December 3-6, 2016; San Diego, California

New Findings in Multiple Myeloma: Independent Conference Coverage of Hematology 2016*
December 3-6, 2016; San Diego, California *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. Sagar Lonial, MD: The 2016 ASH annual meeting showcased key new findings from clinical trials that promise to improve the treatment of patients with multiple myeloma (MM). In this module, Shaji Kumar, MD, and I discuss frontline options for MM including response-adapted use of proteasome inhibitor–based triplets after immunomodulatory drug–based triplets, the use of carfilzomib plus lenalidomide and dexamethasone (KRd), and the optimal use of therapy following an initial autologous stem cell transplantation (ASCT). In the relapsed/refractory setting, we also review the role of minimal residual disease (MRD) after treatment with daratumumab, the use of daratumumab plus pomalidomide and dexamethasone, SC vs IV daratumumab, weekly carfilzomib regimens, and new agents being explored in this setting. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details Full summary slidesets for each of the studies in this highlight slideset are available on Slide credit: clinicaloptions.com Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty Shaji Kumar, MD Department of Hematology
Mayo Clinic Rochester, Minnesota Sagar Lonial, MD Professor and Chair Department of Hematology and Medical Oncology Chief Medical Officer Winship Cancer Institute of Emory University Atlanta, Georgia This slide lists the faculty who were involved in the production of these slides.

Disclosures Shaji Kumar, MD, has disclosed that he has received consulting fees from Kesios and SkylineDx and funds for research support from AbbVie, Celgene, Janssen, Merck, Novartis, sanofi-aventis, and Takeda. Sagar Lonial, MD, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Novartis, and Takeda. This slide lists the faculty who were involved in the production of these slides.

Overview Newly Diagnosed MM R/R MM: Use of Daratumumab
Phase III Myeloma XI: response- adapted use of PI-based triplet after IMiD-based triplet Phase II IFM: KRd in induction and consolidation treatment Phase III STaMINA: single ASCT, single ASCT followed by RVD consolidation, vs tandem ASCT R/R MM: Use of Daratumumab Assessing MRD in pts from POLLUX and CASTOR trials Retrospective analysis of dara/pom/dex in pts with R/R MM Phase Ib trial assessing safety and efficacy of SC daratumumab + rHuPH20 R/R MM: Use of Carfilzomib Phase I/II trial of weekly carfilzomib/pomalidomide/low-dose dexamethasone New Agents in MM ASCT, autologous stem cell transplantation; dara, daratumumab; dex, dexamethasone; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PI, proteasome inhibitor; pom, pomalidomide; R/R, relapsed/refractory; RVD, lenalidomide/bortezomib/dexamethasone.

Newly Diagnosed Multiple Myeloma

Background For pts with ND MM, both PFS and OS improve when treated with: Induction combinations of IMiDs, PIs, and/or steroids followed by high-dose melphalan/ASCT and lenalidomide maintenance Unclear whether further benefit can be realized with additional interventions such as second ASCT or combination consolidation regimens[1-3] Data presented at ASH 2016 include: Phase III Myeloma XI trial investigating response-adapted, sequential use of PI-based triplet after suboptimal response to IMiD-based triplet during induction[4] Phase II IFM study evaluating prolonged use of carfilzomib as a replacement for bortezomib in initial therapy and consolidation regimens[5] Phase III STaMINA trial comparing single ASCT, single ASCT followed by RVD consolidation, and tandem ASCT (all with additional lenalidomide maintenance)[6] ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; MM, multiple myeloma; ND, newly diagnosed; PI, proteasome inhibitor; RVD, lenalidomide/bortezomib/dexamethasone. 1. Barlogie B, et al. Blood. 1997;89: Attal M, et al. N Engl J Med. 2003;349: Cavo M, et al. Blood. 2012;120: Jackson GH, et al. ASH Abstract Roussel M, et al. ASH Abstract Stadtmauer EA, et al. ASH Abstract LBA-1. Slide credit: clinicaloptions.com

Phase III Myeloma XI: Response-Adapted Induction Improves Outcomes in Newly Diagnosed Multiple Myeloma This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

Myeloma XI: Subset Analysis
UK-based multicenter, open-label, parallel group, randomized, controlled phase III trial Induction 1 4 cycles if ASCT eligible; 6 cycles if ASCT ineligible Induction 2 Bortezomib Cyclophosphamide Dexamethasone (n = 289) CRD Newly diagnosed MM pts (N = 583) Max response*: PR or MR ASCT for eligible pts (n = 367) CTD No further induction therapy (n = 294) *Completed ≥ 4 cycles of IMiD-based induction. ASCT, autologous stem cell transplantation; CRD, cyclophosphamide/lenalidomide/dexamethasone; CTD, cyclophosphamide/thalidomide/dexamethasone; IMiD, immunomodulatory drug; MM, multiple myeloma; MR, minimal response; PI, proteasome inhibitor. Shaji Kumar, MD: For patients with newly diagnosed MM, the intent of therapy is maximal reduction and potentially eradication of the tumor burden to rapidly reverse the complications related to the disease with minimal toxicity. However, an ongoing clinical question in MM is how deep the response needs to be prior to an ASCT. Jackson and colleagues[1] sought to answer this question in the phase III Myeloma XI study of induction therapy in 583 patients with newly diagnosed MM. In this study, patients initially received either cyclophosphamide, lenalidomide, and dexamethasone (CRD) or cyclophosphamide, thalidomide, and dexamethasone (CTD). Patients who achieved a maximum response of either PR or minor response after at least 4 cycles were randomized to receive additional induction therapy with bortezomib, cyclophosphamide, and dexamethasone (CVD) or to no further induction therapy. Eligible patients (n = 367) then received ASCT. The primary endpoint for this trial was PFS and OS, and secondary endpoints included assessing improved response vs baseline and proteasome inhibitor effect in high-risk patients. Primary endpoints: PFS, OS Secondary endpoints: improved response vs baseline, PI effect in high-risk pt group Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244.

Myeloma XI: Response Rates
After IMiD Induction After CVD Induction After ASCT No CVD (n = 291) CVD (n = 289) (n = 133) (n = 119) VGPR + CR 4.1 4.5 42.5 39.9 65.0 CR 0.3 3.5 5.9 14.0 VGPR 4.2 39.0 34.0 51.0 PR 84.0 55.0 26.0 MR 7.5 8.3 1.4 1.7 1.5 SD/PD 4.0 1.0 3.8 2.3 ASCT, autologous stem cell transplantation; CVD, cyclophosphamide/bortezomib/dexamethasone; IMiD, immunomodulatory drug; MR, minimal response; PD, progressive disease; SD, stable disease; VGPR, very good PR. Shaji Kumar, MD: Results showed that addition of CVD at the end of induction therapy improved the depth of response: 38% of patients who received CVD improved their response to initial induction from PR or minor response to very good PR or better after CVD. Likewise, patients who received CVD after induction had higher rates of very good PR or better after ASCT as well: 65% vs 39.9% without CVD. 38% improvement in rate of VGPR + CR in pts who received additional induction with CVD 4.5% after IMiD induction to 42.5% after additional CVD induction Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244.

Myeloma XI: PFS and OS (All Pts)
100 27 100 90 80 70 60 40 30 20 50 10 3 9 12 6 15 18 24 21 57 33 39 42 36 45 48 54 51 63 66 Median PFS, Mos (95% CI) No CVD (n = 294) 20 (15-28) CVD (n = 289) 30 (25-36) HR: 0.60 (95% CI: ; log-rank P < .0001) All subgroups favor CVD induction; CVD appears to ameliorate negative survival effect of t(4;14) mutation 90 80 70 60 OS (%) PFS (%) 50 40 3-Yr OS, % (95% CI) No CVD (n = 294) 78.5 ( ) CVD (n = 289) 77.3 ( ) HR: 0.97 (95% CI: ; log-rank P = .8883) 30 20 10 CVD, cyclophosphamide/bortezomib/dexamethasone. Shaji Kumar, MD: Median PFS was also significantly improved by addition of CVD, from 20 months to 30 months (HR: 0.60; P < .0001). However, there was no OS difference at 3 years between the 2 arms. The benefit that was seen with additional CVD induction therapy was seen across all disease groups, including patients with high-risk abnormalities such as t(4;14) and del(17p). 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 Mos Since Randomization Mos Since Randomization Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244. Reproduced with permission.

Myeloma XI: PFS by Subgroup
Level Sex Age ISS Response at baseline Induction t(4,14) del(17p) 1q gain Genetic risk Overall Male Female ≤ 65 yrs > 65 yrs Stage I Stage II PR MR CTD/CTDa CRD/CRDa Absent Present Std risk High risk Std/high risk Ultrahigh risk CRD, cyclophosphamide/lenalidomide/dexamethasone; CTD, cyclophosphamide/thalidomide/dexamethasone; CVD, cyclophosphamide/bortezomib/dexamethasone; ISS, International Staging System; MR, minimal response; Std, standard. Shaji Kumar, MD: Median PFS was also significantly improved by addition of CVD, from 20 months to 30 months (HR: 0.60; P < .0001). However, there was no OS difference at 3 years between the 2 arms. The benefit that was seen with additional CVD induction therapy was seen across all disease groups, including patients with high-risk abnormalities such as t(4;14) and del(17p). 0.05 0.10 0.20 0.50 1.00 2.00 HR Favors CVD Favors No CVD Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244. Reproduced with permission.

Myeloma XI: PFS and OS (Transplant Eligible)
100 Median PFS, Mos (95% CI) No CVD (n = 184) 28 (22-33) CVD (n = 183) 48 (35 to ∞) 100 27 3 9 12 6 15 18 24 21 57 30 33 39 42 36 45 48 54 51 60 63 66 90 90 80 80 70 70 HR: 0.50 (95% CI: ; log-rank P < .0001) 60 60 PFS (%) 50 OS (%) 50 40 40 3-Yr OS, % (95% CI) No CVD (n = 184) 81.2 ( ) CVD (n = 183) 81.5 ( ) HR: 0.83 (95% CI: ; log-rank P = .4535) 30 30 20 20 CVD, cyclophosphamide/bortezomib/dexamethasone. Shaji Kumar, MD: In the transplantation-eligible patient population, findings were similar to those in the overall population: There was a significant median PFS improvement with additional CVD induction (from 28 to 48 months; HR: 0.50; P < .0001) with no OS improvement. In the transplantation-ineligible population, there was also a substantial median PFS improvement, from 8 to 20 months, but again no difference in OS was seen at 3 years. 10 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 Mos Since Randomization Mos Since Randomization Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244. Reproduced with permission.

