New Myeloma Induction Leads to Better Survival

Saad Usmani, MD

Saad Usmani, MD

Successful induction regimens can reduce the burden of disease and prolong the durability of treatment response, time to disease progression, and overall survival for patients with newly diagnosed multiple myeloma, all while minimizing toxicity, according to Saad Usmani, MD, chief of the Plasma Cell Disorders Program and director of clinical research in hematologic malignancies at Levine Cancer Institute of the Carolinas Medical Center in Charlotte, North Carolina.¹

“Picking therapies and then adjusting doses or stopping therapy as needed are extremely important,” Usmani said during a presentation at the inaugural Charlotte Plasma Cell Disorder Congress. “Recognizing that patients are developing adverse events [AEs] from therapy early and then intervening are also essential.”

Triplet combinations are considered optimal for treating patients with newly diagnosed multiple myeloma. The combination of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) is the most commonly used regimen, whereas the triplet of carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) is known to induce deep responses, Usmani said. For certain patients, such as those with renal failure, the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is preferred, he added. Moreover, the regimen of ixazomib (Ninlaro), lenalidomide, and dexamethasone is being explored in clinical studies.

Deep Responses Observed With Chemotherapy Combinations

The phase III SWOG-S0777 trial randomized patients with newly diagnosed disease 1:1 to receive initial treatment with either RVd (n = 242) or lenalidomide and dexamethasone (Rd) alone (n = 229), both followed by Rd maintenance. Results showed that the median progression-free survival (PFS) was 43 months in patients who received RVd versus 30 months in those who received Rd alone (HR, 0.712;P= .002).²

“This trial only validated what we were already practicing in the United States,” Usmani said. “We were already [using] RVd as induction therapy.”

The oral proteasome inhibitor ixazomib was also evaluated in combination with lenalidomide and dexamethasone in an open-label phase I/II trial.³In 64 treatment-naïve patients with newly diagnosed disease, the overall response rate (ORR) observed with the triplet was 92%.

“When we’re thinking about different proteasome inhibitors partnered with lenalidomide/dexamethasone, it will come down to how good that deep response is,” Usmani said. “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 Intergroupe Francophone du Myélome (IFM) study,⁴investigators looked at the safety and efficacy of 4 cycles of KRd followed by autologous stem cell transplant (ASCT) then consolidation with KRd for 4 cycles and lenalidomide maintenance in patients with newly diagnosed disease. The combination was associated with a 2-year PFS rate of 91% and a robust depth of response: 70% of patients achieved minimal residual disease (MRD) negativity after consolidation. However, 17% of patients experienced cardiac and vascular AEs; as such, cardiac toxicity is a concern with this regimen, Usmani said.

ASCT in the Era of Novel Agents

With the addition of several multiagent regimens, ASCT continues to provide benefit in the multiple myeloma space, Usmani said.

ASCT With RVd

In the 2009 IFM study,⁵patients 65 years or younger with newly diagnosed disease received RVd for 3 cycles and then underwent stem cell collection. Participants in the transplant arm (n = 350) then received melphalan at 200 mg/m2 and ASCT followed by RVd consolidation for 2 cycles followed by lenalidomide maintenance, whereas patients in the nontransplant arm (n = 350) received RVd for 5 more cycles followed by lenalidomide maintenance (FIGURE 1).⁵The median PFS in the ASCT arm was 50 months, whereas it was 36 months in the no-transplant arm (P<.001). Although these results are promising, more data are needed to validate the role of early transplantation in multiple myeloma, Usmani said.

ASCT With KRd

To evaluate the role of ASCT with KRd, investigators evaluated data from a phase I/II trial in which KRd induction was followed by randomization to either ASCT or no ASCT followed by KRd consolidation for 4 cycles and KRd maintenance for 10 cycles (FIGURE 2).⁶Results showed that KRd plus ASCT resulted in a 3-year PFS rate of 86% versus 80% with KRd alone.

&ldquo;The bottom line for this particular study was that additional ASCT to the schema deepens the response in terms of MRD negativity,&rdquo; Usmani said. &ldquo;It improves 3-year PFS as well.&rdquo;

Monoclonal Antibodies Generate Excitement

Monoclonal antibodies have a novel mechanism of action that allows for additive or synergistic effects with current agents, they are generally well tolerated, and they can be combined with other immunotherapies.

&ldquo;We are all excited about monoclonal antibodies because they can be [used] with existing regimens without adding a lot of toxicity,&rdquo; Usmani said. &ldquo;They do not have overlapping AEs [adverse events] and they can be [used] to target the bone marrow microenvironment, cancer cells, and immune signals.&rdquo;

The GRIFFIN trial is comparing daratumumab (Darzalex) plus bortezomib, lenalidomide, and dexamethasone (D-RVd) to RVd alone in patients with newly diagnosed disease who are eligible for high-dose therapy and ASCT.⁷The primary aim of the trial is to evaluate dose-limiting toxicities during 1 cycle of D-RVd, Usmani said.

The quadruplet regimen was tolerable, depth of response to the combination deepened during maintenance, and ORR improved over time. Updated results from the trial are expected at an upcoming medical meeting.

Finally, the phase III CASSIOPEIA trial examined bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) with (n = 543) or without (n = 542) daratumumab before and after ASCT in patients with newly diagnosed disease.⁸At day 100 after transplantation, 28.9% of patients who received daratumumab plus VTd in the intent-to- treat population achieved a stringent complete response (OR, 1.60; 95% CI, 1.21-2.12;P= .001).

In response to the CASSIOPEIA data, the FDA approved daratumumab for a supplemental indication in combination with VTD for patients who are newly diagnosed and eligible for ASCT.⁹

&ldquo;Monoclonal-based quadruplets appear to be safe in induction and posttransplant consolidation,&rdquo; Usmani concluded. &ldquo;We are getting deeper responses, adequate stem cell mobilization, as well as an improvement in PFS, but we need long-term follow-up.&rdquo;

References

1. Usmani S. Induction and maintenance strategies for transplant eligible NDMM. Slides presented at: Charlotte Plasma Cell Disorders Congress; August 9-11, 2019; Charlotte, NC.
2. 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.
3. 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.
4. Roussel M, Lauwers-Cances V, Robillard N, et al. Frontline therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by 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. bit. ly/2OQRE0u. Accessed September 9, 2019.
5. 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.
6. 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. bit.ly/31upABp. Accessed September 9, 2019.
7. 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 [news release]. Copenhagen, Denmark: Genmab A/S; July 8, 2019. bit.ly/32ffENb. Accessed July 8, 2019.
8. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.Lancet. 2019;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1.
9. Genamd announces U.S. FDA approval of Darzalex (daratumumab) in combination with bortezomib, thalidomide and dexamethasone for frontline multiple myeloma [news release]. Copenhagen, Denmark: Genmab A/S; September 26, 2019. bit.ly/2n0HRaI. Accessed September 26, 2019.