1. Advances in Multiple Myeloma Diagnosis and Treatment
Beth Faiman, PhD, MSN, APN-BC, AOCN
Nurse Practitioner Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio
This program is supported by an educational grant from Bristol-Myers Squibb.

2. What Is Multiple Myeloma?
Abnormal plasma cells
Cancer of the plasma cells
2015: 26,850 new cases
Median age: 69 yrs (US)
Causes: chemicals, environment
44.9% will survive at 5 yrs; MM patients are survivors
Produce
Genetic and molecular defects
MM, multiple myeloma; SDM, shared decision making.
Patients are living longer than ever with improved diagnostics, newer agents, and better supportive care
44.9% will survive at 5 years
↑ circulating abnormal serum proteins
Faiman B, et al. Multiple myeloma. In: Hematologic malignancies in adults. ONS Publishing. 2014;.SEER stat fact sheets: myeloma. Siegel RL, et al. CA Cancer J Clin. 2015;65:5-29.

3. SDM Clinical Pearl: Patients are living longer than ever and SDM is important to quality, quantity of life

4. Disease Progression in Patients with SMM and MGUS
Spectrum of plasma cell disorders (MGUS): < 1% chance/yr
SMM 10% per yr risk of progression: first 5 yrs
Strategy: identify patients with high-risk of progression; suggest early treatment before organ damage occurs
73% progress by 15 yrs
Probability of Progression (%)
100 80 60 40 20 5 10 15 25
Yrs Since Diagnosis
SMM
MGUS 51 66 73 78 16 4 21
SMM, smoldering multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
An asymptomatic premalignant condition that precedes smoldering MM or MM1,2
Prevalence of MGUS
3% for persons more than 50 years of age4
5% in those more than 70 years of age3
Risk of progression to MM (or a related disorder) is 1% per year1,3
Smoldering Multiple Myeloma
An asymptomatic premalignant disorder that proceeds multiple myeloma1,2
Overall risk of progression
10% per year for the first 5 years, ~ 3% per year for the next 5 years, and 1% per year for the last 10 years1
73% progress by 15 years1
1 Kyle RA, et al. N Engl J Med 2007;356:
2 International Myeloma Working Group. Br J Haematol 2003;121:
3 Jagannath, S. et al. Clin Lymphoma Myeloma Leuk Feb;10(1):28-43.
4 Kyle RA, et al. Curr Hematol Malig Rep Apr;5(2):62-9.
SMM, Smoldering Multiple Myeloma; MGUS, Monoclonal Gammopathy of Undetermined Signficance
Kyle RA, et al. N Engl J Med. 2007;356: Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

5. MM: Clinical Manifestations
Series of genetic mutations, translocations, normal cell turns malignant Hallmarks of myeloma: CRAB (also known as myeloma defining events)
C = Hypercalcemia
R = Renal Complications
MM, multiple myeloma; MDE, myeloma-defining events
FROM PREVIOUS SLIDE: Multiple Myeloma is generally symptomatic. Unlike with MGUS or SMM, there is end organ damage—CRAB criteria--
Calcium elevation (serum calcium >11.5 mg/dL)
Renal insufficiency (serum creatinine >2 mg/dL)
Anemia (hemoglobin <10 g/dL or 2 g/dL <normal)
Bone disease (lytic lesions or osteopenia)
Recurrent infections*
A = Anemia
* Not an MDE, yet relatively common
B = Bone Disease
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

6. Revised IMWG Criteria (2014)
MM, multiple myeloma; IMWG, International Myeloma Working Group; SPEP, serum protein elecrophoresis; UPEP, urine protein electrophoresis; CMP, complete chem panel ; CBC + diff, complete blood count with differential; k/l, kappa/lambda; MPA, monoclonal protein analysis; cyto, cytogenetics; GEP, gene expression profiling; MRI, magnetic resonance imaging; CT, computed tomography; FISH, fluorescence in situ hybridization;
Clonal evolution in a permissive microenvironment. Progression from MGUS to SMM to symptomatic MM involves clonal evolution and heterogeneity, which is not only cell autonomous but also dependent on the interactions of the tumor cells with the bone marrow microenvironment. This includes immune cells such as T-regulatory cells (Tregs), myeloid derived suppressor cells (MDSCs), natural killer (NK) cells, osteoclasts, osteoblasts, angiogenesis, and MSCs.
Republished with permission of American Society of Hematology, from Ghobrial, IM, et al. How I treat smoldering multiple myeloma, Blood. 2014;124: ; permission conveyed through Copyright Clearance Center, Inc.

