To the Editor:
Cancer, SAKK, dual-refractory myeloma, death, neutropenia, neutropenic fever, toxicity, infections, anemia, superior myeloma, PD, Toxicity, myelosuppression, tBased
DISEASE PROGRESSION, NEUTROPENIA, NEUTROPENIC FEVER, ADVERSE EVENTS, DISEASE, EVENTS, INFECTIONS, THROMBOCYTOPENIA, RELAPSED/REFRACTORY MULTIPLE MYELOMA, ANEMIA, MYELOMA, CANCER
Pomalidomide is a third-generation, oral immunomodulatory drug with activity in patients with relapsed/refractory multiple myeloma (rrMM). Pomalidomide (4 mg daily on a 21/28 day cycle), together with weekly dexamethasone, is an established standard treatment for rrMM, resulting in a remarkably consistent progression-free survival (PFS) of 4.0–4.6 months in two phase III trials, MM-003 and MM-010 [More recently, the addition of proteasome inhibitors or monoclonal antibodies to this pomalidomide-dexamethasone backbone has yielded superior myeloma control at the expense of increased toxicity [Thus, strategies to deliver pomalidomide + dexamethasone on a less toxic schedule are of interest. Lacy et al. tested two different pomalidomide total doses in a sequential non-randomized trial (4 mg for a 28/28-day cycle and 2 mg for a 28/28-day cycle) and observed similar activity of both dosing levels in dual-refractory myeloma patients, while the 2 mg dose appeared to have better tolerability [Pomalidomide is commercially available as non-divisible capsules of 1, 2, 3, or 4 mg strength, respectively. The retail price of pomalidomide (950 USD per capsule, independent from capsule strength) links pomalidomide drug costs rather to the number of treatment days than to the actual drug dose delivered. As such, alternate-day treatment schedules may help to reduce the drug costs of pomalidomide treatment. Indeed, several aspects support that alternate-day pomalidomide dosing may be equally effective as standard daily dosing:Pomalidomide has a longer initial plasma half-life (tBased on this, we tested the activity and safety of alternate-day dosing of 4 mg pomalidomide on a 28/28 day schedule in a multicenter, open-label phase 2 trial (OptiPOM; SAKK 39/16) in combination with low-dose weekly dexamethasone, in rrMM patients exposed to or intolerant to lenalidomide and bortezomib [Treatment consisted of continuous oral pomalidomide 4 mg on alternate days of 28-day cycles, plus weekly oral dexamethasone 40 mg (or 20 mg if aged >75 years), until confirmed disease progression (PD) or intolerance. Prophylactic valaciclovir, cotrimoxazole, and acetylsalicylic acid were mandatory, while primary prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed (Supplementary Fig. The primary study endpoint was overall response rate (ORR), defined as minimal response or better (current IMWG criteria), confirmed by a central committee [The trial was constructed by the Swiss Group for Clinical Cancer Research (SAKK) using a non-inferiority design, comparing the ORR of our alternate-day pomalidomide schedule versus standard-dose pomalidomide in MM-003 [Due to premature trial termination, all analyses are descriptive without hypothesis testing. ORR was evaluated in all patients with valid response assessments. PFS (time from registration to disease progression/death) and OS (time from registration to death) were analyzed in an intent-to-treat Kaplan-Meier analysis. Observations were censored on December 31, 2020. Safety was analyzed in all patients who received ≥1 dose of study drug. Between October 2018 and October 2020, 34 patients (median age 75 years, range 52–87) were enrolled at 8 Swiss centers. Median time from myeloma diagnosis was 5.1 years (range 1.9–16.8 years). All patients had received lenalidomide, bortezomib, and an alkylating agent, with a median of 3 (range 2–8) prior lines of therapy. A significant proportion was pretreated with carfilzomib (29%) and daratumumab (27%). Fourteen (41%) patients had high-risk cytogenetic abnormalities (supplemental Table Median treatment duration was 3.6 months, which was overall well tolerated. Toxicity consisted primarily of myelosuppression and infections (Table Treatment-related adverse events ≥3 during treatment phase in present OptiPOM study (alternate-day pomalidomide 4 mg; The ORR was 29.4% (95% confidence interval [CI] 16.9─44.8%), with 3 very good partial responses (VGPRs), 6 partial responses (PRs), and 1 MR; Fifteen patients (44%) achieved stable disease. Eight patients (24%) had PD after cycle 1 (Table Responses and survival rates in present OptiPOM study (alternate-day pomalidomide 4 mg; Importantly, the rate of grade 3/4 events (infections, neutropenia, anemia, thrombocytopenia) of our alternate-day pomalidomide schedule appeared numerically almost 50% lower than that reported for trials using standard dosing, despite the lack of G-CSF prophylaxis and a higher proportion of patients aged >75 years. While mandatory antibacterial and antiviral prophylaxis may have contributed to the low number of infections, the low hematologic toxicity suggests that alternate-day pomalidomide dosing may be a valid strategy to improve safety.Although our cohort differs from phase III trials in the same setting by a lower median number of prior lines of therapy (3 vs 5), the time from diagnosis was comparable. Conversely, the proportion of patients aged > 75 years or carrying high-risk cytogenetics was higher in OptiPOM, and a sizeable number of our patients had already been exposed to next-generation drugs such as carfilzomib and daratumumab.The pharmacokinetics of pomalidomide is dominated by CYP1A2-mediated metabolism. The clinically most important and relevant inhibitors of CYP1A2 in this setting are fluoroquinolones (ciprofloxacin, ofloxacin), so their excess use could in theory explain the preserved efficacy of alternate-day pomalidomide dosing observed. However, antimicrobial prophylaxis was mandatory in our trial with cotrimoxazole, and neutropenic fever was not observed so it can be excluded that excess fluoroquinolone use may have biased the efficacy results in our cohort.The interpretation of our trial data is limited by its premature closure which precludes comparison-based conclusions. However, the cohort of 34 patients treated with alternate-day pomalidomide dosing is the largest reported to date and is consistent with earlier trial data suggesting that pomalidomide treatment on alternate days is active and safe.In summary, our OptiPOM data provide additional evidence that alternate-day pomalidomide dosing may be a reasonable, well-tolerated option to deliver pomalidomide, especially to patients at increased risk for treatment-related toxicity, while at the same time decreasing pomalidomide drug costs. The potential of alternate-day pomalidomide dosing schedules to improve the safety and cost-efficacy of pomalidomide-containing triplets should be clarified in a definite trial.