Braunstein Reflects on the Rise of Quadruplet Therapies in Multiple Myeloma

Marc J. Braunstein, MD, PhD

Triplet therapies have become the accepted standard of care in multiple myeloma, according toMarc J. Braunstein, MD, PhD, who added that emerging quadruplet therapies are also generating excitement in the field.

“As seen in the up-front setting, there has been an explosion of therapies, not just for patients with relapsed/refractory multiple myeloma who progress after induction therapy, but also for patients who progress after multiple lines of therapy,” said Braunstein, an assistant professor in the Department of Medicine at NYU Long Island School of Medicine. “In the field, we appreciate that clonal resistance is truly what leads to shorter remission over time. Now that we have more therapies to offer, we are seeing several new combinations.”

In a special episode of OncLive® On Air, Braunstein, who is also the course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program at NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, highlighted pivotal research on the use of triplet and quadruplet regimens in the up-front and relapsed/refractory settings presented during the 2020 ASCO Virtual Scientific Program.

VRd Remains the Standard of Care in Newly Diagnosed Multiple Myeloma

Carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) did not improve progression-free survival (PFS) in patients with newly diagnosed multiple myeloma, according to results of the phase 3 ENDURANCE (E1A11) trial (NCT01863550).¹

In the randomized analysis, investigators compared the use of KRd with that of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) in treatment-naïve patients with multiple myeloma who had an ECOG performance score of 0, 1, or 2. Patients also had to have acceptable hematological parameters and organ function and measurable disease in serum, urine, or bone marrow to be included. If they had grade 2 or higher peripheral neuropathy or New York Heart Association III or IV heart failure or myocardial infarction less than 6 months before study start, they could not participate.

The first co-primary end point of the trial was PFS for the induction randomization and the second co-primary end point was overall survival (OS) for the second randomization. Key secondary end points included overall response rate, minimal residual disease negativity rate per flow cytometry, time to progression, OS, and toxicity.

“In the field, this trial was patiently awaited for some time because we were eager to see the head-to-head comparison of a triplet regimen that includes either the protostome inhibitor bortezomib or carfilzomib in combination with lenalidomide and dexamethasone, the 2 most common up-front regimens in the space,” explained Braunstein.

A total of 1087 patients were randomized 1:1 to receive VRd (n = 542) or KRd (n = 545). Patients on the VRd arm received 1.3 mg/m² of bortezomib on days 1, 4, 8, and 11 for cycles 1-8 and the same dose on days 1 and 8 for cycles 9-12; 25 mg of daily lenalidomide on days 1-14; and 20 mg of dexamethasone in on days 1, 2, 4, 5, 8, 9, 11, and 12 for cycles 1-4, and then 10 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for cycles 5-8, followed by 10 mg on days 1, 2, 8, and 9 for cycles 9-12. Treatment cycles were repeated every 3 weeks for 12 cycles.

Patients on the KRd arm received 20 mg/m² of carfilzomib on days 1 and 2 and 36 mg/m² on days 8, 9, 15, and 16 of cycle 1 followed by 36 mg/m² on days 1, 2, 8, 9, 15, and 16 for cycles 2-9; 25 mg of lenalidomide on days 1-21, and 40 mg of dexamethasone on days 1, 8, 15, and 22 for cycles 1-4 and 20 mg on days 1, 8, 15, and 22 for cycles 5-12. This treatment cycle was repeated every 4 weeks for 9 total cycles.

Results showed a median PFS of 34.4 months (95% CI, 30.1–not evaluable) in the VRd arm compared with 34.6 months (95% CI, 28.8-37.8) in the KRd arm (HR, 1.04; 95% CI, 0.83-1.31; P = .742). In addition, on the VRd arm, 21 patients (4.0%) experienced a stringent complete response (sCR), 57 (10.8%) achieved a CR, 263 had a very good partial response (VGPR), and 103 patients had a partial response (PR). On the KRd arm, 31 patients (5.9%) achieved a sCR, 65 (12.4%) had a CR, 292 patients (55.5%) experienced a VGPR, and 68 (12.9%) had a PR. The median OS from induction randomization was not yet reached in either arm.

Moreover, treatment-related adverse effects (TRAEs) were mostly grade 3-5 and consisted of peripheral neuropathy, dyspnea, hypertension, heart failure, and acute kidney injury. The TRAEs of interest were cardiac, pulmonary, and renal, as well as peripheral neuropathy.

“One of the criticisms of this study is that it did not include patients with high-risk multiple myeloma who, in prior studies, showed a benefit with carfilzomib,” Braunstein noted. “Notably, approximately 27% of patients in each group went on to receive autologous stem cell transplant, which was not planned according to the design of the study.”

Based on these data, the investigators concluded that VRd should remain the standard of care.

Isatuximab/KRd for Newly Diagnosed, High-Risk Multiple Myeloma

Isatuximab-irfc (Sarclisa) plus KRd can be safely administered in patients with high-risk multiple myeloma, inducing deep responses, according to results from the interim analysis of the GMMG-concept trial presented during the meeting; this was the first study to investigate the quadruplet regimen in this patient population.²

In the multicenter, open-label, phase 2 analysis, investigators evaluated the efficacy of isatuximab, an anti-CD38 monoclonal antibody, in combination with KRd in patients with high-risk, newly diagnosed multiple myeloma. Patients could have received up to 1 cycle of anti-myeloma treatment prior to inclusion. They had to show acceptable organ function in order to participate.

