Since February of this year, the inclusion of Darzalex (daratumumab) in a four-drug regimen (DVTd therapy: daratumumab, vortezomib, thalidomide, and dexamethasone) has been covered by national health insurance for first-line treatment, thereby altering the treatment landscape for patients with multiple myeloma.

Multiple myeloma is a disease in which plasma cells, which produce antibodies in our bodies, transform into blood cancer cells and proliferate primarily in the bone marrow. Just over a decade ago, the progression-free survival period for first-line treatment was approximately 1.5 years. However, the introduction of DVTd therapy has now made long-term survival possible.

In particular, DVTd therapy, which includes the monoclonal antibody drug Darzalex targeting CD38, offers fewer side effects and a high response rate, bringing hope to both patients and medical professionals. The average age at diagnosis for multiple myeloma is about 70 years. Among these patients, only about half are eligible for hematopoietic stem cell transplantation (HSCT). While it is regrettable that DVTd therapy coverage is currently limited to transplant-eligible patients, experts emphasize that this expanded coverage undoubtedly represents a crucial treatment option for transplant-eligible multiple myeloma patients.

“Following the coverage of DVTd therapy for first-line treatment, patient responses have markedly improved, and long-term survival has become possible,” said Professor Yoon Dok-hyun of the Department of Hematology-Oncology at Asan Medical Center in an interview with Korea Biomedical Review. “Darzalex, in particular, has fewer side effects and a high response rate, so medical staff also begin treatment expecting ‘good outcomes.’”

Question: DVTd therapy has been covered for first-line treatment since last February. Do you notice a tangible difference in the clinical site before and after coverage?

Answer: Absolutely. With DVTd therapy now covered by health insurance, we are actively treating eligible patients with it. Just over a decade ago, the progression-free survival (PFS) for first-line treatment of multiple myeloma was only about a year and a half. However, with the introduction of DVTd therapy, long-term survival has become possible, making it difficult to even establish the median survival. Clinical experience with CD38 antibody therapies, including Darzalex, is particularly encouraging. Most patients show a good response, and non-response is very rare. Consequently, treatment is approached with the expectation of a favorable response.

Q: However, the reimbursed DVTd therapy is currently limited to the autologous hematopoietic stem cell transplant group. Do you believe health insurance should also cover DVTd therapy for the non-transplant group?

A: Yes, of course. DVTd therapy needs to be utilized for the non-transplant group as well. Regardless of whether it's the transplant group or the non-transplant group, the efficacy of DVTd therapy is superior to existing treatments. Large-scale phase 3 clinical trial results comparing regimens with Darzalex against standard therapy without it in non-transplant patients are already available. The results were consistent even in elderly patients or cases not involving transplantation. It's regrettable that the treatment environment doesn't reflect reality, despite excellent therapies continuing to emerge. Furthermore, our country falls short of international standards. Therefore, a groundbreaking policy change is necessary.

Q: What does it mean to fall short of international standards?

A: In Korea, the standard therapies for non-transplant patients are VRd and DRd, while DVRd has not yet been approved. However, in Western countries, DVTd therapy is no longer the standard; a more advanced treatment (DVRd therapy) has already become the standard. By the latest standards, Korea is two steps behind.

Drug accessibility varies by country, which inevitably leads to differences in patient survival rates, depending on a country's national economic capacity. Therefore, I hope this treatment is rapidly applied to non-transplant patients as well.

Q: Multiple myeloma often affects older adults. I understand that autologous hematopoietic stem cell transplantation is difficult for those over 70. Given this, I'm curious about the strategies considered for elderly patients or those on the borderline for transplantation.

A: Multiple myeloma is a disease with a high proportion of elderly patients. Particularly in patients over 70, autologous hematopoietic stem cell transplantation is often difficult to apply due to physical limitations or comorbidities. While autologous transplantation offers excellent therapeutic efficacy, it also carries significant side effect burdens, necessitating careful judgment in elderly patients. While no treatment has yet fully replaced transplantation in effectiveness, the emergence of various new drugs has broadened treatment options. Initially, immunomodulatory agents were used, followed by Velcade (bortezomib, a proteasome inhibitor), and more recently, the CD38 antibody therapy Darzalex.

