Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses the evolving role of venetoclax (Venclexta) in relapsed/refractory multiple myeloma.

Although not FDA approved in myeloma, venetoclax has demonstrated activity in patients with relapsed/refractory disease who harbor 11;14 translocations, says Kumar. As such, single-agent venetoclax or venetoclax in combination with dexamethasone could be a valid treatment option for this subgroup of patients who have not responded to other standard combinations, Kumar explains.

Currently, venetoclax in combination with dexamethasone is being evaluated in the randomized phase 3 CANOVA trial (NCT03539744) vs pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory multiple myeloma, concludes Kumar.

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Shaji K. Kumar, MD, discusses the evolving role of venetoclax in relapsed/refractory multiple myeloma.  



Dr. Kumar on the Evolving Role of Venetoclax in Relapsed/Refractory Multiple Myeloma 

Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses the challenges of selecting therapy for patients with heavily pretreated multiple myeloma.

Treatment selection for patients with multiple myeloma who experience multiple relapses can be challenging because they are likely refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, says Kumar. Although retreatment with these therapies may offer patients some benefit, the durability of response is not sustained, Kumar explains. 

As such, novel therapies with unique mechanisms of action that can be utilized in combination strategies are needed, Kumar says. Therapies that have recently been FDA approved for single-agent use could have utility in combination regimens with retreatment agents to extend the durability of responses, concludes Kumar.

Shaji K. Kumar, MD, discusses the challenges of selecting therapy for patients with heavily pretreated multiple myeloma.  



Dr. Kumar on the Challenges of Selecting Therapy in Heavily Pretreated Multiple Myeloma 

Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses treatment selection considerations in multiple myeloma.

Determining the optimal treatment for patients with multiple myeloma who experience early relapse is an area of ongoing research, says Kumar. Currently, in the frontline setting, patients who are eligible for autologous stem cell transplant (ASCT) typically receive a triplet induction regimen, followed by ASCT and lenalidomide (Revlimid) maintenance, Kumar explains. Patients who are ineligible for ASCT will often receive continuous treatment with a lenalidomide-containing combination until disease progression, Kumar says. 

As such, the majority of patients are refractory to lenalidomide at first relapse, Kumar explains. Consequently, lenalidomide is typically omitted from relapsed/refractory therapy options. 

Additionally, treatment selection for subsequent relapses is largely dependent on what other regimens the patient has received, what drugs or combinations they are refractory to, and how they tolerated previous therapies, concludes Kumar.

Shaji K. Kumar, MD, discusses treatment selection considerations in multiple myeloma.  



 Dr. Kumar on Treatment Selection Considerations in Multiple Myeloma 

Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses the emergence of minimal residual disease (MRD) negativity as a surrogate end point in relapsed/refractory multiple myeloma.

Progression-free survival (PFS) has served as the primary end point for multiple registrational clinical trials in  relapsed multiple myeloma, says Kumar. However, as older phase 3 trials continue to mature, overall survival data are beginning to emerge. 

Notably, many recent studies have demonstrated the importance of achieving MRD negativity in patients with multiple myeloma, Kumar explains. As such, MRD negativity is being considered as a surrogate end point in trials. Additionally, data have shown that MRD negativity is associated with improved PFS, further strengthening the notion that depth of response influences PFS, concludes Kumar.

Shaji K. Kumar, MD, discusses the emergence of minimal residual disease negativity as a surrogate end point in relapsed/refractory multiple myeloma.  



Dr. Kumar on the Emergence of MRD Negativity as an End Point in Multiple Myeloma 

Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses sequencing selinexor (Xpovio)-based combinations in relapsed/refractory multiple myeloma.

Patients with multiple myeloma will likely experience multiple relapses within the course of their disease, explains Kumar. As such, novel therapies are needed to ensure options are available to patients who relapse.

Recently, therapies such as selinexor have been added to the armamentarium of triple-class refractory myeloma. Moreover, selinexor, an oral XPO1 inhibitor, plus dexamethasone has demonstrated efficacy in combination regimens with daratumumab (Darzalex), carfilzomib (Kyprolis), pomalidomide (Pomalyst), and bortezomib (Velcade), Kumar says. Notably, although selinexor-based regimens can be considered for patients after first relapse, longer-term follow-up data and durable responses have been observed with monoclonal antibodies and immunomodulatory agents (IMiDs). As such, selinexor-based regimens are more likely to be reserved for later lines of therapy after patients have been exposed to IMiDs, proteasome inhibitors, and monoclonal antibodies, concludes Kumar.

Shaji K. Kumar, MD, discusses sequencing selinexor-based combinations in relapsed/refractory multiple myeloma.  



Dr. Kumar on Sequencing Selinexor-Based Combinations in Multiple Myeloma 

Shaji K. Kumar, MD, a consultant in the Division of Hematology and a professor of medicine with Mayo Clinic, discusses treatment discontinuation in the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

The ENDURANCE trial saw quite a few early discontinuations of treatment, says Kumar. Patients went off of therapy without completing the full 9 to 12 cycles of bortezomib (Velcade) plus lenalidomide (Revlimid) and dexamethasone (Ozurdex; VRd) or carfilzomib (Kyprolis) plus lenalidomide and dexamethasone (KRd). 

