FDA-Approved Drugs Under Investigation in Multiple Myeloma for Actionable Targets The MMRF CureCloud assay uses next-generation sequencing to analyze cell-free DNA (cfDNA) isolated from a patient’s blood sample, to identify clinically relevant genomic alterations based on a unique 70-gene panel. This brochure provides an overview of targeted therapies that are FDA- approved for various tumor types which have activity associated with genomic alterations detected in the CureCloud assay and are under investigation in multiple myeloma. This information is intended to provide context for the results of the CureCloud assay and is not intended to be treatment recommendations. The report that you will receive for patients enrolled in CureCloud should be considered in context with other clinical criteria (e.g., patient history, physical exam), as well as laboratory, pathology, and imaging studies. The selection of any drugs or clinical trials is entirely at the discretion of the treating medical professional. FDA-Approved Drugs for Actionable Targets in Multiple Myeloma (Last update 03/2020) Page 1 Actionable Mutations in Multiple Myeloma and Associated FDA-Approved Targeted Drugs Altered Gene in MM (Type of Alteration) FDA-Approved Targeted Drugs BCL2 (Overexpression) VENCLEXTA (venetoclax) BRAF (non-V600) COTELLIC (cobimetinib) MEKINIST (trametinib) STIVARGA (regorafenib) TAFINLAR (dabrafenib) CCND1 (Translocation and overexpression) IBRANCE (palbociclib) KISQALI (ribociclib) VENCLEXTA (venetoclax) VERZENIO (abemaciclib) CCND2 (Overexpression) IBRANCE (palbociclib) VERZENIO (abemaciclib) CDKN2A (Deficiency) IBRANCE (palbociclib) CYLD (Loss) VENCLEXTA (venetoclax) ZOLINZA (vorinostat) FGFR3 (Translocation and overexpression) BALVERSA (erdafitinib) ICLUSIG (ponatinib) High mutation burden IMFINZI (durvalumab) KEYTRUDA (pembrolizumab) IDH1 TIBSOVO (ivosidenib) VENCLEXTA (venetoclax) IDH2 (p.R172K) IDHIFA (enasidenib) KRAS (Activating) COTELLIC (cobimetinib) MEKINIST (trametinib) TAFINLAR (dabrafenib) ZELBORAF (vemurafenib) NF1 (p.v341fs and copy loss LOH) MEKINIST (trametinib) NRAS (Activating) COTELLIC (cobimetinib) MEKINIST (trametinib) MEKTOVI (binimetinib) TAFINLAR (dabrafenib) ZELBORAF (vemurafenib) FDA-Approved Drugs for Actionable Targets in Multiple Myeloma (Last update 03/2020) Page 2 Clinical Trials of FDA-Approved Targeted Drugs for Actionable Mutations in Myeloma Drug Name Route of FDA-Approved Altered Gene in MM Clinical Trials in MM Data in MM Administration Indication (Type of Alteration) (Level of Evidence)* BALVERSA Oral tablet Locally advanced or metastatic urothelial FGFR3 (Translocation • Myeloma-Developing Regimens Using Genomics NA (erdafitinib) carcinoma and overexpression) (MyDRUG) (NCT03732703) • Testing JNJ-42756493 In Combination With Dexamethasone in MM That Came Back After a Period of Improvement (NCT02952573) • NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors or Lymphomas (NCT02465060) COTELLIC Oral tablet In combination with ZELBORAF BRAF (non-V600) Myeloma-Developing Regimens Using Genomics (MyDRUG) Level 5[1] (cobimetinib) (vemurafenib): unresectable or metastatic (NCT03732703) melanoma KRAS (Activating) Myeloma-Developing Regimens Using Genomics (MyDRUG) (NCT03732703) NRAS (Activating) Myeloma-Developing Regimens Using Genomics (MyDRUG) (NCT03732703) IBRANCE Oral capsule In combination with an aromatase inhibitor CCND1 (Translocation • NCI-MATCH: Targeted Therapy Directed by Genetic Level 2[2] (palbociclib) or fulvestrant: HR-positive, HER2-negative and overexpression) Testing in Treating Patients With Advanced Refractory advanced or metastatic breast cancer Solid Tumors or Lymphomas (NCT02465060) • Phase II trial of the cyclin-dependent kinase inhibitor PD 0332991 in patients with cancer (NCT01037790) CCND2 Phase II trial of the cyclin-dependent kinase inhibitor PD (Overexpression) 0332991 in patients with cancer (NCT01037790) CDKN2A (Deficiency) TAPUR: Testing the Use of FDA Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (NCT02693535) ICLUSIG (ponatinib) Oral tablet Chronic phase, accelerated phase, or blast FGFR3 (Translocation Ponatinib Hydrochloride in Treating Patients With Refractory NA phase CML or Ph+ ALL (± T315I) and overexpression) Metastatic Cancers and Genetic Alterations (NCT02272998) IDHIFA (enasidenib) Oral tablet Relapsed or refractory AML IDH2 (p.R172K) Myeloma-Developing Regimens Using Genomics (MyDRUG) NA (NCT03732703) IMFINZI Intravenous Locally advanced or metastatic urothelial High mutation burden A phase 2 study to determine the safety and efficacy for the PK study[3] (durvalumab) injection carcinoma combination of Durvalumab and Daratumumab in RRMM (NCT02807454) FDA-Approved Drugs