7. Diagnostic Workup Lab tests: Serum protein electrophoresis (SPEP)
Urine protein electrophoresis (UPEP)
Complete metabolic panel (CMP)
CBC + differential
Plasma ratio of free kappa/lamba light chains
Monoclonal protein analysis (MPA)
Bone marrow biopsy:
FISH, cytogenetics, and gene expression profiling (GEP)
Imaging:
Skeletal survey
MRI, CT
PET scan ± MRI, CT
Genetic changes occur
MM, multiple myeloma; IMWG, International Myeloma Working Group; SPEP, serum protein elecrophoresis; UPEP, urine protein electrophoresis; CMP, complete chem panel ; CBC + diff, complete blood count with differential; k/l, kappa/lambda; MPA, monoclonal protein analysis; cyto, cytogenetics; GEP, gene expression profiling; MRI, magnetic resonance imaging; CT, computed tomography; FISH, fluorescence in situ hybridization;
Clonal evolution in a permissive microenvironment. Progression from MGUS to SMM to symptomatic MM involves clonal evolution and heterogeneity, which is not only cell autonomous but also dependent on the interactions of the tumor cells with the bone marrow microenvironment. This includes immune cells such as T-regulatory cells (Tregs), myeloid derived suppressor cells (MDSCs), natural killer (NK) cells, osteoclasts, osteoblasts, angiogenesis, and MSCs.
Ghobrial IM, et al. Blood. 2014;124: Rajkumar SV, et al. Lancet Oncol. 2014;15:e Faiman B. Clin Lymphoma Myeloma Leuk. 2014;14:

8. “Best” Treatment for the Patient?
With so many available therapies, how does one choose the “best”?
Guidelines exist to “guide” decision making
Consider:
Prevention of further organ damage (if present)
Age, morbidities, desire, financial, social status
Biomarkers/cytogenetic risk group (high or low)
2 drugs, 3 drugs, or more?
Clinical trial
Quality of life
NCCN, National Comprehensive Cancer Network; QOL, quality of life; SDM, shared decision making.
Roussel J Clin Oncol 32(25) ; Richardson, Paul G., Siegel, David S., Vij, Ravi, Hofmeister, Craig C., Baz, Rachid, Jagannath, Sundar, Anderson, Kenneth C. (2014). Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood, 123(12), doi: /blood
Richardson, P. G., Xie, W., Jagannath, S., Jakubowiak, A., Lonial, S., Raje, N. S., Anderson, K. C. (2014). A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood, 123(10), doi: /blood
Shah, Jatin J., Feng, Lei, Manasanch, Elisabet E., Weber, Donna M., Thomas, Sheeba K., Turturro, Francesco, Orlowski, Robert Z. (2014). Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma (Vol. 124).
Vij, Ravi, Huff, Carol Ann, Bensinger, William I., Siegel, David S., Jagannath, Sundar, Berdeja, Jesus, Richardson, Paul G. (2014). Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 Results (Vol. 124).
SDM Clinical Pearl: SDM concepts can help guide patient and caregivers to include individual preferences, goals, values
Palumbo A, et al. J Clin Oncol. 2014;32: Rajkumar SV, et al. Lancet Oncol. 2014;15:e

9. When Should Treatment Begin?
Before organ damage occurs (preferable)
Clinical trials (also preferred)
Emphasize pros—benefits—of clinical trials
Access to new drugs
Collect information in logical manner
Can benefit patient, others
Cons and risks also exist and should be discussed with patients, caregivers
Stringent monitoring, placebo, etc
Ghobrial IM, et al. Blood. 2014;124:

10. Increased Treatment Options in MM
MM Therapies Introduction
FDA Approved in MM
1950
1960
1970
1980
1990
2000
2010
2015
2008
Bortezomib frontline
1983
Autologous
transplantation
1958
Melphalan
2003
Bortezomib 3rd line
2012
Carfilzomib
3rd line; Bortezomib SC
1962
Prednisone
2005
Bortezomib 2nd line
1986
High-dose dexamethasone
FDA, US Food and Drug Administration; MM, multiple myeloma; SC, subcutaneous.
The treatment options for patients with multiple myeloma have increased greatly over the last decade. You can see by the diagram in this slide that the left half of the timeline represents 40 years and the right half of the diagram represents 20 years. The number of novel agents and combinations developed in the last 2 decades has changed the treatment paradigm for multiple myeloma. These novel agents have also changed the expected survival for patients with multiple myeloma.
1969
Melphalan +
prednisone
2006
Lenalidomide + dex
2nd line; Thalidomide + dex 1st line
2013
Pomalidomide 3rd line
2014
Bortezomib retreatment
2007
Doxorubicin + bortezomib
2nd line
2015
Panobinostat 3rd line; Lenalidomide 1st line

