IberVd Elicits Durable Responses in Transplant-Ineligible, Newly Diagnosed Multiple Myeloma

Darrell White, MD, FRCPC

The combination of iberdomide (CC-220) plus bortezomib (Velcade) and dexamethasone (IberVd) produced deep responses with a manageable toxicity profile in patients with transplant-ineligible, newly diagnosed multiple myeloma, according to data from the phase 1/2 CC-220-MM-001 trial (NCT02773030) presented at the 2023 International Myeloma Society (IMS) Annual Meeting.¹

At a median follow-up of 12.63 months (range, 3.91-16.43), the regimen elicited an objective response rate (ORR) of 100%, which included a complete response or better rate of 56.25% and a very good partial response or better (VGPR) rate of 87.50% in the efficacy-evaluable population (n = 16).

Among those who achieved a VGPR or better (n = 14), 43% were minimal residual disease (MRD) negative at 10-5. Moreover, 68.8% of patients responded to the combination in less than 6 weeks, and the median time to first response was 0.72 months (range, 0.69-3.91).

“In this cohort of mostly older patients with transplant-ineligible, newly diagnosed multiple myeloma, IberVd showed high efficacy with deep, ongoing responses,” said Darrell White, MD, FRCPC, of Dalhousie University and Queen Elizabeth II Health Services Centre in Halifax, NS, Canada, in a presentation of the data. “The safety profile was manageable with no new safety signals…Iberdomide induced robust Aiolos degradation and immune stimulation in combination with bortezomib and dexamethasone.”

Lenalidomide (Revlimid), in combination with bortezomib and dexamethasone, or more recently, with daratumumab (Darzalex) and dexamethasone, represents the standard of care for patients with newly diagnosed multiple myeloma. Iberdomide is an oral CRBN E3 ligase modulator, which has been shown to have more tumoricidal activity and immune-modulatory effects than immunomodulatory agents like lenalidomide.

Preclinical findings have indicated that IberVd has synergistic antiproliferative activity with deeper apoptosis vs lenalidomide or pomalidomide (Pomalyst) plus Vd in multiple myeloma cell lines. Notably, earlier data from CC-220-MM-001 showed acceptable safety and early efficacy signals with the regimen in those with relapsed or refractory multiple myeloma.

The trial enrolled patients with multiple myeloma with an ECOG performance status of 0, 1, or 2.2 Documented progression on or within 60 days from the last dose of their last myeloma therapy was required for those with relapsed or refractory disease. Patients with newly diagnosed disease needed to have a documented diagnosis of previously untreated, symptomatic multiple myeloma.

If patients had any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent their participation, they were excluded. Other exclusion criteria included having non-secretory multiple myeloma or a prior history of malignancies beyond multiple myeloma unless they were disease free for at least 5 years.

The trial included phase 1 dose escalation and phase 2 dose expansion. The first phase of the research was comprised of 5 cohorts: cohort A received iberdomide alone, cohort B was given iberdomide plus dexamethasone, cohort E received iberdomide plus daratumumab and dexamethasone, cohort F received iberdomide plus bortezomib and dexamethasone, and cohort G received iberdomide plus carfilzomib (Kyprolis) and dexamethasone.

In dose expansion, those from cohorts A and B were moved to cohorts D and I, where they received iberdomide plus dexamethasone and iberdomide plus dexamethasone post-BCMA treatment, respectively. Those in cohorts E and F moved to cohorts J1 and K; these patients all had transplant-ineligible newly diagnosed multiple myeloma, and they received IberVd or iberdomide plus daratumumab and dexamethasone, respectively.

At the 2023 IMS Annual Meeting, investigators reported the first data from the dose-expansion cohort J1, which evaluated IberVd in patients with previously untreated, symptomatic multiple myeloma who had measurable disease and were not candidates for or were not slated to receive autologous stem cell transplant as their first therapy.¹

This cohort received oral iberdomide at 1.0, 1.3, or 1.6 mg on days 1 to 14 in cycles 1 through 8 and on days 1 to 21 in cycle 9 and beyond; subcutaneous bortezomib at a starting dose of 1.3 mg/m2 on days 1, 4, 8, and 11 in cycles 1 to 8; and oral dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 in cycles 1 to 8 and 40 mg weekly in cycle 9 and thereafter. Of note, cycles 1 to 8 were comprised of 21 days and cycles 9 and higher were comprised of 28 days.

