1. May 31 - June 4, 2013 Chicago, Illinois
Multiple Myeloma CCO Independent Conference Coverage 2013 American Society of Clinical Oncology Annual Meeting*
May 31 - June 4, 2013
Chicago, Illinois
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC
This program is supported by educational grants from
This program is supported by an educational grant from

2. About These Slides
In the following slides, you will find highlights of the key studies from this meeting. Be sure to review the slide notes field for each slide for insightful commentary from our expert faculty
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3. Faculty
Kenneth Anderson, MD Kraft Family Professor of Medicine Harvard Medical School Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts Sagar Lonial, MD Professor of Hematology and Oncology Director, Translational Research B-Cell Malignancy Program The Winship Cancer Institute Emory University Atlanta, Georgia
This slide lists the faculty who were involved in the production of these slides.

4. Disclosures
Kenneth Anderson, MD, has disclosed that he has received consulting fees from Celgene, Gilead Sciences, Onyx, and sanofi-aventis. Sagar Lonial, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis, and Onyx.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

5. Outline Newly Diagnosed Myeloma Relapsed/Refractory Myeloma
MPR vs MEL200 ± Lenalidomide Maintenance in NDMM: Phase III Trial
SPMs in Lenalidomide-Treated Patients: Meta-analysis
Carfilzomib + MP in Elderly Patients With Newly Diagnosed MM: Phase I/II
Relapsed/Refractory Myeloma
Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial
Pom + LoDex vs HiDex (MM-003): Analysis of Patients With Moderate Renal Impairment
Phase I/II Partly Randomized Elotuzumab, Lenalidomide, and LoDex (Study 1703)
Phase I/II Daratumumab Monotherapy
Phase I Weekly Ixazomib: Dose Escalation Study
Other: Prognostic Indicators
Deep Sequencing for Minimal Residual Disease Detection in Patients With Myeloma
HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; MEL200, melphalan 200 mg/m2; MM, multiple myeloma; MP, melphalan, prednisone; MPR, melphalan/prednisone/lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival, PD, progressive disease; Pom, pomalidomide; SPMs, secondary primary malignancies

6. Newly Diagnosed Multiple Myeloma

7. MPR vs MEL200 ± Lenalidomide Maintenance in NDMM: Phase III Trial
Second Randomization
Patients younger than 65 yrs of age with NDMM
(N = 402)
Lenalidomide maintenance 28-day courses until PD
First Randomization
MPR six 28-day courses
(n = 202)
No maintenance
Lenalidomide + Dexamethasone four 28-day courses
Lenalidomide maintenance 28-day courses until PD
MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival, PD, progressive disease.
Sagar Lonial, MD:
Boccadoro and colleagues conducted a phase III trial of melphalan/prednisone/lenalidomide (MPR) vs melphalan 200 mg/m2 and autologous transplantation (MEL200) consolidation therapy, with or without lenalidomide maintenance, in patients with newly diagnosed myeloma who had received initial therapy with lenalidomide and dexamethasone (N = 402). The primary endpoint was progression-free survival (PFS). This important study addressed the role and timing of high-dose therapy in autologous transplantation in the context of newer available therapies.
MEL200 2 courses
(n = 200)
No maintenance
Primary endpoint: PFS
Other endpoints: efficacy, safety
Boccadoro M, et al. ASCO Abstract 8509.

8. MPR vs MEL200 ± Lenalidomide Maintenance: MPR vs MEL200 PFS and OS
100 75 50 25 10 20 30 40 60 70
Mos
HR: 1.69 (95% CI: ; P < .0001)
Median PFS, Mos
MPR MEL200
24 38
HR: 1.25 (95% CI: ; P = .27)
5-Yr OS, %
62 71
Patients Without Progression (%)
Survival (%)
MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; OS, overall survival, PFS, progression-free survival.
Kenneth Anderson, MD:
The primary endpoint, median PFS, was significantly longer with MEL200 than with MPR: 38 months vs 24 months, respectively (HR: 1.69; P < .0001). Overall survival (OS) was not significantly different at 5 years: 71% for MEL200 vs 62% for MPR (HR: 1.25; P = .27).
Sagar Lonial, MD:
This is an important study because it continues to show the importance of high-dose therapy in autologous transplantation, at least regarding PFS.
Boccadoro M, et al. ASCO Abstract 8509.

9. MPR vs MEL200 ± Lenalidomide Maintenance: Len Maintenance and Survival
PFS: 48% reduced risk of progression
OS: 38% reduced risk of death
Median PFS, Mos
Lenalidomide maint No maint
37 26
5-Yr OS, %
Lenalidomide maint No maint
75 58
100
100 75 75
Patients Without Progression (%) 50
Survival (%) 50
Len, lenalidomide; MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; OS, overall survival; PFS, progression-free survival.
Kenneth Anderson, MD:
As seen on this slide, the role of maintenance therapy is valuable in this setting. Median PFS was significantly longer with lenalidomide maintenance, at 37 months vs 26 months for no maintenance (HR: 0.52; P < .0001). Likewise, the 5-year OS rate was substantially increased, at 75% for lenalidomide maintenance vs 58% for no maintenance (HR: 0.62; P = .02).
Sagar Lonial, MD:
This result corroborates data presented previously from a randomized phase III study in which there was not only an improvement in PFS with lenalidomide maintenance vs placebo, but an improvement in OS as well. [1]
In the era of novel therapies, the integration of lenalidomide into a transplantation paradigm is extremely relevant. Adding lenalidomide upfront to melphalan and prednisone to improve induction has been addressed by Palumbo and colleagues[2] in the MM-015 trial of melphalan/prednisone/lenalidomide followed by lenalidomide maintenance. Results were so positive that it served as the background for the current phase III trial. As Dr. Lonial noted, in the current phase III study, there was an initial PFS advantage, and with the addition of the lenalidomide maintenance, in the second randomization, an OS advantage.
References
McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:
Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366: 25 25
HR: 0.52 (95% CI: ; P < .0001)
HR: 0.62 (95% CI: ; P = .02) 10 20 30 40 50 60 70 10 20 30 40 50 60 70
Mos
Mos
Boccadoro M, et al. ASCO Abstract 8509.

10. MPR vs MEL200 ± Lenalidomide Maintenance: Best Response
No Maintenance
(n = 204)
P Value CR 23 19
.25
≥ VGPR 48
.93
≥ PR 78 77
.75
CR, complete response; MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response.
Sagar Lonial, MD:
Response rates were not significantly different between MPR and MEL200, although slightly more patients receiving maintenance achieved a complete response (23% vs 19% with no maintenance; P = .25). This also reflects the similar response rates in a study by Palumbo and colleagues.[1] I hypothesized in my discussion of this study at the American Society of Clinical Oncology (ASCO) that there was a higher molecular complete response (CR) rate in the group that received high-dose therapy and autologous transplantation, which might have accounted for the difference in PFS.[2] We need a better understanding of depth of response and how it may account for improved PFS with intensive therapy.
Kenneth Anderson, MD:
I could not agree more. The best news here is that incorporating new treatments into a transplant paradigm can produce molecular CRs with no minimal residual disease, by either multiflow cytometry or polymerase chain reaction (PCR). As Dr. Lonial said, the issue is how to determine the best way to get to that level of response and what it means clinically. Just looking at CR is less meaningful because there can be a big difference in the depth of response in favor of transplantation.
References
Palumbo A, Cavallo F, Di Raimondo F, et al. A phase III trial of melphalan/prednisone/lenalidomide (MPR) versus melphalan (200 mg/m2) and autologous transplantation (MEL200) in newly diagnosed myeloma patients. J Clin Oncol. 2010;28(suppl 15s):Abstract 8015.
Lonial S. Optimizing induction therapy and depth of response. Program and abstracts of the 2013 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2013; Chicago, Illinois.
Boccadoro M, et al. ASCO Abstract 8509.

11. MPR vs MEL200 ± Lenalidomide Maintenance Arm: Adverse Events
Grade 1/2
Grade 3/4
Neutropenia
Anemia
Thrombocytopenia
Infections
Cutaneous Toxicity
DVT
DVT, deep vein thrombosis; MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; SPMs, second primary malignancies.
Kenneth Anderson, MD:
Most adverse events associated with maintenance in this study were grade 1/2, with the exception of neutropenia; approximately 22% of patients had grade 3/4 neutropenia, whereas no other grade 3/4 adverse event affected more than 4% of patients. Of note, grade 1/2 anemia and thrombocytopenia were seen in approximately 20% of patients.
Sagar Lonial, MD:
Some increase in adverse events is to be expected—predominantly neutropenia, anemia, and thrombocytopenia—with maintenance therapy.
Diarrhea
Fatigue
SPMs 5 10 15 20 25 30
Patients (%)
Boccadoro M, et al. ASCO Abstract 8509.

