Triplet vs. Quadruplet Therapy: Choosing the Right Multiple Myeloma Treatment

Multiple myeloma refers to blood cancer found within the plasma cells of bone marrow. It is rarely curable, but treatment can be used to slow down disease progression and support a better quality of life. In the treatment of multiple myeloma, triplet therapy is the current standard of care for most patients, and National Comprehensive Cancer Network Guidelines^® identify standard treatment with triplet therapy as a combination of a proteasome inhibitor, immunomodulatory medication, and corticosteroid.

Results of one clinical trial found that triplet therapy extends patients’ survival, compared to doublet therapy, by 13 months (from 30 months to 43 months). Additionally, overall survival is also improved by 11 months. In general, the study found that patients being treated with triplet therapy have better partial and complete responses, including those measured through DNA (deoxyribonucleic acid) sequencing. 

On the other hand, quadruplet therapy for multiple myeloma adds an anti-CD38 monoclonal antibody to the standard triplet treatment course. However, after two major clinical trials (CASSIOPEIA and GRIFFIN), there remains insufficient evidence to make it the standard of care for all patients with the disease.

Because triplet therapy is more intensive, there is an increased risk of side effects. Common adverse events with treatments using steroids include gastrointestinal distress (ulcers or gastrointestinal bleeding), osteoporosis, weight gain, insomnia, mood changes, elevated blood sugar, and elevated blood pressure or fluid retention. In addition to adverse effects from steroids, patients may experience peripheral neuropathy and diarrhea. Those on quadruplet regimens may also have increased risk of infections, neutropenia, lymphopenia, and infusion-related reactions when compared treatment with triplet regimens. 

ACCCBuzz recently had the opportunity to speak with Jessica Unzaga, PharmD, BCPS, BCOP, pharmacy clinical coordinator at Baptist Health’s Miami Cancer Institute in Miami, Fla, to help consider the use of triplet vs. quadruplet regimens when treating multiple myeloma.

ACCCBuzz: What is triplet therapy referring to in the treatment of multiple myeloma

Dr. Unzaga: Triplet therapy means combining three drugs with different, yet complimentary, mechanisms of action. In newly diagnosed multiple myeloma, we typically utilize a combination of a proteasome inhibitor or chemotherapy agent, along with an immunomodulating agent and corticosteroid. 

ACCCBuzz: What does quadruplet therapy refer to in the treatment of multiple myeloma?

Dr. Unzaga: Quadruplet therapy adds an additional drug with another mechanism and target. 

ACCCBuzz: What medications are typically used in each of these therapeutic regimens?

Dr. Unzaga: Typical first-line regimens in multiple myeloma include a combination of a proteasome inhibitor, immunomodulatory drug, and corticosteroid with or without an anti-CD38 monoclonal antibody. Chemotherapy agents can be given, such as cyclophosphamide, if an immunomodulating agent is not available or unable to be initiated due to renal function.

Second- and third-line regimens utilize additional novel therapies, such as an anti-SLAMF7 monoclonal antibody, XPO1 inhibitor, and other traditional chemotherapies in combination with the other drugs previously mentioned. B-cell maturation antigen (BCMA)-directed therapies, including chimeric antigen receptor T-cell (CAR-T), anti-BCMA monoclonal antibody, and bispecific T-cell engagers are also options that can be utilized as monotherapy in the relapsed and refractory settings.

ACCCBuzz: What are the similarities and differences between triplet vs. quadruplet therapy? 

Dr. Unzaga: Triplet therapy has been standard of care in newly diagnosed and relapse/refractory multiple myeloma for many years. Today, we have some evidence to support quadruplet regimens in frontline transplant eligible multiple myeloma, specifically adding an anti-CD38 monoclonal antibody to the traditional triplet, including a proteasome inhibitor or chemotherapy agent, immunomodulatory, and corticosteroid.

The addition of another drug comes with additional side effects. For example, when adding an anti-CD38 monoclonal antibody to a triplet, clinicians and patients should be aware of and prepare to mitigate the potential increased risk of infections, neutropenia, lymphopenia, and infusion-related reactions, as compared to triplet regimens. Pharmacists play an important role in the prevention and management of side effects by reviewing and recommending prophylactic medications, optimizing dosing, infusion rates or dosage forms to improve safety, adherence, and tolerability.

ACCCBuzz: Is one treatment regimen associated with better clinical outcomes? 

Dr. Unzaga: The CASSIOPEIA and GRIFFIN trials demonstrated favorable, stringent complete response and higher measurable residual disease (MRD)-negative status for patients who achieved complete response in quadruplet therapies. Of note, progression-free survival was improved in the CASSIOPEIA study but not in the GRIFFIN trial. Additional data are needed to determine if quadruplet therapies improve progression-free survival and overall survival.

ACCCBuzz: Do oncology providers have a preference in therapy regimen?

Dr. Unzaga: Because there are some studies that show that MRD negativity is associated with improved progression-free survival and overall survival in patients with multiple myeloma, clinicians are extremely interested to see if quadruplet therapies can improve survival outcomes and in which specific settings and patient risk categories, so that these regimens can be used safely and appropriately.

ACCCBuzz: Is there preferred timing for when patients should receive this therapy regimen (i.e., when first diagnosed, at recurrence, etc.)?

Dr. Unzaga: At this time, sequencing of regimens in multiple myeloma is not fully established. We have standard, primary therapies and a wide variety of second-, third-, fourth-, and even fifth-line options established, based on how the therapies were studied. Many of our sequencing decisions are made based on the patient’s baseline disease status and comorbidities, as well as their ability to comply with the regimen.

Currently, approved quadruplets can be used in the frontline and previously treated settings, depending on those factors previously mentioned and the patient’s response to therapy. In multiple myeloma, we will add a drug from another class or mechanism when we do not see the patient achieving optimal response rates, as well as potentially removing an agent that is no longer showing benefit or the patient is no longer able to tolerate it.

Clinical trials should continue to explore the optimal sequencing of therapy in transplant eligible and ineligible patients to continue to shed light on this important topic.

For more information on multiple myeloma and ACCC’s Changing Operating Treatment Paradigms for Patients with Multiple Myeloma education program, visit the ACCC website or contact Regina Gibson-Burtnick, ACCC program manager.

To access multiple myeloma education and support resources for your patients, including booklets, videos, financial support, and peer-to-peer support, encourage them to visit the Leukemia & Lymphoma Society website.

The Changing Treatment Paradigms for Patients with Multiple Myeloma education program is supported by Johnson & Johnson.