Multiple myeloma (MM) is a type of blood cancer that originates in the plasma cells, which are a type of white blood cell found in the bone marrow. Plasma cells are responsible for producing antibodies that help fight infections. In multiple myeloma, abnormal plasma cells multiply uncontrollably, leading to a range of complications.
Key Characteristics and Symptoms:
- Bone Pain and Lesions: The abnormal plasma cells can cause damage to bones, leading to pain, fractures, and lesions.
- Anemia: The overgrowth of plasma cells in the bone marrow can interfere with the production of normal blood cells, leading to anemia.
- Kidney Damage: Myeloma cells produce abnormal proteins (monoclonal proteins or M proteins) that can accumulate in the kidneys, causing damage and potentially leading to kidney failure.
- Hypercalcemia: Bone destruction releases calcium into the bloodstream, causing elevated levels of calcium, which can result in symptoms like nausea, vomiting, and confusion.
- Frequent Infections: The cancerous plasma cells produce ineffective antibodies, weakening the immune system and making patients more susceptible to infections.
Diagnosis:
Diagnosis typically involves a combination of blood tests, urine tests, bone marrow biopsy, and imaging studies such as X-rays, MRI, or CT scans. Common diagnostic markers include high levels of M proteins in blood or urine and the presence of abnormal plasma cells in the bone marrow.
Standard Therapy for Newly Diagnosed MM
Treatment options for MM depend on the stage and severity of the disease and may include chemotherapy, targeted therapy, immunotherapy, stem cell transplant, radiation therapy, or supportive treatment.
For patients with a newly diagnosed MM the standard treatment typically involves several phases: induction therapy, consolidation (which may include an autologous stem cell transplant (ASCT)) followed by maintenance therapy.
Phase 1: VRD Induction Therapy
Induction Therapy is the initial phase of treatment aimed at reducing the number of myeloma cells as much as possible. The goals are to achieve a significant reduction in the tumor burden, alleviate symptoms, and prepare the patient for subsequent therapies, including ASCT, if appropriate.
- Components of VRD
- Velcade (Bortezomib): A proteasome inhibitor that interferes with the breakdown of proteins in cancer cells, leading to cell death.
- Revlimid (Lenalidomide): An immunomodulatory drug that helps the immune system fight cancer and inhibits the growth of cancer cells.
- Dexamethasone: A corticosteroid that helps reduce inflammation and immune responses and can also kill multiple myeloma cells.
- Duration: Typically involves several cycles (e.g., 3-4 cycles) of treatment, each lasting about 21-28 days. The exact number of cycles may vary based on the patient’s response and the treatment protocol.
Phase 2: VRD Consolidation Therapy
Consolidation Therapy follows induction therapy and often after ASCT. The aim is to further reduce the number of myeloma cells, deepen the patient’s response to treatment, and prolong the duration of remission.
- Components: The same VRD regimen that is used for consolidation.
- Duration: Typically involves several additional cycles of the VRD regimen. The duration and number of cycles for consolidation can vary, depending on the patient’s response and tolerance.
Phase 3: Maintenance Therapy
Maintenance therapy in the context of MM is a prolonged treatment phase following initial induction therapy and consolidation (which may include ASCT). The purpose of maintenance therapy is to maintain the achieved response, prevent relapse, and prolong progression-free survival (PFS) and overall survival (OS).
- Components
- Lenalidomide (Revlimid): The most commonly used drug for maintenance therapy due to its efficacy in prolonging PFS and OS.
- Bortezomib (Velcade): Sometimes used in patients with high-risk disease.
- Ixazomib (Ninlaro): An oral proteasome inhibitor that can be used as maintenance therapy.
- Duration: Maintenance therapy can last for several years or as long as the patient continues to benefit from it without experiencing significant side effects.
Background of the PERSEUS Trial
Daratumumab is a monoclonal antibody used in the treatment of MM. It targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells. By binding to CD38, daratumumab helps the immune system identify and destroy these cancer cells. It is often used in combination with other medications to enhance its effectiveness.
