DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is     current as of May 2...
DISCLAIMER Participants have an implied responsibility to use the newly acquired information      to enhance patient outco...
Disclosure of Conflicts of Interest   Beth Faiman, PhD(c), RN, APRN, BC, AOCN®, reported a financial    interest/relation...
Activity OverviewBeth Faiman, PhD(c), RN, APRN, BC, AOCN®  Cleveland Clinic Taussig Cancer Institute
Learning Objectives               Upon completion of this activity,             participants should be better able to:   ...
Introduction to Faculty Panel   Beth Faiman, PhD(c), RN, APRN, BC, AOCN® (Chairperson)     – Nurse Practitioner     – Cle...
Activity Agenda   6:00 – 6:05 AM Welcome and Activity Overview   6:05 – 6:20 AM Diagnosing Multiple Myeloma   6:20 – 6:...
Diagnosing Multiple Myeloma    Page Bertolotti, BSN, RN, OCN®   The Samuel Oschin Cancer Center    at Cedars-Sinai Medical...
Multiple Myeloma (MM) Overview             A malignant proliferation of a single clone of plasma cells              that ...
Clinical Presentation                    Disease Process                              Clinical Presentation        M prote...
Clinical Presentation (cont.)                 Disease Process                                  Clinical Presentation     R...
Risk Factors     Age                           Median 65–70 years     Race                          Twice as likely in Afr...
Diagnostic Evaluation             Complete history and physical             Laboratory tests             BMB and aspira...
mSMART Risk Stratification of MM                  High Risk                             Intermediate Risk                 ...
Laboratory Tests                            Lab Tests                                                  Common Findings    ...
Laboratory Tests (cont.)                              Lab Tests                                                    Common ...
Imaging                 Test                                                            Finding        Skeletal survey Ext...
IMWG Diagnostic Criteria                 Diagnosis                                          Criteria (all 3 required)     ...
International Staging System (ISS)            Stage              Criteria           Median Survival (months)              ...
The Durie and Salmon Staging System                 Stage I                 Stage II                        Stage III     ...
Key Takeaways   MM is a malignant proliferation of a single clone of    plasma cells that arise from B cells in the bone ...
The Evolving Landscape ofMyeloma Treatment: First-Line    Page Bertolotti, BSN, RN, OCN®   The Samuel Oschin Cancer Center...
Case Study              60-year-old man              July: Chest pain, dyspnea. A stent was placed for               cor...
Case Study:        Baseline CBC and Chemistry   WBC                                         Sodium, Whole Blood    3.70–...
Case Study: CRAB Criteria?             Related organ or tissue involvement (CRAB)                – Calcium > 11.5 mg/dL, ...
Case Study:          Bone Marrow and MM Studies   Bone marrow plasma cell infiltration: 20%   Myeloma FISH panel: Not pe...
Considerations:                       Initial or Induction Therapy             Induction chemotherapy                – Tr...
Should All Patients Receive                      Induction Chemotherapy?                                               Spe...
Initial or Induction Therapy for MM:               Transplant Eligible and Ineligible             Transplant Ineligible   ...
How Do You Treat MM: Specific Doses Transplant Candidate Bortezomib +                               Bortezomib 1.3 mg/m2 S...
Can Induction Therapy Be Individualized?             The Mayo Clinic Approach   Approx. 25% of patients                   ...
Side Effects of Common Therapies: Snapshot                                              Oral Thalidomide                  ...
Important Considerations in MM:                             Bone Disease            Malignant cells produce osteoclast-ac...
Important Considerations in MM:                           Infections             A leading cause of death in myeloma pati...
Important Considerations in MM:                          Peripheral Neuropathy             Damage to the peripheral nervo...
Venous Thromboembolic Events                       (VTEs) in MM            MM is an intrinsically hypercoagulable disease...
Side-Effect Assessment and Management                                             Individualized for Each Patient    What ...
Bortezomib:                        New Data on Survival, Dosing          VISTA trial: 655 patients                       ...
Lenalidomide:                     New Data on Safety, Efficacy             Similar to bortezomib, oral lenalidomide remai...
Is My Patient Responding to Treatment?              Response Assessment*    Response IMWG                                 ...
Case Study (cont.)   Remember our case study?   Does not want to pursue up-front transplant   Induction regimen (clinic...
Case Study (cont.)       After Cycle 5, he was changed to       KAPPA, FREE, SERUM K/L RATIO,                            ...
Case Study: Question 1You are the nurse caring for this patient. Recall his baselinelaboratory studies. He has anemia, ren...
Key Takeaways   There is no‘gold standard’treatment for MM   Newer agents provide improved response rates,    improved s...
The Evolving Landscape of Myeloma  Treatment: Maintenance Therapy  Beth Faiman, PhD(c), MSN, APRN, BC, AOCN®     Cleveland...
Case Study: Maintenance         Mr. P is a 48-year-old with newly diagnosed IgG Kappa          multiple myeloma         ...
Maintenance Therapy Maintenance therapy is the use of ongoing low intensity  chemotherapy to eliminate or suppress the mi...
Thalidomide Maintenance After ASCT         Author/Year                        N              Thalidomide Dose (mg)        ...
Thalidomide Maintenance: MRC Trial                               At Median Follow-Up From Randomization of 38 Months      ...
Lenalidomide Maintenance:                      CALGB 100104 Schema                                             CALGB, ECOG...
PFS and OS at Median Follow-Up of 34 Months                               Median TTP: 46 mos              Median TTP: 27 m...
Lenalidomide Maintenance Post-                                    Transplant:                       IFM 2005-02: Placebo-C...
Lenalidomide Maintenance Post-Transplant:              IFM 2005-02: PFS and OS From Randomization                         ...
MM-015: Study Design                            N = 459, 82 centers in Europe, Australia, and Israel                      ...
MM-015: PFS and OS for Survival          Progression-Free and Overall All Patients                        All Patients    ...
HOVON Trial: Bortezomib Induction            and Maintenance                                                   Randomizati...
Bortezomib Maintenance: Outcomes                                               3-year PFS 48% vs. 42%                     ...
Subgroup Analysis (1)                                                VAD/HDM/                 PAD/HDM/                    ...
Subgroup Analysis (2)                                                   VAD/HDM/                 PAD/HDM/                 ...
Case Study: Maintenance                Conclusion   3 months following ASCT, Mr. P achieved a PR (80%    reduction in ser...
Key Takeaways Maintenance therapy delays recurrence of myeloma and  prolongs PFS Chronic low dose oral agents are prefer...
The Evolving Landscape of    Myeloma Treatment:Relapsed/Refractory Disease Beth Faiman, PhD(c), MSN, APRN, BC, AOCN®    Cl...
Case Study: Mr. P (cont.)   Mr. P remains on lenalidomide 10 mg po daily for 3 years   Develops lower back pain and wors...
How Is Relapse Defined?            Relapse is defined as reappearance of signs and             symptoms of the disease or...
When Do You Treat Relapsed                            Myeloma?             Symptomatic relapse                – CRAB symp...
How Is Refractory Disease Defined?             Refractory disease should fulfill all of the              following criter...
Considerations in Relapsed MM             Disease related                – Indolent, slow, or single site relapse        ...
Treatment of Relapsed Myeloma:                 How Do We Decide?        Existing                     novel agents        ...
Indolent, Slow, or First Relapse                  High-Dose Melphalan and Stem Cell Transplant                     If Defe...
Aggressive, Rapid, Multiple Relapse                           Likely Combination Therapy                       Do Not Wait...
Agents in Phase III Studies             Target             Combination Partner(s)             Pomalidomide       Dexametha...
Molecular Structure of Thalidomide,          Lenalidomide, and Pomalidomide    Structurally similar, but functionally dif...
Relapsed and Refractory Myeloma              Single Agent: Pomalidomide                                                   ...
Relapsed and Refractory Myeloma                        Single Agent: Pomalidomide (cont.)        100                      ...
Relapsed and Refractory Myeloma                           Single Agent: Carfilzomib PX171-003 A1                          ...
Vantage 095: PFS (IAC)                                                                                                    ...
Elotuzumab With Lenalidomide                        and Weekly Dexamethasone                                   Best Respon...
Phase I/II Trial of Perifosine/Bortezomib ±                Dexamethasone in Relapsed/Refractory                           ...
Case Study (cont.)   Mr. P is enrolled in a clinical trial with Lenalidomide,    Elotuzumab and Dexamethasone   He achie...
Key Takeaways   The overall survival of patients with MM has increased    within the last decade   Many new treatments h...
Patient Perspective        Pat KillingsworthColumnist for the Myeloma Beacon
Oncology Nurses Rock!A Long, 5-Year Rollercoaster Ride How to Help Newly DiagnosedPatients Cope: Take a TIME-OUT!
Ignore Median Expectancy NumbersHelp Patients Build A Healthcare Team Don’t Rush to Transplant – Do Your          Homework...
Multiple Myeloma Patient ResourcesInternational Myeloma Foundation (IMF) - www.myeloma.org     The Myeloma Beacon – www.my...
Practical Navigation of a Changing Landscape: Keeping Current on Multiple Myeloma Treatments
Practical Navigation of a Changing Landscape: Keeping Current on Multiple Myeloma Treatments
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Practical Navigation of a Changing Landscape: Keeping Current on Multiple Myeloma Treatments

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The vital role of oncology nurses in the care of patients with MM necessitates the awareness of the latest treatment advances and best practices for side-effect management. This CE-certified activity will provide updates in first-line, maintenance, and relapsed/refractory settings. Expert faculty will articulate the diagnosis, cytogenetics, and staging of the disease, as well as promising novel agents and evidence-based best practices for the management of side effects. To provide insight to attendees of the impact of evolving data on a personal level, a patient with MM will share personal perspectives on the journey from diagnosis, treatment, and overall patient experience.

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Review a downloadable slide deck by Beth Faiman, PhD(c), RN, APRN, BC, AOCN®, covering the most clinically relevant new data reported from Practical Navigation of a Changing Landscape: Keeping Current on Multiple Myeloma Treatments.

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This activity has been designed to meet the educational needs of oncology nurses involved in the care of patients with multiple myeloma (MM).

