On April 1, 2019 Celgene Corporation (NASDAQ: CELG) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has expressed a positive opinion for the two triplets in basis of the IMiD of Celgene, REVLIMID (lenalidomide) and IMNOVID (pomalidomide) (Press release, Celgene, APR 1, 2019, View Source [SID1234534848]).
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The CHMP recommended the approval of the extension of the lenalidomide indication as combination therapy with bortezomib and dexamethasone (RVd) for the treatment of adult patients with newly diagnosed multiple myeloma not eligible for transplantation.
The Committee also recommended the approval of pomalidomide in combination with bortezomib and dexamethasone (PVd) for the treatment of adult patients with multiple myeloma who have received at least one previous lenalidomide treatment.
The final decision of the European Commission, which generally conforms to the CHMP’s recommendations, is expected in about two months.
" The CHMP’s positive opinion regarding the RVd and PVd triplets represents an important extension of therapy options for patients with multiple myeloma, both newly diagnosed and relapsed / refractory after previous treatment lines, " commented Michele Cavo , Full Professor of Hematology, University of Bologna and Director of the "Seràgnoli" Hematology Institute, S. Orsola-Malpighi University Hospital, Bologna – In fact, RVd is configured as a more effective therapeutic alternative with respect to the current standards of first-line treatment of patients who are not eligible to receive an autologous transplant, to which it ensures a significant prolongation both of overall survival (whose median value was higher than 6 years in the pivotal study) that of disease-free progression survival (median value greater than 40 months). Instead, PVd represents one of the most effective combinations currently available for the rescue therapy of relapsed or refractory patients after previous exposure to lenalidomide, and in particular to those who have become refractory to it.» .
The CHMP’s positive opinion for lenalidomide was based on data from SWOG S0777, a phase 3 study that evaluated the triplet with lenalidomide, bortezomib and dexamethasone (RVd) in adult patients with previously untreated multiple myeloma, not immediately eligible for ASCT 1 . The results of the study showed statistically significant improvements both in terms of progression-free survival (PFS) and overall survival (OS) in patients treated with RVd compared to those treated with lenalidomide plus dexamethasone (Rd). The choice of first-line treatment is important 2since over time patients respond less and less to therapy, manifesting increasingly shorter periods of remission in subsequent treatment lines. 3
The CHMP’s positive opinion for PVd was based on data from OPTIMISMM, the first prospective phase 3 study that evaluated the use of the triplet with pomalidomide in patients previously treated with lenalidomide who in most cases (70%) were found refractory to it. 4 This patient population represents a growing unmet medical need for which new therapeutic options are needed.
The OPTIMISMM results showed a significantly higher progression-free survival in patients treated with PVd compared to patients in the Vd treatment arm.
" The positive opinions of the CHMP for our combinations of IMiD RVd and PVd represent wonderful news for patients with multiple myeloma living in Europe, " says Nadim Ahmed , President of the Hematology / Oncology Division of Celgene. " We now hope that the EMA will approve these therapeutic options by making them available to patients, as our goal is to improve their outcomes at different stages of the disease ."
Lenalidomide in combination with bortezomib and dexamethasone, as well as pomalidomide in combination with bortezomib and dexamethasone, are currently not approved in any country.
Information on Celgene immunomodulatory drugs
IMiD agents are small molecules available as an oral therapy for the treatment of certain hematological malignancies owned exclusively by Celgene. It is hypothesized that they have multiple mechanisms of action. It has been observed that T cell activation and proliferation, IL-2 protein proliferation and CD8 + effector T cell activity are observed to increase. They also influence the stimulation and expression of natural killer cells(NK) acting within the cellular environment with the aim of inducing the immune system to attack cancer cells and at the same time directly attack them. In addition to the immunomodulatory properties, a tumoricidal and antiangiogenic activity is also hypothesized. Celgene IMiDs represent a mainstay of research on multiple myeloma with a growing number of studies in combination therapies in different disease settings.
Information on multiple myeloma
Multiple myeloma is a potentially fatal haematological neoplasm, which is characterized by tumor proliferation and suppression of the immune system. 5.6 It is a rare but lethal disease: every year, in Europe, there are 42,000 diagnoses, with about 26,000 deaths due to the disease. 7 The typical course of multiple myeloma includes periods of symptomatic disease alternating with periods of remission and, with time, appearance of refractoriness (non-responsiveness). 8
Information on the SWOG study S0777
SWOG S0777 is a multicenter, phase 3, randomized open trial, aimed at evaluating the efficacy and safety of RVd compared to Rd in the treatment of patients with previously untreated multiple myeloma for whom an autologous transplant of stem cells (ASCT). 1
In this study, 525 patients with newly diagnosed multiple myeloma (NDM) were enrolled with symptomatic and measurable disease aged 18 years or older. Patients were randomized (1: 1) to receive initial lenalidomide treatment with bortezomib and dexamethasone (RVd group) or lenalidomide and dexamethasone therapy only (group Rd). Randomization was stratified based on the ISS stage ( International Staging System, I, II or III ) and intention to transplant (yes vs.no). The RVd regimen was administered in eight cycles lasting 21 days. Bortezomib was administered at a dose of 1.3 mg / m by IV route on days 1, 4, 8 and 11, in combination with oral lenalidomide 25 mg / day on days 1-14 plus oral dexamethasone at a dose of 20 mg / day on days 1, 2, 4, 5, 8, 9, 11 and 12. The Rd regimen was administered in six cycles lasting 28 days. The Rd standard regimen consisted of 25 mg / day of lenalidomide orally on days 1-21 plus 40 mg / day of dexamethasone orally on days 1, 8, 15 and 22. 1