Myeloma XI: PFS and OS (Transplant Ineligible)
100 Median PFS, Mos (95% CI) No CVD (n = 110) 8 (6-15) CVD (n = 106) 20 (15-24) HR: 0.72 (95% CI: ; log-rank P = .0525) 100 90 90 80 80 70 70 60 60 PFS (%) 50 OS (%) 50 40 40 3-Yr OS, % (95% CI) No CVD (n = 110) 72.8 ( ) CVD (n = 106) 69.0 ( ) HR: 1.26 (95% CI: ; log-rank P = .4410) 30 30 20 20 CVD, cyclophosphamide/bortezomib/dexamethasone. Shaji Kumar, MD: In the transplantation-eligible patient population, findings were similar to those in the overall population: There was a significant median PFS improvement with additional CVD induction (from 28 to 48 months; HR: 0.50; P < .0001) with no OS improvement. In the transplantation-ineligible population, there was also a substantial median PFS improvement, from 8 to 20 months, but again no difference in OS was seen at 3 years. 10 10 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 Mos Since Randomization Mos Since Randomization Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244. Reproduced with permission.

Myeloma XI: Adverse Events
Pts received a median of 4 cycles of CVD (range: 1-8) Adverse Events in CVD Arm (n = 264), % Grade 3 Grade 4 Neutropenia 5.7 1.1 Thrombocytopenia 4.9 2.3 Anemia 3.0 Sensory neuropathy 3.4 0.4 Motor neuropathy CVD, cyclophosphamide/bortezomib/dexamethasone. Shaji Kumar, MD: Adverse events (AEs) were as anticipated for patients receiving CVD, including low rates of grade 3/4 hematologic AEs, including neutropenia, thrombocytopenia, and anemia, as well as low rates of grade 3/4 neuropathy. Overall, patients received a median of 4 cycles of CVD induction, with a range from 1-8 cycles of therapy. Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244.

Myeloma XI: Conclusions
Response-adapted use of sequential IMiD- and PI-based therapy can improve treatment efficacy CVD induction improved depth of response 38% of pts improved response to VGPR or better after induction Responses improved after ASCT in both arms but remained deeper in CVD induction arm CVD induction prolonged PFS in both transplant-eligible and transplant-ineligible pts (by 12 and 20 mos, respectively) Positive PFS effects seen in all pt subgroups OS similar between treatment arms ASCT, autologous stem cell transplantation; CVD, cyclophosphamide/bortezomib/dexamethasone; IMiD, immunomodulatory drug; PI, proteasome inhibitor; VGPR, very good PR. Shaji Kumar, MD: Myeloma XI is one of the first trials to prospectively address the question of whether additional treatment before ASCT could improve patient response. Overall, results showed that for patients who failed to achieve better than a PR with initial therapy of either CRD or CTD, employing additional induction treatment with CVD prior to moving to ASCT deepened response prior to and after transplantation, and also lengthened median PFS. One important caveat with this study is that neither CRD nor CTD is a standard induction treatment, at least in the United States. It is possible that if these patients had a more effective initial induction regimen, including both a proteasome inhibitor and an IMiD, the results may have been different. Furthermore, the PFS survival curves show a sharp drop-off in the first 3 months for patients who did not receive the bortezomib-based induction therapy. This is unusual for patients going directly to ASCT, and raises the question of whether these patients had a significant delay between the 4 cycles of initial treatment and the transplantation. Overall, although there may be a role for changing to a bortezomib-based induction therapy, I do not think this study definitively provides an answer to that question. Sagar Lonial, MD: These are challenging findings to apply to clinical practice in the United States. One take-home message is that cyclophosphamide plus an IMiD is a suboptimal upfront induction regimen. As Dr. Kumar mentioned, there is now broad consensus that newly diagnosed patients should receive a combination of an IMiD and a proteasome inhibitor. Regarding the applicability of these data to the US patient population, the median PFS is substantially lower than in other large phase III trials which combined an IMiD and a proteasome inhibitor as induction therapy for MM. These findings are unlikely to change daily clinical practice. Slide credit: clinicaloptions.com Jackson GH, et al. ASH Abstract 244.

IFM Phase II Study: KRd Induction and Consolidation Before Len Maintenance Highly Effective in Newly Diagnosed MM KRd, carfilzomib/lenalidomide/dexamethasone; Len, lenalidomide; MM, multiple myeloma. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

KRd in Newly Diagnosed MM: Phase II Study Design
Open-label, single-arm, multicenter study Primary endpoint: sCR at completion of consolidation Secondary endpoints: ORR at various points, MRD for pts with ≥ VGPR, safety/tolerability, PFS Induction* Carfilzomib 20/36 mg/m² IV Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 20 mg Days 1-2, 8-9, 15-16, (Cycles 1-4) PBSC harvest (high-dose cyclophosphamide) followed by high-dose melphalan 200 mg/m2 and ASCT Pts < 65 yrs of age with symptomatic ND MM (N = 46) Consolidation* Carfilzomib 36 mg/m² IV Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 20 mg Days 1-2, 8-9, 15-16, (Cycles 5-8) Maintenance lenalidomide 10 mg Days 1-21 for 13 cycles* ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; ND, newly diagnosed; PBSC, peripheral blood stem cell; sCR, stringent CR; VGPR, very good PR. Sagar Lonial, MD: Roussel and colleagues[2] conducted a phase II trial of KRd induction therapy in 46 patients aged younger than 65 years with newly diagnosed MM. Of note, the induction dosing for carfilzomib was 20/36 mg/m2, as used in studies by Jakubowiak[3] and Korde.[4] In this trial, stem cells were collected following induction therapy, and then patients received ASCT plus consolidation therapy with KRd for an additional 4 cycles. Patients subsequently received maintenance therapy with single-agent lenalidomide. The primary endpoint was assessing the rate of stringent CR after consolidation therapy. *Mandatory antithrombotic prophylaxis with low molecular weight heparin. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142.

KRd in Newly Diagnosed MM: Responses at End of Consolidation
Endpoint, n (%) End of Consolidation (N = 46) sCR 26 (57) MRD using flow cytometry 32 (70) MRD using next-generation sequencing 23 of 34 (68) ≥ CR 28 (61) ≥ VGPR 39 (85) ORR 41 (89) PD 1 (2) KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; PD progressive disease; sCR, stringent CR; VGPR, very good PR. Sagar Lonial, MD: At the end of consolidation, 57% of patients achieved stringent CR, 68% were MRD negative by next-generation sequencing, and the ORR was 89%. This depth of response is very high and responses occurred more quickly than in previous trials of this combination. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142

KRd in Newly Diagnosed MM: Responses Throughout Treatment
Endpoint (N = 46), n After Induction, n After ASCT, n After of Consolidation, n Best Response, n (%) sCR 9 15 26 32 (70) sCR + CR 11 19 28 35 (76) VGPR 25 18 7 (15) ≥ VGPR 36 37 39 42 (91) PR 6 3 2 -- ORR 42 40 41 46 (100) PD 1 ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease; sCR, stringent CR; VGPR, very good PR. Sagar Lonial, MD: Strikingly, patients continued to deepen their response over time with consolidation therapy. A total of 11 patients achieved a CR or stringent CR after the induction therapy, but after consolidation, these responses had been achieved by 28 patients. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142

KRd in Newly Diagnosed MM: Progression and Survival
PD (n = 3): 1 before ASCT, 2 during maintenance Death (n = 2): 1 during ASCT, 1 during follow-up Median PFS: not reached (95% CI: 27.4 to not reached) Estimated 2-yr PFS: 91% ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; PD progressive disease. Sagar Lonial, MD: With the caveat that these findings represent early follow-up in a small trial, a significant number of patients did well, with an estimated 2-year PFS rate of 91%. However, 3 patients progressed—1 prior to ASCT and 2 during maintenance. In addition, 1 patient died during transplantation and 1 died during follow-up. The median PFS had not been reached at the time of presentation. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142.

KRd in Newly Diagnosed MM: Grade 3/4 Adverse Events
Nonhematologic AE, n KRd Induction Consolidation Infections 7 1 Musculoskeletal disorders 5 2 Cardiovascular disorders -- GI disorders Injury, poisoning, procedural complications Hepatobiliary disorders Skin/subcutaneous disorders General disorders or administration site conditions Grade 3/4 Hematologic AE, n KRd Induction KRd Consolidation Neutropenia 6 12 Lymphopenia 5 17 Thrombocytopenia 1 7 Anemia -- No incidence of peripheral neuropathy reported AE, adverse event; GI, gastrointestinal; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Sagar Lonial, MD: Grade 3/4 AEs included cardiovascular disorders in 5 patients during the induction therapy phase. Infections and musculoskeletal issues were also reported and are not uncommon with KRd. Grade 3/4 hematologic malignancies increased between induction and consolidation. For example, grade 3/4 neutropenia increased from 6 to 12 patients and grade 3/4 lymphopenia from 5 to 17 patients. No peripheral neuropathy was reported. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142

KRd Induction and Consolidation KRd Induction and Consolidation
KRd in Newly Diagnosed MM: Serious AEs and Cardiovascular/Pulmonary Toxicity Serious AE, n KRd Induction and Consolidation (n = 45) Any 30 Infections/infestations 12 Musculoskeletal/connective tissue 9 Cardiac and vascular 8 Blood and lymphatic 3 Injury, poisoning, procedural complications Gastrointestinal disorders 2 General disorders Psychiatric disorders 1 Cardiovascular Toxicity, All Grades, n KRd Induction and Consolidation (n = 45) Cardiac failure 2 Pulmonary embolism Venous thrombosis Intracardiac thrombosis Superficial thrombosis 1 8 Bradycardia Arrhythmia Atrial fibrillation Tachycardia Hypertension 4 Cough Dyspnea 9 5 AE, adverse event; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Sagar Lonial, MD: In total, 30 of the 45 patients experienced serious AEs, including cardiac and vascular (thromboembolic) issues in 8 patients. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142

KRd in Newly Diagnosed MM: Conclusions
8 cycles of induction and consolidation with KRd in pts with ND MM was highly effective 61% CR/sCR at end of consolidation (primary endpoint) 70% of pts with negative MRD at end of consolidation Time to response quicker than standard intensive VRd At time of transplant, 78% achieved ≥ VGPR with KRd vs ~ 50% in historical VRD studies No peripheral neuropathy but cardiovascular toxicity a concern Mechanism of cardiovascular events needs further investigation KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; ND, newly diagnosed; sCR, stringent CR; VGPR, very good PR; VRD, bortezomib/lenalidomide/dexamethasone. Sagar Lonial, MD: There is no question this IMiD–proteasome inhibitor combination is a very active regimen that rapidly produces responses: 70% of patients achieved MRD negativity by the end of consolidation, which is faster than with standard RVD therapy. Although there was no peripheral neuropathy reported, there certainly were concerning cardiovascular events, particularly thromboembolic phenomena, that may have limited the ability to delivery this regimen in a larger patient population. Shaji Kumar, MD: The KRd results from this study by Roussel and colleagues[2] are consistent with the response and the efficacy findings in earlier studies: This is an effective regimen, with fast and deep responses, especially the proportion of patients who achieved MRD negativity. As Dr. Lonial pointed out, this promising efficacy has to be balanced against the potential toxicity, particularly given that this regimen could have a long-lasting influence on MM disease management for years to come. Also, these results should be considered in the context of who is receiving this regimen: younger patients who will receive an ASCT and potentially go on maintenance after that. Findings from ongoing clinical trials comparing KRd vs RVD, especially the ECOG E1A11 trial, will be important to determine the burden of toxicity vs the potential efficacy with each of these regimen. In my clinical practice, we are currently using RVD as induction, with KRd only being used in clinical trials. That is also the case in our practice: KRd is only used in clinical trials. Slide credit: clinicaloptions.com Roussel M, et al. ASH Abstract 1142

