Hydroxychloroquine, Cyclophosphamide, Dexamethasone, and Sirolimus in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of hydroxychloroquine (HCQ) in combination
with rapamycin (sirolimus) and infusional cyclophosphamide and pulse dexamethasone (cy/dex)
for patients with relapsed/ refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To evaluate biological activity and efficacy of the combination of cyclophosphamide,
dexamethasone, rapamycin and hydroxychloroquine in patients with relapsed/refractory
multiple myeloma.

II. To determine whether this treatment regimen results in mammalian target of rapamycin
(mTOR) and autophagy inhibition in primary myeloma cells during therapy and if this
corresponds with treatment responses.

OUTLINE: This is a dose-escalation study of hydroxychloroquine.

Patients receive hydroxychloroquine orally (PO) daily on days 1-28 (days 5-28 of course 1),
sirolimus PO on days -2 to 4, and cyclophosphamide intravenously (IV) continuously and
dexamethasone PO on days 1-4. Treatment repeats every 28 days for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

Inclusion Criteria:

- Histologically confirmed multiple myeloma

- Documented relapse or persistent disease after at least 1 prior therapy containing
both bortezomib and lenalidomide; or at least 2 prior therapies containing bortezomib
in one and lenalidomide in the other, or if intolerant of bortezomib and/or
lenalidomide; prior autologous and allogeneic bone marrow transplantation are allowed

- Need for further treatment for myeloma, as determined by the patient's treating
physician; this is defined as progression of clinical features (worsening anemia,
renal function, bone disease, hypercalcemia, recurrent infections, and constitutional
symptoms) OR biochemical progression (increasing M-spike in serum or urine, involved
serum or urine free light chain over 2 consecutive time points greater than 4 weeks
apart)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Ability to understand and the willingness to sign a written informed consent document

- Birth control is required with full barrier contraceptives or complete abstinence for
the duration of time receiving therapy and for 6 months after completing the last
drug taken

- The need for further treatment: this is defined as progression of clinical features
(worsening anemia, renal function, bone disease, hypercalcemia, recurrent infections,
and constitutional symptoms) OR biochemical progression (increasing M-spike in serum
or urine, involved serum or urine free light chain over 2 consecutive time points
greater than 4 weeks apart)

Exclusion Criteria:

- History of allergic reactions to compounds of similar chemical or biological
composition to rapamycin or hydroxychloroquine

- Patients may not take any of the following medications while on study, but will be
considered eligible if medication is discontinued at least 72 hours (hrs) prior to
first dose of Rapamycin:

- Carbamazepine

- Rifabutin

- Rifampin

- Rifapentine

- St. John's wort

- Clarithromycin

- Cyclosporine

- Diltiazem

- Erythromycin

- Itraconazole

- Fluconazole

- Ketoconazole

- Telithromycin

- Verapamil

- Voriconazole

- Posaconazole

- 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)

- Absolute neutrophil count (ANC) =< 1.0 x 10^9/L

- Platelets =< 50 x 10^9/L for any reason

- Serum creatinine >= 2.5 mg/dL

- Total or direct bilirubin >= 2.0 mg/dL

- Transaminases 2 x the upper limit of normal

- Fasting glucose >= 200 mg/dL

- Serum potassium < 3.4 mmol/l

- Serum phosphorus < 2.4 mg/dl

- 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

- Evidence of other active malignancy, except:

- Basal cell or squamous cell carcinoma of the skin

- Treated carcinoma in situ

- Uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Uncontrolled ongoing infection

- Human immunodeficiency virus (HIV)

- Hepatitis B infection

- Known glucose-6-phosphate dehydrogenase (G6PD) deficiency

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled cardiac arrhythmia

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

- Active graft-versus-host disease (GvHD)

- Inability to understand or unwillingness to sign the informed consent document

- Concurrent anti-myeloma therapy within:

- 7 days of prior corticosteroids

- 14 days of prior antimyeloma agents, including thalidomide or lenalidomide

- 28 days of a different investigational regimen

- 14 days of any radiation

- Women of child-bearing who are unwilling or unable to use an acceptable method to
avoid pregnancy for the entire study period and for up to 30 days after the last dose
of study drug

- Women who are pregnant or breastfeeding

- History of G6PD deficiency

- Known history of HIV infection