Lenalidomide (Revlimid in trademark name) was first approved by the U.S. Food and Drug Administration (FDA) in 2005 and has been widely used to treat multiple myeloma and other hematologic diseases.

In Korea, it has been used in clinical practice for more than 15 years, with indications for multiple myeloma, myelodysplastic syndrome, extranodal cell lymphoma, and vesicular lymphoma added in 2009.

The treatment paradigm for multiple myeloma has changed significantly over the past 20 years. It is now centered on immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PIs). Lenalidomide, a representative immunomodulator, has played a vital role in this change.

In recent years, it has also established new value as a synergistic combination drug with immunotherapy, including bispecific antibodies developed for treating multiple myeloma and lymphoma.

Korea Biomedical Review interviewed Dr. Kim Jin-seok (a professor of hematology at Severance Hospital), chairman of the Multiple Myeloma Research Committee of the Korean Society of Hematology, to learn about the clinical value of lenalidomide in treating multiple myeloma, its current use in clinical practice in Korea, and its prospects.

Question: What is the role of lenalidomide in treating multiple myeloma?

Answer: Lenalidomide is a beneficial long-term agent and essential in treating multiple myeloma. Because multiple myeloma is a complex disease to cure, patients are often treated with a sequence of drugs, and the number of drugs available is limited. The main advantage of lenalidomide is that it can be administered orally and can be used safely over the long term with relatively few side effects and toxicity issues. Having treated many patients, survival is more prolonged in patients who have been on lenalidomide-based therapy for more than five years.

Q: Since January of last year, lenalidomide maintenance therapy has been covered by insurance. What is the optimal duration of lenalidomide maintenance therapy, as there are no restrictions on the duration of use?

A: There is no clear answer to this question. There is insufficient data on maintenance therapy, and the Ministry of Food and Safety’s approval is for continued use until disease progression. Some small data suggests that it is appropriate to continue maintenance therapy for two to three years before stopping, but this is not well supported. As mentioned above, lenalidomide is a drug with long-term benefits, and maintenance therapy, primarily as monotherapy, should be used as long as possible until disease progression

Q: How do you prescribe lenalidomide maintenance therapy in clinical practice?

A: At Severance Hospital, we have our protocol for deciding whether to use maintenance therapy. Patients who are evaluated at three months post-transplant and have a stringent complete response (sCR), which is a higher performance standard than a complete response (CR), and who have a negative MRD (minimal residual disease), are not on maintenance therapy, but we monitor their progression. If they relapse, we may treat them with KRd (carfilzomib/lenalidomide/dexamethasone) therapy.

Patients who need maintenance therapy are treated with maintenance therapy for one year and then undergo another bone marrow biopsy and MRD test. This regularity, despite the high cost of the MRD test, is because the test results change the patient's treatment strategy. In treating multiple myeloma, MRD testing is now used as an important indicator for treatment decisions rather than a predictor of a patient's prognosis, which is why reimbursement for MRD testing is needed.

Q: We understand that the coverage of lenalidomide maintenance therapy has had a significant impact on the treatment of relapsed/refractory patients with subsequent disease progression.

A: Right. Currently, there are three-drug regimens available in Korea for patients who have relapsed or refractory to first-line treatment, such as KRd (carfilzomib/lenalidomide/dexamethasone) and IRd (ixazomib/lenalidomide/dexamethasone). However, suppose the disease progresses while using lenalidomide maintenance therapy after hematopoietic stem cell transplantation. In that case, it is generally considered that resistance to lenalidomide has developed, and the drug cannot be used in the following line of treatment. In addition, since the three-drug RVd (lenalidomide/bortezomib/dexamethasone) regimen is mainly used for first-line treatment in Korea, the only option available for relapsed/refractory patients is the two-drug Kd (carfilzomib/dexamethasone) regimen. Of course, the Vd (bortezomib + dexamethasone) two-drug regimen is also available with coverage. Still, as mentioned earlier, it is not considered because most patients were treated with RVd in the first line.

While there is a high need for newer three-drug regimens that can be covered for relapsed-refractory patients, it is unfortunate that DKd (daratumumab/carfilzomib/dexamethasone), DVd (daratumumab/bortezomib/dexamethasone), and DRd (daratumumab/lenalidomide/dexamethasone) are not covered.

Q: So, is it safe to say that lenalidomide is now an essential drug for newly diagnosed multiple myeloma patients?

A: Correct. Until RVd was reimbursed, the three-drug induction regimen of VTd (bortezomib/thalidomide/dexamethasone) was used for transplant-eligible patients and the three-drug VMP (bortezomib/melphalan/prednisolone) or two-drug Rd (lenalidomide/dexamethasone) regimen was used for non-transplant-eligible patients. However, the RVd regimen is now being used equally in both transplant and non-transplant groups.

Of course, there is an unmet need here as well. In the transplant group, the unmet need is relatively small, but in the non-transplant group, daratumumab is used as a first-line treatment, and there is a significant difference in treatment outcomes. In particular, bortezomib is difficult to use in elderly patients due to toxicity, so the DRd regimen instead of RVd is more comfortable for patients and prolongs survival. However, DRd is not currently available for first-line treatment within the reimbursement system, only Rd and RVd regimens are available, and there is a significant reimbursement need for DRd therapy in the first-line treatment.

Q: With the recent development of immunotherapies, such as bispecific antibodies, lenalidomide has become increasingly popular as a combination drug.

A: As an immunomodulator, lenalidomide activates T cells and NK cells, of which T cells are responsible for directly attacking cancer cells. Therefore, lenalidomide can have a significant synergistic effect when combined with bispecific antibodies or other antibody therapies. Recently, bispecific antibodies targeting anti-B cell maturation antigen (BCMA) have been used in the fourth and fifth line of multiple myeloma. Still, when introduced in the first line, they will be tried in combination with lenalidomide.

Q: What do you see for the future of lenalidomide?

A: Lenalidomide is effective in most lymphoma subtypes, not just multiple myeloma. It is currently only covered for the second-line treatment of small lymphocytic lymphoma. Still, it has already been used pre-application in other lymphomas without coverage in various conditions, including central nervous system lymphoma.

In addition, as mentioned earlier, lenalidomide has antitumor and immunomodulatory effects, so the role of immunotherapy, including immuno-oncology drugs, antibody therapies, and bispecific antibodies, in the treatment of multiple myeloma and lymphoma will only increase as immunotherapy develops.