Only 43.3% of patients who received VRd and 61.6% of those who received KRd completed all cycles of treatment as planned; this was because of several reasons, including patient withdrawal/refusal or switching to an alternative therapy, such as stem cell transplant, adds Kumar.

Even though the trial was intended for patients who were not going to an early transplant, 28.0% of patients on the VRd arm and 26.8% on the KRd arm received a stem cell transplant either before they completed induction therapy or soon after completing induction therapy, concludes Kumar.

Shaji K. Kumar, MD, discusses treatment discontinuation in the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

Dr. Kumar on Treatment Discontinuation in the ENDURANCE Myeloma Trial

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses the rationale for conducting the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

, findings from the ENDURANCE study revealed similar rates of progression-free survival and overall survival with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) compared with carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd).

The study was designed to evaluate whether carfilzomib could replace bortezomib in the treatment of patients with newly diagnosed multiple myeloma, says Kumar.

The rationale stemmed from the fact that both regimens had shown benefit in the newly diagnosed setting, says Kumar. For example, the phase 3 SWOG S0777 study demonstrated an improvement in survival with VRd versus Rd alone in this patient population, explains Kumar. These results led VRd to become the standard of care for patients

However, findings from a phase 2 study (NCT01402284) had also shown that KRd was highly effective in the newly diagnosed setting, concludes Kumar.

Shaji K. Kumar, MD, discusses the rationale for conducting the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.



Dr. Kumar on the Rationale for the ENDURANCE Trial in Multiple Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses stem cell mobilization multiple myeloma.

Although stem cell mobilization is successful in the majority of patients with multiple myeloma, the use of granulocyte colony-stimulating factor (G-CSF) used alone is associated with up to a 10% failure rate, Kumar explains. This rate increases for patients who receive prolonged treatment exposure with lenalidomide (Revlimid), alkylating agents, or daratumumab (Darzalex). 

​Additional techniques such as chemomobilization or mobilization using the use of plerixafor ​(Mozobil), a CXCR4-targeted agent, can be used ​in patients who fail G-CSF–alone mobilization, says Kumar. 

More cells can be collected with chemomobilization compared with G-CSF–alone, and the failure rate is lower, explains Kumar. However, the modality is associated with ​an increased risk of cytopenia, neutropenic fever that could lead to hospitalization, and longer time to mobilization. 

Plerixafor can be used as a risk-adapted strategy based on CD34 counts after G-CSF or on the number of CD34 cells that were gathered in the first collection, says Kumar. The failure rate with this method may be reduced to about 1% to 2% in patients with multiple myeloma.

Shaji K. Kumar, MD, discusses stem cell mobilization multiple myeloma.

Dr. Kumar on Stem Cell Mobilization in Multiple Myeloma 

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses key takeaways from the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

The results from the trial showed similar progression-free survival and overall survival (OS) with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) versus carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) in this setting, says Kumar. The estimated 3-year OS rates were approximately 85% in both arms. Additionally, the overall response rates were comparable between arms. Notably, deeper responses such as the rate of very good partial response, was more common among patients in the KRd arm, says Kumar.

In terms of safety, a higher incidence of grade 3 or higher non-hematological adverse effects was seen in the KRd arm, particularly cardiac, pulmonary, and renal toxicities. However, patients in the VRd arm had a higher risk of peripheral neuropathy. Taken collectively, the results do not provide sufficient evidence that KRd should replace VRd as the current frontline standard of care in newly diagnosed patients with transplant-eligible myeloma. Trials evaluating the addition of monoclonal antibodies to VRd or replacing bortezomib are ongoing, concludes Kumar.

Shaji K. Kumar, MD, discusses key takeaways from the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

Dr. Kumar on Takeaways From the ENDURANCE Trial in Multiple Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses the rate of treatment discontinuation in the phase 3 ENDURANCE (E1A11) trial in newly diagnosed multiple myeloma.

Patients with newly diagnosed multiple myeloma were randomized to received bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) or carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd).

Findings from the study showed that KRd did not improve progression-free survival compared with VRd in this patient population.

Early discontinuation of treatment was relatively common among patients treated in both arms of the ENDURANCE study, says Kumar. About 43% of patients completed the full 12 cycles of VRd and 61.6% of patients completed the full 9 cycles of KRd.

Treatment discontinuation can be attributed to adverse effects, emergence of alterative therapy like stem cell transplant, or patient withdrawal/refusal, says Kumar.

Although the trial was not intended to enroll patients who would eventually go on to receive transplant, around 28% of patients in both arms went on to transplant before or shortly after completing induction therapy, concludes Kumar.

Shaji K. Kumar, MD, discusses the rate of treatment discontinuation in the phase 3 ENDURANCE trial in newly diagnosed multiple myeloma.

Shaji K. Kumar, MD

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