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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

FRONTLINE - Hematology/Oncology

June 2010

Reviewed and edited by:

Kevin W. Song, MD, FRCPC

Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, Clinical Assistant Professor of Medicine, University of British Columbia, Vancouver, British Columbia

Richard LeBlanc, MD, CSPQ, FRCPC

Department of Hematology/Oncology, Hôpital Maisonneuve-Rosemont, Clinical Assistant Professor of Medicine, Université de Montréal, Montreal, Quebec

Based on presentations from:

The American Society of Clinical Oncology (ASCO) Meeting June 4-8, 2010 / Chicago, Illinois

The European Hematology Association (EHA) Congress June 10-13, 2010 / Barcelona, Spain

Introduction

According to global experts, data presented at the ASCO and EHA 2010 annual meetings are immediately relevant to transplant-eligible and -ineligible multiple myeloma (MM) patients. Data from three large, phase III clinical trials provide evidence for the use of lenalidomide as a continuous treatment in both patient populations. Two of the pivotal studies, Intergroupe Francophone du Myélome (IFM) 2005-02 and Cancer and Leukemia Group B (CALGB) 100104, clearly demonstrate that post-autologous stem cell transplant (ASCT) maintenance therapy with lenalidomide resulted in a significant delay in disease progression when compared to placebo. This large benefit in posttransplant therapy, which effectively addresses minimal residual disease in MM, was the reason IFM 2005-02 was identified by ASCO as one of the top six presentations at this year’s meeting.

For transplant-ineligible patients, new data comes from the phase III MM-015 trial presented at EHA. As part of first-line and then continuous treatment, lenalidomide significantly delayed disease progression in newly diagnosed MM patients.

Separately and together, mostly from IFM 2005-02 and CALGB 100104, these data are expected to set new standards of improving outcomes for MM patients.

Disease Background

In Canada, more than 2000 patients are diagnosed with MM each year.¹ It is a cancer largely confined to older individuals, with a median age at diagnosis of approximately 65 years, and only 2% of patients under 40 years.²

For many decades, the standard of care for MM was a combination of melphalan and prednisone (MP); although not curative, it can prolong progressionfree survival (PFS) relative to no treatment.³ In the era of MP therapy, the median survival after diagnosis of MM was approximately three years. However, with newer regimens, particularly ASCT^4,5 and the introduction of novel agents such as lenalidomide, thalidomide and bortezomib, prognosis has improved significantly.^6-9

ASCT is an effective but aggressive intervention with some potential for complications and morbidities. For these reasons, many centres have limited eligibility to patients younger than 65 years of age.

For both transplant-eligible and -ineligible patients, lenalidomide (an immunomodulatory agent) and bortezomib (a proteasome inhibitor) are two novel agents currently approved for treatment of MM in Canada. Due to significant improvements in outcomes with these agents relative to older cytotoxic therapies in recent studies, their introduction is considered practice-changing.

Emerging Data for Transplant-eligible Patients

IFM 2005-02 is a phase III, randomized, placebo-controlled, French co-operative group trial conducted in Europe.¹⁰ A total of 614 patients in first-line treatment, following ASCT within the last 6 months, were randomized to receive lenalidomide consolidation 25 mg/day for 21 of 28 days for 2 cycles followed by 10 to 15 mg/day as maintenance or the same consolidation followed by placebo maintenance. Treatment was continued until relapse (Figure 1). The primary end point was PFS.

Figure 1.

Dr. Michel Attal presented follow-up results of IFM 2005-02 at 36 months’ post-randomization. Although findings are interim results, they clearly demonstrate a degree of benefit for lenalidomide over placebo that Dr. Attal characterized as “unprecedented.” After transplant, lenalidomide produced a 54% reduction (hazard ratio [HR] 0.46; P<0.0000001) in the risk
able 1).

Table 1.

