Waldenstrom’s Macroglobulinemia: Relapsed and Refractory Disease

When Waldenstrom’s macroglobulinemia comes back after treatment or stops responding to therapy, patients and their healthcare teams face new decisions about the best path forward.

Table of contents

• What Relapsed and Refractory Mean
• Treatment Options for Relapsed and Refractory Disease
• Factors That Influence Treatment Choice
• Newer and Emerging Therapies

What Relapsed and Refractory Mean

The term relapsed refers to disease that reappears or grows again after a period of remission (when the cancer was under control or had disappeared). The term refractory is used to describe when the cancer does not respond to treatment, meaning that the cancer cells continue to grow, or when the response to treatment does not last very long.^[1]

Waldenstrom’s macroglobulinemia is a rare type of slow-growing non-Hodgkin lymphoma that remains incurable. Although most patients respond to initial treatment, relapses are inevitable over time. Patients with this disease will eventually experience disease progression following initial treatment.^[2][3]

Treatment Options for Relapsed and Refractory Disease

For patients whose disease relapses or becomes refractory, secondary therapies may be successful in providing additional remissions. Some of the previous therapies can be used or reused depending on a patient’s age, length of remission, stem cell transplant eligibility, and previous toxicities encountered.^[1]

Targeted Therapy Drugs

Targeted therapy uses drugs to target specific molecules on cancer cells or inside them. These molecules help send signals that tell cells to grow or divide. By targeting these molecules, the drugs stop the growth and spread of cancer cells while limiting harm to normal cells.^[4]

Targeted therapy drugs used to treat relapsed and refractory Waldenstrom’s macroglobulinemia include:^[4]

• Rituximab (Rituxan)
• Ibrutinib (Imbruvica)
• Acalabrutinib (Calquence)
• Zanubrutinib (Brukinsa)
• Bortezomib (Velcade)
• Lenalidomide (Revlimid)

Bruton’s tyrosine kinase inhibitors (BTKis), such as ibrutinib, acalabrutinib, and zanubrutinib, are an important class of targeted therapy for this disease. These drugs block a specific protein that cancer cells need to grow and survive.^[2]

Chemoimmunotherapy

Chemoimmunotherapy combines chemotherapy drugs with immunotherapy drugs. Several combinations have proven to be highly effective in the relapsed setting.^[2]

Dexamethasone, rituximab, and cyclophosphamide is a chemoimmunotherapy option that has proven to be highly effective in the relapsed setting. After six complete cycles in 71% of patients with relapsed or refractory disease, the overall response rate was 87%, which included a 4% very good partial response, 64% partial response, and 19% minor response rate.^[2]

Bendamustine combined with rituximab is another immunochemotherapy option. In one retrospective analysis involving 111 relapsed or refractory patients, this combination achieved a major response rate of 74%.^[2]

Other chemotherapy drugs that may be used include:^[4]

• Bendamustine (Treanda)
• Fludarabine (Fludara)
• Cyclophosphamide (Procytox)
• Chlorambucil (Leukeran)
• Cladribine

Corticosteroids, such as dexamethasone or prednisone, may also be given along with chemotherapy.^[4]

Additional Treatment Options

Other therapies to treat relapsed and refractory Waldenstrom’s macroglobulinemia include:^[1]

• Everolimus (Afinitor)
• Ofatumumab (Arzerra) for patients who are intolerant to rituximab
• High-dose chemotherapy followed by a stem cell transplant in select patients

A stem cell transplant may be autologous (patients receive their own stem cells) or allogeneic (patients receive stem cells from a donor).^[1]

Plasma Exchange

Plasma exchange, also called plasmapheresis, involves removing plasma from the blood and replacing it with a substitute. Plasma exchange can be used to treat hyperviscosity syndrome, a condition where people have thicker blood than normal and can have bleeding problems, vision problems, and nervous system problems. This occurs because people with Waldenstrom’s macroglobulinemia have a high amount of immunoglobulin M (IgM) or M-protein in the blood.^[4]

Factors That Influence Treatment Choice

Many disease-related and patient-related factors can influence treatment choice in the relapsed and refractory setting. Understanding of the biology of the disease, including identification of important mutations such as MYD88 and CXCR4, has played a role in treatment advancements and selection.^[2]

Prior treatment with BTK inhibitors appears to be an important factor. In one study of venetoclax treatment, prior treatment with BTK inhibitor was the only factor associated with how long patients remained in remission before their disease progressed.^[5]

Newer and Emerging Therapies

Venetoclax

Venetoclax is a drug that inhibits an antiapoptotic protein called BCL2, which is overexpressed in Waldenstrom’s macroglobulinemia. This drug causes cancer cells to die.^[5]

Venetoclax showed promising activity in treating relapsed and refractory disease. In a study of 76 patients with relapsed or refractory disease treated with venetoclax monotherapy, the overall response rate was 70% and the major response rate was 63%. The median time before disease progression was 28.5 months, and at 2 years, 57% of patients had not experienced disease progression.^[5]

The median number of prior lines of treatment in this study was 3, including treatment with a covalent BTK inhibitor in 82% of patients and an alkylating agent in 71% of patients. This shows that venetoclax can be effective even in heavily pretreated patients.^[5]

In this study, venetoclax dose interruptions or reductions occurred in 41% of patients. Five patients (7%) developed laboratory tumor lysis syndrome, including 3 (4%) with clinical tumor lysis syndrome. Tumor lysis syndrome is a serious condition that can occur when cancer cells break down rapidly and release their contents into the blood.^[5]

Treatments Under Investigation

Several promising new drugs and drug combinations are being studied in clinical trials for the treatment of patients with relapsed and refractory Waldenstrom’s macroglobulinemia, including:^[9]

• 19(T2)28z1XX (Chimeric antigen receptor [CAR] T cell therapy targeting CD19)
• Acalabrutinib (Calquence)
• Daratumumab (Darazalex)
• Tirabrutinib (Velexbru)
• Ulocuplumab
• Venetoclax