Further Evolution of Metronomic Therapy Extended to 28 Days (Metro28) for Relapsed Refractory Multiple Myeloma (RRMM)

Despite the increasing availability of novel agents for RRMM, many patients run out of treatment options due to disease refractoriness and/or progressive toxicities, both hematological (cytopenia) and non-hematological (cachexia, asthenia, renal and cardiopulmonary).Patients who are refractory to both proteasome inhibitors and immunomodulatory agents (IMIDs) carry an ominous prognosis with a median overall survival (OS) of 9 months (Leukemia, Kumar 2013). We previously reported on the efficacy and toxicity profiles of a metronomically scheduled chemotherapy regimen administered over the course of 16 days (Haematologica, Papanikolaou 2014). Encouraged by the results of that treatment, we have since modified metronomic chemotherapy to cover a 28-day period (metro28). The regimen consisted largely of bortezomib 1.0mg/m2 on days 1, 4, 7, 10, 13,16,19, 22,25,28; along with dexamethasone 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 100mg days 1-28, continuous 28 day infusion of doxorubicin 1.0mg/m2 (0.5mg/m2 for Ejection Fraction <40%) and cis-platinum 1.0mg/m2 (0.5mg/m2 for creatinine >2mg/dL), with the addition of arsenic trioxide (ATO) at 0.1mg/kg on each day after bortezomib; and lately vincristine (VCR) at 0.07mg daily dose by continuous infusion for 28 days. Patient characteristics included age >65yr, 46%; female, 33%; cytogenetic abnormalities at any time prior to therapy (CA), 86%; Gene Expression Profile (GEP) 70-defined high risk, 44%. The median number of prior therapies was 8 (1-64), prior transplants, 83% (1, 2, >=3), 20%, 32%, 31%; prior exposure to novel agents including Carfilzomib/Pomalidomide was 81%. Thrombocytopenia prior to treatment was present in 75% including thrombocytopenia <50,000/uL in 15%. Clinical outcomes are depicted in Figure 1. At a median follow up of 8.1 months, the median number of metro 28 cycles administered was 1 (1-5), with 37% achieving a partial response and median OS not yet reached. Interestingly, the 6 month - partial response duration estimate for the patients achieving PR was 53% (Figure 1A), while the one year OS estimate for all patients receiving metro 28 was 59% (Figure 1B). Prognostic factors that held statistical significance in univariate analysis for overall survival were albumin <3.5 g/dl (HR 2.56, P=0.009), beta-2-microglobulin (B2M) ≥3.5 mg/L (HR 3.03, P=0.003), LDH≥ 190 U/L (HR 2.81, P=0.003), GEP-70 High Risk (HR 2.32, P=0.048), GEP-5 High Risk (HR 5.75, P<0.001) (Figure 1C) and GEP PR subgroup designation (HR 3.71, P=0.003). In multivariate analysis, albumin < 3.5 g/dL (HR 2.81, P=0.035), B2M≥ 3.5 mg/L (HR 3.4, P=0.017), GEP PR subgroup (HR 3.8, P=0.012), and GEP-5 High Risk (HR 8.58, P<0.001) (Figure 1C) achieved statistical significance. The majority of cycles administered in the patient population were done in the outpatient setting (81%), while secondary admissions due to regimen toxicity occurred in 36% of the cycles administered. Grade 3 & 4 neutropenia and thrombocytopenia within 3 months from the start of the metronomic treatment were evident in 64% and 78% respectively of the cases. Treatment related mortality was 2%, due to one instance each of grade 5 infection and cerebrovascular event. In conclusion 28 day metronomic therapy is a feasible treatment with acceptable toxicity and encouraging preliminary results both in terms of ORR and OS for RRMM.

Figure 1A

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Figure 1A

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Figure 1B

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Figure 1B

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Figure 1C:

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OS by GEP5

Figure 1C:

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OS by GEP5

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