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

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  • B cells mature to plasma cells and produce antibodies and immunoglobulins to fight infection. When multiple myeloma occurs, these plasma cells become malignant and an overproduction of a single clone occurs. Myeloma cells infiltrate the bone marrow and result in bone destruction, lytic lesions, fractures, hypercalcemia, anemia and renal dysfunction. CRAB: Calcium- hypercalcemia due to bone destruction Renal- renal insufficiency or renal failure due to myeloma kidney Anemia- poor production of RBCs Bone impairment- References: Kyle RA., Rajkumar SV., 2009. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia . 2009 January; 23(1):3 Nau KC., Lewis WD., 2008. Multiple Myeloma: Diagnosis and Treatment. The American Family Physician. 2008 October; 78, Number 7: 855
  • On presentation 97% have M protein in the serum or urine; 96% have clonal plasma cells in the bone marrow; 80% have skeletal involvement; 40-73% are anemic with Hgb <12 g/dL References: Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 7-14 Nau KC., Lewis WD., 2008. Multiple Myeloma: Diagnosis and Treatment. The American Family Physician. 2008 October; 78, Number 7: 855. Rajkumar SV., 2011. Plasma Cell Disorders. Goldman's Cecil Medicine, 24th ed.2011 ; 12. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu /b ooks
  • On presentation 25% have renal impairment with serum creatinine 2 mg/dL or greater; 18-30% with calcium level > 11 mg/dL; 20% with neuropathy; and approximately 1% present with recurrent infections i.e. pneumonia References: Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 7-14 Nau KC., Lewis WD., 2008. Multiple Myeloma: Diagnosis and Treatment. The American Family Physician. 2008 October; 78, Number 7: 855. Rajkumar SV., 2011. Plasma Cell Disorders. Goldman's Cecil Medicine, 24th ed. 2011 ; 12. Retrieved on 1/30/12 from ww.mdconsult.com.mlprox.csmc.edu/books
  • The exact cause is unknown. Risk factors include those 65-70 years old; it ’s twice as likely to occur in African Americans than Caucasians; and more common in men than women. Genetics is also a factor as those with a first-degree relative with MM are at higher risk; External and environmental exposures are also a risk factor including ionizing radiation, pesticides and petroleum. Other factors include obesity and chronic immune diseases i.e. systemic lupus. References: Kyle and Rajkumar, 2012. Multiple myeloma. Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Rajkumar SV., 2011. Plasma Cell Disorders. Goldman's Cecil Medicine, 24th ed. 2011 ; 9. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Tariman JD, et al., 2010: Multiple Myeloma: A Textbook for Nurses, 1 st ed. 2010; Oncology Nursing Society : Chapter 4: 41-49 Okali K., et al 2009. Multiple Myeloma and Systemic Lupus Erythematosus in a Young Woman. J Clin Rheumatol 2009;15: 292–294
  • When MM is suspected, it ’s important to obtain a complete history and physical; there are certain laboratory test and imaging that are very important at baseline A bone marrow biopsy should include: Immunophenotyping: flow cytometry used to study the protein expressed i.e. CD138 , CD 38 and CD56. Conventional cytogenetics- chromosome analysis (abnormal aberration and deletions i.e. ) and karyotype (includes the number, size, shape or chracteristics of the chromosomes) Fluorescence in situ hybridization (FISH): Genetic mapping using fluorescent tags; analysis of chromosomal aberrations and genetic abnormalities (translocations) i.e. 13q & 17p deletion; t(4:14) & t(14;16) Plasma cell labeling index: slide-based immunofluorescent assay; rapid tumor cell division; prognostic factor References: Kyle and Rajkumar, 2012. Multiple myeloma. Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 9-12 National Comprehensive Cancer Network (2012). Clinical practice guidelines in oncology. Multiple myeloma.v.1.2012. Retrieved February 27, 2012, from http://www.nccn.org /
  • Risk stratification was developed to establish prognosis and guide treatment plan accordingly. High risk disease requires aggressive upfront therapy. Further study is needed to determine which course of treatment is best based on cytogenetic abnormalities. GEP: Wnt-signlling antagonist Dickkopf-related protein 1 (DKK1), in inhibitor of osteoblast differentiation, associated with the presence of lytic lesions Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al.Mayo Clin Proc 2009 84:1095-1110 v2 Revised and updated: Jun 2010 retrieved on 2/12/12 from http://msmart.org/newly%20diagnosed%20myeloma.pdf
  • Renal failure and hypercalcemia are oncologic emergencies requiring immediate correction. Treating the underlying cause, multiple myeloma, is key. B2M at baseline is important in staging the disease using the International staging system (ISS). References: Kyle and Rajkumar, 2012. Multiple myeloma. Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 9-12
  • These tests are considered a Myeloma Panel: all tests are required on initial workup and serve as useful “markers” to evaluate response to treatment or progression/relapse disease. References: Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 9-12 Kyle and Rajkumar, 2012. Multiple myeloma. Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Tariman JD, et al., 2010: Multiple Myeloma: A Textbook for Nurses, 1 st ed. 2010; Oncology Nursing Society : Chapter 5: 65-67 Reece D. et al, 2010.Outcome of Patients With IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Retrospective CIBMTR Study. Clinical Lymphoma Myeloma and Leukemia 6(10) 458-463.
  • Oncologic emergency: cord compression requiring immediate intervention (radiation). Nuclear bone scans are considered less sensitive than radiographs in most parts of the skeleton. It is useful in evaluating bone metastasis i.e. in breast cancer. Bone scans may yield negative results in the presence of disease in patients with MM. A skeletal survey sometimes called a myeloma survey is preferable in evaluating the extent of bone disease in patients with MM. References: Dispenzieri A., Lacy M., Greipp P., 2009. Multiple Myeloma. Wintrobe's Clinical Hematology 2009; Chapter 99: 9-12 Kyle and Rajkumar, 2012. Multiple myeloma. Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Retrieved on 1/30/12 from www.mdconsult.com.mlprox.csmc.edu/books Durie B., 2011. Patient Handbook. Multiple Myeloma. International Myeloma Foundation (IMF) Ed 2010/2011. Retrieved on 03/14/2012 from www.myeloma.org
  • MGUS is considered a precursor to MM. There is a lifelong risk of transformation to MM of 1% per year. Treatment is not recommended. Smoldering Myeloma: higher risk of progression to MM than those with MGUS; 10% per year for the 1 st five years, 5% per year for the next 5 years then 1 to 2% per year; requires close observation, every 3-4 months and begin treatment only if progression to MM occurs. Nonsecretory MM- 1 to 5% of myeloma cases References: IMWG: Criteria for the Diagnosis of Myeloma and Guidelines for the Diagnostic Work Up of Myeloma, 2009 retrieved on 2/12/12 from http://myeloma.org/ArticlePage.action?articleId=2970 Kyle RA., Rajkumar SV., 2009. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia . 2009 January; 23(1):3 Rajkumar, SV., 2011. Plasma Cell Disorders. Goldman ’s Cecil Medicine 24 th ed. Retrieved from http://www.mdconsult.com.mlprox.csmc.edu/books/
  • Developed in 2005 as a simple, reliable staging system, inexpensive to reproduce worldwide. B2M is a well recognized prognostic marker. The ISS is an important prognostic indicator. Reference: Greipp et al., 2005. International Staging System for Multiple Myeloma. JCO May 20, 2005 vol. 23 no. 15 3412-3420. Retrieved on 2/12/12 from http://jco.ascopubs.org/content/23/15/3412.full
  • Developed in 1975, still in use today. Based on several factors: amount M protein, serum Hgb level, calcium level, # bone lesions and renal function. This is a complex staging system, difficult to implement. Both the ISS and Durie-Salmon staging systems are important in predicting survival but not useful for therapeutic risk stratification. Reference: Durie BG, Salmon SE. Cancer . 1975;36:842-854. Retrieved on 2/12/12 from http://myeloma.org/pdfs/Durie-SalmonSS.pdf
  • July 2010 he developed chest pain and dyspnea, found to have CAD. A stent was placed into the LAD. On antiplatelet agents he developed hematuria and was then found to have a kidney cancer that was resected in January 2011. After the surgery he developed severe pains in his feet and was felt to have gout. He was treated with colchicine, which helped. Once the gout was better he developed severe mid and lower back pain without trauma. He was prescribed cyclobenzaprine , then an NSAID by his PCP but did not take a lot of the latter. When he went back to see his PCP in March his creatinine and calcium were elevated. He was found to have a monoclonal protein.
  • Notice anemia, elevated creatinine and hypercalcemia
  • This patient qualifies for CRAB diagnosis. See the large lytic lesions in his femur and lesions in calvarium
  • Creatinine was elevated but there was no kidney biopsy since he has only one kidney and a strong suspicion to treat for cast nephropathy. Based on the labs above, would this gentleman require treatment for MM? Yes
  • The key point of this slide is to describe induction chemotherapy. This slide also depicts considerations a few of the many considerations when deciding upon initial therapy
  • Not everyone requires treatment. The most recent results of a Spanish Phase 3 clinical trial indicate that Revlimid in combination with dexamethasone delays disease progression in smoldering multiple myeloma patients who have a high risk of developing symptomatic disease. Specifically, the results showed that high-risk smoldering multiple myeloma patients who received Revlimid plus dexamethasone had a longer time to disease progression and better overall survival than patients who did not receive treatment. These results should be confirmed by long-term follow-up data, especially regarding the difference in overall survival. Abstract 303: Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component  (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: >10% of PCs in BM, serum MC >30g/L, >95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both >PC 10% and MC >30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1-21 plus dexamethasone at dose of 20 mg daily on days 1-4 and 12-15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1-21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn ’t meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5-42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p<0.0001). It should be noted that 13 out of these 28 patients developed bone lesions as a symptom of active MM. Deaths in the Len-dex and no treatment arms were 1 and 2, respectively (p=0·6). Estimated 3-years overall survival (OS) from the inclusion in the trial was 98% for Len-dex arm and 82% for no treatment arm (p=0·05) and this difference was more evident if we evaluate the OS from the moment of diagnosis (HR: 6.7; 95% IC (0.7–57); p=0.03). As far as toxicity is concerned, during induction therapy, no G4 adverse events (AEs) were reported with Len-dex; 1 pt developed G3 anemia, 4 patients G3 asthenia 2 patients G3 diarrhea and 1 patient G3 skin rash; 3 patients developed G2 DVT. During maintenance, no G4 AEs were reported and only 1 patient developed G3 infection. Two patients in the Len-dex arm developed second primary malignancies (SPM): one developed polycythemia vera JAK2+, but the analysis of a frozen DNA sample obtained at the moment of inclusion in the trial demonstrated that JAK2 was already positive. The second-one was a prostate cancer in a patient with previous history of prostate enlargement plus elevated prostate specific antigen (PSA) who was closely followed by the urologist. In conclusion, this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by Len as maintenance significantly prolonged the TTP (HR: 6·2), with a trend to improve the overall survival; in addition, tolerability is acceptable and concerning SPM, no safety warnings are at the present time. Moreover, References Mateos et al, 2011, abstr 303; Khoriaty, R., Hussein, M. A., Faiman, B., Kelly, M., Kalaycio, M., & Baz, R. (2010). Prediction of Response and Progression in Multiple Myeloma With Serum Free Light Chains Assay: Corroboration of the Serum Free Light Chain Response Definitions. [doi: 10.3816/CLML.2010.n.010]. Clinical Lymphoma Myeloma and Leukemia, 10 (1), E10-E13. Rajkumar et al, 2005
  • Two main treatment paths in Multiple Myeloma: Non-Transplant or Transplant Transplant ineligible generally receive systemic therapy which can contains melphalan +/- one of the newer agents to treat MM Transplant eligible patients receive induction therapy, stem cell transplant (usually autologous), maintenance therapy Unfortunately MM is not curable. Eventually nearly all patients relapse and become refractory to further treatment.