11. context could influence treatment choice
SDM Clinical Pearl:
One driving force of SDM is increasing number of equivocal treatment options – inform patients that preferences and
context could influence treatment choice

12. MM Tx: Key Side Effects, Considerations
Drug Class
Name
Key Side Effects
Nursing Considerations
Proteasome inhibitor
Bortezomib
PN, T, M, F
IV, SC; monitor platelets; safe in renal failure
Carfilzomib
PN, C, M, F
Hydration, cardio/pulmonary
Immunomodulatory agent
Lenalidomide
DVT, M, BD, R, D
ASA or LMWH if high risk for clots; weekly CBC x 8 wks
Thalidomide
DVT, M, BD
As above
Pomalidomide
DVT, M, BD, F
C, cardiac; PN, peripheral neuropathy; MS, metabolic syndrome; BD, Birth Defects; D, diarrhea; DVT, deep vein thrombosis; H, hyperglycemia; M, myelosuppression; N, nausea; R, renal dose adjustment necessary; LMWH, low-molecular-weight heparin; CBC, complete blood count; EKG, electrocardiogram; ASA, aspirin; IV, intravenous; SC, subcutaneous; mag, magnesium; K+, potassium.
BD, birth defects; C, cardiac; D, diarrhea; DVT, deep vein thrombosis; F, Fatigue; M, myelosuppression; PN, peripheral neuropathy; R, renal dose adjustment necessary
US Food and Drug Administration. FDA approved drug products.

13. MM Tx: Key Side Effects, Considerations
Drug Class
Name
Key Side Effects
Nursing Considerations
Alkylating agent
Melphalan
M, N
CBC diff monthly; renal dose adjustment
Cyclophosphamide
Corticosteroid
Prednisone
H, MS
Monitor blood sugar, insomnia, weight gain
Dexamethasone
Above
HDAC inhibitor
Panobinostat
C, D
Baseline EKG and mag/K+ monitoring; loperamide for diarrhea
C, cardiac; PN, peripheral neuropathy; MS, metabolic syndrome; BD, Birth Defects; D, diarrhea; DVT, deep vein thrombosis; H, hyperglycemia; M, myelosuppression; N, nausea; R, renal dose adjustment necessary; LMWH, low-molecular-weight heparin; CBC, complete blood count; EKG, electrocardiogram; ASA, aspirin; IV, intravenous; SC, subcutaneous; mag, magnesium; K+, potassium.
C, cardiac; D, diarrhea; DVT, deep vein thrombosis; H, hyperglycemia; M, myelosuppression; MS, metabolic syndrome; N, nausea
US Food and Drug Administration. FDA approved drug products.

14. Preferred Regimens (NCCN)
NCCN Preferred Regimens
Other NCCN Regimens
Initial therapy (induction) for transplant eligible pts (response assessment after cycle 2)
Bor/dex (category 1)
Bor/cy/dex (category 1)
Bor/dox/dex (category 1)
Bor/len/dex (category 1)
Len/dex (category 1)
Car/len/dex
Dex (category 2B)
Liposomal dox/vin/dex (category 2B)
Thal/dex (category 2B)
Maintenance therapy
Bor
Len (category 1)
Thal (category 1)
Bor + pred (category 2B)
Bor + thal (category 2B)
Interferon (category 2B)
Steroids (category 2B)
Thal + pred (category 2B)
Therapy for previously treated myeloma
Repeat primary induction if relapse > 6 mos
Mix/match any drugs
Pom, car, pan
Bendamustine
Bor/vorinostat
Len/bendamustine/dex
bor, bortezomib; dex, dexamethasone; cy, cyclophosphamide; dox, doxorubicin; len, lenalidomide; mel, melphalan; pred, prednisone; thal, thalidomide; car, carfilzomib; vin, vincristine; pan, panobinostat; pom, pomalidomide; SDM, shared decision making; MM, multiple myeloma.
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

15. No clear standard-of-care treatment for newly diagnosed or relapsed MM
SDM Clinical Pearl
No clear standard-of-care treatment for newly diagnosed or relapsed MM
Present options, provide information on treatment risks and benefits, and achieve mutual agreement between patient and provider on treatment

