Drug Profile
Pomalidomide for multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Expert Rev. Hematol. 7(6), 719–731 (2014)
Guillemette Fouquet, Claire Bories, Ste´phanie Guidez, Loı¨c Renaud, Charles Herbaux, Sahir Javed, Thierry Facon and Xavier Leleu* Service des maladies du sang, hoˆpital Huriez, CHRU de Lille, rue M. Polonovski, 59037 Lille, France *Author for correspondence: Tel.: +33 320 446 883 Fax: +33 320 444 094 [email protected]
informahealthcare.com
Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of ‘novel agents’: proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority – if not all – of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This drug profile focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy. KEYWORDS: IMiDs • immunomodulation • multiple myeloma • pomalidomide • relapse refractory
Multiple myeloma (MM), a malignant plasma cell neoplasia characterized by clonal proliferation of plasma cells in the bone marrow, which secrete a monoclonal immunoglobulin most of the time, accounts for approximately 1% of all types of cancers and 10% of hematological cancers, making it the second most frequent hematological malignancy after lymphomas. The annual incidence of MM is about 4–7/ 100,000 in most western industrialized countries and 18 months
[43,45]
52
3 (1–3)
POM MTD: 2.5 mg, 28/28 Cyclophosphamide: 50 mg every other day Prednisone: 50 mg every other day
51
10.4 months
69% at 1 year
33 (29 evaluable)
5 (1–18)
POM: 2, 3 or 4 mg for 21/28, MTD: NR PL Doxorubicin 5 mg/m2 iv., days 1, 4, 8, 11 Dex 40 mg iv. weekly
34.5
–
–
[47,67]
114
5 (3–15)
Clarithromycin–POM–Dex, 4 mg, 21/28
61.4
8.1 months
Not reached
[48,68]
[46]
Dex: Dexamethasone; iv.: Intravenous; MTD: Maximum tolerated dose; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PL Doxorubicin: Pegylated liposomal doxorubicin; POM: Pomalidomide.
and OS were similar for the two schedules of administration. The safety profile was also similar in both groups, but the continuous schedule required more growth factor support and the 21/28 days schedule was therefore preferred. In the natural course of relapses in MM, periods of remission are becoming shorter following each salvage therapy as the disease becomes refractory to anti-myeloma drugs. However, in this IFM study, the time to progression achieved by patients responding to the pomalidomide plus low-dose dexamethasone regimen was superior than the time to progression obtained with their last prior therapy, suggesting that pomalidomide may be able to change the natural history of relapses in MM, particularly in responders. Overall, data suggest that pomalidomide is currently the third most effective therapeutic agent in MM after lenalidomide and bortezomib, at least on the EU perspective where the next generation of proteasome inhibitors is not available yet. Phase III studies
The MM-003 trial, a large multicenter (non-US) randomized Phase III study, included 455 patients with RRMM refractory to both lenalidomide and bortezomib. Patients were randomized to receive pomalidomide 4 mg daily for 21 of 28 days and low-dose dexamethasone (40 mg weekly) or high-dose dexamethasone alone (40 mg if £75 years or 20 mg if >75 years, on days 1–4, 9–12 and 17–20 of a 28-day cycle) [35]. ORRs were 32% versus 11% and clinical benefit rates (‡minor response) were 39% versus 19%, respectively. With a median informahealthcare.com
follow-up of 10 months, the combination of pomalidomide and low-dose dexamethasone compared with high-dose dexamethasone demonstrated a significant benefit in PFS (median 4 months vs 1.9 months, p < 0.0001) and OS (median 13.1 vs 8.1 months, p = 0.009) [36,37]. The impact on OS was significant despite crossover in the high-dose dexamethasone arm: at the time of analysis, 50% of patients assigned to high-dose dexamethasone had received pomalidomide, and by month 16 of study treatment, it was estimated that this percentage would reach 100%. Subsequent analyses were conducted to study the impact of pomalidomide plus low-dose dexamethasone on the quality of life (QoL) in patients with renal insufficiency and in patients with high-risk cytogenetics, as described below [38,39]. The MM-010 Phase IIIb trial (STRATUS) is in progress, investigating pomalidomide plus low-dose dexamethasone in end-stage RRMM patients, with pomalidomide at 4 mg/day on days 1–21 of a 28-day cycle [40]. The primary end point is safety assessment. This study is of critical importance for many countries where pomalidomide is not yet available, not approved or not reimbursed. A US Phase III study is currently ongoing, MM-007, which compares pomalidomide–bortezomib–dexamethasone versus bortezomib–dexamethasone in patients with early RRMM [41]. Combination regimens
Combination regimens are presented in
TABLE 3.