However, there are still limitations on the treatments available to elderly patients in Korea. Under reimbursement criteria, elderly patients often only qualify for the DVd regimen, which combines Velcade and Darzalex (daratumumab) with steroids. More potent antibody combination therapies are either not yet covered by insurance or have limited coverage, making access dependent on participation in clinical trials, private insurance benefits, or personal financial resources. In Korea, no matter how effective a drug is, the significant cost burden associated with long-term use inevitably influences treatment decisions based on health insurance coverage.

Q: Multiple myeloma is characterized by frequent relapses and diminishing treatment efficacy with each subsequent treatment cycle. In this context, the approximately seven-year survival with DVTd therapy is quite encouraging. It is intriguing to see if similar treatment efficacy is observed in the clinical setting.

A: Before DVTd therapy was covered, only single-agent Darzalex was covered for fourth-line treatment. However, when used as monotherapy, the response rate was lower than with combination therapy. Nevertheless, patients who responded maintained good treatment efficacy for a considerable period. Although DVTd has been covered as induction therapy for less than a year, some clinical trial participants have been doing well for over 10 years. In this respect, it is a remarkably effective therapy.

Q: Why is it considered a remarkable treatment?

A: Compared to other therapies, Darzalex has significantly fewer side effects. Agents like bortezomib or lenalidomide cause severe hematologic toxicity, reduced neutrophil or platelet counts leading to weakened immunity, severe skin rashes, peripheral neurotoxicity, and extreme fatigue, among various other side effects. In contrast, Darzalex is perceived by patients as having almost no side effects. While it may have some hematologic toxicity, and during the Covid-19 pandemic, there was an issue with reduced antibody immunity, that risk is now virtually nonexistent. Overall, it can be considered a treatment that improves patients' quality of life.

Q: Starting this month, DVd therapy has been expanded for reimbursement as a second-line or later treatment for multiple myeloma.

A: There has always been a lack of effective drugs for second-line treatment, disappointing both patients and healthcare providers. Having an effective treatment covered by insurance will be a huge help to patients.

Q: For which patient groups should consolidation therapy and maintenance therapy after hematopoietic stem cell transplantation be particularly considered?

A: Maintenance therapy is currently administered to almost all patients. Lenalidomide-based maintenance therapy has demonstrated benefits, including overall survival (OS), in multiple clinical trials and meta-analyses. It is now widely used domestically after belatedly gaining health insurance coverage. However, maintenance therapy does not provide the same effect for all patients. Aggressive maintenance therapy is considered for patients who did not achieve sufficient treatment response or who have high-risk disease (for instance, incomplete remission, poor-risk chromosomal abnormalities).

The role of consolidation therapy is less clear-cut than maintenance therapy. While some clinical trials report benefits from consolidation therapy, other studies show no significant difference. This variation may depend on the intensity of induction therapy, disease characteristics, and the patient's response level.

For example, if near-complete remission was achieved with induction therapy and transplantation alone, the additional benefit of consolidation therapy may be limited. Since there are no remaining cancer cells, i.e., minimal residual disease (MRD), there is no response even with consolidation therapy. Conversely, for patients with residual MRD, additional treatment like consolidation therapy may be beneficial. While the current level of evidence does not clearly define the role and criteria for consolidation therapy, it is considered a potentially helpful treatment for specific patient groups. Therefore, consolidation therapy should be applied selectively, considering the patient's treatment response, MRD status, and the biological characteristics of the disease.

Q: Currently, DVTd consolidation therapy is not covered by insurance in Korea. Which patient groups require consolidation therapy?

A: Consolidation therapy is not universally used worldwide. Since it is not covered by health insurance, I do not administer consolidation therapy outside of clinical trials. However, I've observed that some patients who can cover the costs through private insurance opt for consolidation therapy based on their wishes. These patients likely did not achieve a sufficient response to prior treatment. It's questionable whether repeating the same therapy will yield adequate results for patients who didn't respond sufficiently before. Yet, since there is no definitive answer, whether consolidation therapy is actually applied seems to depend on the patient's preference and the physician's judgment. I hope that the results of the clinical trial I'm currently conducting will help determine which patients require consolidation therapy.

