Thalidomide, Dexamethasone and Pegylated-Liposomal Doxorubicin (ThaDD) for Untreated Multiple Myeloma Patients Aged over 65 Years.

Abstract No standard therapy is still available for older patients with multiple myeloma (MM) despite two third of patients aged over 65 years.The combination melphalan-prednisone yields unsatisfactory results and high-dose therapy can be too toxic or unfeasible.Thalidomide has opened up new horizons also for the treatment of older patients with MM.This multicenter study included patients with de novo symptomatic MM older than 65 years regardless of comorbidities, performance status and renal function. All patients received thalidomide 100 mg continuously, pegylated-liposomal doxorubicin (Caelyx®) 40 mg/m2 on day 1 every 28 days, dexamethasone 40 mg on days 1–4 and 9–12.They also were given warfarin 1.25 mg/day for prophylaxis of thromboembolic disease and ciprofloxacin 250 mg twice daily after a high incidence of infections was recognized. Forty-one patients are valuable for response and toxicity so far.Median age was 72 years (range 64–78) and 63% were older than 70 years. Baseline characteristics are the following: clinical stage III in 30 patients (70%), PS>2 in 7(18%), ISS≥2 in 73%, creatinine≥2 mg/dl in 15%, unfavourable cytogenetics in 33% of patients with a valuable test. Fifteen patients (37%) achieved CR according to the EBMT criteria, 4 (10%) nCR, 4(10%) VGPR, 15(32%) PR, 4(10%) MR and one patient progressed resulting an ORR of 98%.The majority of the best responses were achieved within the first 3 cycles of therapy. Eight patients underwent autologous stem cell transplantation.Side effects were mild or moderate according to NCI scale.Severe non-hematological toxicity consisted of constipation (7%), fatigue (5%), tremors (2%), mucositis (4%).No patients had peripheral neuropathy or PPE more than grade 2. Grade 3–4 neutropenia was seen in 4(10%) of patients but severe infections occurred in 7(17%) without related deaths. DVT occurred in 5 patients (12%) with one case of pulmonary embolism; all cases resolved with common anticoagulant therapies.No patients discontinued the protocol because of toxicity although two patients refused to continue it after the occurrence of pulmonary embolism and septic shock.With a median follow-up of 15 months, EFS and OS at two years were 65% and 70%, respectively.Our study demonstrated that low-dose thalidomide in combination with pegylated-liposomal doxorubicin and high-dose dexamethasone is very effective inducing an ORR and particularly a CR rate higher than those reported with all other treatments, including high-dose therapy.High quality of response positively impacts on EFS and OS. This combination results well tolerated also by older-frail patients but infections and thromboembolic disease require adequate prophylaxis and therapy. An update of these data will be presented.

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Safety and Efficacy of Pegylated Liposomal Doxorubicin In Combination with Dexamethasone and Bortezomib (VMD) or Lenalidomide (RMD) In Multiple Myeloma Refractory/Relapsed Patients

Blood ◽

10.1182/blood.v116.21.5033.5033 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5033-5033

Author(s):