723
Drug Profile
Fouquet, Bories, Guidez et al.
this Phase II trial; subsequent dose escalation of carfilzomib in less heavily treated patients is planned [45].
Table 4. Main side effects observed with pomalidomide, thalidomide [69] or lenalidomide [70] ± dexamethasone in relapsed or refractory multiple myeloma [71]. Pomalidomide
Other combinations Ref.
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Hematological toxicities [29,31,32,34,35,50]
Neutropenia
Grades 3–4: 29–65% Febrile: 18 months. Enrollment is nearly complete in 724
Similar to lenalidomide, it seems that pretty much all agents currently approved and part of the armamentarium of MM can be combined with pomalidomide, including cyclophosphamide [46], doxorubicin [47] or clarithromycin [48]. The ORR with these triplet pomalidomide-based combinations reached approximately 50–55% in end-stage RRMM heavily pretreated patients, refractory to both bortezomib and lenalidomide and exposed to a median of 4–6 lines of therapy. Future developments will look into combination of pomalidomide with novel classes of agents, such as monoclonal antibodies, histone deacetylase inhibitors and pathway inhibitors.
Hematological side effects, essentially myelosuppression, are relatively common with pomalidomide. Neutropenia is the main toxic side effect: grade 3–4 neutropenia has been described in up to 65% of patients, occurring mostly during the first cycles and is usually short-lived. Its incidence is dependent on the dose (4 vs 2 mg/day) and on the number or prior treatment regimens [32,34]. Febrile neutropenia seems relatively infrequent (
Pomalidomide for multiple myeloma Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Expert Rev. Hematol. 7(6), 719–731 (2014)
Guillemette Fouquet, Claire Bories, Ste´phanie Guidez, Loı¨c Renaud, Charles Herbaux, Sahir Javed, Thierry Facon and Xavier Leleu* Service des maladies du sang, hoˆpital Huriez, CHRU de Lille, rue M. Polonovski, 59037 Lille, France *Author for correspondence: Tel.: +33 320 446 883 Fax: +33 320 444 094 [email protected]
informahealthcare.com
Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of ‘novel agents’: proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority – if not all – of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This drug profile focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy. KEYWORDS: IMiDs • immunomodulation • multiple myeloma • pomalidomide • relapse refractory
Multiple myeloma (MM), a malignant plasma cell neoplasia characterized by clonal proliferation of plasma cells in the bone marrow, which secrete a monoclonal immunoglobulin most of the time, accounts for approximately 1% of all types of cancers and 10% of hematological cancers, making it the second most frequent hematological malignancy after lymphomas. The annual incidence of MM is about 4–7/ 100,000 in most western industrialized countries and 18 months
[43,45]
52
3 (1–3)
POM MTD: 2.5 mg, 28/28 Cyclophosphamide: 50 mg every other day Prednisone: 50 mg every other day
51
10.4 months
69% at 1 year
33 (29 evaluable)
5 (1–18)
POM: 2, 3 or 4 mg for 21/28, MTD: NR PL Doxorubicin 5 mg/m2 iv., days 1, 4, 8, 11 Dex 40 mg iv. weekly
34.5
–
–
[47,67]
114
5 (3–15)
Clarithromycin–POM–Dex, 4 mg, 21/28
61.4
8.1 months
Not reached
[48,68]
[46]
Dex: Dexamethasone; iv.: Intravenous; MTD: Maximum tolerated dose; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PL Doxorubicin: Pegylated liposomal doxorubicin; POM: Pomalidomide.