  • The optimal administration and schedule of novel agents used in the treatment of MM is unknown. However, based on previous clinical trials there are several recommended schedules and regiments for transplant and non=transplant candidates. Bortezomib is generally administered for 8 cycles and lenalidomide is ongoing outside of transplant. There are many regimens and too many to list the appropriate dose and schedule, but here are a few of the most common and FDA approved regimens you will see given to patients with newly diagnosed MM> Bortezomib containing regimens are commonly given to transplant – eligible patients and do not impair stem cell harvest. Dexamethasone dosing varies per trial but is generally given day of and after bortezomib. Lenalidomide (Rajkumar et al, 2007) is not FDA approved for newly diagnosed MM but is included in the NCCN guidelines based on the preponderance of phase III trial data to support its safety and efficacy in this population. Thalidomide is not often given by itself but more commonly in combination with bortezomib or PLD. Nontransplant candidates are often administered any of the above treatments yet each regimen can contain melphalan. Prednisone is better tolerated in the elderly population and is preferred steroid over dexamethasone (ludwig et al, 2008) MP+ Thalidomide, MP+ Revlimid and MP+ Velcade are all reasonable options but MPV is the only fda approved combination for Newly dx MM in elderly patients. Here is the dosing schema. Maintenance is controversal but lenaliomide and bortezomib are all commonly used these days (to be discussed later today)
  • How does bone disease in patients with multiple myeloma occur? Malignant cells produce osteoclast-activating factors that destroy bone cells which leads to osteolysis, bone pain, and increased risk of pathologic fracture. Osteoclastic (bone destruction) and osteoblastic (bone rebuilding) activity is essential to healthy bone turnover. This process is uncoupled in myeloma as the degree of bone destruction and osteoblastic stimulation far outweighs osteoblastic activity. In fact, osteoblastic activity is nearly absent in myeloma. Bisphosphonates such as pamidronate and zoledronic acid are potent inhibitors of bone resorption. Acute phase reactions – flulike symptoms, tylenol before and the evening of infusion may diminish Renal dysfunction – monitor for albuminuria which suggests renal tubular damage over time, dose reduction and longer infusion time Osteonecrosis of the jaw Current ASCO 2007 guidelines recommend bisphosphonate treatment for up to 2 years with bisphosphonates but recent data from ASH suggests that there is an anti-myeloma benefit from BPs such as zoledronic acid.
  • Predisposition to infection is the single most dangerous complication of myeloma Although the exact mechanism for the increased risk of infection is not fully understood, the presence of active myeloma in the bone marrow causes an impairment of normal immune functions including a decreased response to antigen stimulation and a decrease in antibody production Infection risk is further increased by therapies used to treat myeloma, such as cytotoxic drugs, autologous or allogeneic stem cell transplantation, and glucocorticoids Patients with myeloma should be instructed to report symptoms of infection immediately In the case of life-threatening infection, IV immunoglobulin may be required Prophylactic treatment with low-dose acyclovir can reduce herpes simplex virus (HSV) and treatment with trimethoprim-sulfamethoxazole (TMP-SMX) is used to prevent Pneumocystis carinii Myeloma patients have a poor antibody response to pneumococcal and influenza vaccines References: Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology . 7th ed. New York, NY: McGraw-Hill; 2006:1501-1533. Durie BGM. Multiple myeloma: cancer of the bone marrow. Concise review of the disease and treatment options. North Hollywood, CA: International Myeloma Foundation; 20010/2011. Available at: http://myeloma.org/main.jsp?source=link&source_link_id=775&type=article&tab_id=13&menu_id=0&id=941. Accessed March 16, 2011. Durie BGM, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation Hematol J . 2003;4:379-398. [erratum Hematol J . 2004;5:285]. Malpas JS, Bergsagel DE, Kyle R, Anderson K. Myeloma Biology and Management . 3rd ed. Philadelphia, PA: Saunders; 2004;261. Multiple Myeloma Research Foundation (MMRF). Symptoms. Norwalk, CT: Multiple Myeloma Research Foundation; 2005. Available at: www.multiplemyeloma.org/about_myeloma/index.html. Accessed January 8, 2008.
  • Peripheral neuropathy, even mild, can be particularly devastating to the individual. This is a challenging event which can impair ones ’ QOL. Drugs such as thalidomide and bortezomib place patients at risk and up to 80% will develop even mild PN symptoms if previously treated. Vincristine and cisplatin are less commonly used but can cause PN as well Small fiber nerve endings can be damaged from the disease or treatment and produce a variety of sensations that range from mild , moderate to severe. Small fibers are most responsible for sensory changes and sensory, small –fiber neuropathy is the most common side effect of treatment. Muscle weakness and motor neuropathy can lead to paralysis if severe, and although uncommon should be monitored for in all patients receiving bortezomib and thalidomide. References: NCI Common Terminology Criteria for Adverse Events v4.0 (CT-CAE): Publish Date: May 28, 2009
  • Patients with MM are at risk for VTE. All patients should be risk –stratified. Considerations are included on this slide
  • Consider for all MM patients What is the risk of VTE? (IMWG guidelines) Increased if prior VTE, receiving lenalidomide, thalidoimide, combination chemotherapy. Also increased if BMi >30, surgery, hospitalization, sedentary Bone health: Do they require bisphosphonates if widespread osteopenia or bone lesions, most recommend aredia or zometa monthly for at least 12-24 mos after baseline dental exam ID: Is your patient at high risk for infection (myelosuppression from disease, treatment) Weekly CBCdiff for 8 weeks with lenalidomide Acyclovir prophylaxis with bortezomib IVIG for recurrent infections and hypogammaglobulinemia Prophyllactic antibiotics for prolonged neutropenia is generally not recommended by infectious disease society of america (IDSA) GI: Anti-emetic prior to bortezomib, doxorubicin Assess for diarrhea, constipation (more common to have diarrhea with bortezomib, long – term lenalidomide; constipation with doxil and especially with opioids) PN: Review increased risk of PN with bortezomib and thalidomide Prompt intervention of holding the bortezomib/thalidomide and decreasing the dose can prevent irreversible PN symptoms. SubQ bortezomib and weekly dosing can prevent incidence of painful grade 3 PN symptoms Monthly monitoring of disease parameters SPEP, UPEP, 24-hr urine, serum free light chains should be performed monthly and at least every 3 mos after remission has been obtained
  • final analysis of the pivotal phase 3 VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, which evaluated a bortezomib-based regimen in treatment-naïve patients with multiple myeloma, upheld the survival benefit seen with bortezomib in previous analyses VISTA included 655 patients with previously untreated multiple myeloma randomized to nine 6-week cycles of MP plus bortezomib (VMP) or to MP alone. Patients were followed up at least every 12 weeks for survival and subsequent therapy use. final analysis was performed at a median follow-up of 60.1 months, which included 95% of the initial patient cohort. At 5 years, mortality risk was reduced by 31% with the VMP (median OS of 56.4 months) and 43.1 months with MP (P = .004). The median time to next treatment was 27.0 months with VMP vs 19.2 with MP (P <.001), treatment-free interval was 16.6 months versus 8.3 months (P <.001), respectively. The benefit of adding bortezomib to the treatment regimen was seen across virtually all subsets of patients, including the elderly, those with stage III disease, and those with creatinine clearance <60 mL/min. However, the small subgroup of patients with documented high-risk cytogenetics did not obtain additional benefit from bortezomib. For this group of 46 patients, median OS was 44.1 months with VMP and 50.6 months with MP.   Bortezomib was not associated with an increased incidence of secondary primary malignancies above the rate seen in the general, healthy population. Hematologic malignancies were observed in 1% of patients in each arm; solid tumors were seen in 5% of the VMP arm and 3% of the MP arm.
  • Similar to bortezomib, oral lenalidomide remains a common treatment for patients with newly diagnosed MM (transplant eligible or ineligible) Lenalidomide works through two key mechanisms: Tumoricidal (kills tumor, makes bone marrow environment less favorable) and immmunomodulatory (increased NK activity, cytokine) Non-transplant: MPR-R vs. MPR vs. MP: Continuous MPR-R reduced risk of progression, maintenance improved PFS 31 mos “ Conclusions : Continuous Len treatment with MPR-R significantly reduced disease progression risk compared with MP and MPR in pts aged 65-75 yrs. MPR induction significantly extended PFS vs MP. To date, MPR-R has provided one of the longest median PFS (31 mos) among other available regimens (bortezomib, melphalan, prednisone: 24-27 mos; melphalan, prednisone, thalidomide: 28 mos; bortezomib, melphalan, prednisone, thalidomide: 37 mos).” Lenalidomide post-transplant maintenance improves PFS (compared to placebo)
  • According to IMWG: these are some criteria and brief definition of relapse Increase of > 25% from lowest response value in any one or more of the following: Serum M-component and/or (the absolute increase must be > 0.5 g/dL) 6 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% 7 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 References: Durie BGM, et al. Leukemia 2006; 20: 1467-1473 Kyle RA, Rajkumar SV. Leukemia 2008;23:3-9
  • 4/11/2011 - 5/18/2011 Bortezomib 1.3mg/m2 iv d1,4,8,11 every 21 days, dexamethasone 40mg d1,2,4,5,8,9,11,12 every 21 days 5/18/2011 - 6/22/11 Bortezomib 1.3mg/m2 iv weekly with dexamethasone 20mg on the day of and after bortezomib Since 6/22/11: Bortezomib 1.3mg/m2 sc (reconstitute at 2.5mg/mL NS and rotate injection sites) d1,8,15,22 every 28 days, dexamethasone 20mg on the day of and after bortezomib, cyclophosphamide 500mg absolute po after bortezomib on d1,8,15 every 28 days Side effects: Mild PNP (discomfort feet). Steroid induced hyperglycemia, managed with diet, glipizide the days of and after dex He tolerates well. PR after 3 cycles but develops pain and tingling; thus bortezomib is reduced to weekly.
