Is There a Role for Metronomic Chemotherapy in Patients with Highly Refractory Multiple Myeloma?

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Metronomic chemotherapy using a multidrug regimen appears beneficial and fairly well tolerated in patients with multiple myeloma that is highly refractory to previous treatments, investigators from the Myeloma Institute for Research and Therapy in Little Rock, Arkansas, reported.1 Their results were presented at this year’s ASCO Annual Meeting.

Metronomic chemotherapy entails the use of repetitive low doses of chemotherapeutic agents, with regimens designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor.

“Multirelapse and multirefractory myeloma represents a great challenge in myeloma therapy. Based on the concept that low-dose continuous application of certain cytotoxic drugs can inhibit tumor progression, we developed a treatment schema of metronomically scheduled therapy for myeloma,” said Xenofon Papanikolaou, MD.

Study Design

The study included 187 patients who received at least one cycle of metronomically scheduled therapy. Their median number of prior therapies was 14 (but ranged up to 51); 79% had prior stem cell transplant, usually multiple transplants, as is the custom at this cancer center.

Treatment was as follows:

  • Bortezomib (Velcade), 1 mg/m2 on days 1, 4, 7, 10, 13 and 16
  • Thalidomide (Thalomid), 200 mg on days 1 to 16
  • Dexamethasone, 20–40 mg on days 1, 4, 7, 10, 13 and 16
  • Doxorubicin, 3 mg/m2 by continuous infusion on days 1 to 16
  • Cisplatin, 1.5–3 mg/m2 continuous infusion on days 1 to 16
  • Sirolimus (Rapamune), 3 mg on day 1, then 1 mg days 2 to 16 (depending on renal function)

These were the most common dosages (80% of cases). Variations included thalidomide, 50–200 mg on days 1 to 16, and doxorubicin, 1–3 mg/m2 by continuous infusion on days 1 to 16.

Key Results

The overall response rate was 65%, which included complete responses (6%), very good partial responses (7%), partial responses (36%), and minor responses (16%). Stable disease was achieved by 15% of the patients.

The median time to best response was 27 days (range of 6 to 203), the investigators reported. Interestingly, according to PET scans, 73% of patients with extramedullary disease had a response. No parameters appeared to be predictive of a response to treatment.

The median overall survival was 1.1 year, and median progression-free survival was 3.7 months.

Hematologic toxicities occurred in most patients, including grade 4 leukopenia (74%), anemia (17%), and thrombocytopenia (89%). “The true effect of metronomic therapy regarding hematologic toxicity [in these patients] is difficult to determine due to the presence of cytopenias prior to the initiation of metronomic therapy,” Dr. Papanikolaou noted.

No grade 5 hematologic toxicities were reported, and the incidence of grade 4 neutropenic fever was only 1%. Nonhematologic toxicities were manageable. Paresthesia and numbness were the most common complaints and were transient. ■

Disclosure: Dr. Papanikolaou reported no potential conflicts of interest.


1. Papanikolaou X, Szymonifka J, Mitchell A, et al: Metronomic therapy for heavily pretreated relapsed/refractory multiple myeloma. 2012 ASCO Annual Meeting. Abstract 8041. Presented June 2, 2012.

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