Phase II Study of Thalidomide, Clarithromycin, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma (T-BiRD)

Phase II Study of Thalidomide, Clarithromycin, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma

A Phase II Study of Thalidomide (THALOMID®), Clarithromycin (BIAXIN®), Lenalidomide(REVLIMID®), and Dexamethasone (DECADRON®) for Subjects With Newly Diagnosed Multiple Myeloma

Study Objectives Evaluate the efficacy of the combination of thalidomide (Thalomid®), clarithromycin (Biaxin®), lenalidomide (Revlimid®), and dexamethasone (Decadron®) as an induction therapy for patients with newly diagnosed multiple myeloma (MM). Evaluate the efficacy of the addition of thalidomide (Thalomid®) to BiRD combination therapy as a therapy to increase the complete response rate for patients with newly diagnosed multiple myeloma. Evaluate the safety of the combination of clarithromycin, lenalidomide, dexamethasone, and thalidomide as a therapy for patients with newly diagnosed MM

This phase II study is a treatment program for patients with newly diagnosed multiple myeloma. Up to 25 patients will be enrolled. Patients who sign consent and fulfill all eligibility criteria will be enrolled to receive the following treatment plan: T-BiRD Therapy: Cycles 1-4 Thalidomide (50mg daily for days 1-7, thereafter 100mg daily for days 8-28 of the first 28 day cycle. Thalidomide will then be given at 100mg/daily for days 1-28 for each subsequent cycle) Clarithromycin (500mg twice daily for each 28 day cycle) Lenalidomide (25 mg daily days 1-21 of every 28 day cycle) and Dexamethasone (40 mg daily on day 1, 8, 15 and 22 of each 28 day cycle) Prophylactic medications will be given. After completing 4 cycles Patients who demonstrate progression of disease will be taken off study. Patients who achieve maximum response (either by achievement of complete remission or stable disease plateau) will be transitioned to maintenance therapy. Patients who achieve VGPR or PR with acceptable toxicity will be given T-BiRD for an additional 2 cycles: cycles 5 and 6. Upon completion of 6 cycles of T-BiRD, Patients who achieve maximum response (either by achievement of complete remission or stable disease plateau) will be transitioned to maintenance therapy. Patients without disease progression or maximum response (either by achievement of complete remission or stable disease plateau) will receive BiRD therapy Patients with disease progression will be taken off study. BiRD therapy will consist of the following: Clarithromycin (500mg twice daily for each 28 day cycle)* Lenalidomide (25mg daily days 1-21 of every 28 day cycle)* Dexamethasone (40mg on days 1, 8, 15, 22 of each 28 day cycle)* Prophylactic medications will be continued. Patients who finished T-BiRD therapy at reduced doses of clarithromycin, lenalidomide or dexamethasone will start BiRD therapy at the same doses of clarithromycin, lenalidomide and dexamethasone on which they ended T-BiRD therapy. Patients who progress on BiRD will reinitiate T-BiRD as follows: Thalidomide (100mg/daily for days 1-28 for each 28 day cycle) Clarithromycin (500mg twice daily for each 28 day cycle)* Lenalidomide (25mg/daily for days 1-21 of each 28 day cycle)* Dexamethasone (40mg days 1, 8, 15, 22 of each 28 day cycle)* Prophylactic medications will be continued Patients who continue to show disease progression after two cycles of T-BiRD will be taken off study. Patients who finished BiRD therapy at reduced doses of clarithromycin, lenalidomide or dexamethasone will start T-BiRD therapy at the same doses of clarithromycin, lenalidomide and dexamethasone on which they ended BiRD therapy. Transition to maintenance therapy: Patients who achieve a resolution of monoclonal gammopathy as detected on serum immunofixation or achieve a plateau of disease (no change in quantitative M-spike as detected on serum immunofixation) for > 2 cycles on either BiRD or T-BiRD therapy will be transitioned to maintenance therapy. Maintenance therapy will be comprised of: Dexamethasone 20 mg weekly (days 1,8, 15, 22 out of a 28 day cycle)* Lenalidomide 25 mg daily for days 1-21 out of a 28 day cycle. (15mg daily will be given days 1 - 21 out of a 28 day cycle to patients with a creatinine clearance of < 40cc / minute).* Prophylactic medications will be continued Patients who finished induction therapy with BiRD or T-BiRD at reduced doses lenalidomide or dexamethasone will start maintenance therapy at the same doses lenalidomide and dexamethasone on which they ended induction therapy. For patients with a creatinine clearance of < 40cc / minute, the lenalidomide dose will be the lower of their last induction therapy dose or 15mg daily on days 1 - 21 out of a 28 day cycle. At the end of every cycle (which may coincide with day 1 of the new cycle), response and toxicity will be evaluated. During cycle 1, patients will have lab work done weekly (CBC with differential and blood electrolytes) and female of childbearing potential will have their pregnancy testing done, see APPENDIX III. All patients will remain on study until disease progression or side effects become excessive. Patients who achieve a stable plateau and are on maintenance therapy as defined above may be taken off study if eligible to proceed to high dose chemotherapy and autologous stem cell transplantation.

All patients were treated with the same regimen, starting with T-BIRD therapy (Cycles 1-4). After 4 cycles, Patients with disease progression will be taken off study. Patients who achieve maximum response will receive maintenance. Patients who achieve VGPR or PR will be given T-BiRD for 2 cycles (cycles 5-6). After 6 cycles of T-BiRD, Patients who achieve maximum response will receive maintenance; those with disease progression will be taken off study; all other patients will receive BIRD. Patients who progress on BiRD will reinitiate T-BiRD. If disease progression continues after 2 cycles, patients will be taken off study. Patients in CR/sCR or that achieve a plateau of disease for > 2 cycles on BiRD or T-BiRD therapy will receive maintenance.