Phase III STaMINA Trial: Similar PFS With Single ASCT, Single ASCT Followed by RVD Consolidation, and Tandem ASCT in Frontline MM Treatment ASCT, autologous stem cell transplantation; MM, multiple myeloma; RVD, lenalidomide/bortezomib/dexamethasone. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

STaMINA: Phase III Study Design
Stratified by risk group (high vs standard) Single ASCT Lenalidomide Maintenance until PD* 10 mg/day for 3 cycles, then 15 mg/day* (n = 257) ASCT-eligible pts ≤ 70 yrs with symptomatic MM and ≥ 2 cycles systemic tx initiated in past 12 mos; no prior progression; adequate organ function (N = 758) Melphalan 200 mg/m² IV ASCT Bortezomib 1.3 mg/m² IV Days 1, 4, 8, 11 Lenalidomide 15 mg Days 1-15 Dexamethasone 40 mg IV Days 1, 8, 15 Four 28-day cycles (n = 254) Lenalidomide Maintenance until PD 10 mg/day for 3 cycles, then 15 mg/day* Tandem ASCT Melphalan 200 mg/m² IV Second ASCT (n = 247) ASCT, autologous stem cell transplantation; MM, multiple myeloma; PD, progressive disease; QoL, quality of life; tx, treatment. Shaji Kumar, MD: ASCT continues to be a major part of the standard of care for eligible patients with symptomatic myeloma. Across multiple trials, including a meta-analysis, maintenance therapy after a single ASCT clearly leads to better PFS and OS.[5,6] However, the question of whether additional treatment approaches can prolong responses is currently being explored. These approaches, including tandem ASCT (ie, 2 transplantations back to back) and additional consolidation therapy with a more intense regimen before the patient transitions to maintenance therapy, have had mixed results. The randomized phase III STaMINA trial (N = 758) was designed to answer compare these approaches.[7] Following an initial ASCT, patients were randomized to either lenalidomide maintenance, which is the typical current approach, or a second transplantation followed by lenalidomide maintenance, or consolidation with 4 cycles of RVD before proceeding to maintenance. The primary endpoint was PFS, with secondary endpoints including OS, ORR, the CR conversion rate, and safety. *Originally given for 3 yrs only but amended to until PD in 2014. Primary endpoint: PFS at 38 mos Secondary endpoints: OS, ORR, CR conversion rate, safety, infections, tx-related mortality, QoL Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1

STaMINA: Baseline Characteristics
Single ASCT (n = 257) RVD Consolidation (n = 254) Tandem ASCT (n = 247) Male 62.6 57.5 59.5 Karnofsky score ≥ 90 66.9 66.5 73.7 High risk (β2-M > 5.5 mg/L or cytogenetics) 23.0 25.6 23.1 Induction regimens before first ASCT RVD CyBorD RD VD Other 55.6 15.6 8.6 12.5 7.8 52.8 13.8 11.0 12.6 9.8 57.1 13.4 9.7 11.3 8.5 ASCT, autologous stem cell transplantation; β2-M, β2-microglobulin; CyBorD, cyclophosphamide/bortezomib/dexamethasone; NA, not applicable; RD, lenalidomide/dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; VD, bortezomib/dexamethasone. Shaji Kumar, MD: The patient population enrolled in the STaMINA trial was similar to other transplantation studies, and the type of treatment given prior to ASCT and the risk levels were similar across treatment groups. Of note, 32% of the patients assigned to the tandem ASCT arm did not ultimately receive a second transplantation, whereas only 12% of patients assigned to RVD consolidation did not receive consolidation therapy. Protocol Compliance, % Single ASCT (n = 257) RVD Consolidation (n = 254) Tandem ASCT (n = 247) Received second intervention NA 88.2 68.0 Started lenalidomide maintenance 94.6 83.1 83.4 Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1.

STaMINA: PFS and OS for Overall Population
PFS (Primary Endpoint) OS 100 80 60 40 20 PFS (%) 12 24 38 38-Mo Estimate, % (95% CI) Tandem ASCT: 56.5 ( ) RVD consolidation: 56.7 ( ) Single ASCT: 52.2 ( ) Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Mos From Randomization 100 80 60 40 20 OS (%) 12 24 38 38-Mo Estimate, % (95% CI) Tandem ASCT: 82.0 ( ) RVD consolidation: 85.7 ( ) Single ASCT: 83.4 ( ) Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Mos From Randomization ASCT, autologous stem cell transplantation; RVD, lenalidomide/bortezomib/dexamethasone. Shaji Kumar, MD: The key take-away message in this trial was that there was no difference in PFS or OS between the 3 different approaches. It is possible that the lack of benefit from tandem transplantation was because approximately one third of the intended patients did not receive a tandem transplantation. However, whereas there may be a trend toward improvement with tandem transplantation in the per protocol analysis, it did not show a significant difference in the estimated rates of PFS at 38 months with tandem ASCT, RVD consolidation, or single ASCT. As in the overall population and per protocol analyses, in patients with high-risk disease, there also was no difference in PFS or OS. Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1. Reproduced with permission.

STaMINA: PFS as Treated/Per Protocol Analysis
1.0 0.8 0.6 Probability of PFS 0.4 38-Mo Estimate, % (95% CI) Tandem ASCT: 61.8 ( ) RVD consolidation: 57.8 ( ) Single ASCT: 52.2 ( ) 0.2 ASCT, autologous stem cell transplantation; RVD, lenalidomide/bortezomib/dexamethasone. Shaji Kumar, MD: The key take-away message in this trial was that there was no difference in PFS or OS between the 3 different approaches. It is possible that the lack of benefit from tandem transplantation was because approximately one third of the intended patients did not receive a tandem transplantation. However, whereas there may be a trend toward improvement with tandem transplantation in the per protocol analysis, it did not show a significant difference in the estimated rates of PFS at 38 months with tandem ASCT, RVD consolidation, or single ASCT. As in the overall population and per protocol analyses, in patients with high-risk disease, there also was no difference in PFS or OS. 12 24 38 Mos From Randomization Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1. Reproduced with permission.

STaMINA: PFS and OS for Pts With High Risk
100 80 60 40 20 PFS (%) 12 24 38 38-Mo Estimate, % (95% CI) Tandem ASCT: 42.2 ( ) RVD consolidation: 48.3 ( ) Single ASCT: 40.2 ( ) Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Mos From Randomization 100 80 60 40 20 OS (%) 12 24 38 38-Mo Estimate, % (95% CI) Tandem ASCT: 79.3 ( ) RVD consolidation: 77.5 ( ) Single ASCT: 79.5 ( ) Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Mos From Randomization ASCT, autologous stem cell transplantation; RVD, lenalidomide/bortezomib/dexamethasone. Shaji Kumar, MD: The key take-away message in this trial was that there was no difference in PFS or OS between the 3 different approaches. It is possible that the lack of benefit from tandem transplantation was because approximately one third of the intended patients did not receive a tandem transplantation. However, whereas there may be a trend toward improvement with tandem transplantation in the per protocol analysis, it did not show a significant difference in the estimated rates of PFS at 38 months with tandem ASCT, RVD consolidation, or single ASCT. As in the overall population and per protocol analyses, in patients with high-risk disease, there also was no difference in PFS or OS. Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1. Reproduced with permission.

STaMINA: Multiple Myeloma Progression
100 38-Mo Estimate, % (95% CI) Treatment-related mortality 4 tandem ASCT arm 3 RVD consolidation arm 1 single ASCT arm 80 Tandem ASCT: 41.7 ( ) RVD consolidation: 42.1 ( ) Single ASCT: 47.2 ( ) 60 Cumulative Incidence (%) 40 20 ASCT, autologous stem cell transplantation; RVD, lenalidomide/bortezomib/dexamethasone. 12 24 38 Mos From Randomization Pts at Risk, n Tandem ASCT RVD consolidation Single ASCT Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1. Reproduced with permission.

STaMINA: Secondary Primary Malignancies
Secondary Malignancy in First 38 Mos Single ASCT (n = 257) RVD Consolidation (n = 254) Tandem ASCT (n = 247) No. of second malignancies 10 15 14 Cumulative incidence,* % (95% CI) 4.0 ( ) 6.0 ( ) 5.9 ( ) Most common malignancy, n Solid tumors, NR Leukemia, 9 Leukemia, 3 *First secondary malignancy. ASCT, autologous stem cell transplantation; NR, not reported; RVD, lenalidomide/bortezomib/dexamethasone. Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1.

STaMINA: Investigator Conclusions
Largest randomized comparison to date of therapeutic approaches after first ASCT in MM in US No difference in PFS, OS after 38 mos No difference between arms for pts with high-risk disease Cumulative incidence of first secondary malignancies similar in first 38 mos After induction therapy with IMiDs and/or PIs for ND MM, tandem ASCT or additional consolidation with RVD followed by lenalidomide maintenance provides no additional PFS or OS benefit vs single ASCT followed by lenalidomide maintenance BMT CTN 07FT and PRIMER will evaluate long-term outcomes with continued lenalidomide maintenance and assess MRD, respectively, in pts from STaMINA ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; MM, multiple myeloma; MRD, minimal residual disease; ND, newly diagnosed; PI, proteasome inhibitor; RVD, bortezomib/lenalidomide/dexamethasone. Shaji Kumar, MD: The data from the STaMINA trial are in contrast to those from the European EMN-02 trial, in which all patients received CyBorD induction therapy; randomization to bortezomib, melphalan, and prednisone; or ASCT (single or double), and then further randomization to consolidation with RVD followed by maintenance lenalidomide or maintenance lenalidomide without consolidation.[8] Results from EMN-02 showed improvement in PFS, including benefit from both consolidation and the tandem transplantation. But, as mentioned, the typical initial therapy in the United States is RVD; the EMN-02 results might reflect the use of suboptimal induction, in which case additional therapy could have an impact. However, for patients receiving an optimal regimen like RVD, which is what 55% of the patients in the STaMINA trial received, additional therapy between the first transplantation and maintenance may not contribute much, at least based on the early results from the STaMINA trial. Sagar Lonial, MD: I agree. The take-home message here is that for patients who do not receive optimal induction therapy, there may be some value to a tandem transplantation. This will likely be an economic decision in countries where physicians cannot give an IMiD and a proteasome inhibitor together. But for clinicians who can give both (and, eventually, other agents like monoclonal antibodies), I suspect the benefit of a tandem transplantation and/or consolidation may be of less value. More data are needed to say this definitively, but these results from a large randomized trial certainly do not support the use of consolidation or a second transplantation. A still-unanswered question is the role of tandem ASCT in high-risk patients. No benefit was seen in this group in the STaMINA trial, whereas the EMN-02 data seem to favor a tandem transplantation in high-risk patients. But as mentioned, there are key differences between the US and European populations and the treatment given in these 2 studies. Agreed. The use of cyclophosphamide for high-risk patients is probably not just suboptimal from a biology perspective, but also suboptimal in terms of the depth of response. An alternative therapy may be needed to achieve a deeper response. Slide credit: clinicaloptions.com Stadtmauer EA, et al. ASH Abstract LBA-1.