<img4309|center>

It is important to note that responses were independent of ß₂-microglobulin levels, cytogenetics, induction regimen or, most importantly, the degree of response that was achieved prior to the consolidation therapy (Table 2). This last point is in contrast to the results of thalidomide in maintenance from the IFM99-02 which demonstrated that the benefit of maintenance was mainly seen in those patients presenting less than a very
(VGPR) posttransplantation. ¹¹

Table 2.

<img4310|center>

Grade 3 or 4 adverse events were uncommon in both the lenalidomide and placebo arms and the discontinuation rates for adverse events (6% vs. 4%) did not differ significantly. The major difference in grade 3 or 4 toxicities was neutropenia, which occurred in 31% of those randomized to lenalidomide vs. 6% of those who received placebo; grade 4 neutropenia was observed in 7% vs. 1%, respectively. However, this neutropenia was not associated with an increased risk of febrile neutropenia (0.1% for lenalidomide maintenance vs. 0% for placebo), although more infections were associated with lenalidomide (8% vs. 4% for placebo). The rates of g
thrombosis (DVT) (0.6% vs. 0.3%) and peripheral neuropathy (0.4% vs. 0.3%) were similar (Table 3).

Table 3.

<img4311|center>

CALGB 100104 is a phase III, double-blind, multicentre, co-operative working group trial conducted in the US.12 A total of 568 patients who had undergone ASCT, without progressive disease 3 months after transplant, were randomized to lenalidomide maintenance (starting at 10 mg/day, escalating to 15 mg/day at three months) or to placebo (Figure 2). The primary end point was time to progression (TTP). There are some important differences between CALGB 100104 and IFM 2005-02:

• CALGB included patients <70 years of age. • CALGB emp
PFS, as the primary objective. • CALGB did not have a consolidation phase. • CALGB allowed for patients to crossover from the placebo group.
4312|center>

After a median follow-up of 12 months in CALGB 100104, the median TTP was 25.5 months in the placebo arm but has not yet been reached in the lenalidomide arm (Figure 3).

Figure 3.

<img4313|center>

According to Dr. Philip L. McCarthy who presented these results on behalf of the CALGB research cooperative, there is a 58% reduction in the risk of disease progression when using lenalidomide post-transplant (HR 0.42; P<0.0001). Pa
4" />ified according to ß₂-microglobulin level and prior exposure to thalidomide or lenalidomide. Post-transplant therapy with lenalidomide prolonged TTP within each
n vs. placebo (Figure 4, 5).

Figure 4.

<img4314|center>

Figure 5.

<img4315|center>

Discontinuation rates with lenalidomide were low (Table 4). Neutropenia (42%), thrombocytopenia (12%), anemia (6%) and documented infection (7%) were significantly more common with lenalidomide than with placebo.

Table 4.

<img4316|center>

Relevance of IFM 2005-02 and CALGB 100104: Expert Opinion

The IFM 2005-02 and CALGB 100104 maintenance studies were presented in sequence at the ASCO meeting and were characterized as two of the most important practice-changing presentations in MM in recent years by Dr. Sergio Giralt.¹³ He was invited to provide independent and expert commentary on the IFM 2005-02 and CALGB 100104 results. According to Dr. Giralt, the results are immediately relevant to the routine management of MM patients eligible for ASCT, particularly because the benefit was seen regardless of ß₂-microglobulin, cytogenetics, type of induction or response to initial therapy.

The similarity of the designs and outcomes of these two studies are mutually reinforcing. The results confirm that post-transplant lenalidomide therapy is an important strategy for improving the likelihood of long-term remission after ASCT for MM. In particular, lenalidomide maintenance addresses the fact that MM patients have residual disease after transplantation, and this maintenance can improve the quality of response and maintain this response over time. Most of the maintenance strategies pursued previously, including corticosteroids, chemotherapy and interferon, had demonstrated a convincing benefit. Of six trials investigating maintenance with thalidomide in post-ASCT patients, only two showed an OS advantage. In one of these two, IFM99-02, posttransplant thalidomide therapy has been associated with an improvement in event-free survival and OS (although not in patients with deletion of chromosome 13 or patients achieving a VGPR or better post-transplantation), but it is accompanied with substantial neurotoxicity, compromising its value as a maintenance treatment due to its adverse effects on quality of life.