Cycles 1-4 • Thalidomide (50mg daily for days 1-7, thereafter 100mg daily for days 8-28 of the first 28 day cycle. Thalidomide will then be given at 100mg/daily for days 1-28 for each subsequent cycle)

During T-BIRD Phase (Cycles 1-4, 5-6, and in the case of T-BIRD re-initiation) • Lenalidomide (25 mg daily days 1-21 of every 28 day cycle) During BiRD phase • 25mg daily days 1-21 of every 28 day cycle) During Maintenance Phase • 25 mg daily for days 1-21 out of a 28 day cycle

During T-BiRD Phase • Clarithromycin (500mg twice daily for each 28 day cycle) During BiRD Phase: • Clarithromycin (500mg twice daily for each 28 day cycle)

During T-BIRD Phase (Cycles 1-4, 5-6, and in the case of T-BIRD re-initiation) • Dexamethasone (40 mg daily on day 1, 8, 15 and 22 of each 28 day cycle) During BiRD Phase: • Dexamethasone (40 mg daily on day 1, 8, 15 and 22 of each 28 day cycle) During Maintenance Phase • Dexamethasone 20 mg weekly (days 1,8, 15, 22 out of a 28 day cycle)

Objective response rate, defined according to the International Myeloma Working Group (IMWG) criteria as greater then or equal to a Partial Response (PR). The best response was recorded. The IMWG criteria can be found here: imwg.myeloma.org/international-myeloma-working-group-imwg-uniform-response-criteria-for-multiple-myeloma/

This was collected from patients for their duration on study treatment. Only the best response was recorded. Best responses were reported at any point of the study, from start of treatment up until removal of study, which occurred up to 57.4 cycles

from baseline to the time of first event that lead to removal from study (defined as progression, death, withdrawal of consent, or removal for toxicity)

Progression determined using International Myeloma Working Group criteria, as defined below. An increase of > 25% from lowest response value one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL)* Urine M-component and/or (the absolute increase must be > 200 mg/24 h) Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL Bone marrow plasma cell percentage; the absolute percentage must be > 10% Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder *if starting serum M protein is greater then 5 g/dL, absolute increase of 1g/dL is sufficient to determine relapse.

Inclusion Criteria: Subject must voluntarily sign and understand written informed consent. Age > 18 years at the time of signing the consent form. Histologically confirmed Salmon-Durie stage II or III MM. Stage I MM patients will be eligible if they display poor prognostic factors (ß2M ≥5.5 mg/L, plasma cell proliferation index ≥5%, albumin of less then 3.0, and unfavorable cytogenetics). Newly diagnosed myeloma. No anti-myeloma therapy within 14 days prior to initiation of study treatment except for corticosteroids with a maximum allowed dosage equivalent to three pulses of dexamethasone (40mg daily for 4 days equals one pulse). Patients may be receiving adjuvant antiresorptive therapy (i.e., pamidronate or zoledronic acid) as routine care. Measurable disease as defined by > 1.0 g/dL serum monoclonal protein, >0.1 g/dL serum free light chains, >0.2 g/24 hrs urinary M-protein excretion, and/or measurable plasmacytoma(s). Karnofsky performance status ≥70% (>60% if due to bony involvement of myeloma. Able to take aspirin daily as prophylactic anticoagulation. (patients intolerant to ASA may use warfarin or low molecular weight heparin) All study participants must be registered into the mandatory RevAssist® and S.T.E.P.S.® programs, and be willing and able to comply with the requirements of RevAssist® and the S.T.E.P.S.® programs. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide and thalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy. Life expectancy ≥ 3 months Subjects must meet the following laboratory parameters: Absolute neutrophil count (ANC) ≥1000 cells/mm3 (1.0 x 109/L) Platelets count ≥ 75,000/mm3 (75 x 109/L) Serum SGOT/AST <3.0 x upper limits of normal (ULN) Serum SGPT/ALT <3.0 x upper limits of normal (ULN) Serum creatinine <2.5 mg/dL (221 µmol/L) Serum total bilirubin <2.0 mg/dL (34 µmol/L) Exclusion Criteria: Patients with non-secretory MM (no measurable monoclonal protein, free light chains, and/or M-spike in blood or urine). Prior history of other malignancies (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless disease free for ≥ 5 years. Myocardial infarction within 6 months prior to enrollment , or NYHA(New York Hospital Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Pregnant or lactating females are ineligible. Given the potential of the study drugs to trigger or worsen HIV viremia and the incidence of opportunistic infections inpatients infected with the HIV virus, HIV-1 or HIV-2 positive patients will be excluded. The interactions of HAART with study drugs have not been determined. Active hepatitis B or hepatitis C infection. Active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program. Any coexisting medical problem or laboratory evaluation that, in the treating physician's or principal investigator's opinion, makes the patient unsuitable to participate in this clinical trial. Known hypersensitivity to dexamethasone, clarithromycin, lenalidomide, or thalidomide. History of thromboembolic event within the past 6 months prior to enrollment.

Mark TM, Bowman IA, Rossi AC, Shah M, Rodriguez M, Quinn R, Pearse RN, Zafar F, Pekle K, Jayabalan D, Ely S, Coleman M, Chen-Kiang S, Niesvizky R. Thalidomide, clarithromycin, lenalidomide and dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma. Leuk Lymphoma. 2014 Dec;55(12):2842-9. doi: 10.3109/10428194.2014.896005. Epub 2014 Mar 25.