Relapsed/Refractory Multiple Myeloma: Daratumumab

Daratumumab in R/R MM: Background
Daratumumab: monoclonal anti-CD38 antibody with multiple modes of action Approved as monotherapy and, in November 2016, with combination Rd or Vd for R/R MM based on PFS benefit in randomized phase III trials POLLUX: daratumumab + Rd vs Rd alone (PFS HR: 0.37; P < .001)[1] CASTOR: daratumumab + Vd vs Vd alone (PFS HR: 0.39; P < .001)[2] Data presented at ASH 2016 includes: Analysis assessing MRD in pts treated in POLLUX and CASTOR[3] Retrospective analysis evaluating risks and benefits of new combination dara/pom/dex in pts with MM refractory to dara and/or pom or naive to both[4] Phase Ib trial assessing safety and efficacy of SC daratumumab + rHuPH20[5] dara, daratumumab; dex, dexamethasone; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; pom, pomalidomide; Rd, lenalidomide/dexamethasone; R/R, relapsed/refractory; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: Daratumumab is an anti-CD38 antibody with multiple modes of action. Due to significant PFS benefits, it is approved in MM as a single agent for patients with at least 3 previous regimens and in combination with lenalidomide and dexamethasone (Rd) (POLLUX study; HR: 0.37)[9] or bortezomib and dexamethasone (Vd) (CASTOR study; HR: 0.39)[10] for patients with at least 1 previous regimen. At the 2016 ASH annual meeting, updates were presented from both the CASTOR and the POLLUX trials, as well as other studies of daratumumab combinations. 1. Dimopoulos MA, et al. N Engl J Med. 2016;375: Palumbo A, et al. N Engl J Med. 2016;375: Avet-Loiseau H, et al. ASH Abstract Nooka AK, et al. ASH Abstract Usmani SZ, et al. ASH Abstract 1149. Slide credit: clinicaloptions.com

Daratumumab Combinations Increase MRD Negativity vs Rd or Vd Alone in Relapsed/Refractory Multiple Myeloma MRD, minimal residual disease; Rd, lenalidomide/dexamethasone; Vd, bortezomib/dexamethasone.

Daratumumab in R/R MM: Pt Characteristics
POLLUX and CASTOR: randomized, multicenter, open-label, controlled phase III studies with ≥ 1 previous therapy for R/R MM POLLUX: daratumumab + lenalidomide/dexamethasone; BM MRD assessed at suspected CR and 3/6 mos after suspected CR for pts who maintained response CASTOR: daratumumab + bortezomib/dexamethasone; BM MRD assessed at time of suspected CR and 6/12 mos after first dose Characteristic POLLUX (N = 286) CASTOR (N = 251) Median prior lines of therapy, n (range) 1 (1-11) 2 (1-10) Prior bortezomib, % 84 66 Prior lenalidomide, % 18 42 BM, bone marrow; MM, multiple myeloma; MRD, minimal residual disease; R/R, relapsed/refractory. Sagar Lonial, MD: In the POLLUX trial of daratumumab plus Rd, patients tended to have received fewer lines of therapy—a median of 1 compared with a median of 2 in the CASTOR study of daratumumab plus Vd.[11] The percentages of patients with previous bortezomib or lenalidomide was slightly different between studies, but this likely reflects the different treatment regimens used for the control arms. Slide credit: clinicaloptions.com Avet-Loiseau H, et al. ASH Abstract 246.

Daratumumab in R/R MM: MRD Negativity
Daratumumab + Rd or Vd significantly improved MRD negativity rate vs Rd or Vd alone MRD-negative events accumulated rapidly and increased over time (within 3-18 mos) MRD Negative, % POLLUX (N = 286) CASTOR (N = 251) Dara + Rd Rd P Value Dara + Vd Vd All pts 10-4 10-5 10-6 31.8 24.8 11.9 8.8 5.7 2.5 < .0001 18.3 10.4 4.4 3.6 2.4 0.8 < .005 < .05 Pts with ≥ CR 65 52 26 42 27 13 60 37 16 35 22 9 -- By cytogenetic risk High* Standard 18 30 10 14 12 2 Dara, daratumumab; MM, multiple myeloma; MRD, minimal residual disease; Rd, lenalidomide/dexamethasone; R/R, relapsed/refractory; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: MRD negativity was an important endpoint in both CASTOR and POLLUX. In the CASTOR trial, bone marrow MRD was assessed at time of a suspected CR and at both 6 and 12 months after first dose of daratumumab-based therapy. In the POLLUX trial, bone marrow MRD was assessed at the time of suspected CR and then again at 3 and 6 months after the suspected CR for patients who maintained their response. In both studies, the daratumumab-containing arm had a much higher incidence of MRD negativity. Whether a cutoff of 10-4, 10-5, or 10-6 was used, there was no question that the addition of daratumumab produced striking MRD negativity rates approximately 2-5 times better than without daratumumab. Regarding MRD negativity, the cutoff of 10-6 is the lowest cutoff value that is reproducible for next-generation sequencing and is the target value for patients with MM when researchers are exploring MRD negativity. Approximately 12.0% of patients in the POLLUX trial achieved MRD of 10-6 with daratumumab vs only 2.5% with Rd. Likewise, in the CASTOR trial, 4.4% achieved MRD of 10-6 with daratumumab vs 0.8% with Vd alone. In high-risk patients, 18% of patients achieved MRD negativity with daratumumab in POLLUX, and 14% in CASTOR, compared with 0% with either Rd or Vd alone. These are striking differences in the depth of response. MRD negativity correlates with prolonged PFS. In both CASTOR and POLLUX, patients with MRD negativity had 12-month PFS rates greater 90% regardless of treatment arm. In addition, the PFS was longer with the triplet regimens vs the doublet regimens for patients with MRD negativity. *Includes pts with t(4;14), t(14;16), or del(17p). Slide credit: clinicaloptions.com Avet-Loiseau H, et al. ASH Abstract 246.

Daratumumab in R/R MM: PFS
Lower risk of progression in pts who achieve MRD negativity, regardless of therapy DRd MRD-negative pts (n = 71); estimated 12-mo PFS > 90% DVd MRD-negative pts (26); estimated 12-mo PFS > 90% Rd MRD-negative pts (n = 16 in POLLUX and n = 6 in CASTOR); estimated 12-mo PFS > 90% Daratumumab + Rd or Vd shows PFS benefit in MRD-positive pts vs doublets alone POLLUX: estimated median PFS NR vs 17 mos for DRd MRD-positive (n = 215) vs Rd MRD-positive (n = 267) pts CASTOR: estimated median PFS NR vs 7 mos for DVd MRD-positive (n = 225) vs Vd MRD-positive (n = 241) pts DRd, daratumumab/lenalidomide/dexamethasone; DVd, daratumumab/bortezomib/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; NR, not reached; Rd, lenalidomide/dexamethasone; R/R, relapsed/refractory; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: MRD negativity correlates with prolonged PFS. In both CASTOR and POLLUX, patients with MRD negativity had 12-month PFS rates greater 90% regardless of treatment arm. In addition, the PFS was longer with the triplet regimens vs the doublet regimens for patients with MRD negativity. Slide credit: clinicaloptions.com Avet-Loiseau H, et al. ASH Abstract 246.

Daratumumab in R/R MM: Conclusions
Addition of daratumumab to either Rd or Vd significantly increased MRD negativity over doublet regimens in POLLUX and CASTOR trials Rapid and durable MRD-negative responses continue to accumulate High-risk pts able to achieve MRD negativity with daratumumab No high-risk MRD-negative pts converted to MRD positive MRD-negative status associated with lower risk of progression Addition of daratumumab to Rd or Vd lowers risk of progression, even among MRD-positive pts MM, multiple myeloma; MRD, minimal residual disease; Rd, lenalidomide/dexamethasone; R/R, relapsed/refractory; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: Clearly, the addition of daratumumab to either Rd or Vd did increase the rate of MRD negativity over the doublet regimens. The daratumumab triplet regimens were able to induce MRD negativity in some high-risk patients as well. MRD negativity conferred better long-term PFS as well. Of importance, patients who failed to achieve MRD negativity still did quite well with the daratumumab-containing regimens. I would not recommend changing therapy if a patient does not achieve MRD negativity. Shaji Kumar, MD: This study clearly shows the importance of MRD in MM, including the relapsed patient population, regardless of treatment. Although this trial does not answer the question of whether changing therapy for an individual patient based on MRD status would make a difference, it does show the importance of these new treatment regimens for patients with relapsed and/or refractory disease. MRD testing is not currently recommended outside of a clinical trial, as we do not yet know what to do with this information, but clinical trials are increasingly asking these questions. In my practice, I am increasingly seeing patients who ask for MRD testing, and if a patient wants to have the test performed, I feel like it is a reasonable request as long as the patient understands that no action may be taken based on the results and that the results only reflect the degree of disease control. I agree that MRD testing is a valuable research tool, but to date, it has no role in routine care other than providing prognostic information. Slide credit: clinicaloptions.com Avet-Loiseau H, et al. ASH Abstract 246.

Daratumumab/Pom/Dex Salvage Beneficial in R/R MM in Single Institution Retrospective Analysis
Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory.