12. MPR vs MEL200 ± Lenalidomide Maintenance: Conclusions
After 4 cycles of lenalidomide + dexamethasone, MEL200 for 2 cycles significantly prolonged PFS in comparison with MPR for 6 cycles in patients with newly diagnosed MM
Lenalidomide maintenance significantly reduced the risk of progression with both MPR and MEL200
OS was similar between MPR and MEL200, but was significantly improved in both groups by subsequent lenalidomide maintenance therapy
MEL200, melphalan 200 mg/m2; MM, multiple myeloma; MPR, melphalan/prednisone/lenalidomide; OS, overall survival; PFS, progression-free survival.
Sagar Lonial, MD:
Clearly, MEL200 produces longer PFS than MPR in newly diagnosed myeloma, and in both regimens, lenalidomide maintenance reduces the risk of progression and improves OS. From my perspective, this trial has 2 important take-home messages. The first is that there continues to be a role for high-dose therapy in autologous transplantation, and the second is that lenalidomide maintenance offers a survival benefit. We now have 2 trials in the posttransplantation setting that have demonstrated a survival benefit for lenalidomide maintenance.
Kenneth Anderson, MD:
It is important to build upon this trial, and others evaluating novel therapy combinations, in studies that will compare novel agents in the transplantation setting. This study evaluated a 3-drug combination; future studies may have 4- or 5-drug combinations. Each combination will need to be weighed against the current standard of care—transplantation.
Boccadoro M, et al. ASCO Abstract 8509.

13. SPMs in Lenalidomide-Treated Patients: Meta-analysis
Search Criteria
Randomized studies
Newly diagnosed multiple myeloma
Randomized to lenalidomide or 1 new drug not including lenalidomide
Data available on SPM
Databases
PubMed, ASCO, ASH, IMWG
ASCO, American Society of Clinical Oncology; ASH, American Society of Hematology; IMWG, International Myeloma Working Group; NDMM, newly diagnosed multiple myeloma; SPMs, secondary primary malignancies.
Sagar Lonial, MD:
Palumbo and colleagues conducted a meta-analysis of multiple data sets, including more than 6000 patients, to identify risk factors that may predict development of second primary malignancies (SPMs) in patients with newly diagnosed myeloma. This was a very large and comprehensive analysis of randomized trials with available data on lenalidomide vs a new drug. Of 6383 patients, 420 developed an SPM.
N = 6383
Lenalidomide (n = 3218)
No lenalidomide (n = 3165)
SPM (n = 420)
Palumbo A, et al. ASCO Abstract 8517

14. SPMs in Lenalidomide-Treated Patients: Cumulative Incidence in Phase III Trials
Hematologic SPMs
Solid SPMs
0.10
0.10
0.09
Lenalidomide No Lenalidomide
0.09
Lenalidomide No Lenalidomide
0.08
0.08
0.07
0.07
HR: 3.8 (95% CI: ; P = .029)
HR: 1.1 (95% CI: ; P = .72)
0.06
0.06
Cumulative Incidence
0.05
Cumulative Incidence
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.01
SPMs, secondary primary malignancies.
Kenneth Anderson, MD:
In this meta-analysis, the risk of hematologic SPMs was higher in patients who received lenalidomide: 3.1% at 5 years vs 1.4% for no lenalidomide (HR: 3.8). However, the 5-year incidence of solid SPMs was very similar with or without lenalidomide (3.8% vs 3.4%, respectively; HR: 1.1).
Sagar Lonial, MD:
There has been concern from some trials that lenalidomide may confer a high risk of solid-tumor SPMs, but in this large analysis, it appears that the incidence of solid tumors is not appreciably different with or without lenalidomide, although there was an unsurprising slight increase in the incidence of hematologic SPMs. 20 40 60 80 20 40 60 80
Mos
Mos
Cumulative Incidence, % (95% CI)
36 Mos
60 Mos
Lenalidomide
1.4 ( )
3.1 ( )
No Lenalidomide
0.4 ( )
1.4 ( )
Cumulative Incidence, % (95% CI)
36 Mos
60 Mos
Lenalidomide
2.6 ( )
3.8 ( )
No Lenalidomide
2.9 ( )
3.4 ( )
Palumbo A, et al. ASCO Abstract 8517

15. SPMs in Lenalidomide-Treated Patients: Different Lenalidomide Combinations
Hematologic SPMs
Solid SPMs
0.10
Lenalidomide + melphalan Lenalidomide + cyclophosphamide Lenalidomide only Melphalan only
0.10
Lenalidomide + melphalan Lenalidomide + cyclophosphamide Lenalidomide only Melphalan only
0.09
0.09
0.08
0.08
0.07
HR: 3.8 (95% CI: ; P < .001)
0.07
HR: 1.09 (95% CI: ; P = .67)
0.06
0.06
Cumulative Incidence
0.05
Cumulative Incidence
0.05
0.04
0.04
0.03
0.03
SPMs, secondary primary malignancies.
Kenneth Anderson, MD:
The investigators stratified the results by the type of lenalidomide combination patients received. Of the 4 types of regimens, the combination of lenalidomide plus melphalan resulted in significantly more hematologic SPMs (HR: 3.8; P < .001) than lenalidomide plus cyclophosphamide, lenalidomide alone, or melphalan alone. That said, the risk with lenalidomide plus melphalan was low, at approximately 0.4%. By contrast, there were no significant differences in the incidence of solid-tumor SPMs between regimens (HR: 1.09; P = .67).
Sagar Lonial, MD:
This was a very nice analysis that showed the risk of hematologic SPMs is highest when lenalidomide is combined with melphalan. Of note, this appears to be the case both in the induction setting and in the immediate posttransplantation period where lenalidomide is given after high-dose therapy; it is the association with melphalan that appears to confer the higher risk.
We have known for a long time that the use of low-dose or high-dose melphalan in transplantation leads to an increased risk of secondary malignancies. This study effectively shows that the effect of lenalidomide on SPMs is primarily in the setting of melphalan use, whether low or high dose. This is a very important finding. Solid tumors often occur in elderly patients; many of the solid tumors in previous reports were prostate cancers in elderly men. This makes sense because as the population ages, more cancers can be expected. Interestingly, other alkylating agents (with fewer data) such as cyclophosphamide may have a lower risk of SPMs than melphalan. The incidence of secondary cancers with melphalan, even low-dose melphalan, took almost 20 years to identify and has been noted primarily in 2 settings: myeloma and ovarian cancer.[1] The take-home message is that secondary cancers are a real risk with lenalidomide in the context of an alkylating agent and, most likely, with melphalan.
Reference
Yang J, Terebelo HR, Zonder JA. Secondary primary malignancies in multiple myeloma: an old nemesis revisited. Adv Hematol. 2012;2012:
0.02
0.02
0.01
0.01 20 40 60 20 40 60 80
Mos
Mos
Palumbo A, et al. ASCO Abstract 8517

16. SPMs in Lenalidomide-Treated Patients: Cumulative Incidence of Death
No lenalidomide
Lenalidomide
0.6
0.6
MM AEs SPMs
MM AEs SPMs
0.4
0.4
Cumulative Incidence
Cumulative Incidence
0.2
0.2 20 40 60 20 40 60
AE, adverse event; MM, multiple myeloma; SPM, second primary malignancy.
Sagar Lonial, MD:
The investigators assessed the incidence of death from adverse events as well as from myeloma and SPMs. Results showed that the risk of death from myeloma was highest regardless of whether patients received lenalidomide or not: the 60-month incidence of death from myeloma was 26.6% with lenalidomide vs 36.3% without lenalidomide.
Of note, in the group that did not receive lenalidomide, the primary cause of death was myeloma, with the secondary cause of death being adverse events. Almost no patients died of SPMs in this group, whereas 2.4% died of SPMs by 60 months in the lenalidomide group. In the lenalidomide arm, myeloma relapsing was a major driver of cumulative incidence of death. However, the incidence of adverse events was much lower than without lenalidomide.
This analysis shows that lenalidomide maintenance can delay or minimize the severity of relapse and related adverse events and, at least in these trials, improved OS as well.
Kenneth Anderson, MD:
This is one of the most important myeloma studies presented at ASCO When we discuss the relative benefits and risks of proposed treatments with patients, we need to put those risks into context. What this slide so beautifully shows is that although there is a risk of secondary cancers with lenalidomide, both the risk of progressive myeloma and adverse events are reduced compared with no maintenance therapy.
The adverse events curve is really important because lenalidomide is well tolerated and reduces myeloma activity. The graph in the right panel demonstrates the importance not only in terms of survival, but also that the relative risk-to-benefit ratio is favorable to lenalidomide, both in terms of quality of life and adverse events. In my opinion, the risk of secondary malignancies is acceptable, as it is quite low.
Mos
Mos
Cumulative Incidence of Death, % (95% CI)
36 Mos
60 Mos MM
14.6 ( )
36.3 ( )
AEs
6.4 ( )
19.2 ( )
SPM
0.7 (0-1.5)
Cumulative Incidence of Death, % (95% CI)
36 Mos
60 Mos MM
13.3 ( )
26.6 ( )
AEs
6.7 ( )
9.8 ( )
SPM
1.0 ( )
2.4 ( )
Palumbo A, et al. ASCO Abstract 8517

