The goal of induction regimens for patients with newly diagnosed multiple myeloma is to reduce the burden of disease and prolong durability of response and overall survival, while minimizing toxicity.
Saad Z. Usmani, MD
The goal of induction regimens for patients with newly diagnosed multiple myeloma is to reduce the burden of disease and prolong durability of response and overall survival (OS), while minimizing toxicity, Saad Usmani MD, FACP, said during a presentation at the inaugural Charlotte Plasma Cell Disorder Congress.
“Picking therapies and then adjusting doses or stopping therapy as needed are extremely important,” added Usmani, chief of Plasma Cell Disorders and director of Clinical Research in Hematologic Malignancies at Levine Cancer Institute, Atrium Health. “Recognizing that patients are developing adverse events (AEs) from therapy early and then intervening are also essential.”
When it comes to treating patients with newly diagnosed multiple myeloma, triplet combinations are considered optimal. The combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) is the most commonly used regimen, while the triplet of carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) is known to induce deep responses, said Usmani. For certain cases, such as renal failure, the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is preferred, he added. Moreover, the regimen of ixazomib (Ninlaro), lenalidomide, and dexamethasone (IRd) is being explored in clinical studies.
Chemotherapy Combinations Induce Deep Responses
The phase III SWOG S0777 trial randomized patients with newly diagnosed disease 1:1 to receive either initial treatment with RVd (n = 242) or Rd (n = 229) alone, both followed by Rd. Results showed that the median progression-free survival (PFS) was 43 months in those who received RVd versus 30 months in those who received Rd alone (HR, 0.709; P = .025).1
“This trial only validated what we were already practicing in the United States,” said Usmani. “We were already utilizing RVd as induction therapy.”
The oral proteasome inhibitor ixazomib was then evaluated in combination with lenalidomide and dexamethasone in an open-label phase I/II trial. In 64 treatment-naïve patients with newly diagnosed disease, the overall response rate (ORR) observed with the triplet was 92%.2
“When we’re thinking about different proteasome inhibitors partnered with lenalidomide/dexamethasone, it will come down to how good that deep response is,” said Usmani. “However, if the [data from the] phase III trials hold true, this will be a reasonable combination option for induction.”
In the small phase II IFM study,3 investigators looked at the safety and efficacy of 4 cycles of KRd in patients with newly diagnosed disease followed by autologous stem cell transplant (ASCT), then followed by consolidation with KRd for 4 cycles, and then lenalidomide maintenance. The combination showed a 2-year PFS rate of 91% and a robust depth of response, with 70% of patients having achieved MRD negativity after consolidation. However, 17% of patients experienced cardiac and vascular AEs; as such, cardiac toxicity is a concern with this regimen, said Usmani.
Examining the Role of ASCT in Era of Novel Agents
With the addition of several multiagent regimens, ASCT continues to maintain benefit in the multiple myeloma space, said Usmani.
Role of ASCT With RVd
In the IFM 2009 study,4 patients ≤65 years of age with newly diagnosed disease were given RVd for 3 cycles, collection of stem cells, followed by melphalan at 200 mg/m2 and ASCT, and VRd consolidation for 2 cycles, followed by lenalidomide maintenance (n = 350), or just RVd for 3 cycles, collection of stem cells, RVd for 5 more cycles, and lenalidomide maintenance (n = 350). The median PFS in the ASCT arm was 50 months compared with 36 months in the arm without transplant (P <.001). Although promising, more data are needed to validate the role of early transplantation in multiple myeloma, said Usmani.
Role of ASCT With KRd
To evaluate the role of ASCT with KRd, investigators evaluated data from 2 separate studies in combination. One study examined KRd, ASCT, followed by 4 cycles of KRd consolidation and maintenance KRd for 10 cycles. Another trial explored consolidation KRd without ASCT, explained Usmani. Results showed that KRd plus ASCT resulted in a 3-year PFS rate of 86% versus 80% with KRd alone.5
“The bottom line for this particular study was that additional ASCT to the schema deepens the response in terms of MRD negativity,” said Usmani. “It improves 3-year PFS, as well.”
Monoclonal Antibodies Generate Excitement
Monoclonal antibodies have generated a lot of excitement in myeloma for several reasons, said Usmani. These agents have a novel mechanism of action that allows for additive or synergistic effects with current agents, they’re generally well tolerated, and they can be combined with other immunotherapies.
“We are all excited about monoclonal antibodies because they can be utilized with existing regimens without adding a lot of toxicity,” said Usmani. “They do not have overlapping AEs and they can be utilized to target the bone marrow microenvironment, cancer cells, and immune signals.”
Moreover, the phase II GRIFFIN trial6 is looking at the combination of daratumumab (Darzalex) plus bortezomib, lenalidomide, and dexamethasone (D-RVd) compared with RVd alone in patients with newly diagnosed disease who are eligible for high-dose therapy and ASCT. The primary aim of the safety run-in of the trial was to evaluate dose-limiting toxicities during 1 D-RVd cycle, said Usmani.
Results showed that the quadruplet regimen was tolerable, depth of response to the combination deepened during maintenance, and overall response rate improved over time. Updated results from the trial are expected at an upcoming medical meeting.
Finally, the phase III CASSIOPEIA trial7 is examining bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) with (n = 543) or without daratumumab (n = 542) before and after ASCT in patients with newly diagnosed disease.
At day 100 after transplantation, 28.9% of patients who received daratumumab plus VTd in the intent-to-treat population achieved a stringent complete response (95% CI, 1.21-2.12; P ≤.001). Moreover, 38.9% of those in the daratumumab arm compared with 26.0% of those in the VTd arm achieved a complete response or better and 63.7% versus 43.5% achieved MRD negativity.
Based on the CASSIOPEIA data, the FDA is currently reviewing a supplemental biologics license application (sBLA) for VTd for the treatment of patients with newly diagnosed multiple myeloma who are eligible for ASCT. The action date on the sBLA is September 26, 2019.
“Monoclonal-based quadruplets appear to be safe in induction and posttransplant consolidation,” concluded Usmani. “We are getting deeper responses, adequate stem cell mobilization, as well as an improvement in PFS, but we need long-term follow-up.”