Summary

This phase II trial studies how well trametinib with or without dabrafenib mesylate works in treating patients with BRAF, KRAS, or NRAS gene mutation and multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and dabrafenib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the objective response rate of 3 treatments (dabrafenib mesylate [dabrafenib]/trametinib combination OR dabrafenib single-agent treatment OR trametinib single-agent treatment) in patients with multiple myeloma whose tumors harbor either a mutation in the BRAF or NRAS or KRAS gene.

SECONDARY OBJECTIVE:
I. To evaluate the safety and tolerability of 3 treatments (dabrafenib/trametinib combination OR dabrafenib single-agent treatment OR trametinib single-agent treatment) in patients with multiple myeloma whose tumors harbor either a mutation in the BRAF or NRAS or KRAS gene.

EXPLORATORY OBJECTIVES:
I. To evaluate the role of circulating multiple myeloma (MM) cells and circulating deoxyribonucleic acid (DNA) in patients treated with dabrafenib/trametinib, or dabrafenib, or trametinib.
II. To determine genetic predictive biomarkers for response or resistance to therapy.
III. To assess the inhibition of the BRAF/MEK/ERK pathway by dabrafenib and trametinib and additional exploratory analyses on remaining material from samples collected during the study (blood, tumor) that could help in the understanding of the action of dabrafenib and trametinib and/or identify potential markers that may correlate with efficacy and safety.

OUTLINE: Patients with BRAF V600 gene mutation are randomized to Arms I or III. Patients with only KRAS or NRAS gene mutations are assigned to Arm II. Patients with BRAF (any BRAF gene mutation) and KRAS, or any BRAF (any BRAF gene mutation) and NRAS gene mutations are assigned to Arm III.

ARM I: Patients receive dabrafenib mesylate orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive dabrafenib mesylate as in Arm I and trametinib as in Arm II. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Eligibility

1. Participants must have a confirmed diagnosis of multiple myeloma as defined by at least one of the following criteria: * Measurable disease by imaging such as plasmocytoma * Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma * Monoclonal protein present in the serum and/or urine * Measurable disease as defined by at least one of the following: ** Immunoglobulin G (IgG) multiple myeloma: Serum monoclonal paraprotein (M-protein) level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Immunoglobulin A (IgA) multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Immunoglobulin D (IgD) multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Light chain multiple myeloma: Serum immunoglobulin free light chain >= 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
2. Participants must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains or by imaging studies; measurable disease is defined as one or more of the following: serum M-protein >= 0.5 g/dL, urine M-protein >= 200 mg/24 hour (h), and/or serum free light chain (FLC) assay: involved FLC level >= 10 mg/dL with abnormal serum FLC ratio
3. Participants with plasma cell leukemia are eligible
4. Relapsed disease after at least 2 lines of therapy
5. Age >= 18 years at the time of signing the informed consent form
6. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
7. Participants with platelet level >= 50,000/mm^3, within 21 days of initiation of protocol therapy for patients in whom < 50% of bone marrow nucleated cells are plasma cells; or platelet count >= 30,000/mm^3 for participants in whom > 50% of bone marrow nucleated cells are plasma cells; transfusion within 7 days of screening is not allowed to meet platelet eligibility criteria
8. Participants with an absolute neutrophil count (ANC) >= 1000/mm^3, within 21 days of initiation of protocol therapy; growth factor within 7 days of screening is not allowed to meet ANC eligibility criteria
9. Participants with hemoglobin level >= 8 g/dL, within 21 days of initiation of protocol therapy; transfusion may be used to meet hemoglobin eligibility criteria
10. Hepatic impairment, defined as total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients with benign hyperbilirubinemia [e.g., Gilbert’s syndrome] are eligible) or
11. Hepatic impairment, defined as aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional ULN, within 21 days of initiation of protocol therapy, or
12. Hepatic impairment, defined as alkaline phosphatase =< 2 x institutional ULN, within 21 days of initiation of protocol therapy
13. Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional upper limit of normal; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to alternate assignment
14. Total bilirubin =< 1.5 x institutional upper limit of normal, except subjects with known Gilbert’s syndrome
15. Creatinine clearance > 40 mL/min
16. Serum calcium or albumin-adjusted serum calcium >= 2.0 mmol/L (8.0 mg/dL) and =< 2.9 mmol/L (11.5 mg/dL)
17. Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) per institutional standard by echocardiogram (ECHO)
18. Harboring a mutation in the BRAF oncogene or the KRAS or the NRAS oncogene
19. Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and agree to use adequate contraception as outlined (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; a pregnancy test is not required for female participants over age 60 who have been postmenopausal for at least 24 months; male participants, even if surgically sterilized (i.e., status post vasectomy) must use a condom during intercourse, and for a minimum of 16 weeks after the last dose of study drug (4 weeks for dabrafenib monotherapy) and should not father a child during these periods, or completely abstain from heterosexual intercourse
20. Ability to understand and the willingness to sign a written informed consent document
21. Participant must be able to swallow pills and retain oral medication and must not have clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

Treatment Sites in Georgia