Investigators sought to evaluate the safety and efficacy of the regimen in this population. They also performed a pharmacodynamic (PD) assessment and MRD evaluation.

In the total population in cohort J1 (n = 18), the median age was 77.5 years (range, 57-84) and 66.7% of patients were male. Most patients were White (94.4%), had an ECOG performance status of 1 (61.1%), and stage II disease by the International Staging System criteria (50.0%). The median time since diagnosis was 0.1 years (range, 0.0-0.4), and more than half of patients (61.1%) had high-risk cytogenetics.

At a median follow-up of 14.0 months (range, 0.7-18.0), 72.2% of patients were still receiving treatment with the regimen. The most common reason for discontinuation was patient withdrawal (16.7%), followed by adverse effects (AEs; 5.6%), and physician decision (5.6%). Notably, only 1 patient discontinued due to an AE in the form of peripheral neuropathy.

At a data cutoff of June 21, 2023, the median treatment duration for evaluable patients (n = 17) was 14.0 months (range, 0.7-18.0) and the median number of cycles received was 16.0 (range, 1.0-21.0). The relative dose intensity of iberdomide was 83.9% (range, 55.1%-100.0%).

Additional data indicated that 94.1% of patients required at least 1 dose modification for iberdomide; 76.5% needed dose interruptions and 47.1% needed dose reductions of the agent. Moreover, 23.5% of these patients needed dose reductions of bortezomib due to peripheral neuropathy.

“Hematologic toxicity was relatively common. Neutropenia was the most common hematologic toxicity, occurring [at all grades] in 35% of patients and grade 3/4 occurring in about 24% [of patients],” White said. “That rate is somewhat lower than [what has been seen with] other combination with iberdomide, such as [with] daratumumab.”

The most common treatment-emergent AEs (TEAEs) experienced by at least 25% of patients who received IberVd included peripheral edema (all grade, 64.7%; grade 3, 5.9%), peripheral sensory neuropathy (64.7%; 5.9%), constipation (58.8%; 5.9%), insomnia (47.1%; 5.9%), fatigue (41.2%; 11.8%), neutropenia (35.3%; 11.8%), pain in the extremity (35.3%; 0%), dyspnea (35.3%; 0%), reduced appetite (35.3%; 0%), thrombocytopenia (29.4%; 5.9%), agitation (29.4%; 0%), dysgeusia (29.4%; 0%), anemia (23.5%; 5.9%), and lymphopenia (23.5%; 0%).

Grade 4 TEAEs included neutropenia (n = 2) and thrombocytopenia (n = 1).

Any-grade infection occurred in 76.5% of patients, and 29.4% of patients experienced grade 3 infections. One patient (5.9%) had grade 4 pneumonia. The most common infections included COVID-19 (any-grade, 29.4%; grade 3, 5.9%) and pneumonia (17.6%; 11.8%). “COVID was seen pretty frequently, probably reflecting the timing of the study but most cases were mild,” White noted.

Data from the PD assessment revealed that when iberdomide was paired with Vd, the regimen resulted in robust substrate degradation, with a median decrease that was greater than 50%, as well as immune stimulation, with a 177% median increase in T-cell proliferation.

“These data support further assessment of iberdomide combinations in the frontline setting,” White concluded.

Editor’s note: Dr White reported receiving honoraria from Amgen, Antengene, Bristol Myers Squibb/Celgene, FORUS Therapeutics, GSK, Janssen, Karyopharm Therapeutics, Pfizer, and Sanofi; and serving as board chair for the Canadian Myeloma Research Group.

References

1. White D, Lipe B, Mesa MG, et al. Iberdomide, bortezomib, and dexamethasone (IberVd) in transplant-ineligible newly diagnosed multiple myeloma: results from the CC-220-MM-001 trial. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-41.
2. A study to determine dose, safety, tolerability, drug levels, and efficacy of CC-220 monotherapy, in combination with other treatments in participants with multiple myeloma. ClinicalTrials.gov. Updated September 7, 2023. Accessed September 28, 2023. https://clinicaltrials.gov/study/NCT02773030