As an oral agent and in contrast to thalidomide, lenalidomide is an attractive choice for maintenance because it is well tolerated with minimal neurological complications. It has demonstrated activity even in patients who have failed high-dose therapy with other agents, and it is both effective and safe when administered for indefinite periods, as Dr. Attal explained. In fact, a high degree of tolerability was observed in both of the phase III studies, and the low rate of dropouts for side effects in both studies provided evidence that it was tolerated to a satisfactory degree by the majority of patients.

Separately and together, the IFM 2005-02 and CALGB 100104 data demonstrated that posttransplant maintenance therapy with lenalidomide significantly improves outcomes. Although other clinical questions remain, including the definition of optimal consolidation therapy and the indications for single vs. double ASCT, the newly established role of lenalidomide post-transplant therapy provides a new foundation on which the next set of advances can be built. Although not demonstrating an improvement in OS with the relatively short follow-up of these trials, the results of these two large, independent, co-operative group studies separately demonstrate the significant advantage of lenalidomide maintenance, thus together reinforcing the conclusion that it should be regarded as a new standard.

Challenging the Need for ASCT in Eligible Patients

Initial results from a phase III randomized trial have raised the possibility that the novel agent lenalidomide may eliminate the need of initial ASCT in MM patients. In this multinational ASCT challenge study that included the participation of the Italian Multip
l patients received a 4-cycle induction of lenalidomide and dexamethasone before being randomized to conventional double ASCT or to a triple drug regimen containing MP and lenalidomide (MPR) for 6 cycles (Figure 6).¹⁴ The primary outcome was PFS, and so far the drug regimen appears to be as effective but better tolerated when compared to ASCT.

Figure 6.

<img4317|center>

At present, with a median follow-up of 14 months, no significant difference has been detected between the two groups in this ASCT challenge study.

PFS is projected at one year to be 91% whether patients received transplant or drug therapy alone (P=0.77). OS at one year was 97% in the MPR group and 98% in the ASCT group, which did not differ significantly (P=0.27), as reported by Dr. Antonio Palumbo. Response rates for MPR vs. transplant have been almost indistinguishable for CR (13% vs. 16%; P=0.82, respectively) and =VGPR (55% vs. 53%; P=0.63, respectively) (Table 5). Although Dr. Palumbo cautioned that this
t yet definitive, the results so far clearly suggest that the combination with the new agent is certainly reducing the difference between drug therapy alone and autologous transplant. If longer follow-up confirms the similarity of benefit between MPR and ASCT in standard-risk patients, it is likely that results will shift more patients to MPR as an alternative to an ASCT, mainly because of greater tolerability.

Table 5.

<img4378|center>

New Induction Strategies in Transplant-eligible Patients

Bortezomib is among agents being tested as induction for ASCT-eligible patients. In a randomized trial yielding preliminary results,¹⁵ 205 patients <66 years old with newly diagnosed MM were randomized to four 21-day cycles of reduced doses of bortezomib plus thalidomide and dexamethasone (vTD) or standard doses of bortezomib plus dexamethasone (VD). Based on greater disease activity with vTD than VD, the authors characterized vTD as “a new alternative.”

In this IFM2007-02 study, vTD was associated with a better =VGPR rate than VD
and after an ASCT, despite the fact that high risk cytogenetics were more frequent in the vTD group (Table 6). Although the author cautioned that stem cell collection was inferior on vTD, this could be overcome by adding cyclophosphamide, which is routinely used with G-CSF in Canada. Perhaps most importantly, Dr. Philppe Moreau emphasized that vTD was associated with a low rate of grade 3 and 4 toxicities, particularly a low rate of peripheral neuropathy.

Table 6.