Analysis of Dara/Pom/Dex in R/R MM: Baseline Characteristics
Retrospective analysis of all pts from Emory University who received daratumumab/pomalidomide/dexamethasone for relapsed or R/R MM from January July 2016 (N = 41) Characteristic Cohort 1: Dara and Pom Naive (n = 19) Cohort 2: Dara and/or Pom Refractory (n = 22) Cohort 3: Dara and Pom Refractory (n = 12) Median age, yrs (range) ≥ 65 yrs of age, % 66 (46-92) 53 63 (32-77) 46 65 (40-74) 50 Male, % 21 54 67 ISS stage I, % 64 High-risk MM,* % 16 32 25 Isotype: IgG/IgA/IgD/FLC, % 58/16/0/26 55/9/5/31 42/0/8/50 Median time since diagnosis, mos (range) 72 (12-149) 65 (16-255) 57 (25-255) Median lines of therapy, n (range) 3 (1-7) 5 (3-13) 6.5 (3-13) Dara, daratumumab; Dex, dexamethasone; FLC, free light chain; ISS, International Staging System; MM, multiple myeloma; Pom, pomalidomide; pPCL, primary plasma cell leukemia; R/R, relapsed/refractory. Sagar Lonial, MD: At my institution, we conducted a retrospective analysis of daratumumab in combination with pomalidomide and dexamethasone in 2 cohorts of patients with relapsed/refractory MM (N = 41), including a smaller third cohort of patients that was a subset of cohort 2.[12] Cohort 1 was naive to both daratumumab and pomalidomide (n = 19), cohort 2 was refractory to either or both agents (n = 22), and “cohort 3” comprised 12 patients from cohort 2 who were refractory to both agents. Approximately 90% of patients in each cohort had undergone previous ASCT, and all had received previous IMiD and proteasome inhibitors. The goal of this analysis was to determine if there is a clinical benefit to the combined use of pomalidomide and daratumumab in patients with resistance to either or both agents prior to this evaluation. *Includes pts with del(17p), t(14;16), and pPCL. Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492

Dara and/or Pom Refractory Dara and Pom Refractory
Analysis of Dara/Pom/Dex in R/R MM: Prior Treatment and Refractory Status Characteristic, % Dara and Pom Naive (n = 19) Dara and/or Pom Refractory (n = 22) Dara and Pom Refractory (n = 12) Previous ASCT 90 91 92 Previous proteasome inhibitor 100 Previous IMiD Refractory Bortezomib Carfilzomib Lenalidomide Melphalan Pomalidomide Daratumumab Bortezomib + lenalidomide Quad refractory* Penta refractory† Refractory to last line of therapy 74 11 73 95 59 69 37 67 ASCT, autologous stem cell transplantation; Dara, daratumumab; Dex, dexamethasone; IMiD, immunomodulatory drug; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. *Lenalidomide, pomalidomide, bortezomib, and carfilzomib. †Lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab. Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492.

Analysis of Dara/Pom/Dex in R/R MM: Responses
Best Response Dara and Pom Naive (n = 19) Dara and/or Pom Refractory (n = 22) Dara and Pom Refractory (n = 12) ORR, n % 17 (89.0) 9 (40.9) 4 (33.3) sCR, n % 7 (36.8) CR, n % 1 (5.3) VGPR, n % 3 (15.8) 1 (4.5) 1 (8.3) PR, n % 8 (42.1) 8 (36.4) 3 (25.0) MR/SD, n % 6 (50.0) PD, n % 4 (18.2) 2 (16.7) Median cycles of tx, n (range) 15 (1-23) 3 (1-8) Dara, daratumumab; Dex, dexamethasone; MM, multiple myeloma; MR, minimal response; Pom, pomalidomide; R/R, relapsed/refractory; sCR, stringent CR; SD, stable disease; tx, treatment; VGPR, very good PR. Sagar Lonial, MD: The ORR for patients naive to daratumumab and pomalidomide was 89%; 17 of the 19 patients responded to this regimen, which suggests it could be one of the most active regimens in relapsed MM to date. In this study, approximately one third of patients achieved a stringent CR, and many of these were high-risk patients with del(17p) and disease progression shortly after a transplantation. In the patients who were refractory to daratumumab and/or pomalidomide, the ORR was 41% and 33% of patients in the subset who were double-refractory achieved a response to the combination. One caution in interpreting the response rates is that the follow-up at the time of presentation was relatively short, and cohorts 2 and 3 received a median of only 3 cycles of therapy (vs 15 cycles in cohort 1). Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492

Analysis of Dara/Pom/Dex in R/R MM: PFS
PFS Dara/Pom/Dex: All Cohorts PFS Dara/Pom/Dex: SD or Better vs No Response PFS Dara/Pom/Dex: Cohort 3 SD or Better vs No Response 1.0 1.0 1.0 0.8 0.8 0.8 ≥ SD ≥ SD 0.6 0.6 0.6 Cumulative Survival Cumulative Survival Cumulative Survival 0.4 0.4 0.4 No response 0.2 0.2 0.2 No response 6 12 18 24 6 12 18 24 6 12 18 24 Dara, daratumumab; Dex, dexamethasone; MM, multiple myeloma; NR, not reached; Pom, pomalidomide; SD, stable disease; R/R, relapsed/refractory. Sagar Lonial, MD: The median PFS for the overall patient population was 7 months but was not reached in the patients naive to daratumumab and pomalidomide at a median follow-up of 17 months. Although the median PFS was only 3 months in the refractory cohort, 1-2 patients had sustained responses, suggesting that some patients may benefit from combined daratumumab and pomalidomide as salvage therapy, even if they were resistant to both of those drugs individually. Mos Mos Mos Efficacy, Mos All Cohorts (N = 41) Dara and Pom Naive (n = 19) Dara and Pom Refractory (n = 12) Median PFS 7 NR 3 Median follow-up 16 17 8 Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492. Reproduced with permission.

Analysis of Dara/Pom/Dex in R/R MM: OS
OS Dara/Pom/Dex: All Cohorts OS Dara/Pom/Dex: Cohort 1 vs Cohort 2 OS Dara/Pom/Dex: Cohort 3 1.0 1.0 1.0 0.8 0.8 0.8 0.6 0.6 0.6 Cumulative Survival Cumulative Survival Cumulative Survival 0.4 0.4 0.4 0.2 0.2 0.2 6 12 18 24 6 12 18 24 6 12 18 24 Dara, daratumumab; Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Sagar Lonial, MD: The OS results are also quite respectable, in all 3 cohorts, which speaks to an emerging recognition in modern myeloma therapy that avoiding alkylator-based therapy may allow patients to receive additional agents beyond relapse. It is also possible that the use of daratumumab may modulate the tempo of relapse, as suggested by early phase I and phase II data from studies by Usmani and colleagues.[13] Mos Mos Mos Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492. Reproduced with permission.

Analysis of Dara/Pom/Dex in R/R MM: Safety
AEs similar to those seen in phase I trial 56% of pts required dose reductions Pomalidomide: 46% 15% discontinued pomalidomide 5% previously intolerant Dexamethasone: 22% Daratumumab: 0% Hematologic AEs generally resolved with dose reduction Grade 3/4 Treatment-Emergent AEs, n (%) Pts (N = 41) Neutropenia 17 (42) Anemia 12 (29) Thrombocytopenia 8 (20) Fatigue 2 (5) Dizziness Hypokalemia Upper respiratory tract infection Dyspnea 1 (3) AE, adverse event; Dara, daratumumab; Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Sagar Lonial, MD: The AEs were not dissimilar to those seen in earlier daratumumab monotherapy studies, suggesting that there is no increase in AEs when combined with pomalidomide and dexamethasone. In this trial, neutropenia was the most common treatment-related grade 3/4 AE, affecting 42% of the 41 patients. A total of 56% of patients required dose reductions, with 42% requiring dose reduction for pomalidomide, 22% with dose reductions for dexamethasone, and no patients needed a dose reduction with daratumumab. Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492.

Analysis of Dara/Pom/Dex in R/R MM: Conclusions
Dara/pom/dex well tolerated with deep responses and long PFS Benefit included pts refractory to proteasome inhibitors and IMiDs Dose reductions in > 50% of pts suggest starting pom at lower dose Investigators conclude that median PFS of 7 mos comparable to pom/dex (STRATUS trial), despite heavily pretreated and refractory pts in current analysis 80% of penta-refractory pts alive at 8-mo follow-up Extended survival results suggest benefits of this regimen should be investigated further Limitations: retrospective, observational analysis with small number of pts and no paired samples or correlatives Dara, daratumumab; Dex, dexamethasone; IMiD, immunomodulatory drug; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Sagar Lonial, MD: Again, the combination of daratumumab, pomalidomide, and dexamethasone is a powerful regimen that can be used even in double-refractory patients. Shaji Kumar, MD: These data are particularly relevant as most patients with MM who have not yet relapsed will encounter daratumumab combinations at time of first relapse in the coming few years. The success of these regimens opens the possibility of using daratumumab in additional combinations. Slide credit: clinicaloptions.com Nooka AK, et al ASH Abstract 492

Phase Ib PAVO Study: SC Daratumumab in Relapsed/Refractory Multiple Myeloma

PAVO: Study Design Open-label, multicenter, dose-finding, proof-of-concept phase Ib study Primary endpoints: Ctrough of daratumumab at cycle 3 Day 1 and safety; secondary endpoints: ORR, CR, DoR, time to response 4-wk treatment cycles Every wk for 8 wks Every 2 wks for 16 wks Every 4 wks thereafter Infusion time 1200 mg: 20 min (60 mL) 1800 mg: 30 min (90 mL) Daratumumab 1200 mg SC + rHuPH20 30,000 U SC (n = 8)* Pts with measurable R/R MM, ≥ 2 lines of therapy, no prior anti-CD38 therapy (N = 53) Daratumumab 1800 mg SC + rHuPH20 45,000 U SC (n = 45)* *Pre/postinfusion medication includes acetaminophen, diphenhydramine, montelukast, and methylprednisolone. DoR, duration of response; IMiD, immunomodulatory drug; MM, multiple myeloma; PI, proteasome inhibitor; R/R, relapsed/refractory. Shaji Kumar, MD: Daratumumab clearly is very effective and will quickly become part of commonly used combination therapy for patients in first relapse and eventually in the upfront setting. However, one of the biggest drawbacks of daratumumab is that the IV infusion is time consuming and a significant portion of patients experience infusion-related reactions with daratumumab. Usmani and colleagues[14] conducted this phase Ib study to examine the feasibility of administering daratumumab infusions SC instead of IV. SC dosing may mitigate some of the infusion-related reactions, and the additional space in SC tissue allows infusion of larger volumes for shorter infusion times. In this proof-of-concept trial, 53 patients with relapse after at least 2 lines of therapy were randomized to daratumumab 1200 mg plus 30,000 U recombinant hyaluronidase or to daratumumab 1800 mg plus 45,000 U hyaluronidase. In both arms, daratumumab was administered SC. Of note, approximately two thirds of the patients were refractory both IMiDs and proteasome inhibitors. Characteristic 1200 mg (n = 8) 1800 mg (n = 45) Prior lines of therapy, median (range) 5 (2-10) 4 (2-11) Refractory to PI only/IMiD only, % 0/13 4/20 Refractory to both PI and IMiD, % 63 58 Refractory to last line of therapy, % 88 71 Usmani SZ, et al. ASH Abstract 1149.

