Phase II trial of nab‐paclitaxel in patients with relapsed or refractory multiple myeloma
Authors: Tania Jain, Amylou C. Dueck, Heidi e. Kosiorek, Brenda F. Ginos, Angela Mayo, Craig B. Reeder, Marta Chesi, Joseph Mikhael, A. Keith Stewart, P. Leif Bergsagel, Rafael Fonseca
Journal: American Journal of Hematology (2016)

To the Editor: Multiple myeloma (MM) remains mostly incurable despite the advent of novel agents including lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab. Paclitaxel is an anti-microtubule agent and nanoparticle albumin bound paclitaxel (nab-paclitaxel) is a formulation of paclitaxel with improved tolerability compared to the solvent-bound formulation 1. Paclitaxel has been studied in MM due to its unique mechanism of action of promoting microtubule assembly. This makes the microtubules resistant to disassembly that is essential for vital interphase and mitotic cellular functions. A study by Dimopoulos et al. exploring the activity of standard chemotherapeutic agents in patients with monoclonal gammopathies, treated for other cancers, had shown that paclitaxel might be active against MM 2. A response in 5 out of 33 (15%) patients with newly diagnosed MM was noted. Later, Miller et al. also reported objective response in 29% patients with previously untreated MM 3. Nab-paclitaxel is an albumin-bound formulation developed to improve the therapeutic effect of paclitaxel and, more importantly, to decrease toxicities seen with solvent-based paclitaxel 4. Nab-paclitaxel was tested in the Vk*MYC mouse model of MM, where it demonstrated anti-tumor activity 5. A response rate of 15–35%, measured by > 50% reduction in M-spike, was noted with single agent paclitaxel in untreated MM. In an analysis by Kortuem et al., which presented the activity of 129 single agents from 228 myeloma trials, paclitaxel was shown to have a 33% activity against MM 6. Activity of novel agents in this report was described as 69% for lenalidomide, 48% for bortezomib, 54% for pomalidomide and 60% for carfilzomib. Based on these observations we also treated one patient on compassionate basis with nab-paclitaxel and were able to exert disease control for several months in this patient who had been previously refractory to multiple lines of therapy for MM. Accordingly, we developed this phase 2 clinical trial for the treatment of MM with nab-paclitaxel in patients with relapsed/refractory MM. This study assessed the efficacy of nab-paclitaxel in patients with relapsed or refractory multiple myeloma using a two-stage Phase 2 Simon optimal design (alpha = 0.10, power = 90%). The first stage required two or more out of 13 evaluable patients to experience a confirmed partial response (PR) or better to continue to the final stage of enrollment. A run-in of six patients was initially completed to confirm tolerability and to ensure at least one patient experienced an unconfirmed minor response before completing the first stage of enrollment. The protocol was registered at clinicaltrials.gov under number NCT01646762. Thirteen patients were enrolled between January 2013 and November 2014. Accrual was temporarily halted after the first six patients were enrolled to review toxicity and response data. At least one patient experienced an unconfirmed minor response and toxicity was acceptable; so enrollment continued to the planned first-stage enrollment target of 13 evaluable patients. Of the 13 patients enrolled, median age was 70 years (range, 46–81 years) and 3 (23.1%) were females. All patients were heavily pre-treated with an average number of prior therapies received being 7.6 (range, 3–12); including novel agents like bortezomib, lenalidomide, pomalidomide, and carfilzomib. Ten (76.9%) patients had received prior autologous stem cell transplantation. Serum M-spike was ≥ 1 g/dL in 5 (38.4%), serum free light chain was ≥ 10 mg/dL in 11 (84.6%), and urine M-spike ≥ 200 mg/24 hr in 3 (23.1%) patients. Median follow-up time was 3.1 months (range, 0.7–19.7 months). Median number of cycles of treatment received was 2 (range, 1–6) and all patients ended treatment. The reason for treatment discontinuation was disease progression in 9 (69.2%) patients, refusal of further treatment in 2 (15.8%) patients, alternate treatments in 1 (7.7%) patient, and death during the study in 1 (7.7%) patient. Disease response was recorded in patients receiving at least one cycle of treatment. The overall response rate (partial response or better) was 2/13 (15%; 95% confidence interval, 1.9–45.5%). Of these, one patient achieved a confirmed very good partial remission (VGPR) by end of cycle 2, which was maintained through cycle 5. Another patient achieved an unconfirmed PR which was followed by progression one cycle later. Four patients (30.8%) were also noted to have stable disease for at least one cycle, while a total of six patients (46.2%) progressed while on treatment. One patient ended treatment after the first cycle and did not have a disease assessment. The observed response data did not meet criteria to continue to the second stage of enrollment and hence, the study was terminated after the first stage. Of the 13 patients evaluated, 4 (30.8%) had dose reductions, 8 (61.5%) had omission of at least 1 dose within a cycle. The most common grade 4 hematological side effect was neutropenia noted in three (23%) patients. Of the non-hematological toxicities, fatigue, nausea, and vomiting, peripheral sensory neuropathy and anorexia were commonly reported; as denoted in table 1. Also, one patient had Grade 5 sepsis in which case death was attributed to progressive myeloma, although drug-induced neutropenia was a contributing factor. Median progression-free survival was 1.6 months (95% confidence interval, 0.9–1.8 months) and median overall survival for this group was 3.7 months (95% confidence interval, 1.7—not reached). As noted in previous studies with paclitaxel, neutropenia was a cause of dose-limiting toxicity with single agent nab-paclitaxel in our study. Although reductions in monoclonal proteins were noted, a desired and sustained disease response rate was not achieved with nab-paclitaxel. This unique mechanism of action of anti-microtubular agents needs to be explored in novel ways to maximize benefit and reduce the toxicities to allow for a clinically meaningful use of this class of drugs in future. Tania Jain1, Amylou C. Dueck2, Heidi E. Kosiorek2, Brenda F. Ginos2, Angela Mayo1, Craig B. Reeder1, Marta Chesi1, Joseph Mikhael1, A. Keith Stewart1, P. Leif Bergsagel1, and Rafael Fonseca1* 1Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona;2Department of Biostatistics, Mayo Clinic, Scottsdale, Arizona