1. Relapsed / Refractory Multiple Myeloma
Dr. E.Elhassadi Consultant Haematologist University Hospital Waterford MMI, Nov 2016

3. Myeloma (C90):
Age-Standardised One-Year Net Survival, England and Wales
Please include the citation provided in our Frequently Asked Questions when reproducing this chart:
Prepared by Cancer Research UK
Original data sources:
Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of Hygiene and Tropical Medicine.

4. Introduction
Almost all patients with multiple myeloma (MM) who had initial treatment will eventually relapse and require further therapy. However many patients achieved a durable disease free period.
Relapsed or refractory MM is usually identified on routine surveillance performed during treatment or after the completion of therapy

5. Definitions
Progressive Disease (PD) is defined as a 25 % increase from the lowest response value in any of the Myeloma Biomarkers .
Refractory myeloma is defined as disease that is non-responsive while on therapy, or progresses within days of last therapy. There are two categories of refractory myeloma
Relapsed-and-refractory myeloma
Primary refractory myeloma
Serum M-protein (absolute increase ≥0.5 g/dL)
Urine M-protein (absolute increase of ≥200 mg/24 hours)
Bone marrow plasma cell percentage (at least 10 percent absolute increase) in patients who lack measurable M protein levels
Difference in the kappa and lambda FLC levels (FLC ratio must be abnormal and absolute change must be >10 mg/dL)
New bone or soft tissue lesions (eg, plasmacytomas)
The development of an otherwise unexplained serum calcium >11.5 mg/dL is also a marker of PD

6. Laboratory Investigations
FBC and U/E
Serum M-protein
Difference in the kappa and lambda FLC levels (FLC ratio must be abnormal and absolute change must be >10 mg/dL)
Urine M-protein (absolute increase of ≥200 mg/24 hours)
Bone marrow plasma cell percentage in patients who lack measurable M protein levels
The development of an otherwise unexplained serum calcium >11.5 mg/dL is also a marker of PD

7. R = Renal Insufficiency Recurrent infections*
Relapsed MM:
Hallmarks of myeloma: CRAB (also known as myeloma defining events).
C = Calcium
SPEP & UPEP
R = Renal Insufficiency
Recurrent infections*
MDE, myeloma-defining event; MM, multiple myeloma.
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)
*Not an MDE, yet relatively common
New bone or soft tissue lesions (eg, plasmacytomas)
A = Anemia
B = Bone Disease
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

8. Overview
Selecting Therapy Based on Specific Patient and Disease Features
Current Recommendations and Treatment Options for Relapsed/Refractory Myeloma
Future Directions in the Salvage Setting

9. When to Consider Retreatment
Need to consider biochemical vs symptomatic relapse
Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of relapse
Caveat: Patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of biochemical relapse

10. Treatment options for patients with relapsed or refractory MM include hematopoietic cell transplantation (HCT), a re-challenge of the previous chemotherapy regimen, or a trial of a new regimen.
Factors used to determine the choice of therapy include a risk stratification of myeloma (ie, high or standard risk disease), prior treatments used, and the duration of response to these treatments.

11. Risk Stratification
Patients who relapse less than 12 months from first-line therapy or relapse on therapy (ie, refractory disease) are considered to have high risk disease even if evaluation by FISH and cytogenetics previously classified their disease as standard risk.
On the other hand, patients previously diagnosed with high risk disease by cytogenetics and/or FISH who relapse more than two years from initial therapy can be considered as having standard risk disease at the time of relapse in the absence of new additional high risk cytogenetic abnormalities

12. When and Why Should a Clinical Trial Be Considered?
Before organ damage occurs (preferred)
Clinical trials (preferred)
Emphasize pros—benefits—of clinical trials
Access to new drugs
Collect information in logical manner
Can benefit pt, others
Cons and risks also exist and should be discussed with pts, caregivers
Stringent monitoring, placebo, etc
Ghobrial IM, et al. Blood. 2014;124:

