Carfilzomib Thalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

  • STATUS
    Recruiting
  • participants needed
    100
  • sponsor
    National University Hospital, Singapore
Updated on 10 August 2022

Summary

All patients with multiple myeloma (MM) are destined to relapse even with the best available approved agents. Median OS from diagnosis in the current era is reported at 5.4 years. Given that myeloma remains an incurable disease, future improved OS is therefore reliant on the expansion of salvage options for patients with RRMM.

Carfilzomib (formerly PR-171) is a tetrapeptide epoxyketone-based irreversible inhibitor of the 20S proteasome. This second-generation proteasome inhibitor (PI) is structurally and mechanistically different to the dipeptide boronic acid PI, bortezomib. Compared to bortezomib, carfilzomib showed less off-target activity that may account for the reduced myelosuppression and reduced neuropathy that is observed compared to bortezomib. As monotherapy, carfilzomib has demonstrated robust and durable activity in heavily pre-treated patients with RRMM in phase I and II trials The idea of combining a PI and an immunomodulatory drug (IMiD) such as thalidomide or lenalidomide is attractive in MM due to the efficacy previously demonstrated with combination bortezomib, thalidomide and dexamethasone. Such efficacy obviates the need for chemotherapy that is known to induce genetic instability and in turn gives rise to secondary cancers. In combination with lenalidomide (25mg), Niesvizky and colleagues have demonstrated a maximum planned dose (MPD) of carfilzomib as 20/27 mg/m2 with promising safety and efficacy. Combination carfilzomib and thalidomide, as opposed to lenalidomide, is practically a more affordable regimen that will be more applicable to the Asia-Pacific region.

Description

All patients will continue treatment for 18 cycles (12 induction cycles, 6 maintenance cycles) unless development of adverse events that require early cessation of treatment. Patients will be followed up for progression and survival until 1 year following the completion of the last patient's final cycle of induction therapy.

Proteasome inhibitors and IMiDs have different but overlapping mechanisms of anti-MM activity. In the clinical setting, both proteasome inhibitors and IMiDs enhance the activity of dexamethasone, and synergy has previously been demonstrated between the first in class proteasome inhibitor, bortezomib[16] and the immunomodulatory drug lenalidomide[17]. Relative to bortezomib, carfilzomib demonstrated increased apoptosis in MM cell lines, and induce high ORR in both bortezomib-nave and resistant patients.

We hypothesise that carfilzomib will induce a synergistic anti-myeloma activity when combined with the first in class immunomodulatory drug thalidomide, and dexamethasone. Thalidomide is a cheaper immunomodulatory drug that is more accessible in the Asia-Pacific region compared to lenalidomide. This makes the combination of carfilzomib, thalidomide and dexamethasone a more viable salvage option for patients in this region.

In the PX-171-006 study, combination carfilzomib lenalidomide and dexamethasone induced a CR/VGPR in 59% of patients. The maximum per protocol doses of carfilzomib (27g/m2) was used safely with full dose lenalidomide (25mg po daily days 1-21 every 28 days) and dexamethasone (40 mg po weekly), and the MTD of carfilzomib was not reached.

Carfilzomib 56mg/m2 was tolerable in phase II trials and induced durable responses in patients with relapsed and/or refractory myeloma. The most common grade 3/4 side effects of lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), and pneumonia (18%) are not expected to overlap significantly with the expected side effects of thalidomide [15].

We will combine carfilzomib 20/56mg per m2 in combination with thalidomide 100mg daily and dexamethasone 40mg weekly. The rationale for dose escalation of carfilzomib to 56mg/m2 is based on two findings: a) the 20/56mg/m2 dose escalation was well tolerated in the PX-171-007 trial and b) no dose limiting toxicities were seen with carfilzomib 20/27mg/m2 when combined with lenalidomide and dexamethasone in patients with RRMM who were heavily pre-treated, in the PX-171-006 and PX-171-009 trial. The rationale for assigning an equal number of patients between the ALLG sites and AMN sites is to avoid bias with respect to potential biological differences between patients in Asia and Australia/New Zealand.

Details
Condition Relapsed and/or Refractory Multiple Myeloma
Treatment Carfilzomib, Thalidomide and Dexamethasone
Clinical Study IdentifierNCT03140943
SponsorNational University Hospital, Singapore
Last Modified on10 August 2022

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