for Actionable Targets in Multiple Myeloma (Last update 03/2020) Page 3 Drug Name Route of FDA-Approved Altered Gene in MM Clinical Trials in MM Data in MM Administration Indication (Type of Alteration) (Level of Evidence)* KEYTRUDA Intravenous • Unresectable or metastatic High mutation burden • Phase 2 Multi-center Study of Anti-PD-1 During Level 5[4] (pembrolizumab) injection melanoma Lymphopenic State After HDT/ASCT for Multiple Level 3[5,6] • Adjuvant treatment of melanoma Myeloma (NCT02331368) Level 2[7-15] • NSCLC • A study of Pembrolizumab in combination with standard Level 1[16] • SCLC of care treatments in participants with Multiple • HNSCC Myeloma (NCT02036502) • cHL • TAPUR: Testing the Use of FDA Approved Drugs That • Primary mediastinal LBCL Target a Specific Abnormality in a Tumor Gene in People • Urothelial carcinoma With Advanced Stage Cancer (NCT02693535) • Microsatellite instability-high cancer • Efficacy and safety study of Pembrolizumab in • Gastric cancer combination with Daratumumab in participants with • Esophageal cancer relapsed refractory Multiple Myeloma (NCT03221634) • Cervical cancer • HCC • Merkel cell carcinoma • RCC • Endometrial carcinoma KISQALI (ribociclib) Oral tablet In combination with an aromatase inhibitor CCND1 (Translocation LEE011 for Patients With CDK4/6 Pathway Activated NA or fulvestrant: HR-positive, HER2-negative and overexpression) Tumors (NCT02187783) advanced or metastatic breast cancer MEKINIST Oral tablet In combination with TAFINLAR (dabrafenib): BRAF (non-V600) • A Study of Dabrafenib and/or Trametinib in Patients Level 5[17-20] (trametinib) • Unresectable or metastatic melanoma With RRMM (NCT03091257) Level 4[21] • The adjuvant treatment of melanoma • NCI-MATCH: Targeted Therapy Directed by Genetic • Metastatic NSCLC Testing in Treating Patients With Advanced Refractory • Locally advanced or metastatic anaplastic Solid Tumors or Lymphomas (NCT02465060) thyroid cancer KRAS (Activating) A Study of Dabrafenib and/or Trametinib in Patients With RRMM (NCT03091257) NF1 (p.v341fs and • NCI-MATCH: Targeted Therapy Directed by Genetic copy loss LOH) Testing in Treating Patients With Advanced Refractory Solid Tumors or Lymphomas (NCT02465060) • Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With RRMM (NCT01989598) NRAS (Activating) A Study of Dabrafenib and/or Trametinib in Patients With RRMM (NCT03091257) MEKTOVI Oral tablet In combination with BRAFTOVI NRAS (Activating) NCI-MATCH: Targeted Therapy Directed by Genetic Testing NA (binimetinib) (encorafenib): unresectable or metastatic in Treating Patients With Advanced Refractory Solid Tumors melanoma or Lymphomas (NCT02465060) STIVARGA Oral tablet • Metastatic CRC BRAF (non-V600) TAPUR: Testing the Use of FDA Approved Drugs That Target NA (regorafenib) • Locally advanced, unresectable or a Specific Abnormality in a Tumor Gene in People With metastatic GIST Advanced Stage Cancer (NCT02693535) • HCC FDA-Approved Drugs for Actionable Targets in Multiple Myeloma (Last update 03/2020) Page 4 Drug Name Route of FDA-Approved Altered Gene in MM Clinical Trials in MM Data in MM Administration Indication (Type of Alteration) (Level of Evidence)* TAFINLAR Oral capsule Single agent: unresectable or metastatic BRAF (non-V600) A Study of Dabrafenib and/or Trametinib in Patients With Level 5[20] (dabrafenib) melanoma RRMM (NCT03091257) Level 4[21] In combination with MEKINIST (trametinib): KRAS (Activating) A Study of Dabrafenib and/or Trametinib in Patients With • Unresectable or metastatic melanoma RRMM (NCT03091257) • Adjuvant treatment of melanoma • Metastatic NSCLC NRAS (Activating) A Study of Dabrafenib and/or Trametinib in Patients With • Locally advanced or metastatic RRMM (NCT03091257) anaplastic thyroid cancer TIBSOVO Oral tablet Newly diagnosed or relapsed or refractory IDH1 Phase Ib/II Investigator sponsored study of the IDH1- NA (ivosidenib) AML mutant inhibitor Ivosidenib (AG120) with the BCL2 inhibitor Venetoclax in IDH1-Mutated Hematologic Malignancies (NCT03471260) VENCLEXTA Oral tablet Single agent: CLL or SLL BCL2 • Study of Venetoclax in Combination With Carfilzomib Real-world (venetoclax) (Overexpression) and Dexamethasone in Subjects With RRMM evidence[22-24] In combination with azacitidine or (NCT02899052) Level 5[25-27] decitabine or low-dose cytarabine: newly • A Study of Venetoclax and Dexamethasone Compared Level 4[21,28] diagnosed AML With Pomalidomide and Dexamethasone in Subjects Level 3[29,30] With RRMM (CANOVA) (NCT03539744) Level 2[31-38] • A Study of Combination Therapy With Venetoclax, Level 1[39,40] Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects With RRMM (NCT03314181) CCND1 (Translocation Myeloma-Developing Regimens