PAVO: Pt Disposition Median follow-up Median duration of treatment
1200 mg: 6.4 mos (range: ) 1800 mg: 4.3 mos (range: ) Median duration of treatment 1200 mg: 2.6 mos (range: ) 1800 mg: 3.4 mos (range: ) 1200 mg (n = 8) 1800 mg (n = 45) Patients who discontinued treatment, % 88 33 Progressive disease 63 27 Withdrawal by consent 13 Physician decision 4 Death 2 Shaji Kumar, MD: The median follow-up time was relatively short at the time of this presentation: 6.4 months for the lower dose and 4.3 months for the higher-dose group. Most of the patients who went off study—88% in the 1200-mg arm and 33% in the 1800-mg arm—did so due to disease progression. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH Abstract 1149.

PAVO: Efficacy PK for 1800-mg SC dose similar to that of 16-mg/kg IV dose Mean concentration-time outcomes for daratumumab mg SC Cmax similar to 16 mg/kg IV dose Cmax lower during initial weekly administration Ctrough higher than with 1200-mg SC dose Response, % 1200 mg (n = 8) 1800 mg (n = 45) ORR 25 38 sCR 2 CR VGPR 7 PR 29 MR 13 11 SD 50 PD 12 MR, minimal response; PD, progressive disease; PK, pharmacokinetic; sCR, stringent CR, VGPR, very good PR. Shaji Kumar, MD: The efficacy in this study is comparable to the initial studies of IV daratumumab as a single agent. So, SC administration does not seem to decrease the ORR: 25% with 1200 mg and 38% with 1800 mg. Regarding pharmacokinetics, the Cmax with the 1800-mg infusion was similar to the 16-mg/kg IV dose, which is currently used in the clinic. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH Abstract 1149.

PAVO: Treatment-Related AEs
AE profile with SC daratumumab consistent with IV daratumumab Treatment-Related AEs, % 1200 mg (n = 8) 1800 mg (n = 45) Drug related 63 62 Serious drug related 13 7 Grade ≥ 3 40 All-grade hematologic > 25% Anemia Thrombocytopenia 25 38 31 18 All-grade nonhematologic > 25% Upper respiratory tract infection Insomnia Decreased appetite 9 Grade 3/4 Treatment-Related AEs, % 1200 mg (n = 8) 1800 mg (n = 45) Anemia 13 Thrombocytopenia 7 Neutropenia Lymphopenia Hypertension 25 4 Fatigue 2 Device-related infection Hyponatremia AE, adverse event. Shaji Kumar, MD: The treatment-related AEs with SC daratumumab were very similar to what has been seen with the IV infusion. However, the infusion-related reactions were less common than anticipated based on the IV infusions. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH Abstract 1149.

PAVO: Infusion-Related Reactions
IRR, % 1200 mg (n = 8) 1800 mg (n = 45) Overall 13 24 Chills 9 Pyrexia Pruritus 4 Dyspnea Flushing 2 Hypertension Hypotension Nausea IRR, % 1200 mg (n = 8) 1800 mg (n = 45) Noncardiac chest pain 13 Oropharyngeal pain 2 Paresthesia Rash Sinus headache Tongue edema Vomiting Wheezing IRR, infusion-related reaction. Shaji Kumar, MD: With the IV infusion of daratumumab, the overall rate of infusion-related reactions is nearly 50%, but in this study it was approximately 24% with daratumumab 1800 mg SC. There were no grade 4 infusion-related reactions in either dosing group, and most of the reactions occurred within the first 4 hours of treatment. No grade 4 IRRs in either dosing group; 1 grade 3 IRR (dyspnea) in 1200-mg group All IRRs occurred during first infusion and within first 4 hrs Slide credit: clinicaloptions.com Usmani SZ, et al. ASH Abstract 1149.

PAVO: Conclusions SC administration of daratumumab + rHuPH20 safe and effective Both dose groups showed responses to SC daratumumab 1800-mg group had deeper responses vs 1200-mg group Preliminary efficacy similar to IV daratumumab: 38% ORR, including 1 sCR AEs for SC daratumumab + rHuPH20 similar to IV daratumumab with no new safety signals Low IRR incidence and intensity with SC daratumumab PK of SC daratumumab 1800 mg similar to 16 mg/kg IV administration AE, adverse event; IRR, infusion-related reaction; PK, pharmacokinetic; sCR, stringent CR. Shaji Kumar, MD: Giving daratumumab as an SC infusion appears feasible and could have significant clinical benefit due to less time in the clinic for patients. In addition, there appears to be a lower rate of infusion-related reactions than with IV infusion, without any compromise in efficacy. These results open the possibility of using this drug in a broader patient population. Sagar Lonial, MD: I agree. In my experience, infusion-related reactions with SC daratumumab are almost nonexistent, which is an important improvement for patients. I am hopeful that this will eventually replace the use of IV daratumumab as more efficacy and safety data become available. Slide credit: clinicaloptions.com Usmani SZ, et al. ASH Abstract 1149.

Relapsed/Refractory Multiple Myeloma: Carfilzomib

Car/Pom/Dex in R/R MM: Background
Many pts with MM relapse and become resistant to IMiDs and bortezomib EFS and OS after therapy with IMiDs and bortezomib: 5 and 9 mos, respectively[1] PI and IMiD combinations commonly used to treat R/R MM Carfilzomib and pomalidomide both approved for R/R MM Carfilzomib weekly may be as effective as twice weekly[2] Multicenter, open-label phase I/II trial assessed MTD and responses with weekly carfilzomib, pomalidomide, and low-dose dexamethasone in pts with R/R MM[3] Car, carfilzomib; Dex, dexamethasone; EFS, event-free survival; IMiD, immunomodulatory drug; MM, multiple myeloma; MTD, maximum tolerated dose; PI, proteasome inhibitor; Pom, pomalidomide; R/R, relapsed/refractory. 1. Kumar S, et al. Leukemia. 2012;26: 2. Berenson JR, et al. Blood. 2016;127: 3. Bringhen S, et al. ASH Abstract 1145. Slide credit: clinicaloptions.com

