Novel Induction Regimens Boost Survival in Newly Diagnosed Myeloma

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.”

References

1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomized, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi: 10.1016/S0140-6736(16)31594-X.
2. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503-1512. doi: 10.1016/S1470-2045(14)71125-8.
3. Roussel M, Lauwers-Cances V, Robillard N, et al. Autologous stem cell transplantation, Krd consolidation and lenalidomide maintenance in newly diagnosed multiple myeloma (NDMM) patients: primary results of the Intergroupe Francophone Du MyéLome (IFM) Krd phase II study. Blood. 2016;128(22):1142. http://bit.ly/2OQRE0u.
4. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi: 10.1056/NEJMoa1611750.
5. Zimmerman T, Raje NS, Vij R, et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (KRd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Blood. 2016;128(22):675. http://bit.ly/31upABp.
6. Genmab Announces Positive Topline Results in the Phase II GRIFFIN Study of Transplant Eligible, Newly Diagnosed Patients with Multiple Myeloma Treated with Daratumumab in Combination with Lenalidomide, Bortezomib, and Dexamethasone. Genmab. Published July 8, 2019. https://bit.ly/32ffENb. Accessed July 8, 2019.
7. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol.2019;37(suppl; abstr 8003).