Cyclophosphamide(Cy)/ Dexamethasone(Dex)/Rapamycin (Rapa)/Hydroxychloroquine (HCQ) for Relapsed or Refractory Myeloma(Rel/Ref MM)

• Evaluation of biological activity [ Time Frame: Duration of the study; Up to 2 years ] [ Designated as safety issue: Yes ]
  To evaluate biological activity of the combination of cyclophosphamide, dexamethasone, rapamycin and hydroxychloroquine in patients with relapsed/ refractory multiple myeloma.
• Evaluation of efficacy [ Time Frame: Duration of the study; up to 2 years ] [ Designated as safety issue: No ]
  To evaluate efficacy of the combination of cyclophosphamide, dexamethasone, rapamycin and hydroxychloroquine in patients with relapsed/ refractory multiple myeloma.

Multiple myeloma (MM) is a type of cancer with an average survival of 3 to 5 years. The disease remains incurable and patients become unresponsive to treatments. Patients also develop organ problems and can have severe side effects from therapy. All of these factors limit treatment options. This protocol will enroll subjects who have MM that has returned after treatment or has stopped responding to treatment. The purpose of this study is to test the safety of rapamycin and hydroxychloroquine (study drugs) at different dose levels. The investigators want to find out what effects, good and/or bad, it has on MM. The study drugs have not been approved by the U.S. Food and Drug Administration (FDA) or any other regulatory agency for general use in this type of cancer and their benefits and side effects are not fully known. These study drugs will be given with standard chemotherapy, cyclophosphamide and dexamethasone, which have both been approved by the FDA for use in this disease. The investigators believe that the combination of standard chemotherapy, with rapamycin and hydroxychloroquine (HCQ), may improve the response outcome compared to standard chemotherapy alone. The investigators think that both study drugs will improve the sensitivity of the myeloma cells in the body to standard chemotherapy, making it easier for the chemotherapy to kill or damage the myeloma cells. However, this combination has never been tried in patients before. In future research studies, the investigators hope to determine how well this drug combination will work in fighting and killing myeloma cells.

• Drug: Hydroxychloroquine
• Drug: Rapamycin

Inclusion Criteria:

• Histologically confirmed multiple myeloma
• Documented relapse or persistent disease after at least one prior therapy (which may include autologous and allogeneic bone marrow transplantation)
• Need for further treatment for myeloma, as determined by the patient's treating physician*
• Age ≥18 years. Both men and women and members of all races and ethnic groups will be included.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix).
• 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 hrs prior to first dose of Rapamycin.

  • Carbamazepine (e.g. Tegretol)
  • Rifabutin (e.g. Mycobutin)
  • Rifampin (e.g. Rifadin)
  • Rifapentine (e.g. Priftin)
  • St. John's Wort
  • Clarithromycin (e.g. Biaxin)
  • Cyclosporin e.g. (Neorla or Sandimmune)
  • Diltiazem (e.g. Cardizem)
  • Erythromycin (e.g. Akne-Mycin, Ery-Tab)
  • Itraconazole (e.g. Sporonox)
  • Fluconazole (e.g. Diflucan)
  • Ketoconazole (e.g. Nizoral)
  • Telithromycin (e.g. Ketek)
  • Verapamil (e.g. Calan SR, Isoptin, Verelan)
  • Voriconazole (e.g. VFEND)Tacrolimus (e.g. Prograf)
• 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)

• Patients with the following cytopenias:

  • ANC <1.0 x 109/L;
  • Platelets < 50 x 109/L for any reason

• Patients with the following chemistry abnormalities:

  • Serum Creatinine > 2.5 mg/dL;
  • Total or Direct Bilirubin > 2.0 mg/dL;
  • Transaminases 2 x the upper limit of normal
  • Fasting Glucose > 200mg/dL
  • Serum potassium < 3.4 mmol/l
  • Serum phosphorus < 2.4mg/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
  • HIV
  • Hepatitis B infection
  • Known 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 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
• HIV infection