Pomalidomide. A last-line treatment option for multiple myeloma.
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Abstract:
Treatment options for multiple myeloma dwindle with each relapse. There is no standard treatment for patients who relapse. Pomalidomide, an analogue of thalidomide and lenalidomide, has been authorised in the EU for the treatment of relapsed and refractory multiple myeloma after at least two previous lines of treatment including lenalidomide and bortezomib. Clinical evaluation of pomalidomide in this setting is based on an unblinded controlled trial in 455 patients who had already received several treatments, including lenalidomide. Nearly one-third of the patients were refractory to thalidomide.The patients were assigned to either high-dose dexamethasone or pomalidomide + low-dose dexamethasone. Pomalidomide prolonged median survival by at least 3 months. It has not been compared to thalidomide. The known adverse effects of pomalidomide include peripheral neuropathy, venous thrombosis, cutaneous disorders and neutropenia. Few cardiac disorders have been reported. Some drug-drug interactions can result in pomalidomide overdose. Pomalidomide is teratogenic. In practice, despite its adverse effects, third-line treatment with pomalidomide is an option for some patients who want to prolong survival by a few weeks: when myeloma is refractory to lenalidomide and thalidomide and their adverse effects were acceptable.Keywords:
Pomalidomide
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A 77-year-old man suffering from back and arm pain was referred for anemia to the hospital by an orthopedic clinic. Serum examination of the patient revealed monoclonal IgA, and he consulted the Sapporo Medical University Hospital, where he was diagnosed with multiple myeloma complicated with AL amyloidosis. He was then enrolled for a randomized double-blind study aimed to compare between melphalan-prednisone (MP) and thalidomide-melphalan-prednisone (MPT) treatments, which revealed the patient to be in the MP arm. This treatment induced a temporary partial response. After progression, he was treated with three variable combinations: 1) bortezomib and MP, 2) lenalidomide and dexamethasone, and 3) pomalidomide and dexamethasone. However, none of these treatments provided a stable response. Further, thalidomide in combination with bortezomib and dexamethasone was provided as the fifth-line treatment. After four cycles of this treatment, he achieved VGPR that lasted for 11 months. Our case report suggests that because there is a lack of a standard strategy for MM that is refractory to several agents, treatment should be selected on the basis of previous treatments and general condition of patients.
Pomalidomide
Melphalan
Refractory (planetary science)
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Background: Patients (pts) with multiple myeloma (MM) are likely to be older adults, and advanced age is associated with lower survival rates, in part due to comorbidities and frailty. Results from the phase 3 OPTIMISMM trial (NCT01734928) demonstrated that pomalidomide (P) in combination with bortezomib + dexamethasone (Vd) significantly improved progression-free survival (PFS) in lenalidomide (LEN)–pretreated pts with relapsed/refractory MM (RRMM) vs Vd, irrespective of age and Eastern Cooperative Oncology Group performance status (ECOG PS). Aims: Here, we report results from a post hoc analysis assessing outcomes of PVd vs Vd in pts with RRMM by frailty status. Methods: Pts with MM and 1–3 prior lines of therapy (including a LEN-containing regimen) who had been randomized 1:1 to PVd or Vd were assessed for frailty. Frailty scores were calculated using age (≤ 75 yr = 0; 76–80 yr = 1; > 80 yr = 2), the Charlson Comorbidity Index (≤ 1 = 0; > 1 = 1), and ECOG PS (0 = 0; 1 = 1; ≥ 2 = 2). Pts were classified as non-frail (NF; combined score: 0 or 1) or frail (F; combined score: ≥ 2). PFS, overall response rate (ORR), and safety outcomes were assessed by treatment group and frailty status. Results: In the intent-to-treat population (N = 559) (data cut-off Oct 26, 2017), 93/281 (33.1%) pts who received PVd and 93/278 (33.5%) who received Vd were frail. Baseline characteristics were similar between treatment groups within each frailty subgroup. Median PFS was longer with PVd vs Vd in NF (P = 0.001) and F (P = 0.006) subgroups (Table). ORR was higher with PVd vs Vd in NF (P < 0.001) and F (P < 0.001) subgroups. Incidence of grade ≥ 3 (G3) treatment-emergent adverse events (TEAEs) was higher with PVd vs Vd in NF (88.1 vs 61.3%) and F (96.8 vs 87.9%) subgroups; peripheral neuropathy, acute renal failure, and hypertension were the most common. Treatment discontinuation due to G3 TEAEs was greater with PVd vs Vd in NF (19.2 vs 18.5%) and F (30.1 vs 20.9%) subgroups. PVd had a longer median treatment duration vs Vd in NF (8.8 vs 5.7 mo) and F (8.9 vs 4.3 mo) subgroups. Image:Summary/Conclusion: Frail pts with RRMM who received PVd had longer PFS and higher ORR than pts who received Vd, consistent with the overall OPTIMISMM results. Frail pts experienced more G3 TEAEs and treatment discontinuations with PVd vs Vd, but treatment duration was longer with PVd vs Vd.