  • He has received three bortezomib doses so far and tolerates well. He still has severe back pain and has trouble walking around due to it. He states he has spent most time in bed since February due to pain. He has not noted weakness or loss of sensation, also denies incontinence for urine or stool. He does not like the feeling he gets when he takes percocet which makes him "goofy" but he has benefited from oxycontin which was recently increased to 20mg twice a day. He tends to have constipation and controls it with MOM and enemas currently. The constipation was worse with the hypercalcemia than now with opiates. He denies nausea and vomiting, any bleeding, dyspnea, PNP symptoms, skin symptoms, or infections. He does have pain in the right rib cage, though, also constant as the back pain. He has had depression in the past but currently feels OK.
  • Older patients randomized between MP and CTDa, younger patients between CTD and C-VAD Thal vs. observation for maintenance: Thalidomide 50 mg/day increasing to 100 mg/day after 4 weeks if well tolerated
  • We thus designed the IFM 200502 protocol. 614 patients from 78 centers were enrolled between 7/2006 and 8/2008 Patients under the age of 65, with a non progressive disease after a tranplant, performed within the last 6 months, were randomized to receive a consolidation treatment with revlimid 25 mg/d , 21 days per month for 2 months followed by maintenance treatment with Placebo untill relapse (arm A) or the same consolidation followed by maintenance with low dose revlimid 10-15 mg/ until relapse (arm B) Randomization was stratified according to beta 2, del 13, and response at time of randomisation (VGPR or not)
  • This result is illustrated on this slide The PFS from randomization of patients treated with lenalidomide or with placebo This benefit of lenalidomide maintenance was observed in all stratified subgroups of patients
  • Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of continuous lenalidomide treatment (melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance [MPR-R]) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) 459 patients were recruited at 82 centers in Europe, Australia, and Israel between February 2007 and September 2008 Approximately 50% of patients had stage III disease, and the median age was 71 years (MPR-R and MPR arms) and 72 years (MP arm) Patients were randomly assigned to receive MP (n = 154), MPR (n = 153), or MPR-R (n = 152) Patients could elect to receive open-label lenalidomide (25 mg/day) ± dexamethasone following disease progression The primary analysis was MPR-R versus MP and the primary endpoint was progression-free survival (PFS) The study was not powered to compare MPR-R vs MPR Following a pre-planned interim analysis at 50% information, an independent data-monitoring committee confirmed the superiority of MPR-R over MP at extending PFS The cutoff for these data was April 15, 2009, allowing for a median follow-up of 9.4 months for PFS A second pre-planned interim analysis at 70% information was conducted for data on December 1, 2009, allowing for a median follow-up period of 21 months for PFS Reference Palumbo A, Delforge M, Catalano J, et al. A phase III study to determine the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients ≥ 65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimen. Blood. 2010;116:273-273.[abstract 622].
  • Improvement in response rates were seen in both arms during maintenance
  • Table 14.2.8.1.2. (Cutoff 01 Apr 2011) Data revised by Min Chen Oct 19 th and Nov 8 th .
  • Table 4.2.1.1.15a (Cutoff 01 Apr 2011) Data revised by M. Chen Oct 19 th and Nov 8 th . Graph added on Nov 10 from SASGRAPH_survival_pfs_inv_rev_vel_itt_ash_runby09NOV11
  • Vantage 095: Vorinostat in Combination with Bortezomib in Salvage Multiple Myeloma Patients: Final Study Results of a Global Phase 2b Trial
  • The ORR for patients refractory to their last treatment was 73% A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma
  • Practical Navigation of a Changing Landscape: Keeping Current on Multiple Myeloma Treatments

    1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of May 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
    2. 2. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses ofagents that are not indicated by the FDA. IMER does not recommend the use of any agent outside of the labeled indications.The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of IMER. Please refer to the official prescribing information foreach product for discussion of approved indications, contraindications, and warnings.
    3. 3. Disclosure of Conflicts of Interest Beth Faiman, PhD(c), RN, APRN, BC, AOCN®, reported a financial interest/relationship or affiliation in the form of: Consultant, Celgene Corporation, Millennium Pharmaceuticals, Inc.; Speakers Bureau, Celgene Corporation, Millennium Pharmaceuticals, Inc., Ortho Biotech Products, L.P. Page Bertolotti, BSN, RN, OCN®, reported a financial interest/relationship or affiliation in the form of: Speakers Bureau, Celgene Corporation, Millennium Pharmaceuticals, Inc. Pat Killingsworth, has no real or apparent conflicts of interest to report.
    4. 4. Activity OverviewBeth Faiman, PhD(c), RN, APRN, BC, AOCN® Cleveland Clinic Taussig Cancer Institute
    5. 5. Learning Objectives Upon completion of this activity, participants should be better able to: Discuss the risk factors, staging, prognostic factors, and cytogenetics of MM Describe recent research in the treatment of patients with newly diagnosed MM Identify new combination therapies for patients who are not candidates for transplant Assess new options for treating patients with relapsed/refractory MM Identify the role and timing of stem cell transplant in MM Outline an evidence-based nursing care plan for MM patients based on common disease and treatment-related symptoms Describe potential side effects from MM treatment with patients and the recommendations for their management
    6. 6. Introduction to Faculty Panel Beth Faiman, PhD(c), RN, APRN, BC, AOCN® (Chairperson) – Nurse Practitioner – Cleveland Clinic Taussig Cancer Institute Page Bertolotti, BSN, RN, OCN® – Oncology Nurse Coordinator – Samuel Oschin Cancer Center at Cedars-Sinai Medical Center Sundar Jagannath, MD – Multiple Myeloma Program Director – Mount Sinai School of Medicine Pat Killingsworth (Patient Speaker) – Columnist for the Myeloma Beacon
    7. 7. Activity Agenda 6:00 – 6:05 AM Welcome and Activity Overview 6:05 – 6:20 AM Diagnosing Multiple Myeloma 6:20 – 6:40 AM The Evolving Landscape of Myeloma Treatment: First-Line 6:40 – 6:50 AM The Evolving Landscape of Myeloma Treatment: Maintenance Therapy 6:50 – 7:10 AM The Evolving Landscape of Myeloma Treatment: Relapsed/Refractory Disease 7:10 – 7:25 AM Patient Perspective 7:25 – 7:30 AM Questions and Answers
    8. 8. Diagnosing Multiple Myeloma Page Bertolotti, BSN, RN, OCN® The Samuel Oschin Cancer Center at Cedars-Sinai Medical Center
    9. 9. Multiple Myeloma (MM) Overview  A malignant proliferation of a single clone of plasma cells that arise from B cells in the bone marrow  Extensive skeletal destruction results in bone pain, fractures, spinal cord compression and hypercalcemia  End organ damage best remembered by the mnemonic CRAB – Calcium – Renal – Anemia – Bone impairmentKyle et al, 2009; Nau et al, 2008.
    10. 10. Clinical Presentation Disease Process Clinical Presentation M protein in serum or urine (97%) Hyperviscocity with excessive M protein in the blood (common in IgA myeloma) Clonal plasma cells (96%) > 10% plasma cells in bone marrow Skeletal involvement (80%) Pain, reduced height, lytic lesions, pathologic fractures, osteoporosis, hypercalcemia Anemia: Hgb < 12 g/dL (40%–73%) Weakness, fatigueHgb = hemoglobin.Dispenzieri et al, 2009; Nau et al, 2008; Rajkumar, 2011.
    11. 11. Clinical Presentation (cont.) Disease Process Clinical Presentation Renal insufficiency (20%–25%): light Serum creatinine 2 mg/dL or greater chain cast nephropathy (myeloma kidney) and hypercalcemia Hypercalcemia: Calcium > 11 mg/dL Anorexia, nausea, lethargy, polydipsia (13%–30%) (excessive thirst), constipation, confusion Neuropathy (20%) Numbness, tingling, carpal tunnel syndrome (consider amyloidosis) Immune function deficiency Recurrent infections, bacteremia, (0.8–1.4 infections per patient-year) pneumonia; “tumor fever” in < 1%Dispenzieri et al, 2009; Nau et al, 2008; Rajkumar, 2011.
    12. 12. Risk Factors Age Median 65–70 years Race Twice as likely in African Americans than Caucasians Gender Slightly more common in men than women Genetics Higher risk in those with a first-degree relative with MM Exposures Ionizing radiation, pesticides, herbicides, fungicides, benzene, petroleum, hair dyes, engine exhaust, furniture worker products Other Factors Obesity and chronic immune stimulation such as systemic lupus erythematosusKyle et al, 2012; Rajkumar, 2011; Tariman, 2010; Okali et al, 2009.
    13. 13. Diagnostic Evaluation  Complete history and physical  Laboratory tests  BMB and aspirate – Immunophenotyping: Flow cytometry and protein expression – Conventional cytogenetics: Chromosome analysis, deletions, and karyotype – FISH: Genetic mapping and translocations – PCLI if available  ImagingBMB = bone marrow biopsy; FISH = fluorescent in situ hybridization; PCLI = plasma cell labeling index.Kyle et al, 2012; Dispenzieri et al, 2009; NCCN, 2012.
    14. 14. mSMART Risk Stratification of MM High Risk Intermediate Risk Standard Risk FISH FISH All other including: del(17p) t(4;14) Hyperdiploidy t(14;16) Cytogenetic del(13) or t(11;14) hypodiploidy t(14;20) t(6;14) PCLI > 3% GEP High-risk signaturemSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; GEP = gene-expression profiling.Dispenzieri-Kumar et al, 2011.
    15. 15. Laboratory Tests Lab Tests Common Findings CBC with differential Anemia (80%) Complete metabolic panel, Elevated creatinine (19%), phosphorus, uric acid hypercalcemia (13%), low albumin LDH Tumor burden β2m Tumor burdenCBC = complete blood count; LDH = lactate dehydrogenase; β2m = beta-2-microglobulin.Kyle et al, 2012; Tariman et al, 2010; Dispenzieri et al, 2009.
    16. 16. Laboratory Tests (cont.) Lab Tests Common Findings SPEP M spike in the beta or gamma region; 97% monoclonal heavy or light-chain protein; < 3% nonsecretory Quantitative immunoglobulins (Igs) IgG (52%), IgA (21%), IgM (< 1%), IgD (2%) SIFE Identifies light/heavy chain types of the M protein Serum FLC Lambda, kappa, and ratio (20% only light chain disease) 24-hour urine: Total protein, UPEP, UIFE Urinary M protein (Bence-Jones proteinuria); 20% lack serum M protein but have urinary M protein; involves renal impairmentSPEP = serum protein electrophoresis; SIFE = serum immunofixation electrophoresis; FLC = free light chain assay;UPEP = urine protein electrophoresis; UIFE = urine immunofixation.Kyle et al, 2012; Tariman et al, 2010; Dispenzieri et al, 2009; Reece et al, 2012.
