Lancet Haematol: Iberdomide treatment of severe pretreatment of multiple myeloma results, cornerstone of future new treatments?

Treatment for multiple myeloma has improved significantly over the past two decades, bringing overall survival to unprecedented levels, but a significant proportion of patients still relapse, requiring new treatments
.
In addition, patients with disease progression (triple-class exposed) after treatment with proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies remain a challenge, with extremely low survival and lack of available standard treatments
.

The Lancet Haematology recently reports the results of a multicenter, multicohort, open-label, phase 1-2 study in oral iberdomide combined with dexamethasone in heavily pretreated RRMM patients
.
A total of 197 patients were enrolled and treated with iberdomide in combination with dexamethasone (90 in a 3+3 designed dose-escalation cohort and 107 in a dose-expansion cohort).

For 28 days/cycle, iberdomide is administered at D1-21, dexamethasone is administered at 40 mg (20 mg > patients aged 75 years) D1, 8, 15, 22, iberdomide is given in phase I in doses of 0.
3 mg to 1.
6 mg, and in phase II at 1.
6 mg
.

The overall response rate for all doses in the dose-escalating cohort was 32%, and the overall response rate was similar in most patient subgroups (including sex, region, and age), but the total response rate was reduced (30%) in the third line of prior ≥treatment and three types of refractory patients; The median duration of response was 10.
4 months
.
The recommended overall response rate at phase II doses in the dose expansion cohort was 26% (1% sCR, 8% VGPR, 18% PR), including prior ≥ 3rd line therapy and three categories of refractory patients
.
The median PFS in the dose-expansion cohort was 3.
0 months, the median duration of response was 7.
0 months, and the median OS was estimated to be 10.
7 months
.

The median duration of treatment in the dose expansion cohort was 16 weeks, overall controllable in terms of safety, low incidence of grade 3 non-haematological adverse events ≥, and few treatment discontinuations
.
Specifically, 60 (56%) patients required one or more dosing interruptions and 20 (19%) patients required one or more dose
reductions.
All patients experienced at least one adverse event during treatment, and 88 (82%) experienced at least one adverse event
during ≥ level 3 treatment.
The most common adverse events during grade 3 treatment ≥ included neutropenia (48 [45%] patients), infection (29 [27%], including COVID-19 [7 (7%)] and pneumonia [9 (8%)]), anemia (30 [28%]), leukopenia (22 [21%]), and thrombocytopenia (23 [22%]).

。 Non-hematologic adverse events ≥ less common during grade 3 treatment, including gastrointestinal disease (6 [6%]), fatigue (3 [3%]), and rash (3 [3%]).

No venous thromboembolism was reported
.
57 of 107 patients (53%) reported serious adverse events during treatment; Five (5%) discontinued iberdomide
due to adverse events.

The good safety profile of Iberdomide may be related to the unique chemical structure of the new generation of cereblon (CRBN) E3 ligase modulators, which, unlike lenalidomide and pomalidomide, are administered as a single enantiomer (S-isomer) and are relatively tolerant to racemic and therefore maintain the S-isoform structure and avoid some non-hematological adverse events associated with classical immunomodulators, making the drug an attractive adjunct to combination therapy
。

But it also needs to be considered that BCMA-targeted therapies (including CAR T and bispecific antibodies) are also in full swing in patients with RRMM with three types of exposure, so the question is whether iberdomide in combination with dexamethasone will have a place in the crowded track of multiple myeloma? Furthermore, despite the lack of head-to-head randomized comparisons, BCMA-targeted agents appear to be more active than iberdomide plus dexamethasone
in terms of overall response rate, depth of response, and duration of response.
For example, in the Majestec-1 study, teclistamab (bispecific antibody) had an overall response rate of 63%, a median PFS of 11.
3 months, and a median duration of response of 18.
4 months
.
CAR T cells had higher response rates, especially cilta-cel in the CARTITUDE-1 study with an overall response rate of 97.
9 percent, with 82.
5 percent of patients achieving sCR and a 27-month PFS rate of 54.
9 percent
.

However, the disadvantages of BCMA-targeted therapy are its high cost, slow delivery, need for hospitalization, and important non-hematologic toxicities, which may limit its use
.
Therefore, classical drugs with predictable safety profiles, such as iberdomide
, are still required for the treatment of advanced MM.
This is especially true for patients who relapse after BCMA-targeted therapy, and patients who relapse after BCMA-targeted therapy with iberdomide combined with dexamethasone also show preliminary clinical activity with an overall response rate of 25%.

In addition, compared to lenalidomide or pomalidomide, iberdomide shows a higher affinity in binding cereblon, which leads to potent degradation of target proteins, including the transcription factors Ikaros and Aiolos, which translates into more potent antimyeloma and immunomodulatory effects
.
iberdomide has been shown to induce B cell depletion, co-stimulate T cell activity, increase interleukin-2 and interferon-γ production, and increase natural killer cell proliferation
.
Overall, immunomodulatory properties make iberdomide an attractive drug to be tested
in combination with novel immunotherapy strategies and other cornerstones of multiple myeloma treatment, such as anti-CD38 monoclonal antibodies.

In conclusion, iberdomide combined with dexamethasone has shown activity and a manageable safety profile in the treatment of three classes of refractory relapse RRMM, supporting further development studies
.
Although the combination is unlikely to be approved for this indication, its superior safety profile and efficacy over previous immunomodulatory drugs may make iberdomide a potential cornerstone
of myeloma treatment.

References

1.
Lonial S,Popat R,Hulin C,et al.
Iberdomide plus dexamethasone in heavily pretreated lateline relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial.
Lancet Haematol .
2022 Oct 6; S2352-3026(22)00290-3.
doi: 10.
1016/S2352-3026(22)00290-3.

2.
Rodriguez-Otero P, San-Miguel JF.
Iberdomide with dexamethasone: a new backbone for myeloma treatment? Lancet Haematol .
2022 Oct 6; S2352-3026(22)00322-2.
doi: 10.
1016/S2352-3026(22)00322-2.