Pomalidomide
Regimen
Progression-free survival
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Pharmacovigilance of patients with multiple myeloma being treated with bortezomib and/or thalidomide
In order to evaluate the main adverse effects of drug protocols using bortezomib and/or thalidomide for the treatment of multiple myeloma, we conducted a prospective study. Data were collected through interviews, clinical observation, and from hospital records. A total of 59 patients were included. There was a predominance of females, 36 (61%) vs 23 (39%) males, and of whites, 49 (83.1%) vs 10 (16.9%) blacks. Age ranged from 40 to 94 years, with a median of 65 years (SD=11.6). Regarding staging at diagnosis, 27 (45.7%) patients were in stage III-A, with 12 (20.3%) patients having serum creatinine ≥2 mg/dL. The main adverse effects in the bortezomib treatment group (n=40) were: neutropenia (42.5%), diarrhea (47.5%), and peripheral neuropathy in 60% of cases, with no difference between the iv (n=26) and sc (n=14) administration routes (P=0.343). In the group treated with thalidomide (n=19), 31.6% had neutropenia, 47.4% constipation, and 68.4% peripheral neuropathy. Neutropenia was associated with the use of alkylating agents (P=0.038). Of the 3 patients who received bortezomib in combination with thalidomide, only 1 presented peripheral neuropathy (33.3%). Peripheral neuropathy was the main adverse effect of the protocols that used bortezomib or thalidomide, with a higher risk of neutropenia in those using alkylating agents. Improving the identification of adverse effects is critical in multiple myeloma patient care, as the patient shows improvements during treatment, and requires a rational and safe use of medicines.
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Melphalan
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Autologous stem-cell transplantation
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Hematologic adverse events (AEs) are commonly encountered in patients with multiple myeloma (MM) owing to the nature of the disease and the adverse effects related to myeloma treatment. Immunomodulatory drugs (eg, thalidomide, lenalidomide, and pomalidomide) and the proteasome inhibitor bortezomib have all been associated with increased rates of anemia, neutropenia, and thrombocytopenia, as well as greater incidences of infection caused by associated immunosuppression. The proteasome inhibitor carfilzomib was recently approved in the United States for the treatment of patients with relapsed and refractory MM. This article reviews the hematologic safety profile of carfilzomib in patients with relapsed/refractory MM, as assessed in a cross-trial safety analysis of four phase II studies, and makes recommendations for the appropriate management of hematologic AEs.
Pomalidomide
Hematologic disease
Refractory (planetary science)
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An 85-year-old female was diagnosed with multiple myeloma(MM)(IgG-l)with t(4 ;14)(p16;q32)in 200X. She received bortezomib with dexamethasone(Vd)therapy and lenalidomide with dexamethasone(Ld)therapy, and she subsequently maintained a very good partial response(VGPR). On day 731, she experienced relapse and was treated with 2 courses of elotuzumab with Ld therapy. However, on day 794, she experienced relapse with plasmacytoma, and was treated with 2 courses of pomalidomide and low-dose dexamethasone(Pd), 2 courses of cyclophosphamide with Pd(PCd), and bortezomib with Pd(PVd)therapies. After 3 courses of PVd therapy, she achieved PR. She has continued to receive 11 courses of PVd therapy and has not suffered any adverse events(BGrade 3). These findings suggest that PVd therapy is a relatively safe and highly efficacious treatment for frail patients with relapsed and refractory MM who have previously received both lenalidomide and bortezomib. Further studies are needed to establish treatment efficacy and safety in frail patients with relapsed and refractory MM with extramedullary disease.
Pomalidomide
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8002 Background: Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent. Pom/dex has demonstrated response rates (≥PR) of 63% in relapsed MM (JCO 2009, 27:5008-5014) and 32% in a lenalidomide-refractory cohort (ASH 2009). The efficacy of pomalidomide in patients who have failed both lenalidomide and bortezomib is unknown and this study was designed to study this question. Methods: Patients refractory to both lenalidomide and bortezomib therapy; defined as relapsing on or within 60 days of stopping each regimen, were enrolled. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis. Results: 35 patients resistant/refractory to lenalidomide and bortezomib were enrolled. The median age was 62 years (range, 39-77). The median time from diagnosis to enrollment was 63 months (range 27-249). 14 patients had high risk molecular markers including loss of 17p (N=5), t(4;14) (N=4) and plasma cell labeling index ≥3% (N=8) The median number of prior regimens was 6 ( 3-9) including 81% with ≥5 prior regimens. Toxicity consisted primarily of myelosuppression: grade 3/4 neutropenia (29%); grade 3/4 thrombocytopenia (3%); and grade 3/4 anemia (9.6%). Grade 3/4 non-hematologic toxicities occurred in 16%: pneumonitis (3%), hyperglycemia (3%), renal failure (3%), fatigue(3%) thrombosis (3%). Grade 1 or 2 neuropathy occurred in 6% (3% grade 1; 3% grade 2). Best responses consist of VGPR 3 pts (9%), PR 8 pts (23%), and MR 5 pts (14%) (ORR 46%). With a median follow-up of 2.7 months, 77% remain progression free, and 94% remain alive. Conclusions: Pom/dex is active and well tolerated in this heavily pre-treated population of dual bortezomib/lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses are seen in 49%. This study confirms therapeutic benefit for Pom/dex in patients relapsing after other novel therapies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene
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Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.
Pomalidomide
Refractory (planetary science)
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Pomalidomide
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