<img4319|center>

Emerging Data for Transplant-ineligible Patients

The advantage of employing continuous therapy with lenalidomide to extend remission was also demonstrated with another phase III trial conducted in transplant-ineligible patients with newly diagnosed MM. The updated analysis of the MM-015 study with 70% of projected events at two years was presented at the EHA by Dr. Palumbo.&l
;

In the MM-015 study, 459 patients with newly diagnosed MM were randomized to one of three treatment arms: MPR followed by maintenance lenalidomide (MPR-R); MPR followed by placebo maintenance; and MP with placebo followed by placebo maintenance. Cycles 1 to 9 consisted of melphalan 0.18 mg/kg on days 1 to 4; prednisone 2 mg/kg on days 1 to 4; and lenalidomide 10 mg/day on days 1 to 2
nce lenalidomide 10 mg/day or placebo on days 1 to 21 until disease progression (Figure 7).

Figure 7.

<img4320|center>

When investigators compared the best response rates, a CR was achieved in 16% of those in the MPR-R arm, 11% of those in the MPR arm and 4% of those in the MP
01). Similarly, the VGPR rate increased almost three times from 12% in the MP arm to 32% in the MPR-R arm with a similar rate at 33% in the MPR arm. PRs were seen in 45%, 35% and 38% of the MPR-R, MPR and MP arms, respectively (Table 7).
21|center>

Median PFS was 13 and 14.1 months for MP and MPR, respectively, in the absence of lenalidomide maintenance therapy. The median PFS has yet to be reached in the arm that has received maintenance with lenalidomide, already translating into a 58% reduction in the risk of progression (HR 0.42; P<0.001) (Figure 8).

Figure 8.

<img4322|center>

Grade 3 and 4 adverse events were mainly hematological. Grade 4 neutropenia occurred in 36% of the MPR-R group vs. 8% in MP controls (Table 8). The incidence of grade 3 infection was, however, reassuringly low in the MPR-R arm at 10% compared with 8% for the MP arm.

Table 8.

<img4323|center>

The safety profile of continuous treatment with lenalidomide is also encouraging because even in patients over the age of 65, hematological toxicity is very limited, with only a 3% incidence of thrombocytopenia and a 2% incidence of neutropenia, remarked Dr. Palumbo. This emphasizes the favourable tolerability of a 10-mg dose of lenalidomide.

Based on these data, Dr. Palumbo characterized MPR-R as a new standard treatment option for non- ASCT-eligible patients with MM.

The results of the MM-015 trial, like the IFM 2005-02 and CALGB 100104 trials conducted in the ASCT population, are considered practice-changing.

Other Options for Newly Diagnosed MM Patients

Several new strategies are now considered reasonable approaches with the emergence of more effective alternatives to MP for patients who are not candidates for ASCT. The addition of a novel agent to MP (MPT, VMP or MPR-R) has been beneficial. Some researchers have looked at the additi
gent to MP. Dr. Palumbo identified an induction regimen of bortezomib and thalidomide (VT) in combination to MP (VMPT), followed by VT maintenance as another potential standard, based on new phase III data from the Italian VMPT trial.¹⁷ The study is a modification of the VMP induction from the VISTA study¹⁸ and the VT maintenance regimen evaluated in the Mateos et al, VMP study presented at the 2009 American Society of Hematology (ASH) meeting.

In the Italian VMP study, 511 patients =65 years old patients not eligible for ASCT with newly diagnosed MM were randomized to VMP or VMPT. VMPT was followed by VT maintenance (Figure 9).

Figure 9.

<img4324|center>

On the VMPT regimen, CR rates climbed from 24% to 38% (P=0.0008) relative to VMP, while PFS rates at three years rose from 40% to 54% (P=0.006). Dr. Palumbo identified VMPT as the only combination so far that has shown superiority to VMP in terms of PFS, although VMPT had the advantage of a maintenance to improve its results.