Gabriele Buda ◽

Enrico Orciuolo ◽

Sara Galimberti ◽

Matteo Pelosini ◽

Mario Petrini

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Response Rates ◽

The Body ◽

High Dose ◽

Combination Regimen ◽

Prior Therapy ◽

Number Of Patients

Abstract Abstract 5033 The pharmacology of pegylated liposomal doxorubicin (PLD) gives rise to a compound with major advantages that could potentially improve response and decrease toxicity. PLD comprises doxorubicin incorporated into polyethylene-glycol-coated liposomes, resulting in a longer circulation time in the body compared with the conventional formulation and a unique toxicity profile. The lower toxicity, especially less cardiotoxicity, is also related to the encapsulation of doxorubicin into microscopic liposomes, which preferentially penetrate and accumulate in tumour vasculature. Because increased angiogenic activity occurs in the bone marrow of patients with multiple myeloma, this pegylated formulation can enhance the delivery of doxorubicin to the tumour site. In addition, because myeloma cells divide slowly, the increased exposure of these cells to doxorubicin has the potential of overcoming resistance and increasing tumour cell killing capacity, theoretically resulting in improved response rates. Between December 2008 and May 2010, we treated a total of 39 MM resistant/refractory patients with two different scheme including PLD. Twenty-five patients were resistant/relapsed after at least one prior therapy including conventional doxorubicin. The scheme therapy was based on VMD: bortezomib (Velcade®: 1.3 mg/m2) as intravenous bolus twice a week for 2 weeks (on days 1, 4, 8 and 11 of each cycle) in a 28-day cycle for a total of 4 cycles; oral dexamethasone (40 mg) on the day of each bortezomib dose and the day after, and PLD (Myocet® 30 mg/m2) on day 4 of each cycle, 1 h after bortezomib infusion. Baseline characteristics are shown in table 1. All 25 patients were evaluable for response. Response rates following VMD showed: 2 patients in nCR (10%), 4 in VGPR (20%), 14 in PR (70%) resulting in an overall response rate (ORR) of 80% (20 patients). Global toxicities were lower and included neutropenia (12.5%), fatigue (25%), thrombocytopenia (25%) and neuropathy (37.5%). In the other group, fourteen patients were treated with RMD a combination regimen of lenalidomide (Revlimid®), PLD (Myocet®) and dexamethasone and 11 patients were eligible for evaluation. All the patients had multiple myeloma resistant or progressed after 1 to 5 previous anti-myeloma regimens including at least one doxorubicin containing scheme. RMD was administered for six 28-day cycle. Lenalidomide 25mg d1-21, Liposomal doxorubicin 30 mg/m2 d4, Dex 40 mg d1-4 and d17-20. Eight of eleven patients (73%) achieved an objective response to the therapy. Respectively, 2 patients (25%) obtained a VGPR and additional 6 patients (75%) a PR. The most common side effects was haematological toxicity with grade neutropenia (32%), thrombocytopenia (32%) and anaemia (18%). Under thrombosis prophylaxis with aspirin 100 mg per day we observed thrombembolic complications in only in one patients. Other non haematological side effects were pain (9%), diarrhoea (9%). Neither neurotoxicity nor constitutional symptoms of grade 3/4 were found. In both of groups no cardiovascular events were reported. Additionally 12 patients of RVM group and 4 patients of RMD group underwent to high dose chemotherapy and successfully collected an adequate number of peripherals stem cells at the first attempt. The introduction of pegylated liposomal doxorubicin, in bortezomib or lenalidomide based regimens, can play a key role in overcoming anthracycline resistance and improving the quality of response without limiting toxicity, especially in patients who have already received at least one prior therapy. We believe that there is a rational basis for the use of PLD as a second-, third-, or fourth-line therapy in patients with advanced MM. Table I. Characteristics of MM Patients undergoing VMD or RMD therapy Characteristics Cases Age at diagnosis (median and range) 65 (44–76) Number of patients VMD 25 (14M, 11F) RMD 14 (10M, 4F) Stage at diagnosis Durie-Salmon (II/III) 10/29 Prognostic Markers b2-microglobulin (m/L.) 2.2 (1.1–35)a Creatinin (mg/dl.) 0.9 (0.5–4.4)a Albumin (g/dl)) 4.0 (2.1–4.9)a Hemoglobin (mg/dl) 11.3 (5.7–16.4)a a Median (Range) Disclosures: No relevant conflicts of interest to declare.

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Level of circulating endothelial cells as new biomarker in patients with multiple myeloma, treated with bortezomib-pegylated liposomal doxorubicin-dexamethasone combination

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.17551 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 17551-17551 ◽

Cited By ~ 1

Author(s):

