Celgene Receives European Commission Approvals for REVLIMID® (lenalidomide) and IMNOVID® (pomalidomide)-based Triplet Combination Regimens for Patients with Multiple Myeloma

The European Commission has approved two of Celgene’s IMiD®-based combination regimens:

  • REVLIMID in combination with bortezomib and dexamethasone (RVd) in adult patients with previously untreated multiple myeloma who are not eligible for transplant
  • IMNOVID in combination with bortezomib and dexamethasone (PVd), in adult patients with multiple myeloma, who have received at least one prior treatment regimen including REVLIMID.

BOUDRY, Switzerland I May 16, 2019 I Celgene Corporation (NASDAQ:CELG), today announced that the European Commission (EC) has approved two new triplet regimens based on Celgene’s proprietary IMiD treatments, REVLIMID (lenalidomide) and IMNOVID (pomalidomide).

REVLIMID in combination with bortezomib and dexamethasone (RVd), is now indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant. In addition, IMNOVID, in combination with bortezomib and dexamethasone (PVd), is now indicated for the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide.

“The approval of these combination therapies marks a significant milestone for patients with multiple myeloma in Europe,” said Nadim Ahmed, President of Hematology/Oncology for Celgene. “With these new triplet regimens we hope to improve outcomes for both newly diagnosed patients as well as those who have relapsed or become refractory to first-line therapy. IMiD agents have brought significant benefit to multiple myeloma patients and we are committed to advancing our pipeline of novel myeloma treatments in order to ensure physicians and patients continue to have new treatment options available to fight this disease.”

The choice of treatment in a first-line therapy setting is important1 as patients progressively become less responsive to therapy, and experience shorter periods of remission at later lines of treatment.2 Studies have shown that RVd can provide newly diagnosed patients that are not eligible for a transplant with a treatment option that significantly prolongs the first remission.3

“Determining first-line therapy is an important consideration in the overall treatment plan for patients with multiple myeloma,” said Prof. Thierry Facon, Professor of Haematology in the Department of Haematology, Lille University Hospital, France. “Since REVLIMID in combination with dexamethasone is already a standard of care in multiple myeloma, we’re excited by the prospect of a new REVLIMID-based triplet option for previously untreated patients who are not eligible for transplant.”

The approval for the REVLIMID triplet (RVd) was supported by data from SWOG S07773, a phase 3 trial evaluating the triplet combination, RVd, in adult patients with previously untreated multiple myeloma.

“Today’s approval for use of the IMNOVID-containing triplet, PVd, as early as first relapse, underscores the potential clinical benefit this regimen can provide to patients following a prior treatment including REVLIMID,” said Prof. Meletios Dimopoulos, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. “REVLIMID-based regimens are often used as a standard of care in newly diagnosed multiple myeloma patients, and there is a growing patient population who become refractory to REVLIMID and need proven treatment options.”

The approval of the IMNOVID triplet (PVd) was supported by data from OPTIMISMM4, the first prospective phase 3 trial to evaluate an IMNOVID-based triplet regimen in patients who were all previously treated with REVLIMID, and the majority (70%) of patients were REVLIMID refractory. Results from OPTIMISMM were recently published in The Lancet Oncology.

Pomalidomide in combination with bortezomib and dexamethasone (PVd) is not approved for any use in the United States

Lenalidomide in combination with bortezomib and dexamethasone (RVd) is not approved for any use in the United States.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system.5,6 It is a rare but deadly disease - around 42,000 people are diagnosed with multiple myeloma in Europe, and approximately 26,000 people die from the disease each year.7 The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission, and eventually, the disease becomes refractory (nonresponsive).8

About SWOG S0777

SWOG S0777 is a randomized, open-label, multicentre, phase 3 study aiming to evaluate the efficacy and safety of RVd compared to Rd in treating patients with newly diagnosed multiple myeloma (ndMM) who were not intending on immediately receiving ASCT.3

SWOG S0777 recruited 525 patients with symptomatic and measurable ndMM aged 18 years and older. Patients were randomly assigned (1:1) to receive either an initial treatment of lenalidomide with bortezomib and dexamethasone (RVd group) or lenalidomide and dexamethasone alone (Rd group) both followed by standard Rd until disease progression. Randomization was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes versus no). The RVd regimen was given as eight 21-day cycles. Bortezomib was given at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1-14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1-21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22.3

Results from SWOG S07773 showed that median progression-free survival (PFS) was significantly improved in patients receiving RVd compared to those receiving REVLIMID and dexamethasone (Rd) alone (42 months versus 30 months; HR 0.76, 95% CI 0.62-0.94; P=0.01). Median overall survival was also significantly improved in patients receiving RVd compared to those receiving Rd (89 months versus 67 months; HR 0.72, 95% CI 0.56–0.94; P=0.013). The rates of overall and complete response were higher in those receiving RVd compared to Rd (overall response: 82% RVd vs 72% Rd; complete response: 16% RVd vs 8% Rd) the duration of response was also significantly longer in those receiving RVd compared to Rd (52 months vs 38 months, respectively).3 The safety of RVd was also consistent with the well-established safety profiles of each drug in the triplet regimen.3