17. SPMs in Lenalidomide-Treated Patients: Conclusions
The risk of hematologic SPMs was higher in patients receiving melphalan + lenalidomide
Similar incidence of solid tumors in all groups
The cumulative incidence of death (any cause) was much higher than the risk of SPM
The benefit/risk profile of lenalidomide treatment remains positive
SPM, second primary malignancy.
Kenneth Anderson, MD:
These are very important data in terms of clinical practice, in my view, and very much in favor of lenalidomide maintenance.
Sagar Lonial, MD:
I concur that the risk-benefit profile for lenalidomide maintenance is favorable and should be discussed with patients. We are encouraging many of our myeloma patients to move forward with lenalidomide maintenance.
Palumbo A, et al. ASCO Abstract 8517

18. Carfilzomib + MP in Elderly Patients With Newly Diagnosed MM: Phase I/II Study
Melphalan (oral) Days mg/m2/day
Prednisone (oral) Days mg/m2/day
Carfilzomib 30-min IV
9 Cycles 1 Cycle = 42 days
IV, intravenous; MM, multiple myeloma, MP, melphalan/prednisone.
Sagar Lonial, MD:
This phase I/II study evaluated the use of carfilzomib plus melphalan/prednisone in older patients with newly diagnosed myeloma. Standard-dose oral melphalan with prednisone was used with escalating doses of carfilzomib. The carfilzomib dose in cycle 1 was 20 mg/m2/day; however, for subsequent doses, it was escalated to 27, 36, or 45 mg/m2/day, depending upon the treatment cohort that was being enrolled in the phase I study.
Carfilzomib Dosing
Cycle 1
Days 1, 2
20 mg/m2/day
Days 8, 9, 22, 23, 29, 30
20, 27, 36, or 45 mg/m2/day
(cohort 1, 2, 3, or 4)
Cycle 2
Days 1, 2, 8, 9, 22, 23, 29, 30
Touzeau C, et al. ASCO Abstract 8513

19. Phase II Results (Carfilzomib 36 mg/m2)
Carfilzomib + MP in Elderly Pts With Newly Diagnosed MM: DLTs and Best Response
Phase I Results
Cohort
Results
1: Carfilzomib 20 mg/m2 + MP
6 pts, 1 DLT of DVT
2: Carfilzomib 27 mg/m2 + MP
6 pts, 1 DLT of grade 3 febrile neutropenia
3: Carfilzomib 36 mg/m2 + MP
4: Carfilzomib 45 mg/m2 + MP
6 pts, 2 DLT of fever and hypotension
MTD: 36 mg/m2
Phase II Results (Carfilzomib 36 mg/m2)
(n = 66)
Best Response
Patients
CR, n (%)
4 (6)
VGPR, n (%)
33 (50)
PR, n (%)
23 (35)
SD, n (%)
6 (9)
PD, n (%)
ORR, %
91%
At least VGPR, %
56%
CR, complete response; DLT, dose-limiting toxicity; DVT, deep vein thrombosis; MTD, maximum tolerated dose; MP, melphalan/prednisone; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.
Sagar Lonial, MD:
The maximum tolerable dose (MTD) of carfilzomib was 36 mg/m2 due to the dose-limiting toxicities (DLTs) of fever and hypotension at the 45-mg/m2 dose. The overall response rate (ORR) was 91%, with 56% of patients achieving a very good partial response (VGPR) or better. To put these data in context, the CR/near-CR rate with melphalan/prednisone/bortezomib (MPV) in a similar small phase I/II study was approximately 20% to 25%, and the VGPR or better rate was 30% to 35%.[1]
Reference
1. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:
Touzeau C, et al. ASCO Abstract 8513

20. Alive Without Progression Alive Without Progression
Carfilzomib + MP in Elderly Patients With Newly Diagnosed MM: PFS and OS
PFS
Median follow-up: 12 mos (68 patients)
Progression: n = 20
Carfilzomib 20 mg/m2: n = 3/6
Carfilzomib 27 mg/m2 : n = 5/6
Carfilzomib 36 mg/m mg/m2: n = 12/54 OS
Death: n = 8
Death from progression: n = 3
1.0
0.8
0.6
Alive Without Progression
0.4
0.2
Median PFS: 22 mos 5 10 15 20
Mos
1.0
MP, melphalan/prednisone; OS, overall survival; PFS, progression free survival.
Kenneth Anderson, MD:
Both PFS and OS were promising in this phase I/II trial: median PFS was 22 months at 1 year of follow-up, and the OS rate was 87%. Fewer patients progressed on a carfilzomib dose of 36 mg/m2 vs 27 mg/m2 or 20 mg/m2.
Sagar Lonial, MD:
It is difficult to read too much into these data at this time, except to suggest that other than death from progression, the survival benefit of this approach, at least in this small study, appears quite reasonable.
0.8
0.6
Alive Without Progression
0.4
0.2
OS: 87% 5 10 15 20
Touzeau C, et al. ASCO Abstract 8513
Mos

21. Carfilzomib + MP in Elderly Patients With Newly Diagnosed MM: Adverse Events
Adverse Events, n (%)
All Grades
Grade 3/4
Anemia
36 (54)
14 (21)
Thrombocytopenia
24 (35)
5 (7)
Neutropenia
15 (22)
Deep vein thrombosis
1 (2)
Congestive heart failure
4 (6)
3 (5)
Atrial fibrillation
Peripheral edema
Hypertension
2 (3)
Peripheral neuropathy
16 (24)
Nausea
21 (31)
Diarrhea
12 (18)
Infection
35 (52)
6 (9)
Fatigue
27 (40)
Insomnia
Elevated liver enzymes
20 (29)
Renal failure
8 patients (11%) discontinued carfilzomib due to adverse events
MM, multiple myeloma; MP, melphalan/prednisone.
Sagar Lonial, MD:
Grade 3/4 adverse events associated with carfilzomib/melphalan/prednisone were, as expected, predominantly hematologic: anemia in 21% of patients and neutropenia in 22%. However, there was a rather low incidence of grade 3/4 infections (9%) and fatigue (2%). Only 11% of patients discontinued carfilzomib due to adverse events, and only 1 patient developed grade 3/4 peripheral neuropathy.
Interestingly, 16 patients developed peripheral neuropathy (all grades), which is somewhat higher than seen with previous carfilzomib-based approaches. In the posttransplant setting, neuropathy will often worsen for patients that have been previously treated with bortezomib before it gets better. Although it will almost always improve, I wonder whether the interaction between alkylator and proteasome inhibitor interaction contributes to a slightly higher risk of peripheral neuropathy.
Kenneth Anderson, MD:
I think it is a very relevant issue. Questions regarding carfilzomib include whether dose escalation improves the extent and frequency of response, which is the desirable outcome, and whether there is a relationship to the adverse effect profile. The relationship between dose and adverse effects is important in all trials; these results are reassuring because these are elderly patients who are not transplant candidates, and there has been concern regarding baseline cardiac or pulmonary toxicity. For example, at a dose of 36 mg/m2, rates of grade 3/4 congestive heart failure and peripheral edema are very low.
It is unknown whether increased rates of neuropathy may emerge with higher doses, or whether there is an interaction with alkylating agents. Initial use of bortezomib was associated with dose- and schedule-dependent neuropathy, which was managed by reducing the dose and decreasing the frequency of administration. One of the major advantages here is a very low incidence of neuropathy in virtually all the studies with carfilzomib, but we do need to monitor whether increasing the dose or using carfilzomib in combinations might increase the incidence of neuropathy.
Touzeau C, et al. ASCO Abstract 8513

