Hydroxychloroquine and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

OBJECTIVES:

Primary

- To establish the dose-limiting toxicities and maximum tolerated dose of
hydroxychloroquine when added to a standard-dose regimen of bortezomib for treatment of
patients with relapsed or refractory multiple myeloma.

Secondary

- To obtain a preliminary estimate of the toxicity rate and response rate of this
combination at the maximum tolerated dose.

- To confirm preclinical evidence showing synergistic effects of hydroxychloroquine and
bortezomib by correlating response rate with blood levels of hydroxychloroquine and
degree of autophagy inhibition in repeated bone marrow samples.

OUTLINE: This is a phase I dose-escalation study of hydroxychloroquine followed by a phase
II study.

- Phase I: Patients receive oral hydroxychloroquine every other day for 2 weeks. Patients
then receive oral hydroxychloroquine 1-3 times daily or every other day and bortezomib
IV twice a week for 2 weeks. Treatment with hydroxychloroquine and bortezomib repeats
every 3 weeks for at least 2 courses in the absence of disease progression or
unacceptable toxicity. Once the maximum tolerated dose (MTD) for hydroxychloroquine is
determined, additional patients are accrued to the phase II portion of the study.

- Phase II: Patients receive hydroxychloroquine (at the MTD determined in phase I) and
bortezomib as in phase I.

Blood and bone marrow samples are collected periodically during the study for correlative
studies by mass spectrometry, proteasome inhibition assays, pharmacokinetic analysis and
assessment of aggresome formation, autophagy inhibition, and apoptosis by protein
electrophoresis and serum free light-chain analysis.

After completion of study treatment, patients are followed periodically.

DISEASE CHARACTERISTICS:

- Histologically confirmed multiple myeloma

- Must meet 1 of the following criteria:

- Relapsed disease documented

- Disease refractory to at least one prior treatment regimen (may include
autologous and allogeneic bone marrow transplantation)

- In need of further therapy for myeloma, as determined by the patient's treating
physician

- No known CNS involvement

- Calvarial lytic lesions or plasmacytomas are not exclusion criteria if there is
no CNS involvement

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy ≥ 3 months

- Absolute neutrophil count ≥ 500/μL

- Hemoglobin ≥ 7 g/dL (with or without transfusion support)

- Platelets ≥ 25,000/μL (with or without transfusion support)

- Total bilirubin ≤ 2 x upper limit of normal (ULN)

- AST/ALT ≤ 2.5 x ULN

- Creatinine ≤ 2 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to and during study treatment

- No baseline peripheral neuropathy ≥ grade 2

- No history of allergic reactions to compounds of similar chemical or biological
composition to bortezomib or hydroxychloroquine

- No known macular degeneration or retinopathy (diabetic or otherwise), porphyria, or
psoriasis

- Well-controlled psoriasis allowed provided under the care of a specialist who
agrees to monitor the patient for exacerbations

- No other conditions that would require therapy with hydroxychloroquine, including but
not limited to, any of the following:

- Systemic lupus

- Rheumatoid arthritis

- Porphyria cutanea tarda

- Malaria treatment or prophylaxis

- No concurrent or prior malignancy except for the following:

- Basal cell or squamous cell carcinoma of the skin

- Treated carcinoma in situ

- Localized prostate adenocarcinoma (stage T1a or T1b) with a stable PSA for a
period of at least 4 months allowed

- Patients with a prior malignancy treated with chemotherapy, biologic agents,
and/or radiation are eligible for this study if they have completed therapy ≥ 4
years previously with no evidence of recurrent disease

- Patients with a prior malignancy treated with surgery alone are eligible for
this study if they have completed therapy ≥ 2 years previously with no evidence
of recurrent disease

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Uncontrolled ongoing infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit compliance with study
requirements

- No prior dose-limiting toxicity due to bortezomib administration

- No inability to understand or unwillingness to sign the informed consent document

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 7 days since prior corticosteroids

- At least 14 days since prior antimyeloma agents, including thalidomide or
lenalidomide

- Concurrent therapy with bisphosphonates allowed at the discretion of the treating
physician

- Concurrent hematopoietic growth factors allowed, including filgrastim (G-CSF) or
pegfilgrastim, epoetin alpha, and darbepoetin alpha

- Concurrent participation in non-treatment studies allowed, if it will not interfere
with participation in this study

- No concurrent radiotherapy except local radiotherapy during the treatment phase of
this study for palliation of pain or prevention of fracture

- No concurrent treatment with a different investigational regimen

- No concurrent therapy with other anticancer agents

- No concurrent participation in other investigational trials that involve novel
therapies