In a relatively small phase II study presented at ASCO, combination lenalidomide/bortezomib/ dexamethasone (RVD), which has demonstrated efficacy in relapsed and refractory MM, showed very high rates of activity with a relatively benign side-effect profile.¹⁹ Presented by Dr. Kenneth C. Anderson, this study included 35 newly diagnosed MM patients. The average age in this study was only 58 and nearly half of patients also received ASCT. The patients received a median of 10 cycles of RVD, which produced a =VGPR in 74% of patients and a =PR in 100%. No impact from adverse cytogenetics on response rates or on PFS was observed. Furthermore, PFS was similar between those who did and those who did not receive ASCT.

Tolerability of the RVD combination was excellent. Grade 3 neuropathy was seen in 2% of patients and grade 3 fatigue was reported by 3%. The grade 3 or 4 hematologic toxicities included lymphopenia in 14%, neutropenia in 9% and thrombocytopenia in 6%. There was no treatment-related mortality.

Dr. Anderson suggested that the results support expanded studies within efforts to identify the best combination of novel agents from the standpoint of both safety and efficacy.

Several combinations are now reasonable options in both newly diagnosed patients who are not candidates for ASCT and in refractory or relapsed patients. Yet the many large and ongoing collaborative studies are expected to eventually single out a more rigorous order of first-, second- and third-line treatments. Clearly, this order will be influenced by both efficacy and safety. Extending survival must involve an acceptable quality of life and this has prompted several studies to focus on tolerability.

Emerging Agents for Refractory/Resistant MM

The improvement in clinical outcomes associated with new regimens containing novel agents, such as lenalidomide, bortezomib and thalidomide, has produced remarkable changes in the prognosis of MM both in transplant-eligible and -ineligible patients, but there is additional promise with other novel agents in development. These are now being explored in secondor third-line treatment regimens. Of new agents for which there are emerging clinical data, pomalidomide, panobinostat and carfilzomib have attracted attention for activity in refractory and resistant MM.

Pomalidomide

Pomalidomide, an immunomodulatory agent with a chemical structure related to lenalidomide and thalidomide, has demonstrated activity in patients resistant to lenalidomide in a safety study that enrolled 35 patients who were refractory/resistant to both bortezomib and lenalidomide.²⁰ In this population, the median number of prior regimens was 6 and 81% had 5 or more prior regimens. Despite this exposure, 46% of patients achieved an overall response in a regimen that combined pomalidomide with dexamethasone.

Co-investigator Dr. Martha Q. Lacy, indicated that the study confirmed therapeutic benefit for the combination of pomalidomide and dexamethasone in patients relapsing after other novel therapies. Although the median follow-up is only 3 months, almost 80% of the patients remain progression-free.

The overall responses consisted of VGPR in 9%, PR in 23% and minor responses in 14%. Although 29% of patients did have grade 3 or 4 neutropenia, only 10% developed grade 3 or 4 anemia and only 3% developed grade 3 or 4 thrombocytopenia. The grade 3 or 4 nonhematologic toxicities of pneumonitis, hyperglycemia, renal failure, fatigue and thrombosis all occurred at a rate of 3%. Although 6% of patients developed neuropathy, none were grade 3 or 4.

Based on these results, Dr. Lacy concluded that the combination of pomalidomide and dexamethasone appeared active and well tolerated in this heavily pretreated population of dual bortezomib/lenalidomiderefractory MM patients. She suggested that larger studies are warranted to confirm a level of safety and efficacy that could permit drug approval.

Carfilzomib The selective proteasome inhibitor carfilzomib has established single-agent activity in patients with relapsed and/or refractory MM. In a small study, it has demonstrated encouraging responses even in patients with substantial renal impairment. No dose adjustments were required and toxicity was considered mild and manageable.²¹

Panobinostat Similarly, panobinostat showed substantial promise in refractory patients when combined with lenalidomide and dexamethasone in a dose-finding safety study.²² Although about 25% of the evaluable patients received the lowest dose of 5 mg—substantially less than the 20-mg dose which appears to offer the best efficacy:safety ratio—17 (57%) of 30 evaluable patients had an overall response, seven patients had stable disease and only six progressed. The senior author of this study, Dr. Maria-Victoria Mateos, Hospital Universitario de Salamanca, Spain, characterized this preliminary evidence of efficacy as very encouraging.