22. Carfilzomib + MP in Elderly Patients With Newly Diagnosed MM: Conclusions
Adverse event profile for carfilzomib in combination with melphalan/prednisone is manageable
Peripheral neuropathy: grades 1 and 2 in 19% and 5%, respectively
Anemia and infection (all grades) were the most common
Additional studies (and longer follow-up) are ongoing
Response rates are favorable compared with other combinations used for frontline treatment of this patient population
MM, multiple myeloma; MP, melphalan/prednisone.
Kenneth Anderson, MD:
Clearly, the adverse event profile for the carfilzomib/melphalan/prednisone combination is manageable, with low rates of peripheral neuropathy, and the response rates are comparable to other frontline therapies in this setting.
This is an important study because carfilzomib has already been approved for treatment of more advanced myeloma. This study helps establish an upfront role for carfilzomib, just as was done with bortezomib. Even though it is an early-phase trial, these data confirm the value of adding carfilzomib to melphalan and prednisone. The MPV combination was the basis for approval of the proteasome inhibitor bortezomib as an initial treatment option. San Miguel and colleagues[1] have shown that the addition of bortezomib to melphalan and prednisone as initial therapy in elderly patients provides a survival advantage of longer than 1 year at 5 years’ follow-up. The question now is whether this more potent proteasome inhibitor, carfilzomib, is equivalent to, or even superior to, bortezomib. We are eagerly awaiting results of the ongoing phase III CLARION trial comparing carfilzomib/melphalan/prednisone to MPV in newly diagnosed, transplantation-ineligible patients with myeloma (planned N = 882).[2]
Sagar Lonial, MD:
One of the potential advantages of carfilzomib is the ability to dose escalate the level of proteasome inhibition. This may result in even better results than with MPV, but it has to be validated in a phase III trial. In summary, these are certainly very encouraging data with a 56% VGPR or better rate. This combination may be superior to any other available melphalan-based combination, but we need additional data and larger studies to better understand its activity.
References
1. San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:
2. ClinicalTrials.gov. A randomized, open-label phase 3 study of carfilzomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in transplant-ineligible patients with newly diagnosed multiple myeloma. Available at: Accessed August 12, 2013.
Touzeau C, et al. ASCO Abstract 8513

23. Relapsed/Refractory Multiple Myeloma

24. Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial Design
Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory)
28-day cycles
POM + LoDex Pomalidomide 4 mg on Days Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22 (n = 302)
Follow-up for OS and SPM until 5 yrs Post enrollment
Until PD*
Patients with relapsed/refractory myeloma (N = 455)
DOR, duration of response; DVT, deep venous thrombosis; LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; POM, pomalidomide; SPM, second primary malignancies.
Sagar Lonial, MD:
The MM-003 phase III trial evaluated high-dose dexamethasone vs pomalidomide plus low-dose dexamethasone in more than 450 patients with relapsed/refractory myeloma. Patients in the pomalidomide arm received treatment until progression, whereas those in the high-dose arm could cross over to receive pomalidomide upon progression. The primary endpoint was PFS.
Kenneth Anderson, MD:
Pomalidomide, a new and potent immunomodulatory drug, received US Food and Drug Administration (FDA) accelerated approval in the United States based on the phase II MM-002 clinical trial in advanced myeloma.[1] In MM-002, patients who received pomalidomide plus low-dose dexamethasone achieved a 34% response rate with a median duration of response of 8 months and a tolerable toxicity profile. The MM-003 trial is an important study, as it may allow pomalidomide to be available in Europe. This is not the kind of trial that could be easily conducted in the United States due to the difficulty of randomizing patients with refractory myeloma to high-dose dexamethasone, which was required by the European authorities.
Reference
1. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Program and abstracts of the 53rd American Society of Hematology Annual Meeting and Exposition; December 10-13, 2011; San Diego, California. Abstract 634.
HiDex Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1-4, 9-12, (n = 153)
Companion trial MM-003C: Pomalidomide 21/28 days
Until PD*
Primary endpoint: PFS
Secondary endpoints: OS, ORR, DOR, safety
*Independently adjudicated in real time.
Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT.
San Miguel JF, et al. ASCO Abstract 8510.

25. Pomalidomide + LoDex vs HiDex: Key Criteria for Pts With Relapsed/Refractory MM
All patients
Refractory to last therapy
≥ 2 previous therapies
≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or adequate previous alkylator therapy
Failed bortezomib and lenalidomide
Progression within 60 days; PR with progression within 6 mos, and/or bortezomib intolerant after ≥ 2 cycles and achieving ≤ MR
Refractory or relapsed/refractory
Primary refractory (never achieved better than PD to any therapy) or relapsed and refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen and then developed PD ≤ 60 days of completing their last treatment)
LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; MR, molecular response; PD, progressive disease; PR, partial response, SD, stable disease.
Kenneth Anderson, MD:
Patients enrolled in MM-003 had failed at least 2 cycles of bortezomib and lenalidomide (alone or in combination) and had refractory or relapsed/refractory multiple myeloma.
San Miguel JF, et al. ASCO Abstract 8510.

26. Pomalidomide + LoDex vs HiDex (MM-003): PFS (ITT Population)
Median PFS, Mos
POM + LoDex (n = 302)
4.0
HiDex (n = 153)
1.9
1.0
0.8
0.6
Proportion of Patients Without Progression
HR: 0.48 P < .001
0.4
0.2
ITT, intent to treat; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; HiDex, high-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide.
Kenneth Anderson, MD:
Results showed that PFS, the primary endpoint, was remarkable and very statistically significant. Median PFS in the pomalidomide arm was twice that in the high-dose dexamethasone arm: 4.0 months vs 1.9 months, respectively (HR: 0.48; P < .001). 4 8 12 16
Mos
San Miguel JF, et al. ASCO Abstract 8510.

27. Pomalidomide + LoDex vs HiDex (MM-003): OS (ITT Population)
1.0
Median OS, Mos
POM + LoDex (n = 302)
12.7
HiDex (n = 153)*
8.1
0.8
HR: 0.74 P = .028
0.6
Proportion of Patients Remaining Alive
0.4
HiDex, high-dose dexamethasone; ITT, intent to treat; LoDex, low-dose dexamethasone; OS, overall survival; POM, pomalidomide.
Kenneth Anderson, MD:
Median OS was also substantially longer with pomalidomide plus low-dose dexamethasone (12.7 months) vs high-dose dexamethasone (8.1 months), with a favorable HR of Of note, one half of the patients in the high-dose dexamethasone arm crossed over to receive pomalidomide.
0.2 4 8 12 16 20
Mos
*76 pts (50%) in the HiDex arm received pomalidomide.
San Miguel JF, et al. ASCO Abstract 8510.

28. Pomalidomide + LoDex vs HiDex (MM-003): AEs
POM + LoDex
(n = 300)
HiDex
(n = 150)
Grade 3/4 hematologic AEs
Neutropenia 48 16
Anemia 33 37
Thrombocytopenia 22 26
Grade 3/4 nonhematologic AEs
Infections 30 24
Pneumonia 13 8
Bone pain 7 5
Fatigue 6
Asthenia 4
Grade 3/4 AEs of interest
DVT/PE 1
Peripheral neuropathy*
Discontinuation due to AEs 9 10
AEs, adverse events; DVT, deep vein thrombosis; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; OS, overall survival; PE, pulmonary embolism; PFS, progression-free survival; POM, pomalidomide.
Kenneth Anderson, MD:
Toxicity was consistent with other trials of pomalidomide plus low-dose dexamethasone. Grade 3/4 neutropenia was more common with pomalidomide than with high-dose dexamethasone (48% vs 16%), but most other adverse events were similar between arms or only slightly more common with pomalidomide.
The main point of this slide is that high-dose dexamethasone—40 mg orally for 4 consecutive days with repeated cycles each month—has its own toxicities. Of note, the incidence of infections was similar between arms. Together with the PFS and OS results, this further validates the exciting discovery that pomalidomide plus low-dose dexamethasone is active and tolerated in very advanced myeloma.
*Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy.
San Miguel JF, et al. ASCO Abstract 8510.

