Treatment of Early Relapsed Multiple Myeloma with Iberdomide, Daratumumab and Dexamethasone
Presentation
Our patient is a 56-year-old female with R-ISS stage 1 IgG kappa multiple myeloma initially diagnosed in 2020. At diagnosis she presented with worsening back pain and fatigue. A PET scan demonstrated multiple lytic lesions throughout the skeleton with an L4 compression fracture requiring kyphoplasty. Initial diagnostic labs included a hemoglobin of 9.9 gm/dL, normal renal function and calcium, an M-spike of 6.4 g/dL of an IgG kappa paraprotein. A bone marrow biopsy demonstrated 40% plasma cells with normal cytogenetics and no abnormalities on FISH. Therefore, the patient was diagnosed with an R-ISS stage I IgG kappa myeloma. She had no other known health issues other than hypothyroidism and was an active swimmer.
At that time, she underwent induction therapy with daratumumab, lenalidomide, bortezomib, and dexamethasone (DRVd) for four cycles followed by autologous stem cell transplant achieving stringent complete response. She then went on lenalidomide maintenance at 10 mg for days 1-21 on a 28-day cycle. She received zoledronic acid for 2 years and continued an antiviral and antithrombotic prophylaxis with aspirin 81 mg daily. She was doing well until 2026 when she had a biochemical relapse with a slow rise in her paraprotein and free kappa light chain (FKLC). She developed right upper extremity pain, and a PET scan noted a new right humeral lesion. A bone marrow biopsy showed no new high-risk features. There was no other pertinent history.
Treatment
Our patient is now 62 years old and progressing on maintenance lenalidomide. At this point, she has many options to consider including CAR-T, bispecific antibodies, and a host of other therapies. We discussed the potential treatment options, including a clinical trial. Iberdomide was just FDA-approved, and our patient had tolerated daratumumab well and not progressed on it. After discussing all the options and weighing the pros and cons of each, our patient preferred to start iberdomide, daratumumab, and dexamethasone (lberDd) and save a CAR-T therapy for later. Our patient initially had a slow progression though once she had a new active lesion we wanted to start her on therapy right away. Her myeloma continues to be standard risk which was also a consideration.
She continues an antiviral with valacyclovir, started on Pneumocystis jirovecii pneumonia prophylaxis since she is receiving dexamethasone, and continued on the aspirin 81 mg daily. We also started her back on zoledronic acid due to the new lytic lesion. Her day-1 paraprotein was 1.24 g/dL and her FKLC was 49 mg/L. Her labs were otherwise stable. After completing one cycle, she had a reduction in her paraprotein and her free kappa normalized. She noted some fatigue, although she remained very active. Her right arm pain resolved on treatment and the plan is to repeat her PET scan after three cycles of therapy. She did experience a drop in her counts with treatment, although her numbers improved by the time she came to start cycle two of therapy. She is early in her treatment, feels very comfortable with the regimen, and is already showing a good response.
Discussion
Iberdomide (Iber) is a first-in-class cereblon E3 ligase modulator (CELMoD) which is a next-generation immunomodulatory agent FDA-approved in August 2026. IberDd was approved for relapsed or refractory myeloma in patients who have had at least one prior line of therapy and included a proteosome inhibitor and an immunomodulatory agent. CELMoDs work by binding to cereblon (CRBN) a protein that lives inside myeloma cells, and have a twenty-fold higher affinity than older immunomodulatory agents like lenalidomide. Myeloma cells need two proteins to survive, Ikaros (IKZF1) and Aiolos (IKZF3). Iber directs the cell’s disposal system (the proteasome) to destroy these proteins leading to cell death. While it does cause cell death, it also enhances immune activation. Because of the complete binding, it successfully bypasses many common mutations that make myeloma cells resistant to lenalidomide or pomalidomide. This produces a faster and deeper immunomodulatory and antitumor effects reversing T-cell exhaustion.1-5
Early trials4 showed activity of CELMoDs in combination with Iber and dexamethasone (dex) and IberDd with an overall response rate (ORR) of 26.2% in Iber and dex vs 48% with IberDd. The phase III EXCALIBER-RRMM trial evaluated IberDd vs standard daratumumab, bortezomib, dexamethasone (DVd) in 939 randomized patients who had 1-2 prior lines of therapy. The dual primary endpoints were minimal residual disease- (MRD) negative compete response (CR) rates and progression free survival (PFS). MRD-negative CR was doubled in the IberDd arm at 41.1% vs 20.7 in DVd. PFS reached 42 months for IberDd vs 20 months for DVd, and ORR was 88.9% with IberDd vs 76.1% with DVd. The most common side effects include neutropenia all grades at 90.2% with infections at 78.9%. Venous thromboembolism was 6.4%. Iber dosing is a 1-mg tablet given days 1-21 on a 28-day cycle with or without food, daratumumab, and hyaluronidase-fihj subcutaneous injection are weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks for cycles 7+. Dexamethasone is weekly with adjustments commonly occurring.3
For this patient, she had many options for the next line of therapy with this early relapse. Choosing IberDd, she will need to be monitored closely for neutropenia and adding filgrastim as needed can help maintain her white count and not delay treatment. Iber can overcome resistance to lenalidomide or pomalidomide making it a good choice for someone who has progressed on a prior immunomodulatory agent. IberDd offers a deep, durable response and avoids exhausting T cells, so T-cell–redirected therapies are still available for future use.
APPs have more treatment modalities to consider when discussing next treatment options and need to consider what type of relapse, risk factors, prior lines of therapy, and rate of progression when choosing a new line of therapy. This was also an opportunity to have a shared decision with our patient about treatment options and her preference.
This case is an example of an early relapse with many options, and we need to be strategic about next therapy while taking into consideration what is important to our patient. APPs continue to be an important member of the care team when discussing and deciding the next line of therapy.
References
Matyskiela ME, Zhang W, Man HW, et al. A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J Med Chem. 2018;61(2):535-542. doi:10.1021/acs.jmedchem.6b01921
Thakurta A, Pierceall WE, Amatangelo MD, Flynt E, Agarwal A. Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Oncotarget. 2021;12(15):1555-1563. Published 2021 Jul 20. doi:10.18632/oncotarget.27973
Lonial S, Dimopoulos MA, Berdeja JG, et al. EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma. Future Oncol. 2025;21(14):1761-1769. doi:10.1080/14796694.2025.2501920
Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822-e832. doi:10.1016/S2352-3026(22)00290-3
Lonial S, Dimopoulos MA, Gavriatopoulou M, et al. Iberdomide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (EXCALIBER-RRMM): an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. Published online September 25, 2026. doi:10.1016/S1470-2045(26)00450-X