Shaji K. Kumar, MD

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A look at clinical trial efficacy data on daratumumab plus bortezomib and venetoclax for multiple myeloma treatment.

Venetoclax in Combination with Daratumumab for Multiple Myeloma Treatment

Shaji Kumar, MD, a hematologist at the Mayo Clinic and chair of the Plasma Cell Disorders Scientific Committee at the American Society of Hematology, discusses how risk assessments and new drug combinations could influence treatment of patients with newly diagnosed multiple myeloma.

According to Kumar, the current standard of care for early-stage multiple myeloma is a proteasome inhibitor in combination with immunomodulatory drugs or monoclonal antibodies. Multiple regimens may be used depending on if patients are eligible for stem cell transplant. Eligible patients receive induction therapy with dexamethasone prior to a single transplant. After the transplant, patients can receive lenalidomide maintenance (Revlimid). High-risk patients may be given daratumumab (Darzalex) plus a combination of bortezomib, lenalidomide, and dexamethasone (VRd).

Patients who are transplant-ineligible may receive daratumumab until disease progression. For high-risk disease, modified lenalidomide, bortezomib, and dexamethasone (VRd-Lite) may be given with a proteasome inhibitor or other immunomodulatory drug.

Kumar suggests that targeted treatment could be improved with new drug combinations in frontline treatment. Combinations with better response and lower toxicity can allow patients to stay on treatment for a longer period. He also points to improvements in treatment based on risk assessments such as the Revised International Staging System (R-ISS) risk factors and minimum residual disease (MRD) testing to assess the efficacy of treatment. MRD measures the number of remaining myeloma cells in the bone marrow while a patient is in remission, which can predict disease progression and relapse.

 A couple of areas that we focused on were looking at the concept of risks of rapid therapy, how can we change the treatments based on some of the commonly used risk factors like the R-ISS staging system? Also, [we are] talking about the concept of a dynamic risk assessment because patients' outcomes can vary based on how what kind of response they get, how deep a response, how long will MRD negativity last, and so forth. So, I think that's one aspect of how we will tailor therapy in the up-front setting, and maybe even in the setting of relapsed disease.

I think the other concept is one of using multidrug combinations to provide us with a limited-duration therapy so that patients can stay on treatment for a very, very long time. But it can help with both toxicity related to therapy as well as the cost of care. So, how can we use some tools like MRD testing to guide us towards more scientifically defining the ideal duration of therapy for individual patients?

Shaji Kumar, MD, discusses how risk assessments and new drug combinations could influence treatment of patients with newly diagnosed multiple myeloma.

Risk Assessments Can Improve Tailored Treatment for Multiple Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, addresses an important unanswered question that remains in the treatment landscape of newly diagnosed multiple myeloma, which is whether 3- or 4-drug regimens should be used in the frontline setting.

This is the biggest question that is being explored in phase 3 studies at this time, Kumar says. There are now 3 effective classes of drugs available in multiple myeloma, which include proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.

The standard of care for newly diagnosed patients is a proteasome inhibitor with a monoclonal antibody and bortezomib with lenalidomide (Revlimid) and dexamethasone, and this is the standard for both patients who are eligible and ineligible stem cell transplant. However, Kumar says this is being challenged with the introduction of daratumumab (Darzalex) to the clinic. The phase 3 MAYA study demonstrated that bortezomib could be replaced with daratumumab, and this is an effective strategy for the treatment of patients who are ineligible for stem cell transplant.

Shaji K. Kumar, MD, addresses an important unanswered question that remains in the treatment landscape of newly diagnosed multiple myeloma, which is whether 3- or 4-drug regimens should be used in the frontline setting.

Should Frontline Myeloma Treatment Include a 3- or 4-Drug Regimen?

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses how patients with multiple myeloma respond to different types of therapy.

The different approaches used for stem cell mobilization are successful in a majority of these patients, according to Kumar. When physicians granulocyte colony-stimulating factor (G-CSF) alone for mobilization, there is up to 10% failure rate, and the rate goes up if the patient has been treated for a longer period of time and if they have been given treatments such as lenalidomide (Revlimid), alkylating agents, or newer therapies like daratumumab (Darzalex).

For patients who did not experience benefit on G-CSF alone, additional techniques are available, including chemotherapy or plerixafor mobilization. Plerixafor is a CXCR4 targeted agent for patients with myeloma. Kumar says that when plerixafor is used in a risk adapted strategy based on the CD34 counts, after the G-CSF, or based on the number of CD34 cells collected, the failure rate is reduced to 1% to 2% for patients in this setting.

With chemotherapy mobilization, physicians have the opportunity to collect more cells in patients than when using G-CSF alone and the failure rate is lower, Kumar explains. This also has increased cost and toxicity for patients, such as cytopenias, longer time to mobilization, and management of neutropenic fever if it requires hospitalization.

Kumar believes that these different strategies need to be selected based on each individual patient and the clinical context.

<< View more resources and information regarding multiple myeloma

Shaji K. Kumar, MD, discusses how patients with multiple myeloma respond to different types of therapy.

Analyzing the Outcomes With Different Treatment Techniques in Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses the management of newly diagnosed patients with multiple myeloma.

Treating Patients With Newly Diagnosed Multiple Myeloma

Shaji K. Kumar, MD, professor of medicine, Mayo Clinic, discusses the results of a phase II trial of single agent MLN9708 in patients with relapsed multiple myeloma not refractory to bortezomib.

16% of patients had a pre-specified response (minimum minor response by end of Cycle 2 or partial response by end of Cycle 4)

35% of patients had partial response or better under the approach of receiving MLN9708 alone and adding dexamethasone if it did not work well

The most common side effects in this trial (fatigue, drop in platelet counts, nausea, and diarrhea) were well managed

Articles

Shaji K. Kumar, MD, discusses the results of a phase II trial of single agent MLN9708 in patients with relapsed multiple myeloma not refractory to bortezomib.