A phase one trial of carfilzomib, bendamustine, and dexamethasone in relapsed and/or refractory multiple myeloma

AP-HP, GHU Paris-Saclay, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin Bicêtre, France INSERM, Institut National de la Santé et de la Recherche Médicale Université Paris Saclay (COMUE), Le Kremlin-Bicêtre, France CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France Neurology Department, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre, Le Kremlin Bicêtre, France INSERM U1195 & Paris Saclay University, Le Kremlin Bicêtre, France Faculté de Médecine, Université Paris Saclay, Le Kremlin Bicêtre, France

A phase one trial of carfilzomib, bendamustine, and dexamethasone in relapsed and/or refractory multiple myeloma To the Editor: The incorporation of novel agents including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs) to myeloma treatment regimens have led to substantial gains in overall survival in patients with multiple myeloma over the last 10-15 years.
However, alkylating agents remain an important option in the myeloma therapeutic armamentarium, and their use in combination with novel agents have shown to be an effective treatment strategy for both newly diagnosed and relapsed and/or refractory myeloma patients. 1 Bendamustine is an alkylating agent with a unique structure containing both a nitrogen mustard group and a benzimidazole ring. The latter may also confer antimetabolite properties to bendamustine, which is absent in other alkylator drugs commonly used in myeloma such as melphalan and cyclophosphamide. 2 Moreover, mechanistic studies suggest that bendamustine induces more extensive and durable doublestranded DNA breaks compared to other alkylator drugs, possibly through activation of a more complex base excision DNA repair pathway rather than the alkyltransferase DNA repair mechanism. 3 The safety and efficacy of bendamustine have been demonstrated in combination with IMiDs 4 and the first generation PI bortezomib. 5 More recently, the safety and efficacy of bendamustine in combination with the irreversible second generation PI carfilzomib have been reported in newly diagnosed multiple myeloma patients. 6 We herein report the results of a phase one investigator-initiated study of carfilzomib, bendamustine, and dexamethasone in relapsed and/or refractory multiple myeloma patients (RRMM) (NCT02095834).
In part two of the study, enrollment of an additional 19 patients was planned at the maximum tolerated dose (MTD). During cycles 4-12, the dosing frequency of bendamustine decreased to day 1 only and dexamethasone to days 1, 2, 15, and 16. Starting cycle 13, the dose frequency of carfilzomib decreased to days 1, 2, 15, and 16 and dexamethasone to days 1 and 2 only. Prophylactic granulocyte colony-stimulating factor was not mandated per protocol.  Table S2. The median age was 63 years and median prior lines of therapy was four (range 1-12). A total of 14 (82%) patients were refractory to lenalidomide, seven (41%) patients refractory to pomalidomide, 12 (71%) patients refractory to bortezomib, six (35%) patients refractory to carfilzomib, and 12 (71%) patients dual refractory to both IMiDs and PIs. High-risk FISH including del 17p, t(4;14), t (14;16), +1q21, and/or -1p were present in seven (50%) out of 14 patients with evaluable FISH data.
In the part one dose-escalation phase, three patients each were treated at dose levels one, two, and three, and there were no DLTs. At dose level four, there were two DLTs among six patients treated including one patient with grade three sinusitis, and one patient who had a > 14 day delay to the start of cycle 2 day 1 due to grade three sinus tachycardia. Subsequently, two additional patients were enrolled at dose level three with no DLTs after which the study was prematurely closed to new patient enrollment due to other competing studies.
Given that there were zero DLTs among five DLT-evaluable patients Among 17 response-evaluable patients treated on study, the overall response rate (ORR, ≥ partial response) was 88% and ≥ very good partial response (VGPR) rate was 53% (  Figure S2).
In this phase one study, we demonstrate the safety and preliminary efficacy of the combination of carfilzomib, bendamustine, and dexamethasone in RRMM. The MTD for this study was established at lower doses of carfilzomib and bendamustine compared to a recent phase one study evaluating this combination in newly diagnosed myeloma patients. 6 In that study, the MTD was established at bendamustine 90 mg/m 2 on Patients receiving HMAs had received a median of two prior therapies (range 0-5). Nine patients (75%) received azacitidine (of which one was in conjunction with ruxolitinib), two patients (17%) received decitabine, and one patient (8%) received decitabine and then azacitidine