29. Pomalidomide + LoDex vs HiDex (MM-003): Conclusions
Pomalidomide + LoDex significantly improved PFS and OS vs HiDex
Median PFS: 4.0 vs 1.9 mos
Median OS: 12.7 vs 8.1 mos
Benefit of pomalidomide + LoDex was sustained regardless of refractoriness to bortezomib and lenalidomide, even as last previous therapy
Grade 3/4 neutropenia, febrile neutropenia, and infections occurred more often with pomalidomide + LoDex vs HiDex
Investigators conclude that pomalidomide + LoDex should be considered a new standard of care in this population
HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival.
Sagar Lonial, MD:
The MM-003 trial is an important study, as it may allow pomalidomide to be available in Europe. This is not the kind of trial that could be easily conducted in the United States due to the difficulty of randomizing patients with refractory myeloma to high-dose dexamethasone, which was required by the European authorities. What is quite striking is that, even with a significant proportion of patients crossing over and receiving pomalidomide after progression on dexamethasone, the OS difference continues to hold up and the PFS difference is remarkable. This study further confirms the data from the MM-002 trial showing that pomalidomide is a very active agent in the context of refractory myeloma. [1]
Kenneth Anderson, MD:
These are exciting data. The FDA granted accelerated approval to pomalidomide for relapsed/refractory myeloma in February 2013, so it is now actively used in the clinic. The ongoing phase III OPTIMISMM clinical trial is evaluating the addition of pomalidomide to low-dose dexamethasone plus bortezomib in patients with relapsed/refractory myeloma and up to 3 previous therapies including lenalidomide.[2] This particular trial will hopefully lead to accelerated approval in Europe. Subsequently, pomalidomide may be evaluated in combination with low-dose dexamethasone and bortezomib for patients with earlier disease.
References
Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Program and abstracts of the 53rd American Society of Hematology Annual Meeting and Exposition; December 10-13, 2011; San Diego, California. Abstract 634.
ClinicalTrials.gov. A phase 3, multicenter, randomized, open-label study to compare the efficacy and safety of pomalidomide, bortezomib and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Available at: Accessed August 12, 2013.
San Miguel JF, et al. ASCO Abstract 8510.

30. POM + LoDex vs HiDex in Pts With Mod Renal Impairment (MM-003 Substudy): PFS
Patients With Baseline CrCl < 60 mL/min
PFS: Patients With Baseline CrCl ≥ 60 mL/min
1.0
Median PFS 4.0 mos 1.9 mos
1.0
Median PFS 4.0 mos 2.0 mos
POM + LoDex (n = 95) HiDex (n = 59)
POM + LoDex (n = 205) HiDex (n = 93)
0.8
0.8
HR: 0.47 P < .001
HR: 0.50 P < .001
Proportion of Patients Without Progression
0.6
Proportion of Patients Without Progression
0.6
0.4
0.4
0.2
CrCl, creatinine clearance; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; MM, multiple myeloma; Mod, moderate; PFS, progression-free survival; POM, pomalidomide.
Kenneth Anderson, MD:
Weisel and colleagues conducted an analysis of the MM-003 trial, focusing on the role of renal impairment (creatinine clearance of less or greater than 60 mL/min). The PFS advantage in favor of pomalidomide/low-dose dexamethasone was significant in both contexts (median PFS: 4.0 months with pomalidomide vs ~2 months with high-dose dexamethasone; P < .001), suggesting that pomalidomide is safe to use, without dose reduction, in patients with renal dysfunction. That is important because lenalidomide requires reduced doses in the context of renal compromise.
Sagar Lonial, MD:
Pomalidomide is considered a hybrid between lenalidomide and thalidomide. Its metabolism and excretion may be closer to thalidomide, allowing use in the context of renal insufficiency. A phase I clinical trial is currently evaluating the pharmacokinetics of pomalidomide in patients with relapsed/refractory myeloma and various levels of renal dysfunction.[1]
Reference
1. ClinicalTrials.gov. A phase 1 multi-center, open-label, dose-escalation study to determine the pharmacokinetics (PK) and safety of pomalidomide (POM) when given in combination with low dose dexamethasone (LD-DEX) in subjects with relapsed or refractory multiple myeloma (RRMM) and impaired renal function. Available at: Accessed August 12, 2013.
0.2 4 8 12 16 4 8 12 16
Mos
Mos
Weisel KC, et al. ASCO Abstract 8527

31. Baseline CrCl < 60 mL/min
POM + LoDex vs HiDex in Pts With Mod Renal Impairment (MM-003 Substudy): ORR
≥ PR: 33%
≥ MR: 41%
≥ PR: 28%
≥ MR: 36% 90 80 5 6
≥ PR: 8%
≥ MR: 12%
≥ PR: 11%
≥ MR: 17% 70 28 22 60 8 10
Patients (%) 50 3 7 6 8
≥ VGPR PR MR SD 40 30 49 42
CrCl, creatinine clearance; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; Mod, moderate; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; SD, stable disease; VGPR, very good partial response.
Sagar Lonial, MD:
In MM-003, substantially more patients with renal impairment achieved a partial response or better with pomalidomide plus low-dose dexamethasone (28%) than with high-dose dexamethasone (8%). In addition, 6% of patients in this group receiving pomalidomide achieved greater than VGPR vs none with high-dose dexamethasone. These response rates compare favorably to those in patients without renal impairment.
Kenneth Anderson, MD:
The advantage is consistently seen with pomalidomide plus low-dose dexamethasone, and it is reassuring that the extent of response is not compromised in the patients with renal dysfunction. Patients whose myeloma progresses toward relapse or relapsed/refractory disease more commonly have renal dysfunction. So this is a very important option for patients. 20 44 44 10
POM + LoDex
HiDex
POM + LoDex
HiDex
Baseline CrCl < 60 mL/min
Baseline CrCl ≥ 60 mL/min
Weisel KC, et al. ASCO Abstract 8527

32. Baseline CrCl < 60 mL/min
POM + LoDex vs HiDex in Pts With Mod Renal Impairment (MM-003 Substudy): AEs
AE, %
Baseline CrCl < 60 mL/min
Baseline CrCl ≥ 60 mL/min
POM + LoDex
(n = 95)
HiDex
(n = 59)
(n = 203)
(n = 90)
Grade 3/4 hematologic events in ≥ 10%
Neutropenia 48 19 14
Anemia 39 42 30 32
Thrombocytopenia 20 36 23
Leukopenia 5 3 10
Grade 3/4 nonhematologic events in ≥ 10%
Infections 33 25
Hyperglycemia 1 2 4
Grade 3/4 events of interest
DVT/PE
Peripheral neuropathy
Discontinuations due to AEs 12 7
AEs, adverse events; CrCl, creatinine clearance; DVT, deep vein thrombosis; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; MM, multiple myeloma; Mod, moderate; PE, pulmonary embolism; POM, pomalidomide
Sagar Lonial, MD:
Rates of grade 3/4 adverse events were similar in patients with and without renal compromise. For example, neutropenia in pomalidomide-treated patients was seen in 48% of both groups. Likewise, anemia was seen in 39% of patients with renal impairment vs 30% in those without renal impairment.
Kenneth Anderson, MD:
As a general rule, there was not more toxicity in any of these categories, whether or not a patient had renal dysfunction. This provides further evidence of activity and tolerability in patients with myeloma and renal compromise.
Weisel KC, et al. ASCO Abstract 8527

33. POM + LoDex vs HiDex in Pts With Moderate Renal Impairment: Conclusions
Prescribing information for pomalidomide will be updated with dose recommendations for patients with renal impairment following the end of the ongoing MM-008 trial
Poor renal function (baseline CrCl < 60 mL/min) does not affect efficacy and safety of pomalidomide + LoDex in this patient population
As in the overall study population, pomalidomide + LoDex prolonged PFS compared with treatment with HiDex in both subgroups
Tolerability in the pomalidomide group was acceptable and similar across groups
CrCl, creatinine clearance; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; PFS, progression free survival; POM, pomalidomide.
Kenneth Anderson, MD:
Pomalidomide is an active agent—with improvements in both PFS and OS—that can be used even in patients who have compromised renal function. This is clearly a major advance in the treatment of myeloma.
Sagar Lonial, MD:
I agree. Patients with renal dysfunction can have more adverse effects with therapy in general, but in this study, there was no significant difference between the normal and abnormal renal function groups, suggesting pomalidomide can be used safely.
Weisel KC, et al. ASCO Abstract 8527

34. Phase I/II Study: Elotuzumab, Lenalidomide, and LoDex in Relapsed/Refractory MM
Elotuzumab 10 mg/kg IV + Lenalidomide PO + Dexamethasone PO
(n = 36)
Patients with relapsed/refractory MM previously treated with 1-3 therapies (N = 73)
Until disease progression, unacceptable toxicity, or death
Elotuzumab 20 mg/kg IV + Lenalidomide PO + Dexamethasone PO +
(n = 37)
IV, intravenous; LoDex, low-dose dexamethasone; MM, multiple myeloma; PO, orally.
Sagar Lonial, MD:
In the phase II portion of this study, 2 doses of elotuzumab (10 and 20 mg/kg) were evaluated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed/refractory myeloma with up to 3 previous therapies (N = 73).
Kenneth Anderson, MD:
This is a very important trial. Elotuzumab is a monoclonal antibody that targets the CS1 antigen. As a single agent in the setting of relapsed/refractory myeloma, it produced only stable disease. This study was designed to determine whether improved responses could be obtained in combination with lenalidomide and low-dose dexamethasone.
Phase I (N = 25); patients treated with elotuzumab 5, 10, or 20 mg/kg in 28-day cycles using standard dose-escalation design
Phase II (N = 73); stratified by number of previous lines of therapy, previous thalidomide/thalidomide analogues
Lonial S, et al. ASCO Abstract 8542.