    17. 17. Imaging Test Finding Skeletal survey Extent of bone involvement (head-to-toe X rays of axial bones), osteolytic lesions, osteopenia, osteoporosis Bone density Bone loss MRI Location and size of plasmacytomas, fractures, R/O cord compression PET Extent of disease and response to treatment; useful in nonsecretory diseaseMRI = magnetic resonance imaging; PET = positron emission tomography; R/O = rule out.Kyle et al, 2012; Dispenzieri et al, 2009; Durie, 2011.
    18. 18. IMWG Diagnostic Criteria Diagnosis Criteria (all 3 required) MGUS < 3 g/dL M protein; < 10% clonal plasma cells; no end organ damage Smoldering (asymptomatic) ≥ 3 g/dL M protein; ≥ 10% clonal plasma cells; no end myeloma organ damage Active (symptomatic) myeloma > 10% clonal plasma cells M protein in serum and/or urine (unless nonsecretory); At least 1 of the following CRAB features: C - Calcium > 11.5 mg/L R - Renal dysfunction, serum creatinine > 2 mg/dL A - Anemia with Hgb < 10 g/dL B - Bone involvement with lytic lesions or osteoporosis Solitary plasmacytoma of bone Single plasmacytoma (biopsy proven), no plasma cells in bone marrow and no end organ damageIMWG = International Myeloma Working Group; MGUS = monoclonal gammopathy of undetermined significance.IMWG, 2009; Kyle et al, 2009; Rajkumar, 2011.
    19. 19. International Staging System (ISS) Stage Criteria Median Survival (months) I Serum β2m < 3.5 mg/L 62 Serum albumin ≥ 3.5 g/dL II Neither stage I nor III 44 III Serum β2m ≥ 5.5 mg/L 29Greipp et al, 2005.
    20. 20. The Durie and Salmon Staging System Stage I Stage II Stage III Low Cell Mass Intermediate Cell Mass High Cell Mass, Subclass A or B All of the Following: Fitting Neither Stage I 1 or More of the Following: • Hgb value > 10 g/dL nor Stage III • Hgb value < 8.5 g/dL • Serum calcium value • Serum calcium value > 12 mg/dL normal or < 10.5 mg/dL • Advanced lytic bone lesions (scale 3) • Bone X ray, normal • High M component production rates bone structure (scale 0), IgG value > 7 g/dL IgA value > 5 or solitary bone g/dL plasmacytoma only • Bence-Jones protein > 12 g/24 hours • Low M component production rates: IgG • A: Relatively normal renal function value < 5 g/dL; IgA (serum creatinine value) < 2.0 mg/dL value < 3 g/dL • B: Abnormal renal function (serum • Urine light chain M creatinine value) > 2.0 mg/dL component on Examples: Stage IA (low cell mass with electrophoresis (Bence- normal renal function) Stage IIIB (high Jones protein) cell mass with abnormal renal function) < 4 g/24 hoursDurie et al, 1975.
    21. 21. Key Takeaways MM is a malignant proliferation of a single clone of plasma cells that arise from B cells in the bone marrow Most patients present with bone pain and anemia Cytogenetic evaluation of the bone marrow is important for risk stratification and management of the disease The myeloma panel should be monitored closely to evaluate response to therapy or relapse disease Diagnosing MM at an early stage prevents organ damage such as renal failure and fractures
    22. 22. The Evolving Landscape ofMyeloma Treatment: First-Line Page Bertolotti, BSN, RN, OCN® The Samuel Oschin Cancer Center at Cedars-Sinai Medical Center
    23. 23. Case Study  60-year-old man  July: Chest pain, dyspnea. A stent was placed for coronary artery disease. Placed on an antiplatelet agent.  August: Developed hematuria and proteinuria. Treated for UTI.  November: Severe mid and lower back pain without trauma. Fatigue “no better since stent.” UA/C&S: 2+ proteinuria, hematuria; no bacteria.  UPEP: Immunofixation positive for kappa light chainsUTI = urinary tract infection; UA = urinalysis; C&S = culture & sensitivity.
    24. 24. Case Study: Baseline CBC and Chemistry WBC  Sodium, Whole Blood 3.70–11.00 k/uL 15.80 (H) 135–146 mmol/L 131 (L) RBC  Potassium, Whole Blood 4.20–6.00 m/uL 3.79 (L) 3.5–5.0 mmol/L 5.1 (H) Hgb  Chloride, Whole Blood 13.0–17.0 g/dL 7.7(L) 98–110 mmol/L 101 Hematocrit 21.2 (L)  Glucose, Whole Blood 65–100 mg/dL 260 (H) Platelets 150–400 k/uL 262  BUN, Whole Blood (iSTAT) 10–25 mg/dL 37 (H) Neut % 39.5%–74.0% 93.0 (H)  Creatinine, Whole Blood (iSTAT) 0.70–1.40 mg/dL 3.1 (H) ANC 1.45–7.50 k/uL 14.80 (H)  Calcium 8.5–10.5 mg/dL 14.3 Lymph % 15.9–47.3% 5.3 (L)  Protein, Total 6.0–8.4 g/dL 6.4 Abs Lymph 1.00–4.00 k/uL 0.80 (L)  Albumin 3.5–5.0 g/dL 4.0 Liver Function Normal
    25. 25. Case Study: CRAB Criteria?  Related organ or tissue involvement (CRAB) – Calcium > 11.5 mg/dL, actual value: 14.3 mg/dL – Renal (creatinine > 2 mg/dL), actual value: 3.1 mg/dL – Anemia (Hgb < 10 g/dL or 2 g/dL below LLN), actual: 7.7 g/dL – Bone/skeletal survey: Diffuse abnormal appearance of the pelvis. 2 large lytic lesions right femur. Calvarial lesions.  Additional testing? Calvarium Femur – BMB cytogenetics, FISH – “Myeloma labs” (SPEP, UPEP, sFLC)LLN = lower limit of normal.
    26. 26. Case Study: Bone Marrow and MM Studies Bone marrow plasma cell infiltration: 20% Myeloma FISH panel: Not performed; Cytogenetics: 46,XY ISS stage: Albumin: 3.6 g/dL, β2m: 6.0 mg/L (III) Salmon Durie Stage: Stage III (Hgb < 8.5g/dL, Ca ≥ 12 mg/dL, ≥ 3 lytic bone lesions, total IgG > 7 g/dL, IgA > 5 g/dL, or Bence-Jones protein > 12 g/24 hrs) B (creatinine ≥ 2 mg/dL) Monoclonal proteins at diagnosis – Serum M spike: Negative – Serum kappa free light chains: 3014.0 mg/L – Urinary M protein: 2.81 g/24 hrs Diagnosis: Symptomatic MM kappa light chain type Does this patient require treatmennt for MM?
    27. 27. Considerations: Initial or Induction Therapy  Induction chemotherapy – Treatment given to “induce” a response  The ideal initial or induction therapy should – Rapidly and effectively control disease – Reverse disease-related complications – Decrease the risk of early death – Be easily tolerated with minimal/manageable toxicity – Not interfere with the ability to collect stem cells for transplantation (if a transplant candidate based on age, desire, health status)Kumar et al, 2009.
    28. 28. Should All Patients Receive Induction Chemotherapy? Spectrum of Plasma Cell Dyscrasias Low M component, no CRAB High M component, no CRAB CRAB MGUS Smoldering MM MM  Only patients with symptomatic MM (CRAB) require treatment  Evidence that patients with “smoldering” MM can benefit from early treatment with lenalidomide + dexamethasone – This should only be recommended in the context of a clinical trial  A percentage of patients with MGUS may never require treatment – Increased sFLC ratio, higher M protein may indicate a group more likely to progress to symptomatic MM  3 key agents given today: Bortezomib, lenalidomide, and thalidomide in combination with corticosteroidsMateos et al, 2011; Khoriaty et al, 2010; Rajkumar et al, 2005.
    29. 29. Initial or Induction Therapy for MM: Transplant Eligible and Ineligible Transplant Ineligible Transplant Eligible Melphalan +/- Induction Therapy • Bortezomib Non-Alkylator Based • Lenalidomide • Thalidomide • Other Early Delayed Autologous Autologous Transplant Transplant  Supportive care should be considered at diagnosis and throughoutNCCN, 2012; Kumar et al, 2009.
    30. 30. How Do You Treat MM: Specific Doses Transplant Candidate Bortezomib + Bortezomib 1.3 mg/m2 SC/IV Days 1, 4, 8, 11 + dexamethasone Dexamethasone 20 mg PO Day 1, 2, 4, 5, 8, 9, 11, 12 (+ cyclophosphamide, lenalidomide, or thalidomide) Lenalidomide + Lenalidomide 25 mg PO Days 1–21, q28d + dexamethasone Dexamethasone 40 mg PO wkly (+ bortezomib 1.3 mg/m2 wkly or BID?) (+/- bortezomib?) Thalidomide + Thalidomide 200 mg PO Days 1–28 + dexamethasone Dexamethasone 40 mg PO Days 1–4, 9–12, 17–20 x 4 28-day cycles (+ bortezomib or PLD?) (+ bortezomib or PLD?) – LESS COMMON TO GIVE THAL UPFRONT Non-Transplant Candidate Any of the novel agents Prednisone is often substituted for dexamethasone (elderly poor tolerance) Melphalan + any of MPV: 9 6-wk cycles of melphalan 9 mg/m2 PO + prednisone 60 mg/m2 PO Days 1–4 and/ the above or bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32 during Cycles 1–4 and Days 1, 8, 22, 29 during Cycles 5–9 Maintenance May improve PFS; ongoing studiesPO = oral; MPV = melphalan, prednisone, bortezomib; PLD = pegylated liposomal doxorubicin; PFS = progression-free survival.NCCN, 2012; Rajkumar et al, 2007; San Miguel et al, 2008; Kumar et al, 2008; Ludwig et al, 2009; Jagannath et al, 2004;Thalomid® prescribing information, 2012.
