Treatment Paradigm for R/R Multiple Myeloma Continues to Expand

Natalie S. Callander, MD

While initial disease control in multiple myeloma has improved, relapse is almost always inevitable. However, there are many treatment options available for this patient population, according to a presentation at the NCCN 2021 Virtual Congress: Hematologic Malignancies.

For patient with myeloma who are stem cell transplant eligible, the standard line of therapy is an induction combination of 3 to 4 drugs (daratumumab [Darzalex], bortezomib, dexamethasone [Ozurdex], and thalidomide [Thalomid]), followed by consolidation and stem cell transplant, which is then maintained with lenalidomide, bortezomib, daratumumab, or Ixazomib (Ninlaro). For patients who are not eligible for stem cell transplant, the standard of care if induction followed by continuous therapy. The median progression-free survival using these therapies is often 3 to 5 years.

Relapse is defined in laboratory parameters as > 0.5 mg/dl M protein, > 200 mg/24 hours urinary monoclonal protein, and > 10 mg/dl of involved light chain. Progression by new events is defined as the reemergence of anemia, renal insufficiency, or hypercalcemia, new bone lesion or fracture, and new extra medullary deposit.

After progression, reevaluation of several parameters such as organ, renal, and liver function should be performed. Additionally, a biopsy of the bone marrow and suspicious lesions should be performed along with advanced imagine.

“Clinical assessment is important here. Is the patient more symptomatic now than they were at their initial diagnosis or conversely, maybe this really just does just look like lab abnormalities, the patient is otherwise fine,” said presenter Natalie S. Callander, MD, a professor of hematology oncology at the University of Wisconsin-Madison School of Medicine and Public Health.

When choosing a treatment after relapse, several factors need to be taken into consideration. These include information on previous treatment such as the class of agents previously received and other factors, such as age, proximity to clinic, and coverage of oral chemotherapy agents. 

Several options exist for patients who have received previous treatments. According to Callander, induction of monoclonal antibodies should be strongly considered. Additionally, FDA approved triplet regimens include:

• Daratumumab, lenalidomide, dexamethasone
• Pomalidomide, elotuzumab, dexamethasone
• Isatuximab, pomalidomide dexamethasone
• Daratumumab, carfilzomib, dexamethasone
• Isatuximab, carfilzomib, dexamethasone

The combination of daratumumab, pomalidomide, and dexamethasone is one of the most commonly selected combinations for the first relapse. Phase 2 data suggests an overall response rate (ORR) of 60%. Data from the phase 3 APOLLO trial (NCT03180736), which compared the efficacy of pomalidomide and dexamethasone with or without daratumumab. With daratumumab, ORR was 69% versus 46% without it. The median PFS was 16 months.

In terms of the safety, the most common grade 3/4 AEs were neutropenia (68% in the experimental group vs. 51% in the control group), anemia (17% versus 21%), and thrombocytopenia (17% vs. 18%). Serious AEs occurred in 50% of patients in the experimental arm and in 39% of patients in the control arm. Treatment-emergent deaths were reported in 7% of each group.²

Data from the phase 3 CANDOR trial (NCT03158688) supports the use of carfilzomib, daratumumab, and dexamethasone in this patient population. The median PFS was not reached and the ORR was 84%. Grade 3 of higher AEs were reported in 82% of patients in the experimental group and 74% of patients in the control group. In the experimental group, AE lead to discontinuations in 22% of patients compared with 25% of patients in the control arm.³

The phase 3 IKEMA study (NCT03275285) found that the triplet combination of isatuximab, carfilzomib and dexamethasone produced better responses compared carfilzomib and dexamethasone alone. Patients (n = 302) were randomized 3:2 to receive either the triplet combination (n = 179) or the double combination. The primary end point was PFS. Key secondary end points include ORR and micro residual disease (MRD).

The ORR rate of the experimental triple was 86.6% compared to the ORR of the control of 82.9%. Complete responses were seen in 39.7% of patients in the experimental arm and 27.6% of patients in the control arm. MRD negativity was observed in 29.6% of patients in the experimental arm versus 13.0 in the control.

Treatment-related AEs were seen in 77% of patients in the experimental group versus 67% of patients in the control group. In the experimental group, serious AEs occurred in 59%. In the control group, it was 57% of patients. AEs lead to treatment discontinuation in 15% of patients in the experimental arm and in 14% of patients in control arm.⁴

During late relapse, the fitness and stability of the patients increases in importance. Clinical trials should be considered along with the addition of an alkylator. For patients who never underwent a stem cell transplant, one should be strongly considered. The survival of triple class refractory patients tends to poor. For patients who received at least 4 prior lines of therapy, the NCCN currently recommends the combination of selinexor (Xpovio) and dexamethasone.

“Late relapse clinical trial if possible, many of these patients aren't eligible because of poor counts or other issues. So, selinexor combinations around belantamab mafodotin and CAR T if the patient is stable enough, alkylators and of course, salvage autologous stem cell transplant should always be thought about in this space as well,” said Callander

Selinexor inhibitors XPO1 through reversible covalent modification. In patients who a median number of 7 prior lines of therapy, the ORR was 26.2%. Most AEs were grade 1 or 2 in nature. Grade 3 AEs were reported in 25% of patients and no grade 4 AEs were reported.⁵

Bispecific T-cell engagers also remain an option. Elranatamab has an ORR of 75% and teclistamab has an ORR of 65%. Talqeutamab has an ORR of 63% and cevostamab has an ORR of 61%.

Success has also been seen with selected myeloma CAR T-cell therapies. These include idecabtagene vicleucel (Abecma), which has an ORR of 81% and a duration of response (DOR) of 10.9 months and 25.5 months if it’s a complete response. The KarMMa study (NCT03361748) found that the agent was safe, with the vast majority (78%) of AEs being grade 1/2. Ciltacabtagene autoleucel has an ORR of 98% and a DOR of 22 months.⁶

“One of the things that's quite gratifying about CAR T, if you've had any patients who received it or treated them, is that the response rates are quite fast. Within a month, typically,” said Callander.

_REFERENCE:

_{1.Callander N. Maneuvering the complex web of treatment options for relapsed/refractory multiple myeloma. Presented at the NCCN 2021 Virtual Congress: Hematologic Malignancies. October 14-16.}

_{2.Dimopoulos M, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomized, phase 3 trial. Lancet Oncol. 2021;22(6):801-812. doi: 10.1016/S1470-2045(21)00128-5}

_{3.Dimopoulos M, Quach H, Mateos M, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0.}

_{4. Moreau P, Dimopoulous M, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4}

_{5.Chari A, Vogel D, Gavriatopoulou M, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019; 381:727-738. doi:10.1056/NEJMoa1903455}

_{6.Munshi N, Anderson L, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021; 384:705-716 doi:10.1056/NEJMoa2024850}