n = 34, 72%) patients with serial measurements available with plitidepsin as monotherapy.
The addition of low-dose dexamethasone improved the response rate, the type of response, and its duration in patients showing suboptimal response (including two patients who showed stabilization of their initial response in two subsequent cycles and two patients with initial stable disease); the ORR increased up to 28% (an additional patient achieved a partial response but confirmatory test was missing), and importantly, some responses occurred in patients who were considered refractory to last prior therapy (42% of patients in this cohort) and one patient proceeded to receive salvage transplantation after nine courses following a >90% M protein reduction. Furthermore, the plitidepsin and dexamethasone combination resulted in longer median TTP values (4.2 versus 2.3 months with plitidepsin alone; P = 0.0045), suggesting that the responses achieved with plitidepsin may last longer with dexamethasone addition.
There are several limitations in this study that may jeopardize the interpretation of these data; in particular, the absence of a concurrent control arm with either plitidepsin or dexamethasone alone precludes any formal comparison. Additionally, the limited number of patients that were treated over a long period of time, which also coincided with the availability of new and very active compounds such as bortezomib, thalidomide and lenalidomide, made the study population very heterogeneous. Furthermore, two patients had dexamethasone addition while they were showing a minimal response or after they had reached a plateau in an already achieved partial response because this was interpreted as clinically suboptimal; this made the real duration of response while on plitidepsin alone difficult to assess. In addition, it should be taken into account that M protein measurements were done before each infusion (every two weeks) during treatment with plitidepsin alone whereas standard clinical practice should be done on a monthly basis; this may have also influenced or biased in some way management decisions. Owing to these limitations, the results shown here should be regarded as descriptive. Nevertheless, they are in line with our preclinical studies showing that plitidepsin was able to induce cytotoxicity in myelomatous plasma cells obtained from patients with clinical resistance to most current antimyeloma treatments, including combination chemotherapy regimens, autologous stem cell transplantation, and novel agents such as bortezomib or thalidomide and their combinations. They also confirm the in vitro potentiating effect seen with dexamethasone.
Although these results are inferior to those obtained with bortezomib or lenalidomide (22, 23), they compare favorably with those obtained with most other novel molecules, when they were formerly evaluated as single agents in relapsed or refractory multiple myeloma. The rationale for further development of several of the new agents was their singular mechanism of action and the potential synergistic activity with backbone antimyeloma drugs (corticosteroids, alkylating agents, proteasome inhibitors, and immunomodulatory drugs). In this regard, despite the low clinical activity of these drugs when used as monotherapy, their preclinical combinations, when used in patients, translated into promising clinical results; this was the case of molecules such as heat shock protein-90 inhibitors (24), histone deacetylase inhibitors (25–29), AKT inhibitors (30, 31), or the novel monoclonal antibody against interleukin 6 (32). A similar rationale would apply for plitidepsin based not only on the efficacy here observed but also based on its singular mechanism of action and the capacity to synergize with other drugs as shown in our preclinical studies (17).
Plitidepsin both as single agent and in combination with dexamethasone was well tolerated in this population of heavily pretreated patients. The overall safety profile was similar to what occurs in solid tumor patients, with mild to moderate asthenia, myalgia, and transient and reversible ALT/AST and/or mild CPK elevations as more relevant toxicities (33). Rather expectedly, the combination of plitidepsin plus dexamethasone was associated with a slight increase in muscular events, which were in general mild and both reversible and not life threatening. Grade 4 CPK elevations, although not associated with clinical rhabdomyolysis, were twice more often with plitidepsin plus dexamethasone than with plitidepsin alone (16% versus 8%). On the other hand, dexamethasone addition resulted in less ALT/AST increases as compared with plitidepsin alone. The hematologic toxicity profile seen in this study confirms that plitidepsin has no relevant bone marrow toxicity which facilitates its use in combination with other drugs. Despite extensive ECG monitoring, no life-threatening ventricular arrhythmias were detected in any of the 51 treated patients. Atrial fibrillation occurred in three patients, although its incidence was similar to what is expected in an age-matched healthy population (34).
Significantly, the clearance and volume of distribution of plitidepsin in this study were higher than those found in patients with solid tumors. However, as plitidepsin DLTs in previous studies were mostly nonhematologic (i.e., transaminase increase and/or muscular events) and appeared at similar incidences in patients with solid tumors than in those with hematologic malignancies,9 it is unlikely that multiple myeloma patients would have tolerated a higher plitidepsin dose. Alternatively, some characteristics of multiple myeloma patients can explain these PK findings. Anemia is almost universal in these patients; as plitidepsin has an important distribution into the cell components of blood, anemia may have resulted in a higher amount of drug available to distribute to peripheral tissues, thus increasing the Vss. In addition, plitidepsin is highly protein bound in plasma (97% in humans), and relative hypoalbuminemia in multiple myeloma patients due to high paraproteinemia levels is very common. PK parameters in this study were calculated from samples obtained during the first cycle only. Therefore, dose reductions and dose delays are not taken into account in the study of PK/pharmacodynamics relationships. This could explain the lack of relationship between purely exposure PK parameters (Cmax and AUC) and efficacy/toxicity outcomes. However, plasma half-life, which is a dose-independent parameter, seems to play a role in those patients showing response to treatment. The fact that responding patients also had 35% higher plitidepsin concentrations at one week is in line with this finding.
In summary, despite the aforementioned limitations, plitidepsin has shown limited but reproducible single-agent activity with a favorable toxicity profile. This activity seems to have been enhanced with dexamethasone addition while being tolerable in this heavily pretreated population. Evaluation of the role of plitidepsin in combination with other active drugs in the treatment of relapsed/refractory multiple myeloma patients merits further study.
Disclosure of Potential Conflicts of Interest
J. Blade: Consultant/Advisory Board, Pharmamar. C.S. Mitsiades: Licensing Royalties, Pharmamar. J. San Miguel: Research Funding, Pharmamar.
We acknowledge the work done by Martin Cullell-Young (medical writer, Pharma Mar) in the preparation of the manuscript.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Presented at the American Society of Hematology (ASH) 2008 Annual Meeting. “Mateos MV, Cibeira, MT, Richardson PG, Bladé J, Prosper F, Oriol A, de la Rubia J, Alegre A, Lahuerta JJ, García-Sanz R, Mitsiades CS, Espinoza J, Anderson KC, San Miguel JF. Final results of a phase II trial with plitidepsin (Aplidin®) alone and in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood 2008, 112(11): Abstract 3700.”
- Received February 23, 2010.
- Revision received April 20, 2010.
- Accepted April 20, 2010.