    31. 31. Can Induction Therapy Be Individualized? The Mayo Clinic Approach Approx. 25% of patients Approx. 75% of patients mSMART 2.0: Classification of active MM Newly Diagnosed Myeloma Eligible for Transplantation High Risk Standard Risk High Risk Intermediate Standard Risk Risk 4–6 cycles of CyBorD or 4 cycles of Rd FISH FISH All other VRd including: del(17p) t(4;14) Collect Stem Cells Collect Stem Cells t(14;16) Cytogenetic Hyperdiploidy del(13) or t(14;20) Autologous stem cell Autologous Continue hypodiploidy t(11;14) transplant stem cell OR Rd GEP PCLI ≥ 3% t(6;14) transplant • High-risk Bortezomib-based signature maintenance Consider Lenalidomide maintenance Newly Diagnosed Myeloma Not Eligible for Transplantation High Risk Standard Risk VMP or CyBorD RdRd = lenalidomide, dexamethasone; VRd = bortezomib plus Rd; CyBorD = cyclophosphamide, bortezomib, dexamethasone;VMP = bortezomib, melphalan, prednisone.Dispenzieri-Kumar, 2011.
    32. 32. Side Effects of Common Therapies: Snapshot Oral Thalidomide Oral Lenalidomide IV/SC Bortezomib PN √ √ DVT √ √ Myelosuppression √ √ √ Neutropenia Neutropenia, Thrombocytopenia thrombocytopenia, anemia Hypotension √ Fatigue, weakness √ √ √ Sedation √ Rash √ √ GI disturbance √ √ √ Constipation Constipation, diarrhea Nausea and vomiting, diarrhea Dose modifications to address side effects can optimize adherence, allow patients to remain on regimen longer!DVT = deep vein thrombosisThalomid® prescribing information, 2012; Velcade® prescribing information, 2012;Revlimid® prescribing information, 2011; Palumbo et al, 2011.
    33. 33. Important Considerations in MM: Bone Disease  Malignant cells produce osteoclast-activating factors (hormones, cytokines) that destroy bone cells – Leads to osteolysis, bone pain, and pathologic fracture  BP (pamidronate, zoledronic acid) inhibit bone destruction – Monitor patients for • Acute phase reactions (flulike sxs, chills) • Renal dysfunction – Dose reduce BP for decreased CrCl, longer infusion time – Monitor for albuminuria, a sign of tubular damage • Osteonecrosis of the jaw (ONJ) – Baseline and ongoing dental exams – Hold BP if jaw painBP = bisphosphonates; CrCl = creatinine clearance; ONJ = osteonecrosis of the jaw.Tariman et al, 2010; Kyle et al, 2007; Morgan et al, 2010a.
    34. 34. Important Considerations in MM: Infections  A leading cause of death in myeloma patients  Ig levels decreased (hypogammaglobulinemia)  Infiltration of bone marrow by plasma cells  Cytotoxic therapy, transplant and glucocorticoids  Interventions – Prompt reporting of symptoms – Intravenous immunoglobulin (IVIG) prophylaxis for frequent infections – Poor response to pneumococcal and influenza vaccines – Herpes zoster oral prophylaxis (bortezomib)Barlogie et al, 2006; Durie at al, 2003; Malpas et al, 2004; NCCN, 2012.
    35. 35. Important Considerations in MM: Peripheral Neuropathy  Damage to the peripheral nervous system caused by injury, inflammation, or degeneration of peripheral nerve fibers (sensory, motor, autonomic)  Incidence of CIPN is increasing – More neurotoxic drugs have been developed, patients are living longer  Thalidomide and bortezomib (vincristine, cisplatin less commonly used)  Sensory, motor, autonomic  Signs and symptoms: Numbness, tingling, pain  Monitoring: Symptom assessment, test sensation, DTRs, gait, proprioception Grade 1 Grade 2 Grade 3 Grade 4 Peripheral Sensory Asymptomatic; loss Moderate symptoms; Severe symptoms; Life-threatening; Neuropathy of reflexes limiting instrumental limiting selfcare urgent intervention ADLs ADLs indicated If pain: Reduce 1 level or change to Hold and/or reduce wkly STOPADLs = activities of daily life; CIPN = chemotherapy-induced peripheral neuropathy; DTR = deep tendon reflexes.Tariman et al, 2008; Wickham, 2007; Thalomid® prescribing information, 2012; Velcade® prescribing information, 2012;NCI.v4.0 (CT-CAE), 2009; Richardson et al, 2011.
    36. 36. Venous Thromboembolic Events (VTEs) in MM  MM is an intrinsically hypercoagulable disease associated with a higher risk of thromboembolic events  Higher risk for DVT/PE in patients treated with conventional chemotherapies plus novel therapies (thalidomide, lenalidomide) – Prior VTEs, surgery, immobility, obesity require LMWH/warfarin – All patients should receive ASA unless contraindicated  Dx: Duplex ultrasound, spiral CT if PE suspected  Prevent: Ambulate, SCDs, antiembolism stockings (questionable benefit), exercise  Prophylaxis if high risk as abovePE = pulmonary embolism; SCD = sequential compression device; LMWH = low molecular weight heparin;ASA = acetylsalicylic acid.Rome et al, 2008; Musallam et al, 2010; Menon et al, 2008.
    37. 37. Side-Effect Assessment and Management Individualized for Each Patient What is the risk of VTE? Increased if prior VTE, receiving IMiDs, etc. Bone health Are bisphosphonates indicated? Infectious diseases Is your patient at high risk for – Wkly CBC, differential for infection? 8 wks with lenalidomide (myelosuppression from – Acyclovir prophylaxis with disease/treatment) bortezomib – IV Ig for recurrent infections (a result of hypogammaglobulinemia) GI Antiemetic prior to bortezomib, Assess for diarrhea, doxorubicin constipation PN Review increased risk of PN with Prompt intervention can bortezomib and thalidomide prevent irreversible PN symptoms Monthly monitoring of SPEP, UPEP, 24-hr urine, sFLC disease parametersIMiDs = immunomodulatory drugs.IMF, 2011; Kyle et al, 2007; NCCN, 2012; Smith et al, 2008.
    38. 38. Bortezomib: New Data on Survival, Dosing  VISTA trial: 655 patients VMP (mos) MP (mos) ineligible for transplant Median OS 56.4 43.1  US, transplant eligibility – Age, desire, social, financial Median time 27 19.2 to next  Patients randomized to 9 6-wk treatment cycles of MP plus bortezomib (VMP) or to MP alone Wkly bortezomib: Significantly less severe PN (3%)  New evidence for dosing of compared with twice-wkly IV without a change in bortezomib – Once-wkly IV response – SC Bortezomib SC is not inferior to IV by overall response rateMP = melphalan, prednisone; OS = overall survival; TTP = time to progression. Bortezomib SC not different from IV bySan Miguel et al, 2011; Moreau et al, 2011.
    39. 39. Lenalidomide: New Data on Safety, Efficacy  Similar to bortezomib, oral lenalidomide remains a common treatment for patients with newly diagnosed MM (transplant eligible or ineligible)  Tumoricidal and immunomodulatory  Non-transplant: MPR-R vs. MPR vs. MP – Continuous MPR-R reduced risk of progression, maintenance improved PFS 31 mos  Lenalidomide post-transplant maintenance improves PFS (compared to placebo)MPR = melphalan, prednisone, lenalidomide; MPR-R = MPR plus lenalidomide maintenance.Palumbo et al, 2010, 2011; McCarthy et al, 2011; Attal et al, 2011.
    40. 40. Is My Patient Responding to Treatment? Response Assessment* Response IMWG Response IMWG sCR CR as below plus normal FLC ratio PD Increase of ≥ 25% from + absence of clonal cells in bone lowest response value: marrow by IHC Serum ≥ 0.5 g/dL; CR Neg IFE on the serum + urine, Urine ≥ 200 mg/24 hrs; disappearance of any soft tissue Bone marrow plasma cell plasmacytomas and < 5% BM PCs (BMPCs) ≥ 10% VGPR Serum and urine M protein Relapse See above and/or CRAB detectable by IFE but not on electrophoresis or ≥ 90% reduction in serum M protein + urine M protein level < 100 mg/24 hrs *Note: This is not inclusive PR Serum and urine M protein of all response categories. detectable by immunofixation but not on electrophoresis or ≥ 50% reduction in serum M proteinIHC = immunohistochemistry; CR = complete response; sCR = stringent CR; PR = partial response;VGPR = very good partial response; PD = progression disease.Durie et al, 2006; Kyle et al, 2008
    41. 41. Case Study (cont.) Remember our case study? Does not want to pursue up-front transplant Induction regimen (clinical trial) – Bortezomib 1.3 mg/m2 IV Day 1, 4, 8, 11 q21days – Dexamethasone 40 mg Day 1, 2, 4, 5, 8, 9, 11, 12 q21days – Cyclophosphamide 500 mg absolute po on Day 1, 8, 15 q28days Side effects – Mild PN after Cycle 3 (discomfort feet) – Mild steroid induced hyperglycemia, managed with diet, glipizide Decided to withdraw consent for clinical trial
    42. 42. Case Study (cont.)  After Cycle 5, he was changed to KAPPA, FREE, SERUM K/L RATIO, Mo/Ref Rng 3.3 - 19.4 mg/L 0.26 - 1.65 bortezomib SC (reconstitute at 2.5 January 3014.0 (H) >1255.83 (H) mg/mL NS and rotate injection sites) February 911.9 (H) >379.96 (H) based on new data March 939.4 (H) 391.42 (H) April 550.0 (H) 110.00 (H)  After 8 cycles: Continues on May 419.1 (H) 83.82 (H) Sept* 93.7 (H) >39.04 (H) bortezomib Days 1, 8, 15, 22 November 5.8 (H) >23.25 (H) q28days; neuropathy has improved January 7.4 1.48 from Grade 2 to Grade 1 PN with pain February 5.4 1.08  Switched from cyclophosphamide to Component M Spike Quant 24 Hr lenalidomide 5 mg Days 1–21 in Mo/ Ref Rng Low: 0.00 gm/24 Hr January 1.391 September to deepen response March 1)0.074 2)0.215 April 0.193  Now has achieved a complete Sept <0.093 remission which remains sustained November 0.134 January 0.00 No M Spike Detected February 0.00 No M Spike DetectedNS = normal saline.