Phase I/II Trial: Weekly Carfilzomib, Pomalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Car/Pom/Dex in R/R MM: Phase I/II Study Design
Multicenter, open-label trial Phase I: 15 pts enrolled in 4 carfilzomib dose cohorts: 27, 36, 45, and 56 mg/m2 Phase II ISS stage I (n = 17), stage II (n = 25) 48 pts treated at MTD: 27 mg/m2 (6 pts from phase I and 42 from phase II) Pts with MM who relapsed on or are refractory to last tx (≤ 3 lines of previous therapy); refractory to lenalidomide, and refractory or naive to bortezomib; ECOG PS 0-2 (N = 48) Pomalidomide 4 mg PO Days 1-21, 1 wk off Dexamethasone 20 mg PO Days 1, 8, 15, 22 Carfilzomib (phase II dose) 27 mg/m2 IV Days 1, 8, 15 Primary endpoints: MTD (phase I), ORR (phase II) Secondary endpoints: safety, DoR, PFS, TTP, TTNT, OS Car, carfilzomib; Dex, dexamethasone; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; MM, multiple myeloma; MTD, maximum tolerated dose; Pom, pomalidomide; PS, performance status; R/R, relapsed/refractory; TTNT, time to next treatment; TTP, time to progression, tx, treatment. Shaji Kumar, MD: Despite the use of IMiDs and bortezomib, many patients with MM are destined to relapse, after relatively short median event-free survival (5 months) and OS (9 months).[15] KRd—or carfilzomib at higher doses in combination with only dexamethasone—has become one standard-of-care option for treatment of relapsed MM. Bringhen and colleagues[16] conducted a phase I/II study of weekly carfilzomib with pomalidomide and dexamethasone (KPomD) in patients who are refractory to lenalidomide and refractory or naive to bortezomib. This combination has been quite effective in small trials of patients who relapsed after multiple therapies, and this phase I/II study included patients who relapsed on or are refractory to their last therapy. In the phase I portion of this trial, carfilzomib doses were escalated from 27 mg/m2 to 56 mg/m2 in 15 patients. In phase II portion, 48 patients (including 6 from the phase I enrolment) were treated at the maximum tolerated dose of 27 mg/m2, which is the standard dose currently used in combination with Rd. All patients received carfilzomib in combination with pomalidomide and dexamethasone. The primary endpoint was ORR. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Managing Cardiopulmonary Risk
Risk factor evaluation BP monitoring 24 hrs/day Before and after carfilzomib administration Pt at-home diary BP target: < 140/90 mm Hg If BP ≥ 140/90 mm Hg or diastolic BP ↑ ≥ 20 mm Hg, carfilzomib withheld Use RAAS inhibitors, calcium channel blockers and/or diuretics, or β-blockers BP, blood pressure; Car, carfilzomib; Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; RAAS, renin angiotensin aldosterone system; R/R, relapsed/refractory. Shaji Kumar, MD: Managing the risk factors, especially the cardiopulmonary risk, is critical with carfilzomib. In this study, the investigators carefully monitored blood pressure and other issues that could indicate cardiac AEs. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Baseline Demographics
Characteristic Phase I (n = 15) Phase II (n = 42) Total (N = 57) Median age, yrs (range) 62 (41-84) 62 (45-81) Age ≥ 65 yrs, % 40 38 39 ISS stage, % I II/III 60 62 56 44 Unfavorable profile, % del(17p) 33 13 24 14 26 17 Median time since diagnosis, yrs (range) 3.75 ( ) 3.75 ( ) Previous therapies, % Transplant Lenalidomide Primary refractory Relapsed/refractory Bortezomib 67 100 87 70 74 28 72 96 16 19 Car, carfilzomib; Dex, dexamethasone; ISS, International Staging System; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Treatment Exposure
Characteristic Phase I (n = 15) Phase II (n = 42) Total (N = 57) Median cycles received, n (range) 10 (1-28) 8 (0-18) 8 (0-28) Number of treatment cycles, % ≥ 4 ≥ 8 73 60 52 70 51 Pts with treatment beyond cycle 8, % Pts remaining on treatment, % 33 31 32 Reason for discontinuation, % AEs PD Other 20 13 6 54 8 14 47 5 AE, adverse event; Car, carfilzomib; Dex, dexamethasone; MM, multiple myeloma; PD, progressive disease; Pom, pomalidomide; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Results
Response rates CR/nCR: 6% VGPR: 26% ORR: 64% CBR: 85% Median time to PR: 2.07 mos Median follow-up 13.6 mos (IQR: ) Median PFS: 9.2 mos; 35% without progression at 1 yr Median OS: NR; 70% alive at 1 yr Car, carfilzomib; CBR, clinical benefit rate; Dex, dexamethasone; IQR, interquartile range; MM, multiple myeloma; nCR, near CR; NR, not reached; Pom, pomalidomide; R/R, relapsed/refractory; VGPR, very good PR. Shaji Kumar, MD: Overall, the combination was fairly well tolerated. Patients received a median of 8 cycles of therapy, with approximately 30% remaining on treatment at the time of this presentation. However, 14% discontinued treatment due to AEs. The ORR was 64%, which is promising in this group of patients with many lines of previous therapy. The responses were relatively acute, with a median time to PR of approximately 2 months. The median PFS was approximately 9 months, with a relatively short follow-up of 13.6 months. Approximately one third of the patients remained free of progression after 1 year of therapy. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Safety
AEs resulting in dose reduction: ~ 18%; discontinuation: ~ 5% Highest all-grade AEs (≥ 20%): neutropenia, infections, fatigue/fever, thrombocytopenia, peripheral neuropathy, anemia Highest grade 3/4 AEs (≥ 10%): neutropenia, anemia, thrombocytopenia Cardiovascular AEs Without New Procedures and 36/45 mg/m2 With New Procedures and 27 mg/m2 P Value All grade All events Major events Hypertension 78 33 44 19 4 15 .001 .02 .06 Grade 3/4 56 8 2 6 .003 .01 .009 Grade 5 22 -- AE, adverse event; Car, carfilzomib; Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Shaji Kumar, MD: AEs were as expected with this combination, including hematologic toxicity with grade 3/4 neutropenia, anemia, and thrombocytopenia reported in more than 10% of patients. The cardiac toxicity in this group of patients appeared to be less serious with the 27-mg/m2 dose along with careful monitoring—grade 3/4 cardiovascular AEs were seen in 56% of patients with the 36/45-mg/m2 dose without the additional monitoring procedures in place vs 8% with the 27-mg/m2 dose with careful monitoring, and grade 5 events were seen in 22% and 0%, respectively. The AE data from this trial highlighted the advantages of careful risk factor evaluation and close monitoring of patients who are receiving carfilzomib. The trial protocol outlined specific monitoring procedures, including blood pressure monitoring before and after carfilzomib administration along with patient monitoring 24 hours per day with the use of an at-home diary for patients to record their own blood pressure. The target blood pressure for patients was < 140/90 mm Hg, and if measures read ≥ 140/90 mm Hg (or diastolic pressure increased ≥ 20 mm Hg), carfilzomib was withheld. Clinicians used Renin angiotensin aldosterone system (RAAS) inhibitors, calcium channel blockers and/or diuretics, or β-blockers to help successfully manage any changes in blood pressure. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Car/Pom/Dex in R/R MM: Conclusions
Combination of carfilzomib, pomalidomide, and dexamethasone active in R/R MM using a once-weekly dosing schedule Compared with historical data Response rates better than single-agent pomalidomide or carfilzomib and similar to carfilzomib/pomalidomide/dexamethasone using a twice-weekly dosing schedule AE rates similar between once- and twice-weekly dosing More pts reduced dose or discontinued in twice-weekly arm With monitoring used to optimize BP, lower incidence of all-grade and 3/4 cardiovascular events AE, adverse event; BP, blood pressure; Car, carfilzomib; Dex, dexamethasone; MM, multiple myeloma; Pom, pomalidomide; R/R, relapsed/refractory. Shaji Kumar, MD: The ORR with weekly KPomD was better than with single-agent pomalidomide or carfilzomib and fairly similar to the ORR expected with twice-weekly dosing. Carfilzomib given once weekly appears be quite effective, and without the logistical challenge of having patients travel to the clinic twice per week. With careful monitoring to optimize each patients’ blood pressure, cardiovascular AEs were manageable and lower than that previously seen with weekly dosing. Sagar Lonial, MD: KPomD is clearly a very active salvage regimen for patients, but the toxicity associated with twice-weekly dosing, particularly with long-term treatment, is a concern. In the original trial of this combination by Shah and colleagues,[17] 27 mg/m2 was the carfilzomib maximum tolerated dose using a twice-weekly schedule. However, the investigators subsequently were able to escalate the dose to 45 mg/m2 twice weekly in combination with pomalidomide. These results provide some measure of comfort that twice-weekly dosing can be used to reach a response and then can be shifted to weekly dosing without fear of decreasing the response. This can make long-term treatment easier for patients, with a more convenient schedule. However, twice-weekly treatment at the higher dose continues to be investigated in a phase I/II trial. Yet, it should be noted that patients receiving this combination still need to be monitored, particularly with higher doses of carfilzomib, to minimize potential AEs. In our clinic, patients are carefully monitored, especially during the initial infusions. Our nursing staff with these agents to understand what to watch for. However, for community practices that only treat a handful of patients with MM each year, having this information on careful monitoring used in this trial will help clinicians become more comfortable with how to observe or anticipate potential adverse events. Slide credit: clinicaloptions.com Bringhen S, et al. ASH Abstract 1145.

Relapsed/Refractory Multiple Myeloma: New Agents

New Agents in R/R MM: Background
Many pts with MM become refractory to traditional treatment options, including lenalidomide, pomalidomide, bortezomib, and carfilzomib as well as to daratumumab or other monoclonal antibodies Data from novel agents presented at ASH 2016 include: Phase II STORM trial with first-in-class XPO1 inhibitor selinexor plus dexamethasone in pts with heavily pretreated, quad-refractory and penta- refractory MM[1] Trial of PD-1 monoclonal antibody pembrolizumab combined with pomalidomide and dexamethasone in pts with R/R MM[2] Phase I study with BCL-2 inhibitor venetoclax in pts with previously treated MM, particularly with t(11:14) cytogenetic abnormality[3] MM, multiple myeloma; RR, relapsed/refractory; XPO1, exportin 1. 1. Vogl DT, et al. ASH Abstract Badros AZ, et al. ASH Abstract 490. 3. Kumar S, et al. ASH Abstract 488. Slide credit: clinicaloptions.com

Phase II STORM Trial: Selinexor + Dexamethasone Is Active in Patients With Heavily Pretreated Refractory MM MM, multiple myeloma.

Selinexor Mechanism of Action
XPO1 is the nuclear exporter for the majority of TSPs, the GR, and eIF4E- bound oncoprotein mRNAs Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression CYTOSOL Tumor suppressors XPO1 Tumor suppressors p53 XPO1 Par-4 Nuclear pore complex PP2A pRB GR, glucocorticoid receptor; MM, multiple myeloma; mRNA, messenger RNA; TSP, tumor suppressor protein; XPO1, exportin 1. Sagar Lonial, MD: Many reasonable options exist for treatment of relapsed/refractory MM that have been shown to extend survival of patients in this setting. However, many patients become refractory to these traditional treatment options, including lenalidomide, pomalidomide, bortezomib, and carfilzomib, as well as to new agents such as daratumumab or elotuzumab. Cancer cells use the process of nuclear-cytoplasmic transport through the nuclear pore complex to effectively evade many anticancer agents.[18] XPO1 is a nuclear exporter that is overexpressed in MM cells. Selinexor is a first-in-class XPO1 inhibitor that blocks the nuclear-cytoplasmic transport of some tumor suppressors or other proteins, which is important because preventing nuclear export of these proteins restores endogenous tumor suppression, thereby selectively eliminating tumor cells. SINE p21 Nuclear envelope IkB Tumor suppressors BRACA1 p27 NUCLEUS eIF4E Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491. Reproduced with permission.

STORM: Study Design Phase II clinical trial: selinexor plus low-dose dexamethasone for heavily pretreated pts with MM refractory to most recent treatment (N = 79; median age: 68 yrs) Quad: refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide Penta: quad refractory and also daratumumab or isatuximab (anti-CD38 antibodies) Creatinine clearance ≥ 20 mL/min, WBC count ≥ 1500/mm3, ANC ≥ 1000/mm3, platelet count ≥ 75,000/mm3 (≥ 30,000/mm3 if plasma cells ≥ 50% of marrow cellularity) Treatment: selinexor 80 mg plus dexamethasone 20 mg twice weekly; reductions or interruption as needed for toxicity Group 1: 6 doses/28-day cycle (3 wks on/1 wk off) Group 2: 8 doses/28-day cycle (4 wks continuously) Primary endpoints: ORR and DoR (IRC assessed) Secondary endpoints: PFS and OS ANC, absolute neutrophil count; DoR, duration of response; IRC, independent review committee; MM, multiple myeloma; WBC, white blood cell. Sagar Lonial, MD: Vogl and colleagues conducted a phase II clinical trial of selinexor plus low-dose dexamethasone in patients (N = 79) with MM who were quad‑refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide or penta‑refractory (quad-refractory and also refractory to daratumumab or isatuximab).[19] In other words, this is a very advanced patient population. Treatment interruptions or reductions were allowed as needed for toxicity. The primary endpoints were ORR and duration of response. Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491.

STORM: Treatment-Related AEs
Tx-Related AE in ≥ 10% of Pts, % Grade 1 Grade 2 Grade 3 Grade 4 Total (N = 79) Nausea 41 25 8 -- 73 Anorexia 19 28 3 49 Vomiting 30 10 4 44 Diarrhea 34 5 43 Dehydration 1 11 Dysgeusia 6 Fatigue 15 33 63 Weight loss 13 Thrombocytopenia Anemia 27 Leukopenia 14 32 Neutropenia 24 Lymphopenia 9 Hyponatremia 20 22 42 CPK increase Dizziness Fever Selinexor dose modifications Interruptions (52%) Reductions (37%) Discontinuation (18%) Manageable with supportive care measures Antiemetics Appetite stimulants Hematopoietic growth factors Thrombopoietin receptor agonists Salt supplementation AE, adverse events; CPK, creatinine phosphokinase; tx, treatment. Sagar Lonial, MD: The AEs were similar to those seen with other selinexor-based approaches: anorexia, nausea, vomiting, diarrhea, loss of taste. These are all fairly common AEs from the earlier studies of selinexor as a single agent. Hematologic malignancies were the primary grade 3/4 AE, with 59% experiencing grade 3/4 thrombocytopenia and 28% with grade 3/4 anemia. Of note, more than one half of patients (52%) had some form of treatment interruption, with 37% experiencing reduction or discontinuation by 18%. However, many AEs were manageable with supportive care measures, including antiemetics, appetite stimulants, hematopoietic growth factors, thrombopoietin receptor agonists, and salt supplementation. Vogl DT, et al. ASH Abstract 491.

