SARCLISA (isatuximab) (myélome multiple)
Reason for request
Favourable opinion for reimbursement in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
What therapeutic improvement?
Therapeutic improvement compared to the carfilzomib plus dexamethasone combination.
Role in the care pathway?
Over the last decade, numerous medicinal products have been added to the therapeutic arsenal for the second and later-line treatment of multiple myeloma, such as: daratumumab (DARZALEX), ixazomib (NINLARO), carfilzomib (KYPROLIS) or pomalidomide (IMNOVID), always in combination. For a first relapse, the choice between these treatments should take into account whether or not the patient is refractory to lenalidomide and prior exposure to daratumumab as first-line therapy, as well as the level of evidence and the toxicity profile.
From the second relapse, in patients who have already been treated with VELCADE (bortezomib) and REVLIMID (lenalidomide), IMNOVID (pomalidomide) has an MA in combination with dexamethasone. However, given the evolution of the care pathway in multiple myeloma, with new medicinal products having been added to the therapeutic arsenal in earlier treatment lines, the role of IMNOVID (pomalidomide) in combination with dexamethasone has become more limited. In addition, earlier use of IMNOVID (pomalidomide) from the second line of treatment in combination with bortezomib and dexamethasone is likely to substantially reduce the benefit of pomalidomide-dexamethasone dual therapy in subsequent treatment lines. FARYDAK (panobinostat) combined with bortezomib and dexamethasone, represents a last-resort treatment option for patients with recurrent and/or refractory myeloma, having previously received two lines of treatment, including bortezomib and an immunomodulator. DARZALEX (daratumumab) is also an option in patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent; however, its earlier use (currently possible from first-line therapy) in the context of combination with a proteasome inhibitor (PI) or an IMiD, substantially reduces the benefit of this monotherapy in subsequent treatment lines. Recently, SARCLISA (isatuximab) has been added to the care pathway, in combination with pomalidomide and dexamethasone in patients having received at least two prior treatments including lenalidomide and a PI.
Otherwise, in heavily pretreated patients in the very advanced stages of the disease, in particular those whose disease is refractory to at least one IP, one immunomodulatory agent, and an anti-CD38 monoclonal antibody such as daratumumab (DARZALEX), until recently there were no validated treatment options and patients were usually in a situation where all the treatment options had been exhausted. BLENREP (belantamab mafodotin) was recently added to the care pathway as monotherapy for the treatment of multiple myeloma in adult patients, who have received at least four prior therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
Role of the medicinal product in the care pathway
Given the demonstrated superiority of the Isa-Kd protocol combining SARCLISA (isatuximab) with KYPROLIS (carfilzomib) plus dexamethasone (Kd) until progression compared to the Kd combination in terms of progression-free survival and pending the final results in terms of overall survival, the Isa-Kd combination is the treatment option to be favoured over the Kd combination in adult patients with multiple myeloma (MM) who have received at least one prior therapy.
The role of the Isa-Kd protocol, compared to the protocols currently recommended from the second line of treatment, in particular protocols including the other anti-CD38 antibody DARZALEX (daratumumab) and a proteasome inhibitor, such as the KdD protocol (carfilzomib, daratumumab and dexamethasone) and the DVd protocol (daratumumab, bortezomib and dexamethasone) or an immunomodulatory agent, such as the DRd protocol (daratumumab, lenalidomide and dexamethasone), is not known. In particular, the choice between these different treatment options should take into account whether or not the patient is refractory to lenalidomide and prior exposure to daratumumab as first-line therapy, the patient’s characteristics (age, comorbidities), as well as the level of evidence and the toxicity profile.
Given the similar mechanism of action, targeting the CD38 receptor, and the non-inclusion in the IKEMA study of patients refractory to an anti-CD38 antibody received in a prior treatment line (exclusion criterion), the Committee does not recommend the use of SARCLISA (isatuximab) in patients refractory to an anti-CD38 antibody. In addition, no robust data supports the value of re-using SARCLISA (isatuximab) in patients previously treated with an anti-CD38 antibody but not refractory to an anti-CD38 antibody.
The Committee wishes to draw the attention of prescribers to the need for specific vigilance with respect to the risk of immune deficiency induced by the long-term administration of SARCLISA (isatuximab), as it did for DARZALEX (daratumumab). An excess of sometimes severe infectious episodes, particularly respiratory tract infection (including with opportunistic microorganisms), was observed in the IKEMA study arm receiving SARCLISA (isatuximab). The benefit/risk ratio of the long-term continuation of SARCLISA (isatuximab) injections must also be reassessed regularly, particularly in the event of an infectious episode.
The Committee deems that the clinical benefit of SARCLISA (isatuximab) is substantial in the indication “in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy”.
Clinical Added Value
the Committee considers that SARCLISA (isatuximab) in combination with KYPROLIS (carfilzomib) plus dexamethasone (Isa-Kd protocol), provides a minor clinical added value (CAV IV) compared to the KYPROLIS (carfilzomib) plus dexamethasone combination in the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.