and OS were similar for the two schedules of administration. The safety profile was also similar in both groups, but the continuous schedule required more growth factor support and the 21/28 days schedule was therefore preferred. In the natural course of relapses in MM, periods of remission are becoming shorter following each salvage therapy as the disease becomes refractory to anti-myeloma drugs. However, in this IFM study, the time to progression achieved by patients responding to the pomalidomide plus low-dose dexamethasone regimen was superior than the time to progression obtained with their last prior therapy, suggesting that pomalidomide may be able to change the natural history of relapses in MM, particularly in responders. Overall, data suggest that pomalidomide is currently the third most effective therapeutic agent in MM after lenalidomide and bortezomib, at least on the EU perspective where the next generation of proteasome inhibitors is not available yet. Phase III studies
The MM-003 trial, a large multicenter (non-US) randomized Phase III study, included 455 patients with RRMM refractory to both lenalidomide and bortezomib. Patients were randomized to receive pomalidomide 4 mg daily for 21 of 28 days and low-dose dexamethasone (40 mg weekly) or high-dose dexamethasone alone (40 mg if £75 years or 20 mg if >75 years, on days 1–4, 9–12 and 17–20 of a 28-day cycle) [35]. ORRs were 32% versus 11% and clinical benefit rates (‡minor response) were 39% versus 19%, respectively. With a median informahealthcare.com
follow-up of 10 months, the combination of pomalidomide and low-dose dexamethasone compared with high-dose dexamethasone demonstrated a significant benefit in PFS (median 4 months vs 1.9 months, p < 0.0001) and OS (median 13.1 vs 8.1 months, p = 0.009) [36,37]. The impact on OS was significant despite crossover in the high-dose dexamethasone arm: at the time of analysis, 50% of patients assigned to high-dose dexamethasone had received pomalidomide, and by month 16 of study treatment, it was estimated that this percentage would reach 100%. Subsequent analyses were conducted to study the impact of pomalidomide plus low-dose dexamethasone on the quality of life (QoL) in patients with renal insufficiency and in patients with high-risk cytogenetics, as described below [38,39]. The MM-010 Phase IIIb trial (STRATUS) is in progress, investigating pomalidomide plus low-dose dexamethasone in end-stage RRMM patients, with pomalidomide at 4 mg/day on days 1–21 of a 28-day cycle [40]. The primary end point is safety assessment. This study is of critical importance for many countries where pomalidomide is not yet available, not approved or not reimbursed. A US Phase III study is currently ongoing, MM-007, which compares pomalidomide–bortezomib–dexamethasone versus bortezomib–dexamethasone in patients with early RRMM [41]. Combination regimens
Combination regimens are presented in
TABLE 3.
723
Drug Profile
Fouquet, Bories, Guidez et al.
this Phase II trial; subsequent dose escalation of carfilzomib in less heavily treated patients is planned [45].
Table 4. Main side effects observed with pomalidomide, thalidomide [69] or lenalidomide [70] ± dexamethasone in relapsed or refractory multiple myeloma [71]. Pomalidomide
Other combinations Ref.
Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Hematological toxicities [29,31,32,34,35,50]
Neutropenia
Grades 3–4: 29–65% Febrile: 18 months. Enrollment is nearly complete in 724
Similar to lenalidomide, it seems that pretty much all agents currently approved and part of the armamentarium of MM can be combined with pomalidomide, including cyclophosphamide [46], doxorubicin [47] or clarithromycin [48]. The ORR with these triplet pomalidomide-based combinations reached approximately 50–55% in end-stage RRMM heavily pretreated patients, refractory to both bortezomib and lenalidomide and exposed to a median of 4–6 lines of therapy. Future developments will look into combination of pomalidomide with novel classes of agents, such as monoclonal antibodies, histone deacetylase inhibitors and pathway inhibitors.
Hematological side effects, essentially myelosuppression, are relatively common with pomalidomide. Neutropenia is the main toxic side effect: grade 3–4 neutropenia has been described in up to 65% of patients, occurring mostly during the first cycles and is usually short-lived. Its incidence is dependent on the dose (4 vs 2 mg/day) and on the number or prior treatment regimens [32,34]. Febrile neutropenia seems relatively infrequent (
