New Multiple Myeloma Guideline Assigns Preferred Regimens for Primary, Maintenance Therapy

Orlando, FL—The 2018 National Comprehensive Cancer Network (NCCN) updated guideline on the management of multiple myeloma assigns preferred status to certain treatment regimens, and designates others as recommended or useful in certain circumstances. The recommendations are broken down into primary therapy for transplant and nontransplant candidates, and maintenance therapy. Shaji K. Kumar, MD, Chair of the NCCN Multiple Myeloma Panel, and Professor of Medicine, Mayo Clinic Cancer Center, Rochester, MN, reviewed the updated guideline at the 2018 NCCN conference. This update “gives a little more guidance as to which regimen to use, especially now that we have so many different combinations available,” said Dr Kumar.

Transplant-Eligible Patients

For newly diagnosed patients who are eligible for transplant, the preferred regimens are bortezomib (Velcade) plus lenalidomide (Revlimid) and dexamethasone (VRd; category 1) and bortezomib plus cyclophosphamide and dexamethasone. The VRd regimen was designated as preferred based on results from the SWOG S0777 clinical trial, which compared VRd with the 2-drug regimen of lenalidomide and dexamethasone (Rd) as initial therapy for multiple myeloma in patients who met CRAB (calcium elevation, renal impairment, anemia, and bone involvement) criteria. After a median follow-up of 55 months, median progression-free survival (PFS) was 43 months with VRd versus 30 months with Rd (P = .0037). The median overall survival (OS) was 64 months with Rd compared with 75 months with VRd (P = .025). This OS improvement was not associated with significant worsening of toxicity, noted Dr Kumar, with the exception of peripheral neuropathy and gastrointestinal events associated with bortezomib. “Based on these results, the combination of bortezomib, lenalidomide, and dexamethasone has become the standard initial therapy for patients diagnosed with multiple myeloma, outside of a clinical trial,” Dr Kumar said. After induction therapy, eligible patients should be considered for autologous stem-cell transplant (ASCT), although continuing drug therapy and/or maintenance therapy is an option for patients who prefer it. In the IFM 2009 clinical trial, 79% of patients who had a transplant had no minimal residual disease versus 65% of patients in the VRd-alone group. The median PFS was also superior in the transplant group. Maintenance therapy with lenalidomide after ASCT improves OS, except for those with stage III disease, and those with high-risk cytogenetics, Dr Kumar said. In high-risk patients, bortezomib should be considered as maintenance therapy. Use of tandem stem-cell transplant improves OS in patients with deletion 17p.

Transplant-Ineligible Patients

In patients who are not candidates for transplant, 3 regimens are considered preferred primary therapy, according to the guideline:

• VRd (category 1)
• Lenalidomide plus low-dose dexamethasone (category 1)
• Bortezomib plus cyclophosphamide and dexamethasone.

The preferred maintenance therapy for transplant-ineligible patients is lenalidomide (category 1).

Relapsed Disease

For patients with relapsed multiple myeloma, “we do have a lot of choices, because there have been multiple phase 3 trials that have been done in the setting of relapsed disease,” Dr Kumar said. The following regimens are preferred for relapsed multiple myeloma:

• Repeat primary induction therapy, if the relapse occurs >6 months after the initial treatment
• Bortezomib plus doxorubicin and dexamethasone
• Carfilzomib (Kyprolis) twice weekly plus dexamethasone (category 1)
• Carfilzomib plus lenalidomide and dexamethasone (category 1)
• Daratumumab (Darzalex) plus bortezomib and dexamethasone (category 1)
• Daratumumab plus lenalidomide and dexamethasone (category 1)
• Elotuzumab (Empliciti) plus lenalidomide and dexamethasone (category 1)
• Ixazomib (Ninlaro) plus lenalidomide and dexamethasone (category 1).

Practical Tips

Overall, patients with relapsed multiple myeloma should be assessed for response after each cycle of therapy, said Dr Kumar. Biochemical recurrence does not always warrant the start of a new therapy. And a triplet regimen using 2 active classes plus dexamethasone is generally preferred over doublet therapy, based on OS improvements observed in clinical trials. In addition, performance status, age, and comorbidities should be considered when selecting therapy, as well as previous or residual toxicities. Patients should be treated to maximum response and use 1 drug as maintenance therapy until disease progression or intolerance to therapy. “The key thing is to use at least 1 new drug from a class that these patients have not been exposed to,” Dr Kumar said, although this is “easier said than done,” because patients have often received several lines of therapy before the relapse.

Supportive Care

The guideline recommends that all patients who use primary multiple myeloma therapy should receive bisphosphonates (category 1) or denosumab (Prolia, Xgeva), and be monitored for renal dysfunction and osteonecrosis of the jaw while receiving a bisphosphonate. Low-dose radiotherapy can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or for impending cord compression. Among the other supportive care recommendations is timely diagnosis of and intervention for infection.