Upon completion of induction, all patients received ongoing maintenance with 25 mg oral lenalidomide once a day for 21 days plus 40 mg oral dexamethasone once a day for days 1, 8, 15, and 22 of each 28-day cycle.3

About OPTIMISMM

OPTIMISMM is the first phase 3 trial designed to compare the safety and efficacy of PVd versus Vd, as an early line of therapy in patients with relapsed and refractory multiple myeloma (with 1-3 prior regimens of therapy) and prior REVLIMID-exposure, including REVLIMID-refractory patients.4

The multi-center, international, open-label, randomized phase 3 clinical trial included 559 patients (281 patients in the PVd arm and 278 in the Vd arm). Demographic, baseline, and prior disease characteristics were generally well balanced between the two treatment arms. The median number of prior lines of therapy was two, while more than one third had one prior line of treatment (40% across both treatment arms). All patients had prior treatment with REVLIMID with the majority being REVLIMID refractory (71%in the PVd arm vs 69% in the Vd arm) and 70% vs 66%, respectively, were refractory to their last treatment. Median follow-up was 16 months.4

Patients were stratified based on age, number of prior anti-myeloma regimens, and β2-microglobulin levels. Patients were randomized 1:1 to receive PVd or Vd until disease progression. In 21-day cycles, patients received IMNOVID 4 mg/d 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 cycles 9 and beyond; and dexamethasone 20 mg/d (10 mg if aged > 75 years) on the days of and after receiving bortezomib treatment.4

Results from OPTIMISMM4 showed that patients receiving PVd achieved a significantly longer PFS than those in the Vd treatment arm (median PFS 11.2 months vs. 7.1 months, respectively [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease progression or death by 39% in the PVd arm. In an exploratory sub-group analysis of patients with one prior line of therapy, median progression-free survival with PVd was 20.7 months vs 11.6 months with Vd (95% CI: 7.52, 15.74). In these patients, the benefit of PVd was observed independent of whether they were refractory or non-refractory to prior therapy with lenalidomide.

Neutropenia (PVd 42% vs Vd 9%), infections (PVd 31% vs Vd 18%), and thrombocytopenia (PVd 27% vs Vd 29%) were among the most frequently reported grade 3/4 treatment-emergent adverse events. Rates of grade 3/4 deep vein thrombosis (PVd: 0.7% versus Vd: 0.4%) and pulmonary embolism (PVd: 4.0% versus Vd: 0.4%) were low, and no events were fatal. Second primary malignancies occurred in 3.2% of patients treated with PVd and 1.5% of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease. Patients discontinuing treatment due to adverse events were 10.7% for PVd versus 17.6% for Vd. The safety of PVd was consistent with the well-established safety profiles of each drug in the triplet therapy.4

About Celgene’s Immunomodulatory Drugs

IMiD® agents are Celgene’s proprietary small molecule, orally available compounds for the treatment of some blood cancers. IMiD agents are hypothesized to have multiple mechanisms of action. They have been found to increase activation and proliferation of T cells, and proliferation of the IL-2 protein and activity of CD8+ effector T cells. IMiD agents have also been found to affect the stimulation and expression of natural killer (NK) cells, working within the environment of the cell to stimulate the immune system to attack the cancer cells, as well as attack the cancer cells directly. In addition to immunomodulatory properties, IMiD agents are hypothesized to have tumoricidal and antiangiogenic activity. Celgene’s portfolio of IMiD agents have become a foundation of multiple myeloma research, with a growing number of studies exploring these compounds as combination partners across a range of settings of the disease.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company's website at www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, Facebook and YouTube.

References:

1 Liwing et al. Br J Haematol. 2014; 164(5):684-93.
2 Kumar SK et al. Mayo Clin Proc 2004; 79(7): 867–874.
3 Durie B, et al. Lancet. 2017;389:519-527.
4 Richardson P et al. OPTIMISMM: Phase 3 trial of pomalidomide, bortezomib, and low‐dose dexamethasone vs bortezomib and low-dose dexamethasone in lenalidomide-exposed patients with relapsed or refractory multiple myeloma (Abstract)
5 Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.
6 Pratt G, et al. Br J Haematol. 2007; 38(5):563-79.
7 European Cancer Information System. Estimates of cancer incidence and mortality in 2018, for all countries. Available at: https://ecis.jrc.ec.europa.eu/explorer.php Last accessed: March 2018
8 Hulin C et al. Leuk Res. 2017; 59: 75–84. 2

SOURCE: Celgene

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