The results of the SWOG S0777 1 study showed a significant improvement in median progression-free survival (mPFS) in patients treated with RVd vs. Rd (42 vs. 30 months; HR 0.76, 95% CI 0.62-0.94; P = 0.01). A significant improvement in median overall survival with respect to Rd was also observed with RVd (89 vs. 67 months; HR 0.72, 95% CI 0.56-0.94; P = 0.013). The overall response and complete response rates were superior in patients treated with RVd compared to Rd (global response: 82% RVd vs 72% Rd; complete response: 16% RVd vs. 8% Rd). The safety of RVd was also in line with the consolidated safety profiles of each drug in the triplet. 9.10
Upon completion of the induction, all patients received continuous maintenance therapy with lenalidomide orally at 25 mg once a day for 21 days plus oral dexamethasone at a dose of 40 mg once a day on days 1 , 8, 15 and 22 of each cycle lasting 28 days. 1
Information on the OPTIMISMM study
OPTIMISMM is the first phase 3 comparative study on the safety and efficacy of PVd vs. Vd, as an early therapy line in patients with relapsed and refractory multiple myeloma (with 1-3 previous therapeutic regimens) and previous exposure to lenalidomide, including patients refractory to it. 4
This international, multi-center, phase 3, randomized, open-label study involved 559 patients (281 patients in the PVd arm and 278 in the Vd arm) with previous demographic, basal and pathological features generally well balanced between the two treatment arms . The median number of previous treatment lines was two, while over one third of patients had received a previous treatment line (40% in both treatment arms). All patients had previously been treated with lenalidomide: most were refractory to lenalidomide (71% in the PVd vs. arm69% in the Vd arm); last treatment refractoriness was observed in 70% and 66% of cases respectively. The median follow-up was 16 months. 4
The results of the OPTIMISMM study showed a significantly higher PFS in patients treated with PVd compared to patients in the Vd arm (11.20 vs. 7.10 months [P = <0.0001, HR 0.61; 95% CI: (0.49-0.77)]), with a 39% reduction in the risk of disease progression or death in the PVd arm. In an exploratory analysis on the subgroup of patients undergoing a previous treatment line, the median progression-free survival (mPFS) was 20.73 months with PVd vs.11.63 months with Vd (HR 0.54; p = 0.0027). In these patients, the benefit of PVd was independent of refractoriness or non-refractory to previous lenalidomide therapy. The safety of PVd was in line with the established safety profiles of each drug in the triplet. 7.11
Patients were stratified according to the following criteria: age (≤75 years vs. > 75 years), number of previous therapeutic regimens for myeloma (1 vs. > 1) and β2-microglobulin levels (from <3.5 mg / L vs. ≥ 3.5 to ≤ 5.5 mg / L vs.> 5.5 mg / L). Patients were randomized 1: 1 to receive PVd or Vd. In 21-day cycles, patients received pomalidomide 4 mg / day on days 1-14 (PVd arm only); bortezomib 1.3 mg / m2 on days 1, 4, 8 and 11 of cycles 1-8 and on days 1 and 8 of cycle 9 and subsequent; and dexamethasone 20 mg / day (10 mg if age was> 75 years) on days when treatment with bortezomib was expected and on subsequent days. 4
Information on REVLIMID (lenalidomide)
Lenalidomide is approved in Europe as a monotherapy and is indicated for the maintenance therapy of adult patients with newly diagnosed multiple myeloma who have undergone an autologous stem cell transplant. Lenalidomide as a combination therapy is approved in Europe, the United States, Japan and about 25 other countries for the treatment of adult patients with multiple previously treated myeloma (MM) who are not eligible for transplantation. It is also approved in association with dexamethasone for the treatment of patients with MM who have received at least one previous therapy in almost 70 countries in Europe, the Americas, the Middle East and Asia
Lenalidomide is also approved in the United States, Canada, Switzerland, Australia, New Zealand and in several Latin American countries, as well as in Malaysia and Israel, for the treatment of transfusion-dependent anemia due to myelodysplastic syndromes (MDS) to low or intermediate-1 risk, associated with an isolated cytogenetic abnormality with deletion of 5q, with or without further cytogenetic abnormalities, as well as in Europe for the treatment of patients with transfusion-dependent anemia due to low or intermediate-1 myelodysplastic syndromes , associated with an isolated cytogenetic abnormality with deletion of 5q, in cases where other therapeutic options have proved insufficient or inadequate.
It is also approved in Europe and the United States for the treatment of patients with relapsed or refractory mantle lymphoma (MCL) after two previous therapies, one of which includes bortezomib. In Switzerland, Lenalidomide is indicated for the treatment of patients with relapsed or refractory MCL after previous therapy with bortezomib and chemotherapy / rituximab.
Lenalidomide is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical studies.
About IMNOVID (pomalidomide)
Pomalidomide administered in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have undergone at least two previous therapies, including both lenalidomide and bortezomib and with demonstrated progression of the disease during the last therapy. It belongs to the class of so-called immunomodulatory drugs (IMiD ).
Pomalidomide was initially approved in the United States in 2013 in association with dexamethasone for the treatment of patients with multiple myeloma who received at least two previous therapies including lenalidomide and a proteasome inhibitor and with demonstrated progression of the disease during or within 60 days of completion of the latest therapy.
In 2013 it was approved in the EU, in association with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma, who underwent at least two previous therapies, including both lenalidomide and bortezomib and with demonstrated progression of the disease during the last therapy.
It is also approved in a total of 66 countries in the world, including Australia, Canada, Japan and Switzerland, for use in association with dexamethasone for indications similar to those approved in the United States and the EU.