Q: What is the clinical trial you are conducting?

A: I am conducting an Asian multinational clinical trial with Professor Kim Ki-hyun's team at Samsung Medical Center to evaluate the necessity of consolidation therapy after induction and consolidation therapy, including antibody therapy. After induction therapy, followed by hematopoietic stem cell transplantation and maintenance therapy, patients are randomly divided: half (50 out of 100) receive additional consolidation therapy, while the other half undergo maintenance therapy alone without consolidation. We will compare the outcomes across the entire patient cohort and perform subgroup analyses based on patients' biological characteristics. By analyzing subgroups of patients who responded well versus those who did not by the second year of treatment, the study aims to infer the efficacy of consolidation therapy. It is hoped this will provide evidence to identify a “specific patient group” who could benefit from consolidation therapy.

Q: Multiple myeloma is a disease where drug development is highly active. How do you envision the development of multiple myeloma treatments and the evolving treatment paradigm?

A: Multiple myeloma is one of the most actively researched areas in hematologic malignancies for drug development. Recently, the treatment paradigm has been rapidly evolving, centered not only on existing therapies but also on immunotherapies. Key novel drugs include immunomodulators such as lenalidomide, proteasome inhibitors like Velcade, CD38 antibody therapies represented by daratumumab (Darzalex), and bispecific antibodies or CAR-T cell therapies. Recently, clinical trials combining bispecific antibodies with CAR-T are underway, and the development of trispecific antibodies targeting two or three targets simultaneously is also actively progressing. The pace of new drug development is extremely rapid, drawing the attention of researchers and medical professionals worldwide.

The U.S. FDA and Europe’s EMA have traditionally relied on progression-free survival (PFS) as a primary basis for approving new drugs. However, as treatment efficacy improves and survival periods lengthen, it has become increasingly time-consuming for newly developed therapies to demonstrate superior outcomes. In reality, large-scale Phase 3 clinical trials alone require years for patient recruitment and follow-up, with some taking nearly a decade from trial initiation to publication of results. Delays in clinical trials and the approval process can lead to wasted investment and resources, prompting efforts to improve this situation.

Consequently, the FDA and the EMA have recently begun recognizing minimal residual disease (MRD) as a key basis for new drug approvals. MRD is a highly sensitive test capable of detecting minute amounts of cancer cells remaining in patients after treatment, making it a precise benchmark for evaluating treatment efficacy. Clinical trials utilizing MRD are evaluating whether patients who test MRD-negative during treatment can discontinue medication, or whether switching to more potent therapies benefits patients with residual MRD. This approach goes beyond simply enhancing treatment efficacy; it aims to optimize therapy tailored to each patient's individual response. Future multiple myeloma treatments are highly likely to evolve toward an MRD-based precision medicine model.

No matter how innovative a treatment may be, it is not universally applicable to all patients. In fact, many effective new drugs developed to date have often shown better responses in intermediate or low-risk patients rather than high-risk patients. Future strategies may shift towards assessing a patient's risk level early in treatment and prioritizing the use of more potent immunotherapies or drugs with novel mechanisms for high-risk patients.

However, I have experienced reimbursement cuts for using a three-week on, one-week off regimen for lenalidomide maintenance therapy in my patients, despite its proven benefit in reducing side effects, simply because it deviated from the approved daily dosing schedule. Such rigid systems make it difficult to implement patient-tailored treatment strategies.

In conclusion, future multiple myeloma treatment will evolve around three key trends: expanded use of immunotherapies, MRD-guided precision therapy, and a shift towards personalized strategies. However, translating these changes into actual clinical practice requires clinical trial results and institutional support. What is clear is that the direction of treatment is rapidly shifting away from “the same treatment for all patients” toward finding “the most appropriate treatment for each individual patient.”