16. “Hot” Trials and Topics in MM
Smoldering MM: do nothing, do something, or go for it!
Lenalidomide + dex or observation[1,2]
Carfilzomib + len + dex; len maintenance[3,4]
Newly diagnosed, transplant eligible[5,6]
Note that maintenance is integrated into current trials
Numerous trials!
Carfilzomib, elotuzumab, ixazomib, and pomalidomide ± transplant
MM, multiple myeloma; dex, dexamethasone, len, lenalidomide; SDM, shared decision making.
Len btz dex ± ASCT Ph 3 (NCT )
Ixazomib or placebo after ASCT Ph 3 (NCT )
Len mel, ASCT, len maint Ph1,2 (NCT )
Carf len dex Ph 2 (NCT )
Elotuzumab len btz dex Ph 2 (NCT )
Panobinostat len btz dex Ph 1,2 (NCT )
Carf cyclo dex Ph 1 (NCT )
1. Mateos MV, et al. N Engl J Med. 2013;369: Mateos MV, et al. ASH Abstract Landgren O, et al. ASH Abstract Landgren O, et al. ASH Abstract Rajkumar SV, et al. Lancet Oncology. 2014;15:e538-e ClinicalTrials.gov.

17. SDM Clinical Pearl: Facilitate deliberation and decision making on clinical trial participation; discuss drug, randomization, trial logic, time commitment, costs, patient’s right to refuse or stop clinical trial participation at any time

18. “Hot” Trials and Topics in MM
NDMM/Transplant Ineligible
Relapsed/Refractory MM
FIRST trial[1]
Continuous Rd vs Rd x 18 cycles vs MPT x 18 cycles
OS favors continuous Rd; benefit sustained whether > 75 or < 75 yrs
Proteasome inhibitors
Carfilzomib (ASPIRE)[3]
Ixazomib (oral)[4]
Oprozomib (oral)[5]
Bortezomib retreatment (IV/SC)[6]
Weekly carfilzomib, cyclophosphamide, and prednisone[2]
Generally safe and tolerated in elderly pts
Monoclonal antibodies
Elotuzumab + len + dex[7]
Daratumumab (anti CD38)[8]
SAR (anti CD38)[9]
BTK inhibitor
Ibrutinib ± dexamethasone[10]
NDMM, newly diagnosed multiple myeloma; MM, multiple myeloma; Rd, lenalidomide + low-dose dexamethasone; MPT, melphalan/prednisone/thalidomide; OS, overall survival; IV, intravenous; SC, subcutaneous; len, lenalidomide; dex, dexamethasone
1. Benbouker L, et al. N Engl J Med. 2014;371: Palumbo A, et al. ASH Abstract Stewart AK, et al. ASH Abstract Richardson PG, et al. Blood. 2014;124: Vij R, et al. ASH Abstract Oriol A, et al. Hematology. 2014;Dec 10:[Epub ahead of print]. 7. Richardson PG, et al. ASH Abstract Plesner T, et al. ASCO Abstract Martin TG, et al. ASH Abstract Vij R, et al. ASH Abstract 31.

19. MAb-Based Targeting of Myeloma
Antibody-dependent cellular cytotoxicity (ADCC)
Complement-dependent cytotoxicity (CDC)
Apoptosis/growth arrest via targeting signaling pathways
Effector cells
C1q
C1q
CDC MM MM
FcR
Daratumumab (CD38) SAR (CD38)
Daratumumab (CD38) SAR (CD38)
Elotuzumab (anti-CS1, SLAMF-7) mechanism of action may be two fold: 1) a passive targeted immunotherapy by targeting myeloma cells expressing SLAMF-7 leading to ADCC and, (2) an active immunotherapy by activating NK cells expressing SLAMF-7, promoting NK mediated cell death of myeloma cells.[ Balasa B, Yun R, Belmar NA, Fox M, et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways. Cancer Immunol Immunother Jan;64(1):61-73.] The active immunotherapy mechanism may enhance the tumor specific ADCC. This humanized monoclonal antibody when used as a monotherapy has shown minimum responses (stable disease but no objective responses), but provides benefit as assessed by objective responses when combined with lenalidomide and dexamethasone
ADCC MM
MAbs have unique targets
New research continues to distinguish targets even further
Hope for personalized treatment
Elotuzumab (anti-CSI, SLAMF7) Daratumumab (CD38) SAR (CD38)
Tai YT, et al. Bone Marrow Res. 2011;2011: Balasa B, et al. Cancer Immunol Immunother. 2015;64:61-73.

