Rafael Fonseca, MD, interim director of Mayo Clinic Cancer Center and director, Innovation and Transformational Relationships at Mayo Clinic, weighs the risks and benefits of quadruplet regimens in patient with multiple myeloma.

The question of whether a quadruplet regimen is necessary in myeloma has been raised, particularly because of the potential for toxicities, according to Fonseca. However, the incremental toxicities associated with a these regimens are generally minimal. In fact, proteasome inhibitors and corticosteroids represent a greater challenge with regard to toxicity compared with quadruplets, says Fonseca.

Although there is an added expense that is incurred due to the extra agents included in these regimens, the long-term pharmacokinetic outcomes of quadruplets in this population is highly anticipated, according to Fonseca. If some patients are able to convert deep responses into durable ones and if some are able to avoid relapse, then the downstream benefit of these approaches could be monumental, Fonseca concludes.

Videos

Rafael Fonseca, MD, weighs the risks and benefits of quadruplet regimens in patient with multiple myeloma.

Dr. Fonseca on Weighing the Risks With Potential Benefits of Quadruplet Regimens in Myeloma

Rafael Fonseca, MD, interim director, Mayo Clinic Cancer Center, director, Innovation and Transformational Relationships, Mayo Clinic, discusses key data in multiple myeloma.

Clinical trials in multiple myeloma fall under 2 broad categories: studies that are important for patients undergoing stem cell transplant and studies that are important for those receiving conventional combination treatments without transplant, Fonseca says.

Studies, such as the phase 3 CASSIOPEIA trial, fall into the former category, says Fonseca. In CASSIOPEIA, patients with newly diagnosed multiple myeloma were randomized to receive induction and consolidation therapy with daratumumab (Darzalex) plus bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) or VTd alone. The results showed that the addition of daratumumab deepened responses over time, Fonseca says.

Furthermore, updated results from the phase 2 GRIFFIN trial showed that the addition of daratumumab to lenalidomide (Revlimid), bortezomib, and dexamethasone (RVd) versus RVd improved depth of response in transplant-eligible patients with newly diagnosed disease. Finally, the ongoing MASTER trial (NCT03224507) is evaluating the role of daratumumab with carfilzomib (Kyprolis), lenalidomide, and dexamethasone, Fonseca explains. The study has demonstrated early efficacy and stringent complete responses among patients in this space.

Notably, these trials demonstrated that therapies that can induce deeper responses result in long-term benefit for patients, Fonseca concludes.

Rafael Fonseca, MD, discusses key data in multiple myeloma. 

Dr. Fonseca Discusses Key Data in Multiple Myeloma  

Rafael Fonseca, MD, interim director, Mayo Clinic Cancer Center, director, Innovation and Transformational Relationships, Mayo Clinic, discusses the emergence of minimal residual disease (MRD) in multiple myeloma.

Although the utility of MRD remains somewhat controversial in multiple myeloma, ClonoSEQ, a next-generation sequencing assay that evaluates MRD, was approved in September 2018 for patients with multiple myeloma or acute lymphoblastic leukemia. Additional methods for measuring MRD, such as EuroFlow and Mass Spectrometry, are currently under investigation in this space. 

However, despite this approval, how to best utilize MRD as a biomarker to inform treatment decisions remains a largely unanswered question in myeloma, Fonseca explains. In clinical practice, Fonseca says that routinely testing for MRD is important for patients who  complete transplants on day 100, as well as those who achieve deep and durable complete remissions. Moreover, it is important to discuss the results of MRD assessments with patients as those who are MRD negative appear to have a reduced risk of relapse compared with MRD-positive patients, concludes Fonseca.

Rafael Fonseca, MD, discusses the emergence of minimal residual disease in multiple myeloma.  



Dr. Fonseca on the Emergence of MRD in Multiple Myeloma 

Rafael Fonseca, MD, hematologist, Mayo Clinic, discusses the use of fluorescence in situ hybridization (FISH) testing in diagnosing patients with myeloma.

By definition, every patient with myeloma will have genetic abnormalities. High risk is determined by FISH, but many people are not using FISH correctly, says Fonseca. They’re sending the bone marrow without consideration for sorting of the cells, or otherwise marking of the cells. Pathology labs are looking at the nuceli of the bone marrow which doesn’t provide the right information. The correct information is important for physicians to think about high-risk markers, subsequent maintenance strategies, and counseling approaches.

Induction chemotherapy is a highly effective treatment, but leaves no viable plasma cells behind. Therefore, physicians who see patients who have received 1 or 2 cycles of induction therapy have lost the opportunity to look at plasma cells following treatment. Consequently, there is no opportunity to know if a FISH report is normal or not, he says.

Rafael Fonseca, MD, hematologist, Mayo Clinic, discusses the use of fluorescence in situ hybridization (FISH) in diagnosing patients with myeloma.

Dr. Fonseca on FISH Testing in Patients With Myeloma

Rafael Fonseca, MD, professor of Medicine, Mayo Clinic, discuses the recent FDA approval of daratumumab (Darzalex) in combination with lenalidomide and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy.

The approval is based on findings from the phase III POLLUX and CASTOR studies. In the POLLUX trial, adding daratumumab to lenalidomide and dexamethasone reduced the risk of progression or death by 63% versus lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma.

In the CASTOR trial, the addition of daratumumab to bortezomib and dexamethasone reduced the risk of progression or death by 61% compared with the 2 drugs alone for patients with recurrent or refractory multiple myeloma. 

Additionally, Fonseca says these approvals are a major step forward because the triplet regimens have the ability to induce deep responses in patients experiencing relapse. He added that, from a safety viewpoint, daratumumab is generally well tolerated following the first infusion in patients. For a patient who can maintain disease control in the long-term with this regimen, it is a very exciting mark in the field.

Dr. Fonseca on FDA Approval of Daratumumab Triplets in Multiple Myeloma

Rafael Fonseca, MD, professor of Medicine, Mayo Clinic, discusses some of the ongoing and recently presented clinical trials that could be potentially practice changing for the treatment of patients with multiple myeloma during the 2016 

 State of the Science Summit on Treatment of Hematologic Malignancies.

Many ongoing trials are using a backbone of lenalidomide/dexamethasone plus another agent. Previously, the backbone was bortezomib (Velcade) plus dexamethasone with an added treatment, Fonseca explains. These include the addition of proteasome inhibitors such as carfilzomib (Kyprolis) and ixazomib (Ninlaro), as well as monoclonal antibodies such as elotuzumab (Empliciti) and daratumumab (Darzalex).

In the POLLUX trial, which looked at daratumumab plus lenalidomide/dexamethasone, up to 43% of patients achieved a complete response, he adds, with a median duration of disease control that has not yet been reach.

Rafael Fonseca, MD, professor of Medicine, Mayo Clinic, discusses some of the ongoing clinical trials that could be potentially practice changing for the treatment of patients with multiple myeloma.

Rafael Fonseca, MD

Articles

Dr. Fonseca on Weighing the Risks With Potential Benefits of Quadruplet Regimens in Myeloma

Dr. Fonseca Discusses Key Data in Multiple Myeloma

Dr. Fonseca on the Emergence of MRD in Multiple Myeloma

Dr. Fonseca on FISH Testing in Patients With Myeloma

Dr. Fonseca on FDA Approval of Daratumumab Triplets in Multiple Myeloma

Dr. Fonseca on Pivotal Trials in Multiple Myeloma