A. Gevorgyan ◽

V. Pitini ◽

C. Arrigo ◽

G. Altavilla ◽

C. Naro ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Circulating Endothelial Cells ◽

High Dose ◽

Healthy Controls ◽

Newly Diagnosed ◽

High Dose Melphalan ◽

Stem Cell Collection

17551 Background: Bortezomib is a proteasome inhibitor and has effects on both multiple myeloma (MM) tumor cells and stromal cells. Recent data suggests that relative levels of circulating endothelial cells (CECs) may serve as surrogate markers of myeloma activity. Hence, we assay the number of CECs by cell phenotype, to explore the activity and response to treatment with BMD (Bortezomib, Myocet, Dexametasone) in previously untreated MM patients. Methods: Twelve pts. with newly diagnosed multiple myeloma were enrolled in this study. Panel of monoclonal antibodies and appropriate analysis gates were used to enumerate CECs. Patients received Bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, pegylated liposomal doxorubicin (30 mg/m2-Myocet) on day 1 and dexamethasone (40 mg/daily for 4days) for four cycles (q21) before Cyclophosphamide (5 g/m2) and G-CSF mobilization, followed by peripheral blood stem cell collection. The pts received high-dose Melphalan (MEL200) with PBSC transplantation. Samples of healthy controls were used to compare CECs levels. Results: After the treatment with BMD 4 patients had a complete remission, 2 nCR, 5 VGPR and 1 PD. All pts. underwent PBSC mobilization and 11 out of 12 were mobilized, with a median of 3.50 × 106 CD34+ cells/Kg collected with a median of 2 (range 1–4) collection procedures. Responding pts. (11) received high-dose Melphalan with stem cell transplantation. The median time to reach neutrophil and platelet regeneration was 13.5 days and 13 days respectively. In healthy controls (N° 18) mean values of CECs were 0.05% (0.1–0.62). Before treatment with BMD mean CECs level in study patients was 0.79% (0.54–1.53). After BMD treatment CECs in responding pts. was 0.07% (0.1–0.70; p < 0.01). Conclusion: BMD combination therapy in newly diagnosed MM pts. has a high response rate, it does not influence on subsequent stem cell collection, is associated with modest toxicity, furthermore, CECs value can serve as new biomarker for myeloma activity. No significant financial relationships to disclose.

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Pegylated Liposomal Doxorubicin in Salvage Chemotherapy for Multiple Myeloma Patients

Current Cancer Therapy Reviews ◽

10.2174/1573394711309010001 ◽

2013 ◽

Vol 9 (1) ◽

pp. 1-7

Author(s):

Alessandra Romano ◽

Giuseppina Uccello ◽

Paolo Spina ◽

Rosario Cunsolo ◽

Calogero Vetro ◽

...

Keyword(s):

Multiple Myeloma ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Salvage Chemotherapy

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Pegylated liposomal doxorubicin re-challenge in patients with ovarian cancer relapse: a multicenter retrospective study

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2018-000034 ◽

2019 ◽

Vol 29 (1) ◽

pp. 153-157 ◽

Cited By ~ 1

Author(s):

Elisa Tripodi ◽

Gennaro Cormio ◽

Ugo De Giorgi ◽

Giorgio Valabrega ◽

Daniela Rubino ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Liposomal Doxorubicin ◽

Objective Response ◽

Pegylated Liposomal Doxorubicin ◽

Complete Response ◽

Recurrent Ovarian Cancer ◽

Hematological Toxicity ◽

Cancer Relapse ◽

Platinum Agent

BackgroundPegylated liposomal doxorubicin (PLD) is an active and well-tolerable treatment in ovarian cancer relapse, either alone or in combination with other drugs. No data are available on the possibility to rechallenge PLD treatment in long survivor patients with recurrent ovarian cancer, as evaluated for platinum agent, paclitaxel and gemcitabine. The aim of the present study was to evaluate the anti-tumor activity and the toxicity profile of re-challenge of PLD in recurrent ovarian cancer patients.MethodsData on 27 patients with epithelial ovarian cancer treated in the last ten years (2007-2017) with palliative PLD rechallenge were included in this multicenter retrospective Italian study.ResultsThe objective response rate to PLD re-treatment were complete response in 19%, partial response in 30% and stable disease in 37%. Only 1 case of G4 hematological toxicity was reported. No patient experienced severe cardiac impairment (G2-4).ConclusionPLD rechallenge represents an active and safe possibility of treatment for long survivor ovarian cancer patients.

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Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-130689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5701-5701

Author(s):

Justin King ◽

Mark A. Fiala ◽

Scott R. Goldsmith ◽

Keith E. Stockerl-Goldstein ◽

Mark A. Schroeder ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Older Patients ◽

Research Funding ◽

Small Sample ◽

Poor Performance Status ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

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A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4774.4774 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4774-4774

Author(s):

James R. Berenson ◽

Laura V. Stampleman ◽

Alberto Bessudo ◽

Peter J. Rosen ◽

Leonard M Klein ◽

...

Keyword(s):

Multiple Myeloma ◽

Progressive Disease ◽

Liposomal Doxorubicin ◽

Phase 1 ◽

Single Agent ◽

Pegylated Liposomal Doxorubicin ◽

Great Promise ◽

Phase 2 ◽

Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

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