Study Design and Methods:
- Participants: 709 transplantation-eligible patients with newly diagnosed MM
- Study Design: Randomly assigned to one of the two treatment groups
- D-VRd Group: Subcutaneous daratumumab combined with VRd induction and consolidation therapy with lenalidomide maintenance therapy
- VRd Group: VRd induction and consolidation therapy and lenalidomide maintenance therapy alone
Rationale for the PERSEUS Trial
The Perseus trial was designed to evaluate the efficacy and safety of combining daratumumab with the VRd regimen in patients with newly diagnosed multiple myeloma who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT). The primary objective was to compare progression free survival between the two arms as well as look at overall response, minimal residual disease rates, complete response, safety, and overall survival.
Key Results:
- The median follow up was 47.5 months which showed disease progression or death risk significantly lower in the D-VRd group compared to the VRd group.
- Progression-Free Survival at 48 Months was 84.5% in the D-VRd arm compared to 67.7% in the VRd alone arm
- Patients who achieved a complete response was 87.9% in the D-VRd arm compared to 70.1% in the VRd arm
- Minimal Residual Disease (MRD)-Negative Status was achieved in 75.2% of patients in the D-VRd arm compared to 47.5% in the VRd alone group.
- Sustained MRD Negativity- 64% of patients in the D-VRd group stopped daratumumab after achieving sustained MRD negativity.
Implications for Clinical Practice:
On July 30, 2024, the FDA approved the use of daratumumab in combination with VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for an autologous stem cell transplant. The FDA approval of this regimen has several implications for both caregivers and patients as well as physicians
For Patients and Caregivers
- Expanded Treatment Options: The approval introduces a new combination therapy option, potentially improving outcomes for newly diagnosed multiple myeloma patients. The addition of daratumumab may enhance treatment efficacy compared to previous regimens.
- Improved Efficacy: Daratumumab can enhance the effectiveness of the existing regimen. This could lead to deeper and more sustained responses.
- Synergistic Effects: Combining different mechanisms of action is expected to provide a synergistic effect, leading to deeper and more durable responses.
- Potential Side Effects: While daratumumab is generally well-tolerated, its addition to the treatment regimen may introduce new side effects or intensify existing ones. Patients will need to be monitored closely for adverse effects and manage any that arise. Caregivers will also need to be prepared for managing the complexities of this new regimen, including monitoring side effects and coordinating with healthcare providers
- Impact on ASCT: The combination regimen aims to optimize the patient’s response before ASCT, potentially leading to better transplant outcomes and prolonged disease remission.
- Patient education: Patients and caregivers need to educate themselves about the new treatment regimen, including how daratumumab is administered (subcutaneously with hyaluronidase), potential side effects, and the importance of adherence to the treatment plan.
For healthcare providers:
- Updated Treatment Protocols: Providers will need to integrate the new combination therapy into treatment protocols by adjusting patient plans based on eligibility and disease characteristics, while also staying informed about its efficacy, administration, and side effects through ongoing training and education.
- Patient Management: Providers must closely monitor patients for side effects and treatment responses, regularly assessing and adjusting supportive care as needed, while also managing specific adverse effects associated with daratumumab and its combinations to ensure quality of life.
- Enhanced Communication: Providers need to educate patients and caregivers about the new regimen, including subcutaneous daratumumab administration and what to expect, while coordinating with other healthcare team members like pharmacists and nursing staff to ensure a coordinated approach to patient care.
- Treatment Planning and Decision-Making: Providers must evaluate patients’ clinical characteristics and treatment goals to select those who will benefit most from the new regimen and determine eligibility for ASCT, ensuring personalized treatment plans.
- Impact on Clinical Trials and Research: The approval may influence ongoing research and clinical trials, potentially leading to new studies on the regimen’s efficacy and safety, and providers may explore further innovations in treatment regimens and combinations across different patient demographics.
About the author
Dr. Daniel Landau is a distinguished board-certified hematologist/oncologist renowned for his exceptional contributions in the field. With an illustrious career spanning across esteemed institutions like the Orlando Health Cancer Institute and the Medical University of South Carolina, Dr. Landau’s expertise shines in both genitourinary oncology and hematology. .
Engage with Dr. Landau’s expertise and ignite your curiosity on “Ask MedOnCMD” as he invites you to explore the vast landscape of oncology with a fresh outlook.