The primary end point of the trial was minimal residual disease (MRD) negativity by flow cytometry to a sensitivity of 10-5and the secondary end point was PFS. Tertiary end points included ORR, duration of MRD negativity, OS, and quality-of-life (QOL) assessment.

“This was an investigator-initiated study that ultimately evaluated a quadruplet regimen, which is the trend that we are pursuing these days in terms of up-front therapy,” noted Braunstein.

In the analysis, 153 patients were randomized 1:1 based on transplant eligibility. In arm A, 117 transplant-eligible patients received 6 cycles of isatuximab plus KRd induction, 4 cycles of isatuximab plus KRd consolidation, and isatuximab plus KR maintenance. In arm B, 36 transplant-ineligible patients received the same course of treatment with 2 additional cycles of isatuximab plus KRd induction.

The interim analysis reported on a total of 50 patients: 46 in arm A and 4 in arm B. Results showed an ORR of 100% with the quadruplet, a VGPR or greater of 90%, a CR/sCR of 46%. In arm A, 41 of 46 patients achieved a VGPR or greater, while all patients in arm B achieved a VGPR. MRD was assessed in a total of 33 patients in arm A during induction and results showed that 20 patients were MRD negative, 11 were MRD positive, and 2 were not evaluable.

With regard to safety, the most common hematologic treatment-emergent AEs (TEAEs) reported were grade 3 or 4 and consisted of leukopenia (26%), neutropenia (34%), lymphopenia (28%), anemia (10%), and thrombocytopenia (14%).

Any-grade nonhematologic TEAEs included upper-respiratory tract infections (18%), pyrexia (12%), rash (16%), peripheral sensory neuropathy (16%), nasopharyngitis (10%), hypertension (12%), cardiac failure (4%), and infusion reaction (32%). No deaths were reported on the study.

“We now have doublet, triplet, and quadruplet up-front regimens for patients with newly diagnosed multiple myeloma,” Braunstein said. “The more agents you combine synergistically to target the plasma cell clones, the deeper response rates you can achieve and that consistently correlates with longer remissions.”

Belantamab Mafodotin Triplet for Relapsed/Refractory Multiple Myeloma

Belantamab mafodotin in combination with bortezomib and dexamethasone (B-Vd) demonstratedan acceptable safety profile, according to preliminary findings from a cohort of the phase 1/2 DREAMM-6 trial also presented during the meeting.³

In the 2-part, open-label, phase 1/2 study, investigators evaluated the safety and efficacy of the addition of belantamab mafodotin to B-Vd, 2 standard-of-care doublet regimens, in patients with relapsed/refractory multiple myeloma who have previously received at least 1 line of therapy. To be eligible for the trial, patients had to have measurable disease, acceptable organ function, and an ECOG performance status of 0 to 2. Those who underwent previous autologous stem cell transplant and those who were not candidates for transplant were permitted, along with those who were refractory to bortezomib.

The primary end points of the trial were safety, tolerability, and ORR as defined by the International Myeloma Working Group Uniform Response Criteria. Key secondary end points included preliminary clinical activity, further safety/tolerability examination, pharmacokinetic assessments, and the health-related QOL impact of the combination.

In arm A, belantamab mafodotin was combined with lenalidomide and dexamethasone (B-Rd) and, in arm B, belantamab mafodotin was combined with B-Vd.Part 1 was a dose-escalation phase and part 2 is an ongoing dose-expansion phase for each of the arms with either single (day 1) or split dosing (day 1 and 8) for belantamab mafodotin at 2.5 mg/kg or 3.4 mg/kg.

Results on 18 patients who received the 2.5-mg/kg dose of B-Vd experienced an ORR of 78% (95% CI, 52.4%-93.6%). In addition, patients demonstrated a clinical benefit rate of 83% (95% CI, 58.6%-96.4%) and the VGPR was 50%. The duration of response with the combination had not yet been reached.

Moreover, 89% of patients experienced grade 3 or 4 AEs. Dose reductions were required in 72% of patients because of AEs and all patients experienced a dose interruption or delay due to keratopathy and/or thrombocytopenia. Notably, all toxicities were found to be clinically manageable.

“I believe belantamab mafodotin offers a unique therapeutic approach, which is very much needed in [patients with] refractory multiple myeloma,” Braunstein concluded.

References

1. Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma: Results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl 18):LBA3. doi:10.1200/JCO.2020.38.18_suppl.LBA3
2. Weisel K, Asemissen AM, Besemer B, et al. Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial. J Clin Oncol. 2020;38(suppl 15): 8508. doi:10.1200/JCO.2020.38.15_suppl.8508
3. Nooka AK, Stockerl-Goldstein K, Quach H, et al. DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2020;38(suppl 15):8502. doi:10.1200/JCO.2020.38.15_suppl.8502