In 46 patients evaluable for safety, grade 3 or 4 thrombocytopenia was observed in 44% and grade 3 or 4 neutropenia was observed in 37%. Other side effects included gastrointestinal complaints, fatigue, reduced appetite, insomnia and muscle weakness. There was one case of DVT, but it is not known whether it was treatment-related. Some of the adverse events were recorded at the highest dose levels which may not be required to achieve adequate efficacy with this agent.

In fact, although there are potential safety issues, the high rate of activity is encouraging because there are a number of strategies that may improve tolerability while preserving anti-tumour effects. Dr. Mateos stated that future studies would incorporate a lower dexamethasone dose and a non-continuous panobinostat dosing schedule.

Summary

Data presented at the 2010 annual meetings of ASCO and EHA are immediately relevant to transplanteligible and -ineligible MM patients. The large benefit of post-transplant therapy with lenalidomide, which addresses the treatment of minimal residual disease in MM, is the most significant new finding at ASCO 2010. According to Dr. Giralt, the lenalidomide posttransplant therapy results are practice-changing.

From the EHA and the update of the MM-015 study, the use of early and continued lenalidomide was defined as a new standard of care for newly diagnosed transplant-ineligible patients by Dr. Palumbo.

Although many clinical questions remain, the newly established role of continuous lenalidomide treatment provides a new foundation on which the next set of advances can be built.

References

1. Canadian Cancer Society. Canadian Cancer Statistics 2008 at http://www.cancer.ca/Canada-wide/About%20cancer/Cancer% 20statistics/Canadian%20Cancer%20Statistics.aspx?sc_lang=en.

2. Cancer reference information. What are the risk factors for multiple myeloma? Revised: 08/04/2006. American Cancer Society. Available at http://www.cancer.org/docroot/CRI/content, Accessed June 29, 2010.

3. Alexanian et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 1969;208:1680-5.

4. Attal et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 1996;335(2):91-7.

5. Child et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348(19):1875-83.

6. Kumar et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111(5):2516-20.

7. Kastritis et al. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia 2009;23(6):1152-7.

8. Rajkumar et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11(1):29-37.

9. Mateos et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 2010;28(13): 2259-66.

10. Attal et al. Lenalidomide maintenance after transplantation for myeloma. ASCO 2010, Abstract 8018.

11. Attal et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006;108(10):3289-94).

12. McCarthy et al. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. ASCO 2010, Abstract 8017.

13. Giralt S. Discussion: Post-transplant maintenance therapies. ASCO 2010, Oral abstract session.

14. Palumbo 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. ASCO 2010, Abstract 8015.

15. Moreau et al. Comparison of reduced-dose bortezomib plus thalidomide plus dexamethasone (vTD) to bortezomib plus dexamethasone (VD) as induction treatment prior to ASCT in de novo multiple myeloma (MM): Results of IFM2007-02 study. ASCO 2010, Abstract 8014.

16. Palumbo et al. A Phase 3 study to determine the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients =65 years with newly diagnosed multiple myeloma (NDMM). EHA 2010, Abstract 0566.

17. Boccadoro et al. Bortezomib, melphalan, prednisone, and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide (VT) for initial treatment of elderly multiple myeloma patients. ASCO 2010, Abstract 8013.

18. San Miguel et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Eng J Med 2008; 359(9):906-17.

19. Anderson et al. Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma (MM): Final results of a multicenter phase I/II study. ASCO 2010, Abstract 8016.

20. Lacy et al. Activity of pomalidomide plus dexamethasone (Pom/ dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). ASCO 2010, Abstract 8002.

21. Badros et al. Phase II study of carfilzomib in patients with relapsed/ refractory multiple myeloma and renal insufficiency. ASCO 2010, Abstract 8128.

22. Mateos et al. Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). ASCO 2010, Abstract 8130.