13. Factors in Selecting Treatment for Relapsed/Refractory Myeloma
Disease-related factors
Duration of response to initial therapy
High-risk vs low-risk status
Biochemical disease progression, or symptomatic?
Other co-morbid conditions
Treatment-related factors
Previous therapy exposure (relapsed or refractory)
Toxicity of regimen (combination vs single agent)
Mode of administration (eg, oral or IV)
Patient-related factors

14. Relapsed/Refractory Myeloma: Preferred Regimens
NCCN Category 1
Bortezomib
SC vs IV administration
Bortezomib/PLD
Carfilzomib /Lenalidomide/ Dexamethasone
Panobinostat / Bortezomib/ Dexamethasone
Lenalidomide/ Dexamethasone
NCCN Category 2A
Repeat primary induction therapy if relapse at > 6 mos
Bortezomib combinations
With Dex; len / Dex; Thalidomide
Carfilzomib
Cyclophosphamide
High-dose or with Bort /Dex or Len/Dex
Pomalidomide /Dexamethasone
Thalidomide/ Dexamethasone
DCEP, DT-PACE, or VTD-PACE
Bort/dex, bortezomib, dexamethasone; DCEP, dexamethasone, cyclophosphamide, etoposide, cisplatin; dex, dexamethasone; DT-PACE, dexamethasone, thalidomide plus cisplatin, doxorubicin, cyclophosphamide, etoposide; len/dex, lenalidomide, dexamethasone; NCCN, National Comprehensive Cancer Network; PLD, pegylated liposomal doxorubicin; SC, subcutaneous; VTD-PACE, bortezomib, thalidomide, dexamethasone plus cisplatin, doxorubicin, cyclophosphamide, etoposide.

15. Treating Indolent, Slow-Growing Myeloma in First Relapse
IMiD-Based Salvage
PI-Based Salvage
Transplant-Based Salvage
Initial treatment with Bortezomib
Underlying PN
Initial treatment with IMiD
Previous bortezomib therapy but good or long response
Renal dysfunction
Transplant not part of initial therapy
Long remission post transplant
IMiD, immunomodulatory drug; PN, peripheral neuropathy.

16. Treating Relapsed/Refractory Myeloma
Carfilzomib-Based Salvage
Pomalidomide-Based Salvage
Other Salvage
Intolerance or resistance to bortezomib
Dexamethasone- sparing treatment as part of a combination
Intolerance to IMiDs
Lenalidomide refractory
Refractory to standard-dose PI
Pts with del(17p)?
Refractory to pomalidomide and carfilzomib
Monoclonal antibody candidate
Clinical trials
IMiD, immunomodulatory drug; PI, proteasome inhibitor.

17. Treating Aggressive Myeloma With Rapid, Multiple Relapses
Likely Combination Therapy
Do Not Wait for Symptomatic Relapse
Chemotherapy-Based Salvage
Chemotherapy + Novel Agent
Transplant-Based Salvage
DCEP vs DT-PACE
Oral vs IV chemo
Performance status of pt plays important role
Combinations of lenalidomide/ bortezomib and other chemotherapy agents
Likely to be short lived
Rapid disease control
Reconstitute marrow
DCEP, dexamethasone, cyclophosphamide, etoposide, cisplatin; dex, dexamethasone; DT-PACE, dexamethasone, thalidomide plus cisplatin, doxorubicin, cyclophosphamide, etoposide; len/dex, lenalidomide, dexamethasone.

18. Summary of Combination Therapy in RR MM
Median Lines of Tx:
ORR
Median Lines of Tx:
PFS/TTP OS 2 3 4 5 2 3 4 5
100 80 60 40 20 35 NR 26 87 85 30 10 30 29 9 71 64 67 65 65 70 25 60 55 4 20 20 10 NR
ORR (%)
Survival (Mos) 11 NR 10 NR 15 11 NR 4 13 31 10 5
Bor, bortezomib; C, cyclophosphamide; D or d, dexamethasone; K, carfilzomib; P, pomalidomide; R, lenalidomide; V, bortezomib
RD*[1]
PVd[4]
Vd*[5]
CRD[7]
CPd[8]
Pd*[9]
Kd[10]
RD*[1]
PVd[4]
CPd[8]
Pd*[9]
Kd[10]
KRd*[2]
RVD*[3]
KPd[11]
KRd*[2]
RVD*[3]
KPd[11]
CyBorD[6]
CyBorD[6]
*Data from phase III trials, all others from phase I or II trials
1. Dimopoulos M, et al. N Engl J Med. 2007;357: Stewart AK, et al. N Engl J Med. 2015;372: Richardson PG, et al. Blood. 2014;123: Lacy MQ, et al. ASH Abstract Mikhael JR, et al. Br J Haematol. 2009;144: Monge J, et al. ASCO Abstract Morgan JG, et al. Br J Haematol. 2007;137: Baz R, et al. ASH Abstract San Miguel J, et al. Lancet Oncol. 2013;14: Lendvai N, et al. Blood. 2014;124: Shah JJ, et al. ASH Abstract 690.

19. Salvage Auto Transplant in the Relapsed Setting: Reasonable Option?
Recent data from Mayo Clinic Transplant Center suggests that auto SCT2 appears safe and effective treatment for relapsed MM (N = 98)
ORR: 86%; median PFS: 10.3 mos; median OS: 33 mos
Rate of TRM: 4%, suggesting a favorable benefit-to-risk ratio
Shorter TTP after auto SCT1 predicts shorter OS post auto SCT2
TTP After Auto SCT1
Median From Auto SCT2, Mos (Range)
PFS OS
< 12 mos
5.6 (3-8)
12.6 (4-23)
< 18 mos
7.1 (6-8)
19.4 (10-42)
< 24 mos
7.3 (6-10)
22.7 (13-62)
< 36 mos
7.6 (7-12)
30.5 (19-62)
Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:

20. Maintenance Therapy Factors influence maintenance therapy decision :
previous maintenance therapy
Treatment continuation until disease progression
Side effects and toxicities profile
Patients preference
Availability of alternative maintenance therapy
Disease risk

21. “Best” Treatment for the Pt?
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?
Pt preferences and goals
Clinical trial availability
Quality of life
Palumbo A, et al. J Clin Oncol. 2014;32: Rajkumar SV, et al. Lancet Oncol. 2014;15:e

23. New Agents and Regimens Approved for RRMM in 2015
Treatment
Number of Previous Lines of Therapy
Carfilzomib (proteasome inhibitor) + Lenalidomide + Dexamethasone*
1-3
Elotuzumab (anti-SLAMF7 mAb) + Lenalidomide + Dexamethasone
Ixazomib (proteasome inhibitor) + Lenalidomide + Dexamethasone
≥ 1
Panobinostat (HDAC inhibitor) + Bortezomib + Dexamethasone
≥ 2
Daratumumab (CD38-targeted mAb) monotherapy
≥ 3
HDAC, histone deacetylase; mAb, monoclonal antibody.
*Carfilzomib monotherapy 20/56 mg/m2 IV previously approved for pts with RRMM.

24. CASTOR: PFS in Total Study Population
1.0
1-yr PFS
0.8
60.7%
0.6
PFS (%)
0.4
DVd Vd
Median PFS, Mos NR
7.2
26.9%
0.2
DVd, daratumumab/bortezomib/dexamethasone; NR, not reached; Vd, bortezomib/dexamethasone; VGPR, very good PR.
HR: 0.39 (95% CI: ; P < .0001) 3 6 9 12 15
Mos
Palumbo A, et al. ASCO Abstract LBA4. Reproduced with permission.

25. CYBORD LD
RVD
ZDEX
CATD
TIDE VD
CPD
ASCT
Ben VD

26. DARA

27. Overall Conclusions
Triplet combination approaches should be considered when appropriate
Combination treatment with either Bortezomib, Carfilzomib, and/or Pomalidomide with Dexamethasone active and well tolerated
Novel agents in combination can achieve prolonged responses even in relapsed disease
Optimal management approaches should emphasize improving QOL by identifying potential complications of therapy and minimizing long-term toxicity
New classes of agents and second-generation agents have activity and are of considerable interest
MRD, minimal residual disease; QoL, quality of life.