35. Phase I/II Elotuzumab, Lenalidomide and LoDex: Best Responses
Response, n (%)
Phase II Elotuzumab 10 mg/kg
Phase II Elotuzumab 20 mg/kg
Total
Patients, n 36 37 73
ORR (≥PR), n (%)
(95% CI)*
33 (92)
(78-98)
28 (76)
(59-88)
61 (84)
(73-91)
CR/stringent CR, n (%)
5 (14)
4 (11)
9 (12)
VGPR, n (%)
18 (50)
14 (38)
32 (44)
PR, n (%)
10 (28)
10 (27)
20 (27)
< PR, n (%)
3 (8)
9 (24)
12 (16)
CR, complete response; LoDex, low-dose dexamethasone; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
Kenneth Anderson, MD:
The response rates to both doses of elotuzumab were remarkable: 92% for the 10-mg/kg dose and 76% for 20 mg/kg. Moreover, 50% of patients receiving 10 mg/kg and 38% receiving 20 mg/kg achieved VGPR.
*By Clopper-Pearson method.
Lonial S, et al. ASCO Abstract 8542.

36. Proportion of Progression-Free Patients
Phase I/II Elotuzumab, Lenalidomide and LoDex in Relapsed/Refractory MM: PFS
100 90 80 70 60
Proportion of Progression-Free Patients 50 40 30
Median Time to Progression/Death 10 mg/kg (n = 36): 33 mos (95% CI: NA)
20 mg/kg (n = 37): 18.6 mos (95% CI: )
Total (n = 73): 25.8 mos (95% CI: ) 20 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
LoDex, low-dose dexamethasone; MM, multiple myeloma; NA, not available; PFS, progression-free survival.
Kenneth Anderson, MD:
The PFS results suggested a slightly more favorable PFS with the lower elotuzumab dose: Median PFS was 33 months for the 10-mg/kg dose vs 18.6 months with the 20-mg/kg dose, shown here. However, this may not be statistically significant.
Sagar Lonial, MD:
I noted that in both elotuzumab dosing groups, the saturation of CS1 was almost identical. The median PFS of 33 months with the 10-mg/kg dose is more than double that seen with lenalidomide plus high-dose dexamethasone in the MM-009 or MM-010 trials (median: 13.4 months).[1] If these data hold up in the upcoming phase III study (planned N = 750),[2] this will be one of the longest PFS times seen with a 3-drug combination in this setting. The dose used in the phase III trials was 10 mg/kg.
References
1. Dimopoulous MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:
2. ClinicalTrials.gov. A phase 3, randomized, open label trial of lenalidomide/dexamethasone with or without elotuzumab in subjects with previously untreated multiple myeloma. Available at: Accessed August 12, 2013.
Mos
Median PFS:
In the 10 mg/kg cohort: 33 mos (median follow-up of 20.8 mos)
In the 20 mg/kg cohort: 18 mos (median follow-up of 17.1 mos)
Patient follow-up is ongoing
Lonial S, et al. ASCO Abstract 8542.

37. Phase II Study of Elotuzumab, Lenalidomide, LoDex: Grade 3/4 AEs
Before and after 18 mos of treatment
51 patients received therapy for more than 18 mos across both dosages
Most treatment-related AEs occurred within 18 mos of therapy
Grade 3/4 AE,* n (%)
Onset
Elotuzumab 10 mg/kg + Len/Dex
Elotuzumab 20 mg/kg + Len/Dex
≤ 18 mos
(n = 39)
> 18 mos
(n = 20)
(n = 59)
(n = 31)
Neutropenia
8 (21)
1 (5)
13 (22)
1 (3)
Thrombocytopenia
10 (17)
Lymphopenia
10 (26)
5 (9)
Anemia
5 (13)
7 (12)
Hyperglycemia
2 (5)
Fatigue
3 (8)
Diarrhea
4 (10)
2 (10)
3 (5)
Leukopenia
4 (7)
Hypokalemia
Pneumonia
2 (7)
AEs, adverse events; Len/dex; lenalidomide/dexamethasone; LoDex, low-dose dexamethasone.
Sagar Lonial, MD:
In this study, grade 3/4 adverse events were similar between arms. For example, by 18 months, approximately 21% of patients at each dose had experience neutropenia, with thrombocytopenia reported in 21% of patients receiving elotuzumab 10 mg/kg vs 17% for 20 mg/kg.
Kenneth Anderson, MD:
The tolerability of elotuzumab in this study was quite good. Many of the toxicities are those expected from antibody treatment, and with premedication, elotuzumab is very well tolerated.
Lonial S, et al. ASCO Abstract 8542.
*In ≥ 5% of patients across elotuzumab 10 and 20 mg/kg.

38. Phase II Study of Elotuzumab, Lenalidomide, and LoDex: Conclusions
ORR: 84% among the phase II cohort
Higher rate observed with elotuzumab 10 mg/kg vs 20 mg/kg (92% vs 76%)
Median PFS (follow-up ongoing)
Elotuzumab 10-mg/kg arm: 33.0 mos (95% CI: not yet reached)
Elotuzumab 20-mg/kg arm: 18.6 mos (95% CI: )
Elotuzumab fairly well tolerated in combination with lenalidomide/dexamethasone
2 phase III trials are ongoing evaluating elotuzumab at mg/kg
LoDex, low-dose dexamethasone; ORR, overall response rate; PFS, progression-free survival.
Kenneth Anderson, MD:
As mentioned, elotuzumab produced very high response rates, up to 92% in the 10-mg/kg group. The marked prolongation of PFS was much longer than expected. As seen with responses, PFS, and adverse events, the 10-mg/kg dose was overall superior to 20 mg/kg. This is not a big surprise, as with biological therapies like antibodies, dose may not be as important as with traditional treatments.
Sagar Lonial, MD:
I agree. Fortunately, the phase III trials are evaluating 10 mg/kg in the experimental arms; hopefully data will emerge in the next 2 years.
Lonial S, et al. ASCO Abstract 8542.

39. Phase I/II Study: Daratumumab Monotherapy in Relapsed/Refractory MM
Dose-Escalation Cohorts Part 1
Expansion Cohort
Open label, weekly IV infusion, 8 wks
Dose escalation 3+3 scheme*
0.005►0.05 ►0.1 ►0.5 ►1.0 ►2.0 ►4.0 ►8.0 ►16.0 ►24.0 mg/kg
Ongoing evaluation of several cohorts and dose schedules
Primary endpoint: safety
Secondary endpoint: pharmacokinetics, IMWG efficacy, immunogenicity
Patients treated until disease progression, unacceptable toxicity, or for a maximum of 24 mos
ECOG, Eastern Cooperative Oncology Group; IMWG, International Melanoma Working Group; IV, intravenous; MM, multiple myeloma; PS, performance score.
Sagar Lonial, MD:
Lokhorst and colleagues conducted a phase I/II study of daratumumab, an anti-CD38 monoclonal antibody, in patients with relapsed/refractory myeloma. In this study, a 3+3 dose-escalation scheme was used to determine safety, then several dose schedules were chosen for evaluation in the expansion cohort.
CD38 is strongly expressed on all myeloma cells. It is also expressed on activated cells, including granulocytes, monocytes, B cells, and T cells. In addition, CD38 is expressed on endothelial cells, which raises the concern as to whether myeloma cells can be targeted with this humanized antibody and still have a favorable therapeutic index. Off-target effects may have an impact on tolerability, and so far, all looks good, but more data is still needed.
*Start with predose at 10% of full dose, max 10 mg, 3 wks delay after first full dose, governed by independent data monitoring committee .
Inclusion criteria: patients with advanced MM requiring systemic therapy; relapsed/relapsed and refractory disease with ≥ 2 previous lines of therapy and without further established therapy; pts with ECOG PS 0-2; patients with life expectancy > 3 mos
Lokhorst H J, et al. ASCO Abstract 8512.