    43. 43. Case Study: Question 1You are the nurse caring for this patient. Recall his baselinelaboratory studies. He has anemia, renal insufficiency,hypercalcemia, and lesions on his bone survey. He will startCycle 1 of treatment.What supportive care therapy would you consider to beimportant? 1) Granulocyte stimulating factor (GCSF) 2) Platelet transfusions 3) Bone marrow transplant 4) Bisphosphonates, acyclovir 5) None of the above
    44. 44. Key Takeaways There is no‘gold standard’treatment for MM Newer agents provide improved response rates, improved survival Nurses play an important role in side-effect recognition, management Newer dosing strategies can decrease side effects Personalized care plans are necessary for all patients
    45. 45. The Evolving Landscape of Myeloma Treatment: Maintenance Therapy Beth Faiman, PhD(c), MSN, APRN, BC, AOCN® Cleveland Clinic Taussig Cancer Institute
    46. 46. Case Study: Maintenance  Mr. P is a 48-year-old with newly diagnosed IgG Kappa multiple myeloma  M spike at diagnosis: 5.2 g/dL  CRAB features at presentation – Renal insufficiency (creatinine 2.8 mg/dL) – Anemia (Hgb 8.8 g/dL)  Receives 4 cycles of induction chemotherapy with bortezomib and dexamethasone and undergoes ASCT  Would he be a candidate for maintenance therapy?ASCT = autologous stem cell transplant.
    47. 47. Maintenance Therapy Maintenance therapy is the use of ongoing low intensity chemotherapy to eliminate or suppress the minimal residual tumor clone over a prolonged period of time Maintenance therapy is administered when the disease is in remission, either undetectable or at a low level The purpose of maintenance therapy is to prolong remission duration and thereby, life expectancy Immunomodulatory molecules are well suited for maintenance therapy, as they can be administered orally at low doses for a prolonged period of time
    48. 48. Thalidomide Maintenance After ASCT Author/Year N Thalidomide Dose (mg) PFS / OS / Duration EFS Attal et al, 2006 597 Thalidomide 200 (median dose) + + vs. observation / progression Spencer et al, 2006 243 Thalidomide 200 + prednisone + + vs. prednisone / 12 months Maiolino et al, 2008 212 Thalidomide 200 + dexamethasone + NS vs. dexamethasone / 12 months Barlogie et al, 2006* 668 Thalidomide 400 / progression + NS (+ in high-risk) Morgan et al, 2010a* 820 Thalidomide 100 / progression +/- NS (if optimal relapse Rx) Lokhorst et al, 2010* 550 Thalidomide 50 / progression + - Stewart et al, 2010 332 Thalidomide 200 + prednisone + NS vs. observation / 48 months*Thalidomide also given as part of induction therapy.PFS = progression-free survival; EFS = event-free survival; OS = overall survival; NS = not significant.
    49. 49. Thalidomide Maintenance: MRC Trial At Median Follow-Up From Randomization of 38 Months 100 100 Maintenance, N = 407 No maintenance, N = 410 80 80 HR [95% CI] = 1.45 [1.22, 1.73], p = .0003Patients (%) Patients (%) 60 60 40 40 Maintenance, N = 408 No maintenance, N = 410 20 20 HR [95% CI] = 0.91 [0.72, 1.17], p = 0.40 0 12 24 36 48 60 72 0 12 24 36 48 60 72 PFS (months) OS (months)  Thalidomide maintenance improves PFS with no OS advantageHR = hazard ratio; CI = confidence interval.Morgan et al, 2010b.
    50. 50. Lenalidomide Maintenance: CALGB 100104 Schema CALGB, ECOG, BMT-CTN Registration Restaging Randomization Days 90–100 Placebo D-S Stage 1-3, ≤ 70 years ≥ 2 cycles of induction Mel 200 CR Attained SD or better PR Lenalidomide* ≤ 1 yr from start of therapy ASCT ≥ 2 x 106 CD34 cells/kg SD 10 mg/d with ↑↓ (5–15 mg) Patient stratification based on diagnostic β2m level and prior thalidomide and lenalidomide use during inductionCALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; BMT-CTN = Blood andMarrow Transplant-Clinical Trials Network; CR = complete response; PR = partial response; SD = stable disease;β2m = beta-2-microglobulin.McCarthy et al, 2011.
    51. 51. PFS and OS at Median Follow-Up of 34 Months Median TTP: 46 mos Median TTP: 27 mos p = .027 p < .0001  Survival at 3 years is 88% for the lenalidomide and 80% CALGB 100104, for placebo arm patients, HR = 0.62 (95%CI = 0.40–0.95) Follow-Up 10/31/11  35 deaths in the lenalidomide arm and 53 deaths in the placebo armTTP = time to progression.McCarthy et al, 2011.
    52. 52. Lenalidomide Maintenance Post- Transplant: IFM 2005-02: Placebo-Controlled Trial Phase III Randomized, Study Design N = 614 Patients, From 78 Centers, Enrolled Between 7/2006 and 8/2008 Patients < 65 Years, With Non-Progressive Disease, ≤ 6 Months After ASCT in First-Line Randomization: Stratified According to β2m, del(13), VGPR Consolidation: Lenalidomide alone 25 mg/day po Days 1–21 q28days for 2 months Arm A Arm B Placebo Lenalidomide (n = 307) (n = 307) until relapse 10–15 mg/d until relapse  Primary end point: PFS  Secondary end points: CR rate, TTP, OS, feasibility of long-term lenalidomideIFM = Intergroupe Francophone du Myelome; del(13) = deletion 13; VGPR = very good partial response;Attal et al, 2011.
    53. 53. Lenalidomide Maintenance Post-Transplant: IFM 2005-02: PFS and OS From Randomization (4/2011) Median F/U: 36 months post-random, 46 months post-diagnosis PFS OS 1.00 1.00 Rev (n = 307) p = .79 0.75 0.75 0.50 0.50 p < 10 -9 0.25 0.25 Placebo (n = 307) 0.00 0.00 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 Placebo Lenalidomide Revlimid Placebo Lenalidomide RevlimidAttal et al, 2011.
    54. 54. MM-015: Study Design N = 459, 82 centers in Europe, Australia, and Israel Open-Label Double- Blind Treatment Phase Extension Phase Cycles (28-day) 1-9 Cycles 10+ MPR-R RANDOMIZATION M: 0.18 mg/kg, days 1-4 Maintenance P: 2 mg/kg, days 1-4 Lenalidomide R: 10 mg/day po, days 1-21 10 mg/day days 1-21 MPR Lenalidomide M: 0.18 mg/kg, days 1-4 Disease (25 mg/day) P: 2 mg/kg, days 1-4 Placebo Progression +/- R: 10 mg/day po, days 1-21 Dexamethasone MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 Placebo PBO: days 1-21  Stratified by age (< 75 vs. > 75 years) and stage (ISS I/II vs. III)  Primary comparison: MPR-R vs. MPPalumbo et al, 2011b.
    55. 55. MM-015: PFS and OS for Survival Progression-Free and Overall All Patients All Patients Median PFS 4-year OS MPR-R 31 months MPR-R 59% MPR 14 months MPR 58% 100 MP 13 months 100 MP 58% 75 HR 0.898 75 P = .579 Patients (%) Patients (%) 50 HR 0.395 50 P < .001 HR 1.089 P = .648 25 HR 0.796 25 P = .135 0 0 0 10 20 30 40 0 10 20 30 40 50 60 Time (Months) Time (Months) TTP HRHR advantages were similar: MPR-R vsMP = 0.337; MPR vs MP = 0.826 • TTP advantages were similar: MPR-R vs. MP = 0.337; MPR vs. MP = 0.826 HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival; TTP, time to progression.MP = melphalan; P = prednisone; R = lenalidomide.Palumbo et al, 2011b.
    56. 56. HOVON Trial: Bortezomib Induction and Maintenance Randomization Bortezomib 1.3 mg/m2 Doxorubicin 9 mg/m2 3 x VAD 3 x PAD Dexameth 40 mg CAD + GCSF CAD + GCSF Mel 200 + PBSCT Mel 200 + PBSCT In GMMG 2nd Allogeneic In GMMG 2nd Mel 200 + PBSCT Mel 200 + PBSCT Tx Thalidomide Bortezomib maintenance Maintenance 50 mg/day for 1.3 mg/m2 / 2 weeks 2 years for 2 yearsCAD = coronary artery disease; GCSF = granulocyte colony-stimulating factor; PBSCT = peripheral blood stem cell transplant.Sonneveld et al, 2010.
    57. 57. Bortezomib Maintenance: Outcomes 3-year PFS 48% vs. 42% 3-year OS 78% vs. 71% Progression free survival Overall survival 100 100 B: PAD 75 p = .005 75 Cumulative percentage Cumulative percentage p = .02 A: VAD B: PAD 50 50 A: VAD 25 25 N F N D A: VAD 373 243 A: VAD 373 120 B: PAD 371 215 B: PAD 371 93 0 0 0 12 24 36 months 48 0 12 24 36 months 48 At risk: At risk: A: VAD 373 289 199 110 30 A: VAD 373 320 290 174 63 B: PAD 371 321 237 118 39 B: PAD 371 336 306 191 79 10 Nov 2010-15:14:3410 Nov 2010-15:14:01 VAD PAD CR/nCR 34 49 < .001 ≥ VGPR 55 76 .001 ≥ PR 83 91 .003 nCR = near complete response. Sonneveld et al, 2010.
    58. 58. Subgroup Analysis (1) VAD/HDM/ PAD/HDM/ Thalidomide Bortezomib N PFS at OS at N PFS at OS at 36 mos 36 mos 36 mos 36 mos (%) (%) (%) (%) All 373 40 70 371 48 78 ISS 1 168 50 81 167 55 86 ISS 2 65 32 70 93 45 71 ISS 3 101 29 50 73 37 68 Creatinine 0–2 mg/dL 328 44 75 336 48 78 > 2 mg/dL 44 12 32 34 49 72 p < .01 in univariate analysisISS = International Staging System.Sonneveld et al, 2010.
    59. 59. Subgroup Analysis (2) VAD/HDM/ PAD/HDM/ Thalidomide Bortezomib N PFS at OS at N PFS at OS at 36 mos 36 mos 36 mos 36 mos (%) (%) (%) (%) All 373 40 70 371 48 78 -13/13q- 155 29 58 134 40 79 t(4;14) 33 20 40 31 28 60 17p- 39 16 17 19 22 61 p < .01 in univariate analysis All data FISH, -13/13q- also karyotype if availableFISH = fluorescent in situ hybridization.Sonneveld et al, 2010.
    60. 60. Case Study: Maintenance Conclusion 3 months following ASCT, Mr. P achieved a PR (80% reduction in serum m protein) – M spike 0.49 g/dL Renal insufficiency and anemia resolved – Creatinine normal 0.8 g/dL – Hbg 13.4 g/dL Would he be a candidate for maintenance therapy? ANSWER: Yes (based on data presented) Began maintenance with lenalidomide 10 mg po daily
    61. 61. Key Takeaways Maintenance therapy delays recurrence of myeloma and prolongs PFS Chronic low dose oral agents are preferable for maintenance strategy Bortezomib and lenalidomide are better suited for high-risk disease There is a slight increase in incidence of second malignancy after lenalidomide maintenance following melphalan New agents may be appropriate for maintenance studies – Carfilzomib, pomalidomide, oral proteasome inhibitors (MLN9708, ONX0912)
    62. 62. The Evolving Landscape of Myeloma Treatment:Relapsed/Refractory Disease Beth Faiman, PhD(c), MSN, APRN, BC, AOCN® Cleveland Clinic Taussig Cancer Institute
    63. 63. Case Study: Mr. P (cont.) Mr. P remains on lenalidomide 10 mg po daily for 3 years Develops lower back pain and worsening anemia Bone survey – L2 vertebral compression fracture and calvarial lesions consistent with disease progression Labs – M spike February 2012: 0.95 g/dL – M spike March 2012: 1.32 g/dL (confirms disease progression) – Hgb 9.2 g/dL, creatinine 1.3 mg/dL Mr. P has relapsed myeloma What are his treatment options?
    64. 64. How Is Relapse Defined?  Relapse is defined as reappearance of signs and symptoms of the disease or signs of increasing disease and/or end organ dysfunction (MDE) that are felt related to the underlying myeloma 1) Reappearance or increase in paraprotein serum and/or urine – serum M spike, sFLC or BJP in urine 2) Development of new soft tissue plasmacytomas or bone lesions or increase in the size of existing lesion on imaging 3) Hypercalcemia 4) Development of anemia 5) New or worsening kidney function 6) Hyperviscosity requiring therapeutic interventionMDE = myeloma-defining event; sFLC = serum free light chain; BJP = Bence Jones protein.Lonial, 2010; Bird et al, 2011; Anderson et al, 2008.
    65. 65. When Do You Treat Relapsed Myeloma?  Symptomatic relapse – CRAB symptoms: HyperCalcemia, Renal impairment, Anemia, Bone lesion, new plasmacytoma, bone lesions  Clinically significant relapse – Doubling of paraprotein • (M spike > 1 g/dL, BJP > 500 mg/day, sFLC level > 200 mg/L)  Asymptomatic biochemical relapse should not be treated  Goals: Control of disease, decrease morbidity  Nurses can ensure ongoing evaluation for risk of VTE, skeletal events, infections, neuropathyBird et al, 2011; Anderson et al, 2008.
    66. 66. How Is Refractory Disease Defined?  Refractory disease should fulfill all of the following criteria – Should have failed > 2 lines of therapy – Should have PD after treatment with all 4 classes of drugs • Cytotoxic agents (melphalan, cyclophosphamide, anthracyclines, bendamustine) • Immunomodulatory agents (thalidomide, lenalidomide) • Proteasome inhibitor (bortezomib) • Glucocorticoids (prednisone, dexamethasone) – Should be progressing on the last line of therapy or within 60 days of discontinuing treatmentPD = progressive disease.Lonial, 2010; Anderson et al, 2008.
    67. 67. Considerations in Relapsed MM  Disease related – Indolent, slow, or single site relapse – Rapid and multiple sites of relapse – Extramedullary disease, CNS, plasma cell leukemia – Additional genetic changes  Patient related – Poor performance – Poor renal function – Poor hematopoietic reserve  Treatment related – Prior drug exposure (relapsed or PD on therapy) – Ongoing toxicity from prior therapyCNS = central nervous system.Mohty et al, 2012; Richardson et al, 2010; Lonial, 2010.
    68. 68. Treatment of Relapsed Myeloma: How Do We Decide?  Existing novel agents – Thalidomide, bortezomib, lenalidomide  Existing older agents – Dexamethasone, prednisone, cyclophosphamide, melphalan, anthracyclines  Clinical trial options  Single agent vs. combinationNCCN, 2012; Laubach et al, 2009; Blade et al, 2009.
    69. 69. Indolent, Slow, or First Relapse High-Dose Melphalan and Stem Cell Transplant If Deferred During First-Line of Therapy Lenalidomide Bortezomib Thalidomide Based Salvage Based Salvage Based Salvage  Initial Tx with Bz  Initial Tx with IMiD  Prior  Renal dysfunction bortezomib/lenalid  Underlying PN  High-risk genetics; omide  Good risk 1q+, del(17p), t(4;14)  Cytopenia  Severe renal impairment Clinical Trial OptionsTx = therapy; Bz = bortezomib; PN = peripheral neuropathy; IMiD = immunomodulatory drugs.Lonial et al, 2011.
    70. 70. Aggressive, Rapid, Multiple Relapse Likely Combination Therapy Do Not Wait for Symptomatic Relapse Chemotherapy Chemotherapy + Transplant Based Salvage Novel Agent Based Salvage  DCEP vs. DT-PACE  Combinations of  Additional stem cells Len/Bz and other in storage chemo agents  Long remission after first transplant  Cytopenia Clinical Trial OptionsDCEP vs. DT-PACE = dexamethasone/cyclophosphamide/etoposide/cisplatin vs.dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos/phanide/etoposide; Len = lenalidomide.Lonial et al, 2011.
    71. 71. Agents in Phase III Studies Target Combination Partner(s) Pomalidomide Dexamethasone Carfilzomib Lenalidomide, Dexamethsone Vorinostat Bortezomib Panobinostat Bortezomib Elotuzumab Lenalidomide, Dexamethsone Perifosine BortezomibCourtesy of US NIH, 2012.
    72. 72. Molecular Structure of Thalidomide, Lenalidomide, and Pomalidomide  Structurally similar, but functionally different both qualitatively and quantitativelyDVT = deep vein thrombosis.Kotla et al, 2009; Thalomid® prescribing information, 2010; Revlimid® prescribing information, 2010.
    73. 73. Relapsed and Refractory Myeloma Single Agent: Pomalidomide POM POM + LoDEX (n = 108) (n = 113) ORR (≥ PR) % 13 34 ≥ MR % 29 45 CR % 1 1 PR % 12 33 VGPR % 2 9 MR % 16 12 SD % 50 37 PD % 10 6 NE % 11 12 Median time to response, months 2.9 1.9 Median DOR, months 8.5 7.9 Discrepancies in totals are due to rounding.  Disease control (≥ SD) observed in 81% of overall patientsPOM = pomalidomide; ORR = overall response rate; PR = partial response; MR = minor response;CR = complete response; VGPR = very good partial response; SD = stable disease; NE = non-event;DOR = duration of response.Richardson et al, 2011.
    74. 74. Relapsed and Refractory Myeloma Single Agent: Pomalidomide (cont.) 100 100 POM + LoDEX POM + LoDEX 80 POM 80 POMPatients (%) Patients (%) 60 60 40 40 20 20 0 0 0 5 10 15 20 0 5 10 15 20 PFS (months) OS (months)  Median PFS: POM + LoDEX 4.7 months; POM alone 2.7 months  Median OS: POM + LoDEX 16.9 months; POM alone 14 months ~ Median OS for patients with PD as best response; 5.4 monthsPFS = progression-free survival; OS = overall survival.Richardson et al, 2011.
    75. 75. Relapsed and Refractory Myeloma Single Agent: Carfilzomib PX171-003 A1 ORR CBR DOR All patients (N = 257) 24 34 8.3 PD on or within 60 days (N = 227) 24 34 8.3 Proportion of Patients Surviving Proportion of Patients Without Progression Months Since Study Entry Months Since Study Entry Median PFS: 3.7 months Median OS: 15.5 monthsCBR = clinical benefit response; ORR = overall response rate.Siegel, Martin, et al, 2010.
    76. 76. Vantage 095: PFS (IAC) BTZ + BTZ + Vorinostat Placebo Events 201/317 216/320 100 Median PFS 7.63 months 6.83 months 90 (95% CI) (6.9–8.4) (5.7–7.7) 80 HR (95% CI) 0.774 (0.64–0.94) 70 p Value 0.01 60 VGPR 28 21 PFS (%) 50 PR 28 19 ORR 56 41 40 30 20 BTZ + Vorinostat 10 BTZ + Placebo 0 0 5 10 15 20 25 Time (months)IAC = independent adjudication committee; CI = confidence interval; HR = hazard ratio.Siegel et al, 2011.
    77. 77. Elotuzumab With Lenalidomide and Weekly Dexamethasone Best Response (IMWG Criteria) Elotuzumab Elotuzumab 10 mg/kg 20 mg/kg Total Patients, n 36 37 73 ORR (≥ PR), n (%) 33 (92) 27 (73) 60 (82) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 14 (39) 12 (32) 26 (36) PR, n (%) 14 (39) 11 (30) 25 (34) < PR, n (%) 3 (8) 10 (27) 13 (18)  At a median follow-up of 14.1 months, the median PFS was not reachedIMWG = International Myeloma Working Group.Lonial et al, 2011.
    78. 78. Phase I/II Trial of Perifosine/Bortezomib ± Dexamethasone in Relapsed/Refractory Myeloma (N = 73) Median No. of Treatment Cycles Received: 8  Median prior Rx in Bz refractory patients: 6  Median prior Rx in Bz relapsed patients: 4  Median prior Bz in Bz refractory patients: 2  Median prior Bz in Bz relapsed patients: 1  45/84 patients (54%) had Dex added to Peri/Vel  39/84 (46%) patients had Peri/Vel onlyMR = minimal response; Bz = bortezomib.Richardson et al, 2011.
    79. 79. Case Study (cont.) Mr. P is enrolled in a clinical trial with Lenalidomide, Elotuzumab and Dexamethasone He achieves a VGPR (> 90% reduction in serum M-protein) after 3 months of therapy Side effects of myelosuppression were mild and controlled with appropriate dose adjustments He continues on therapy per clinical trial protocol until relapse
    80. 80. Key Takeaways The overall survival of patients with MM has increased within the last decade Many new treatments have become available The diagnosis of MM has transitioned to a chronic disease thus supportive care must be ongoing Future research is directed at newer targets using a more “novel” approach
    81. 81. Patient Perspective Pat KillingsworthColumnist for the Myeloma Beacon
    82. 82. Oncology Nurses Rock!A Long, 5-Year Rollercoaster Ride How to Help Newly DiagnosedPatients Cope: Take a TIME-OUT!
    83. 83. Ignore Median Expectancy NumbersHelp Patients Build A Healthcare Team Don’t Rush to Transplant – Do Your Homework First
    84. 84. Multiple Myeloma Patient ResourcesInternational Myeloma Foundation (IMF) - www.myeloma.org The Myeloma Beacon – www.myelomabeacon.com www.multiplemyelomablog.com www.mymultiplemyeloma.com Books by Pat Killingsworth Living with Multiple Myeloma Stem Cell Transplants from a Patient’s Perspective Found on: www.multiplemyelomablog.com

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