20. Nursing Considerations for Novel MM Therapies Based on Clinical Trials
Category
Agents
Key Nursing Considerations
Oral proteasome inhibitors
Ixazomib
Oprozomib
Adherence
GI toxicity
Monoclonal antibodies
Elotuzumab (SLAMF7)
Daratumumab (anti CD38)
SAR (anti CD38)
Infusion reaction
Premedicate
Tyrosine kinase inhibitor
Ibrutinib (BTK)
Decreased blood counts
Drug interactions

21. Responding to Treatment or Progressing?
Newer laboratory techniques to assess “deeper” responses to treatment New criteria have been established Prompt identification of disease progression can prevent organ damage
Response: Abnormal M-protein should decrease with therapy
Example of Response: Serum M-Protein
Beginning M spike: 3.1 g/dL
Cycle 1: 1.5 g/dL = PR (50%)
Cycle 2:
0.52 g/dL = PR
Cycle 3: 0.10 g/dL = VGPR (90%)
Cycle 4: g/dL = unconfirmed CR?
VGPR, very good partial response; CR, complete response.
Key Concepts: Response and progression are two poorly – understood concepts among patients, nurses and providers.
New response criteria adds additional categories of Stringent Complete Response (sCR) and Complete Response (CR) to reflect new testing methods that can detect minimal residual disease at more sensitive levels
Molecular CR = CR criteria and Negative allele specific PCR Test (sensitive to 105)
Immunophenotypic CR = sCR criteria plus negative bone marrrow by next generation flow (multiparametric flow with > four colors)
Emphasize nursing implications: Patient advocacy
Palumbo A, et al. J Clin Oncol. 2014;32: Durie BM, et al. Leukemia. 2006;20:

22. Responding to Treatment or Progressing?
Newer laboratory techniques to assess “deeper” responses to treatment New criteria have been established Prompt identification of disease progression can prevent organ damage
Progression: M-protein goes up; watch for signs of progression such as bone pain, fatigue, infections
Example of Progression
Cycle 24 = 0.00 g/dL
Cycle 25 = 0.33 g/dL
Cycle 26 = 0.72 g/dL
VGPR, very good partial response; CR, complete response.
Key Concepts: Response and progression are two poorly – understood concepts among patients, nurses and providers.
New response criteria adds additional categories of Stringent Complete Response (sCR) and Complete Response (CR) to reflect new testing methods that can detect minimal residual disease at more sensitive levels
Molecular CR = CR criteria and Negative allele specific PCR Test (sensitive to 105)
Immunophenotypic CR = sCR criteria plus negative bone marrrow by next generation flow (multiparametric flow with > four colors)
Emphasize nursing implications: Patient advocacy
Palumbo A, et al. J Clin Oncol. 2014;32: Durie BM, et al. Leukemia. 2006;20:

23. Supportive Care Bone: 85% will develop bone disease
All should receive monthly bisphosphonates after dental exam; monitor renal function long term
Infection: major cause of death in MM
Impaired antibody formation after antigenic stimulations
Immunizations: pneumococcal (PCV13, PPSV23), seasonal inactivated influenza
Shingles prophylaxis (proteasome inhibitor, transplant)
Renal: monitor status, dose reductions may be necessary
Acute renal failure can occur due to NSAIDs, CT dyes, antibiotics
Hydrate (carefully), monitor monthly
MM, multiple myeloma; PCV13, pneumococcal conjugate vaccine; PPSV23, pneumococcal polysaccharide vaccine; NSAIDS, nonsteroidal anti-inflammatory drugs; CT, computed tomography.
Bilotti E, et al. Clin J Oncol Nurs. 2011;15(suppl):5-8. Miceli TS, et al. Clin J Oncol Nurs. 2011;15(suppl):9-23. Faiman B, et al. Clin J Oncol Nurs. 2011; MMWR. 2014;46:1-24.

24. Long-term Effects of Treatment
Diarrhea (lenalidomide)
Peripheral neuropathy (bortezomib, MM, diabetes)
Secondary cancers
Cardiovascular/pulmonary disease
Health maintenance is important as patients are at risk for same illnesses as those without MM
Financial
Chronic illnesses are costly
Loss of income, hospital and medical bills can be high
Refer to patient care organizations, copay foundations
MM, multiple myeloma.
Faiman B. J Adv Pract Oncol. 2013;4: Kurtin S, et al. Clin J Oncol Nurs. 2013;17(suppl):7-11. Faiman B, et al. Blood. 2013;122:5397.

25. Conclusion
Advances in understanding bone marrow microenvironment have led to drug discovery
New drugs provide hope for longer remissions
Ongoing research will prove whether a deeper response translates to improved survival
Supportive care and side effect management
Plethora of treatment options, risks/benefits, and side effects should be reviewed with patients prior to starting on therapy
Support patients who are willing and able to participate in SDM process

26. Go Online for More CCO Coverage of Multiple Myeloma!
Pocket guide of key nursing perspectives using shared decision making Downloadable slideset on shared decision making in multiple myeloma from the live symposium plus more offerings on multiple myeloma
clinicaloptions.com/Oncology