40. Phase I/II Daratumumab Monotherapy Study: IMWG Response and PFS
4-24 mg/kg (n = 12) median follow up time: 18.4 wks (0-53) mg/kg (n = 20) median follow up time: 8.6 wks (0-29) MR PR
100
100 90 90 80 80
n = 32
n = 20
n = 12 70 70 60 60
Response Rate (%)
Alive Without Progression (%) 50 50
Log-rank test P = .007 40 40 30
IMWG, International Melanoma Working Group; MR, molecular response; PFS, progression-free survival; PR, partial response.
Kenneth Anderson, MD:
These are very exciting data. In this dose-escalation trial, patients who received at least 4 mg/kg daratumumab had very high response rates: nearly 70% achieved at least a minimal response, and more than 40% had a partial response. In comparison, fewer than 10% of patients receiving 2 mg/kg or less responded. Likewise, median PFS in patients who received 4 mg/kg was 18.4 weeks. Even though only a dozen patients were treated, this activity is impressive in this far-advanced patient population. Median PFS for those who received 2 mg/kg or less was 8.6 weeks (P = .007).
Based on these data, the FDA granted daratumumab what is called ”breakthrough therapy status.” In plain terms, what this means is that there is an opportunity for daratumumab, if the data hold up in future trials, to receive an even more expedited approval to treat advanced multiple myeloma. 30 20 20 10 10 1 2 3
All Patients
≤ 2 mg/kg
≥ 4 mg/kg 4 5 6 7 8
Mos From Start of Treatment
Lokhorst H J, et al. ASCO Abstract 8512.

41. Phase I/II Daratumumab Monotherapy Study: Adverse Events
Part 1 (N = 32)
Bronchospasm
1 patient: grade 2 (2 mg/kg) (2 days later grade 3)
1 patient: grade 2 (24 mg/kg)
Anemia
1 patient: grade 3 (0.1 mg/kg) (DLT)
Thrombocytopenia
1 patient: grade 4 (0.1 mg/kg)
AST > 5.2 x upper limit of normal
1 patient: grade 2 and grade 3 (1.0 mg/kg) (DLT)
Cytokine release syndrome
1 patient: grade 2 (0.1 mg/kg)
AST, aspartate aminotransferase; DLT, dose-limiting toxicity.
Kenneth Anderson, MD:
Adverse effects of daratumumab, as noted here, include grade 3/4 anemia and thrombocytopenia. Otherwise, adverse events were as expected in general with antibody therapy.
Lokhorst H J, et al. ASCO Abstract 8512.

42. Phase I/II Daratumumab Monotherapy Study: Conclusions
Daratumumab showed a favorable safety profile as monotherapy
A reduction in paraprotein was observed for 47% of heavily pretreated patients who received 8 wks of daratumumab as monotherapy in doses up to 24 mg/kg
In 31% of these patients, this reduction qualified to a CR
15.5% patients achieving PR and 15.5% patients achieving MR
67% of patients receiving doses ≥ 4 mg/kg achieved a CR
5 patients achieving PR (42%)
3 patients achieving MR (25%)
Increased exposure to daratumumab correlated with longer PFS
CR, clinical response; MR, molecular response; PFS, progression-free survival; PR, partial response.
Kenneth Anderson, MD:
Although this is an early phase I/II study, daratumumab does appear very positive in terms of response rates. Approximately one half of the patients who received doses of 4 mg/kg or higher, which appear to be the most active, achieved responses. In addition, patients had a reduction in paraprotein level. It is very early, but there may be an emerging PFS benefit.
Of note, daratumumab is going forward together with lenalidomide/dexamethasone, similarly to elotuzumab. A phase I/II study of this combination is under way in patients with relapsed/refractory myeloma (planned N = 50).[1]
Sagar Lonial, MD:
Currently, there is no approved antibody with single-agent activity in advanced myeloma. It is ironic—a disease that makes too much antibody does not have an antibody to treat it. I am really encouraged by the single-agent activity of daratumumab, and I agree that combining it with lenalidomide makes a lot of sense. I think the infusion reactions that have been seen in the early experience are not dissimilar from what was seen with elotuzumab as well. With appropriate premedication and optimal dosing, the risk of significant infusion reactions may be reduced.
Reference
1. ClinicalTrials.gov. An open label, international, multicenter, dose escalating phase I/II trial investigating the safety of daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Available at: Accessed August 12, 2013.
Lokhorst H J, et al. ASCO Abstract 8512.

43. Phase I Dose-Escalation Study: Weekly Ixazomib: Dose
Expansion cohort (n = 31)
Relapsed/refractory (n = 11)
Refractory to most recent therapy (PD while on/within 60 days of last therapy)
Oral single-agent ixazomib (MLN9708) administered on Days 1, 8, and 15 of a 28-day cycle, for up to 12 cycles*
Dose-escalation cohort
(n = 32)
3+3 schema†
0.24►0.48 ►0.8 ►1.2 ►1.68 ►2.23 ►2.97 ►3.95 mg/m2
Bortezomib-relapsed (n = 10)
Relapsed after previous bortezomib therapy but not refractory
MTD established
Proteasome-inhibitor naive (n = 6)
Relapsed after ≥ 1 therapy including IMiD, no proteasome inhibitor
DLT, dose-limiting toxicity; IMiD, immunomodulatory drug; MTD, maximum tolerated dose; ORR, overall response rate; PD, progressive disease.
Sagar Lonial, MD:
Kumar and colleagues conducted a phase I dose-escalation study of single-agent ixazomib in 32 previously treated patients with relapsed and/or relapsed/refractory multiple myeloma. Once the MTD was established, 31 patients were treated in 4 expansion cohorts.
Kenneth Anderson, MD:
Bortezomib, a boronic acid proteasome inhibitor, has been available for more than a decade and can be given either intravenously or subcutaneously. Ixazomib is also a boronic acid proteasome inhibitor but is given orally. In this particular study, it was given weekly because its half-life is 3-4 days.
Primary goal: safety, tolerability, MTD
Other Endpoints: ORR, plasma pharmacokinetics
Previous carfilzomib (n = 4)
Received previous carfilzomib and with refractory/ relapsed disease
*Patients could receive prolonged treatment if benefitting from therapy. †Based on cycle 1 DLTs
Kumar S, et al. ASCO Abstract 8514.

44. Phase I Weekly Ixazomib: Response to Treatment
Response, n
Patients Evaluable for Response (n = 50)
ORR, %
95% CI PR 9 18
9-31
VGPR (in the 3.95 mg/m2 cohort) 1
Minimal response
10-34
Patients remaining in response
4 out of 10 with a duration of disease control of up to 9.8 mos SD 15
Response-Evaluable Patients at MTD (n = 31) MR 8 26
≥ MR
MR, molecular response; MTD, maximum tolerated dose; ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good partial response.
Kenneth Anderson, MD:
As shown on this slide, the ORR at the MTD was 26%—all partial responses. Among all dose cohorts, some patients experienced durable disease control approaching 10 months.
Kumar S, et al. ASCO Abstract 8514

45. Phase I Weekly Ixazomib: AEs
Type of AE, %
Dose-Escalation Cohorts (n = 32)
Expansion Cohorts (n = 31)*
Total (N = 60)
Any AE 97
100 98
Any drug-related AE 81 90 85
Any grade ≥ 3 AE 50 84 65
Any drug-related grade ≥ 3 AE 41 71 53
Any SAE 22 48 35
Any drug-related SAE 9 29 18
Dose reduction due to AEs 19 45 32
Discontinuation due to AEs 13 12
On-study death 3 2
AE, adverse event; MTD, maximum tolerated dose; SAE, serious adverse event.
Kenneth Anderson, MD:
This table shows the adverse events associated with ixazomib. Of note, ixazomib-related grade 3/4 events were seen in more than half of the study population. However, overall, ixazomib was quite well tolerated. In particular, only 19% of patients in the dose-escalation cohorts needed to reduce the dose due to adverse events, and only 13% discontinued due to adverse events. Neuropathy, which has been the main concern with bortezomib, occurs with ixazomib but at a very low frequency.
Sagar Lonial, MD:
I agree that the low incidence of neuropathy is a major advantage.
In our experience giving bortezomib intravenously, a high peak level is initially achieved, but then falls off. The use of subcutaneous administration avoids that peak level and provides more area under the curve, which is even further enhanced when given weekly. Ixazomib is similar in that it does not produce the same peak levels as with intravenous bortezomib and does produce increased area under the curve. This may be part of the reason it is so well tolerated.
*Includes 3 patients from MTD dose-escalation cohort.
Kumar S, et al. ASCO Abstract 8514