STORM: Efficacy (Independent Review)
100 5 15 13 35 12 21 ORR: 21% CBR: 33% 4 17 8 44 19 ORR: 21% CBR: 29% 7 13 20 17 23 ORR: 20% CBR: 40% 6 14 10 41 8 22 ORR: 20% CBR: 29% 4 19 22 ORR: 22% CBR: 41% 80 VGPR PR MR SD PD NE 60 Pts (%) 40 20 CBR, clinical benefit rate; DoR, duration of response; MR, minimal response; NE, not evaluable; PD, progressive disease; SD, stable disease; VGPR, very good PR. Sagar Lonial, MD: Overall responses to selinexor occurred relatively quickly and occurred in approximately 1 in 5 of these patients with either quad-refractory or penta-refractory disease. In addition, many patients who did not achieve a traditional response to therapy were able to achieve stable disease. For those patients who did achieve a response, some of those responses were quite durable, with a median duration of response in this study of 5 months. The median OS was 9.3 months, and median PFS was 2.3 months. Overall (n = 78) Quad (n = 48) Penta (n = 30) 6 Doses per Mo (n = 51) 8 Doses per Mo (n = 27) Median time to response: 1 mo Median DoR: 5 mos Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491.

STORM: Responses by Cytogenetic Risk
100 5 14 23 50 9 ORR: 18% CBR: 41% 6 29 18 35 12 ORR: 35% CBR: 53% ORR: 38% CBR: 63% CBR: 33% 13 25 ORR: 50% 33 67 80 50 VGPR PR MR SD PD 60 Pts (%) 40 50 20 CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; SD, stable disease; VGPR, very good PR. Standard Risk (n = 22) All High Risk* (n = 17) del(17p) (n = 8) t(4;14) (n = 4) del(17p) and t(4;14) (n = 3) *1 pt with t(14;16) achieved PR; 1 pt with del(17p) and t(14;16) had PD (not included in graph). Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491.

Mos Following Initiation of Selinexor Treatment
STORM: DoR Penta Quad Penta Quad Penta Quad Penta Quad Refractory Status Penta Quad Median time to response: 1 mo Median DoR: 5 mos Quad Penta DoR, duration of response; VGPR, very good PR. VGPR pts PR pts On study Off study Quad Quad Quad Quad 2 4 6 8 Mos Following Initiation of Selinexor Treatment Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491. Reproduced with permission.

STORM: OS and PFS Median OS for all pts: 9.3 mos; ≥ MR: not reached
OS and PFS: All Pts OS and PFS: Pts with ≥ MR 100 100 OS (all) PFS (all) Survival (%) 50 Survival (%) 50 OS ( ≥ MR) PFS ( ≥ MR) N = 78 N = 26 5 10 15 20 5 10 15 20 MR, minimal response. Sagar Lonial, MD: The median OS was 9.3 months, and median PFS was 2.3 months. Mos Following Initiation of Selinexor Treatment Mos Following Initiation of Selinexor Treatment Median OS for all pts: 9.3 mos; ≥ MR: not reached Median PFS for all pts: 2.3 mos; ≥ MR: 5.5 mos Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491. Reproduced with permission.

STORM: Conclusions Selinexor plus low-dose dexamethasone shows promise for treating pts with heavily pretreated (quad-refractory and penta-refractory) MM ORR: 21% Median DoR: 5 mos Median OS: 9.3 mos Median PFS: 2.3 mos Response rates similar in overall population and in pts with high-risk cytogenetic abnormalities AEs were manageable with dose interruptions and reductions and supportive care AE, adverse event; DoR, duration of response. Sagar Lonial, MD: These data show the promising efficacy of this first-in-class agent, but one question for selinexor is how to maximize the duration of therapy by combining with either bortezomib or carfilzomib. Early studies of both these combinations were also presented at the 2016 ASH annual meeting.[20,21] The ORR in the bortezomib study was 77%, and the ORR in the carfilzomib study was 64%, which shows some improvement over the ORR of approximately 20% in the STORM trial. In addition to the improved efficacy, it is probable that much of the gastrointestinal toxicity may be mitigated by combining selinexor with a proteasome inhibitor or by using additional antiemetic strategies. Based on all of these data, I think selinexor will have a role in MM therapy after the optimal dose schedule and combination regimens are determined. Shaji Kumar, MD: Yes, the selinexor data are quite interesting. It is unclear to me why toxicity may be less with the combination regimens. In any case, in this group of patients who are quad-refractory or penta-refractory, the OS and duration of response were certainly longer than anticipated. Slide credit: clinicaloptions.com Vogl DT, et al. ASH Abstract 491.

Phase II Study: Pembrolizumab Plus Pomalidomide and Dexamethasone Active in Relapsed/Refractory Multiple Myeloma

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Background
PD-1/PD-L1 pathway blockade being exploited in several cancers to restore cytotoxic T-cell activity and anticancer immunity[1] Pembrolizumab: humanized anti–PD-1 monoclonal antibody Pomalidomide: immunomodulatory thalidomide analogue indicated in combination with dexamethasone for pts with MM and ≥ 2 previous treatments including lenalidomide and a PI with progression ≤ 60 days of last regimen Current study evaluates the safety and efficacy of pembrolizumab combined with pomalidomide and dexamethasone in pts with R/R MM[2] MM, multiple myeloma; PI, proteasome inhibitor; R/R, relapsed/refractory. Slide credit: clinicaloptions.com 1. Boussiotis VA. N Engl J Med. 2016;375: Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Study Design
Exploratory trial Primary endpoint: safety Secondary endpoints: ORR, PFS, OS Exploratory endpoints: correlation of BL levels of PD-1 and PD-L1 in BM with response Mo 24 Pts with R/R MM and 2 lines of previous tx including IMiD and PI; ECOG PS < 2 and adequate organ function; no active autoimmune disease requiring treatment or history of severe autoimmune disease (N = 48) Pembrolizumab* 200 mg IV Days 1, 14 + Pomalidomide 4 mg PO Days Dexamethasone 40 mg† PO Days 1, 7, 14, 21 Q28D Pembrolizumab 200 mg IV/mo + Pomalidomide 4 mg PO + Dexamethasone 40 mg† PO Responders †Pts > 70 yrs of age received 20 mg. *First 6 pts received pembrolizumab on Day 1 only. BL, baseline; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; MM, multiple myeloma; PI, proteasome inhibitor; PS, performance status; R/R, relapsed/refractory; tx, treatment. Sagar Lonial, MD: In an exploratory trial, Badros and colleagues[22] combined pembrolizumab with pomalidomide and dexamethasone in 48 patients with relapsed MM after 2 previous regimens, including an IMiD and a proteasome inhibitor. The primary endpoint for this trial was safety, with the efficacy endpoints of ORR, PFS, and OS as secondary endpoints. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Prior Therapy
Characteristic Pts (N = 48) Median time from diagnosis to study, yrs (range) 4 (1.2-26) Median lines of earlier therapy (range) 2 lines, % 3 lines, % > 3 lines, % 3 (2-5) 35 38 27 Previous therapy, % ASCT Bortezomib Carfilzomib Lenalidomide Thalidomide 72 100 50 98 2 Refractory, % Proteasome inhibitors IMiDs + proteasome inhibitors 79 90 73 ASCT, autologous stem cell transplantation; IMiD, immunomodulatory drug; MM, multiple myeloma; R/R, relapsed/refractory. Sagar Lonial, MD: This was a fairly heavily pretreated group of patients, with a median time from diagnosis to study entry of 4 years. Patients were resistant and refractory to typical agents used to treat this population: 90% were refractory to lenalidomide, nearly 80% to proteasome inhibitors, and 73% of the patients were refractory to both IMiDs and proteasome inhibitors. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Adverse Events
All Grades Grade > 3 In > 30% of pts Fatigue Neutropenia Hyperglycemia Thrombocytopenia Anemia Dizziness Constipation URT infection Dyspnea Edema In > 20% to 30% of pts Lymphopenia Muscle spams Rash Diarrhea Infection Pneumonia Nausea In ≥ 10% to 20% of pts Hypotension Peripheral neuropathy Arrhythmia irAEs in any pt Pneumonitis (12%)* Hypothyroidism (10%) Adrenal Hepatitis Vitiligo Hypothyroidism Pneumonitis irAE, immune-related adverse event; MM, multiple myeloma; R/R, relapsed/refractory; URT, upper respiratory tract. Sagar Lonial, MD: AEs are similar to pomalidomide and dexamethasone alone, with the exception of pneumonitis in 12% of patients. Some of those cases of pneumonitis may have been infection related, but many were able to be resolved with the use of traditional systemic corticosteroids. Clinicians using this combination need to be aware of immune-related AEs associated with PD-1 inhibitors. However, as these PD-1 and PD-L1 inhibitors are being employed more often for other tumor types in clinical practice, many clinicians are becoming more aware of how to anticipate and manage these potential AEs. *With ground glass opacification in 6 pts who presented with cough, shortness of breath, low-grade fever. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Safety
Outcome Pts (N = 48) Median no. of cycles (range) 8 (3-23) Median follow-up, mos 9.6 Dose reduction, n (%) Pembrolizumab, n* Pomalidomide, n† Dexamethasone, n‡ 22 (49) 2 13 7 Discontinuation due to regimen toxicity, n (%) Pneumonitis, n Shortness of breath, n Fatigue, n 5 (11) 3 1 Deaths, n 9 Disease progression, n 23 MM, multiple myeloma; R/R, relapsed/refractory. Sagar Lonial, MD: AEs are similar to pomalidomide and dexamethasone alone, with the exception of pneumonitis in 12% of patients. Some of those cases of pneumonitis may have been infection related, but many were able to be resolved with the use of traditional systemic corticosteroids. Clinicians using this combination need to be aware of immune-related AEs associated with PD-1 inhibitors. However, as these PD-1 and PD-L1 inhibitors are being employed more often for other tumor types in clinical practice, many clinicians are becoming more aware of how to anticipate and manage these potential AEs. *Pneumonitis, n = 2. †Fatigue, n = 5; neutropenia, n = 3; rash, n = 2; palpitation, n = 1; muscle spasm, n = 1; peripheral neuropathy, n = 1. ‡Uncontrolled hyperglycemia, n = 3; weight gain, n = 2; cellulitis, n = 1; lack of sleep, n = 1. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Efficacy
Response, % Full Efficacy Population (N = 45) Refractory to 2 Classes (n = 32) High-Risk Cytogenetics (n = 27) ORR 65 68 56 Clinical benefit 72 69 60 Best response sCR CR VGPR PR MR SD PD 7 2 20 36 23 5 3 18 44 22 4 41 31 sCR + CR + VGPR, % 29 24 15 MM, multiple myeloma; MR, minimal response; PD, progressive disease; R/R, relapsed/refractory, sCR, stringent CR; SD, stable disease; VGPR, very good PR. Sagar Lonial, MD: The ORR for pembrolizumab, pomalidomide, and dexamethasone was 65% (PR or better); 72% including those with a minimal response. A significant percentage of patients—29%—had very good PR or better in the full efficacy population. In the high-risk patients and refractory patients the rate of very good PR or better was 15% and 24%, respectively. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Full Efficacy Population
Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Duration of Response and Survival Outcome, Mos (95% CI) