Combination Therapies Dominate NCCN Guidelines for Multiple Myeloma

Wayne Kuznar

June 2017, Vol 7, No 6 - NCCN 2017 Conference Highlights


Orlando, FL—The ideal treatment in 2017 for patients with newly diagnosed multiple myeloma is a combination of bor­tezomib (Velcade), lenalidomide (Revlimid), and dexamethasone. Bortezomib-based maintenance therapy is particularly relevant in patients with high-risk disease and residual disease, and in the relapsed setting, triplet therapy is preferred over doublet therapy. These are among the key therapeutic points in the current National Comprehensive Cancer Network (NCCN) guideline for the management of multiple myeloma (version 3.2017), said Shaji K. Kumar, MD, Professor of Medicine, Mayo Clinic Cancer Center, Rochester, MN, at the 2017 NCCN annual conference. He discussed the use of current therapies based on the NCCN guidelines.

Initial Therapy

The ideal initial therapy for patients with multiple myeloma would rapidly control the disease, reverse disease-related complications, and decrease the risk for early death, which remains at 10% to 15% within the first year of diagnosis, said Dr Kumar.

For transplant-eligible patients, adding bortezomib to lenalidomide and dexamethasone increases the depth of response, progression-free survival (PFS), and overall survival (OS) compared with doublet therapy.

“This particular regimen should be the standard of care for newly diagnosed myeloma patients, especially those who are going to stem-cell transplant,” he said. Two other bortezomib-containing triplet therapies are listed as preferred regimens in the NCCN guideline, including bortezomib plus doxorubicin and dexamethasone (category 1), and bortezomib plus cyclophosphamide and dexamethasone.

Recently completed clinical trials show the potential value of other combination therapies in patients with newly diagnosed disease. One such combination is bortezomib plus thalidomide (Thalomid) and dexamethasone, which produced superior rates of very good partial response over bortezomib plus cyclophosphamide and dexamethasone in the IMF 2013-04 phase 3 clinical trial.

In another clinical trial, 8 cycles of carfilzomib (Kyprolis) plus lenalidomide and dexamethasone were associated with a very good partial response of approximately 90%, with or without stem-cell transplant, and a near complete response rate of 81% with transplant. This regimen is being compared with the standard combination of bortezomib plus lenalidomide and dexamethasone as induction therapy in a phase 3 clinical trial.

“One of the disadvantages to this regimen is that patients have to come back once or twice a week to get an injection of proteasome inhibitor,” said Dr Kumar.

The all-oral triplet regimen with ixazomib (Ninlaro) plus lenalidomide and dexamethasone is included in the NCCN guideline as another treatment option for patients with newly diagnosed multiple myeloma. More than 60% of patients achieved very good partial response with this regimen after 12 cycles of therapy.

Daratumumab (Darzalex) and elotuzumab (Empliciti) are approved for the treatment of patients with relapsed multiple myeloma, and ongoing clinical trials are examining the addition of daratumumab to frequently used backbone regimens as initial therapy. The next area of research will focus on adding a monoclonal antibody to a triplet therapy to further increase the depth of response, Dr Kumar predicted.

After initial therapy, autologous stem-cell transplant (ASCT) increases the depth of response to a complete or very good partial response, and approximately 15% of patients achieve minimal residual disease (MRD)-negativity, he added, translating into improved PFS. Until an improvement in OS is confirmed, patients with multiple myeloma who are eligible for ASCT can delay it until the first disease relapse.

In patients who undergo ASCT and no additional therapy, the median time to disease progression is approximately 2 to 2.5 years. Consolidation therapy and prolonged maintenance therapy are 2 approaches to lengthen the time to disease progression.

In a meta-analysis of phase 3 clinical trials, maintenance therapy with lenalidomide after ASCT was associated with a 26% reduction in mortality risk, representing an estimated 2.5-year increase in the median OS compared with no maintenance therapy. Patients with adverse-risk cytogenetics do not appear to benefit from lenalidomide maintenance therapy; therefore, bortezomib may be an effective treatment option in these patients.

For nontransplant candidates, the NCCN guideline lists several therapies as preferred regimens, including bortezomib plus cyclophosphamide and dexamethasone; bortezomib plus lenalidomide and dexamethasone (category 1); and lenalidomide plus low-dose dexamethasone in older, frail patients (category 1), with bortezomib or lenalidomide as maintenance therapy (category 1).

Adjunctive treatment includes bis­phosphonates for all patients with newly diagnosed multiple myeloma who are receiving primary antimyeloma therapy: zoledronic acid every 12 weeks is as effective as every 4 weeks in reducing the risk for skeletal-related adverse events. Patients should have a dental examination before starting therapy with bisphosphonates. Low-dose radiation therapy can also be administered as palliative treatment for uncontrolled pain.

State-of-the-Art Treatment for Relapsed Disease

In the majority of patients, multiple myeloma will relapse even with modern therapies, with a median time to relapse of 4 to 5 years, said Dr Kumar. Carfilzomib doubles PFS compared with bortezomib when used in combination with dexamethasone in patients with relapsed disease, and recent data also show an improvement in OS.

In addition, carfilzomib plus lenalidomide and dexamethasone improved the median PFS, with a trend toward an OS improvement, which may lead to the FDA approval of this combination in the relapsed setting.

Ixazomib plus lenalidomide and dexamethasone improved the median PFS by approximately 6 months compared with the doublet therapy, with no worsening of toxicity. The addition of elotuzumab to lenalidomide and dexamethasone improved the median PFS by more than 4 months.

“All of these trials have been in early-stage relapse, so 1 to 3 prior lines of therapy,” noted Dr Kumar.

Recent data of daratumumab combined with lenalidomide and dexamethasone in patients with relapsed multiple myeloma resulted in an “impressive improvement” in the median PFS, with a hazard ratio (HR) of 0.37 (P <.001). In another clinical trial, daratumumab plus bortezomib and dexamethasone also significantly improved the median PFS (HR, 0.39; P <.001).

Even more striking about these 2 clinical trials was the high rate of patients who achieved MRD-negativity—60% to 65%—“suggesting that even in these patients with relapsed disease, we can get very deep responses [by] adding new classes of drugs to the existing agents,” said Dr Kumar.

Salvage second ASCT has been shown to improve the median PFS in patients who had at least 18 months of PFS after their first transplant, Dr Kumar added.

Ongoing Clinical Trials

Several new classes of drugs are in early-phase clinical trials of multiple myeloma, including selinexor, a first-in-class exportin-1 inhibitor that induces nuclear retention and the activation of tumor-suppressor proteins; venetoclax (Venclexta), a small-molecule inhibitor of BCL2 that is approved for the treatment of chronic lymphocytic leukemia and has been shown to induce apoptosis in multiple myeloma lines; and the combination of pembrolizumab (Keytruda), pomalidomide (Pomalyst), and dexamethasone, which produced a very good partial response of 29% and an overall response rate of >60% in patients with relapsed multiple myeloma who had a median of 5 previous lines of therapy. Investigation of chimeric antigen receptor T-cell therapy is also ongoing, including a pilot study in which CTL019 was shown to eradicate multiple myeloma tumor cells.