46. Phase I Weekly Ixazomib: DLT
DLT occurred in 3 patients
2 out of 4 patients treated at a dose of 3.95 mg/m2
Grade 3 events: nausea, vomiting, diarrhea, and erythema multiforme
1 of 6 DLT-evaluable patients treated at 2.97 mg/m2
Grade 3 events: nausea, vomiting, and diarrhea
In all 3 cases, DLTs were resolved and patients were continued on a lower dose
MTD of weekly oral ixazomib: 2.97 mg/m2
This dose level was used for the treatment of patients in the 4 expansion cohorts
DLT, dose-limiting toxicity; MTD, maximum tolerated dose.
Kenneth Anderson, MD:
Dose-limiting toxicities occurred in 3 patients. Two were gastrointestinal and 1 was skin toxicity. These resolved and the patients were able to restart at a lower dose. The MTD of ixazomib was defined as 2.97 mg/m2.
Kumar S, et al. ASCO Abstract 8514

47. Phase I Weekly Ixazomib Dose-Escalation Study: Conclusions
Single-agent oral ixazomib MTD established as mg/m2 on a weekly (Days 1, 8, and 15 every 28 days) dosing schedule
Oral ixazomib generally well tolerated and manageable
Adverse events consisted mostly of hematologic and GI symptoms with a low rate of discontinuations
Pharmacokinetic profile supports weekly oral dosing
Phase I data suggest clinical activity in relapsed and/or refractory myeloma patients (median 4 previous lines of therapy)
GI, gastrointestinal; MTD, maximum tolerated dose.
Sagar Lonial, MD:
Our experience with ixazomib, either with the weekly or twice-weekly schedule, has been positive. As mentioned, the lower incidence of neuropathy with an oral agent is a major advantage. The pharmacokinetics (longer half-life) of ixazomib are such that weekly dosing may be a better option with fewer adverse effects than twice-weekly dosing. We need additional data to feel comfortable with that, but it certainly does look like it is very active alone in bortezomib-sensitive patients and in combination with lenalidomide as part of induction therapy.
Kenneth Anderson, MD:
A planned phase III trial will evaluate the addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed myeloma. The possibility that ixazomib could be approved as the first oral proteasome inhibitor is exciting by itself, but the potential for combinations with other oral agents like lenalidomide makes it even more appealing.
Kumar S, et al. ASCO Abstract 8514

48. Other: Prognostic Indicators

49. Deep Sequencing for MRD Detection in Patients With Myeloma
Bone marrow samples obtained from 68 patients treated with same agents in 2 clinical trials (GEM00 and GEM05)
Samples from diagnosis analyzed to identify myeloma clonotype
Samples from follow-up evaluated to identify whether MRD was present following CR or VGPR after transplantation (younger patients) or after induction therapy (older patients)
Sample collection
Clonality test for all receptors
Identify cancer clones based on frequency
100 10
V-J 1
CR, complete response; MRD, minimal residual disease; VGPR, very good partial response.
Kenneth Anderson, MD:
Martinez-Lopez and colleagues conducted an analysis of myeloma clonotype and minimal residual disease (MRD) in samples from 68 patients with myeloma enrolled in the GEM00 and GEM05 clinical trials.
Sagar Lonial, MD:
This is a really interesting concept that will merit more attention in the next few years, as there has been great interest in looking for MRD using different methodologies. In early comparisons, flow cytometry appears similar to PCR in predicting outcomes. This study shows deep sequencing as an alternative way to look at MRD. Looking for clonality via immunoglobulin gene receptor changes may be able to identify whether there were additional or different mutations in residual cells over time that might guide treatment of patients with relapsed myeloma. .1
Clone Frequency (%)
.01
D-J
.001
.0001
Tumor biopsy sample
V-J
D-J
Martinez-Lopez J, et al. ASCO Abstract 8511.

50. Deep Sequencing for MRD Detection: Correlation of Ig Sequencing vs Flow Cytometry
34 of 46 samples were positive by both techniques
9 MRD samples were negative
3 were discordant
100
10-1
r2 = 0.9
10-2
10-3
Flow Cytometry
10-4
10-5
MRD, minimal residual disease.
Sagar Lonial, MD:
This graph shows a comparison of MRD detection using sequencing vs flow cytometry. The results show a nice correlation between the 2. Only 3 samples were discordant between flow cytometry and sequencing.
10-6
10-6
10-5
10-4
10-3
10-2
10-1
100
Sequencing
Martinez-Lopez J, et al. ASCO Abstract 8511.

51. Deep Sequencing for MRD Detection: Prognosis of MRD by Sequencing
PFS OS
1.0
1.0
MCR 1/10 relapsed Non-MCR 33/45 relapsed
MCR 1/10 deaths Non-MCR 17/45 deaths
0.8
0.8
0.6
0.6
Cumulative Proportion Surviving
Cumulative Proportion Surviving
0.4
0.4
MCR, molecular complete response; MRD, minimal residual disease; OS, overall survival; PFS, progression free survival.
Sagar Lonial, MD:
This slide shows the ability of deep sequencing to predict for outcomes. Patients who were negative for MRD by sequencing had improved PFS and OS (P = .02 for both). Only 1 of 10 patients who achieved a molecular complete response relapsed vs 33 of 45 patients without molecular complete response. Likewise, deaths occurred in 1 vs 17 patients, respectively. This indicates that deep sequencing is probably quite valid for MRD detection.
0.2
0.2
P = .02
P = .02 24 48 72 96
120
144 24 48 72 96
120
144
Mos
Mos
Martinez-Lopez J, et al. ASCO Abstract 8511.

52. Deep Sequencing for MRD Detection: Prognosis of MRD by Flow Cytometry
PFS OS
1.0
1.0
ICR 2/8 relapsed Non-ICR 26/38 relapsed
ICR 0/8 deaths Non-ICR 15/38 deaths
0.8
0.8
0.6
0.6
Cumulative Proportion Surviving
Cumulative Proportion Surviving
0.4
0.4
ICR, immunophenotypic complete response; MRD, minimal residual disease; OS, overall survival; PFS, progression free survival.
Sagar Lonial, MD:
This slide shows that PFS and OS outcomes by flow cytometry are quite similar to deep sequencing, at least in this very small series. One of the real powers of deep sequencing is the ability to identify mutations that are developing in the MRD-positive clone and use that information to potentially change or select alternative therapies. This predictive ability is not possible with flow cytometry or PCR alone. In my view of this small, early study of deep sequencing, it may not be superior to flow cytometry in terms of predicting relapse, but it may be superior in terms of providing information of use in the context of early relapse or MRD positivity.
0.2
0.2
P = .001
P = .04 24 48 72 96
120
144 24 48 72 96
120
144
Mos
Mos
Martinez-Lopez J, et al. ASCO Abstract 8511.

53. Deep Sequencing for MRD Detection in Patients With Myeloma
Assessing MRD by sequencing is relevant to most patients with myeloma
Has similar results to multiparametric flow cytometry
This tool is useful for patient risk stratification and can be used to define molecular CR in myeloma
Use of deep sequencing may add to the design of patient- specific treatment approaches, such as
Decreasing therapy for MRD-negative patients or
Continuing/increasing treatment for MRD-positive patients
CR, complete response; MRD, minimal residual disease.
Kenneth Anderson, MD:
Today, novel therapies are able to achieve extended responses that were previously unattainable, including molecular complete responses. The question is, “what is the best way to measure minimal residual disease?” Deep sequencing, if it can be widely applied, I think, is probably going to win over flow cytometry and PCR. Advances are happening so quickly in genomic technologies that soon sequencing will be able to be done on bone marrow or blood samples very quickly and at a reasonable cost. Importantly, deep sequencing is able to detect abnormal cells with high sensitivity. Those abnormal cells evolve genomic changes over time that underlie the relapse of disease.
Sagar Lonial, MD:
We are very excited about the idea of using sequencing for MRD detection; at least in the early analysis, its predictability is similar to flow cytometry and holds a powerful potential for offering additional information. It may be able to help determine how to approach patients with MRD or relapse, as well as evaluate clonal evolution over time.
Martinez-Lopez J, et al. ASCO Abstract 8511.

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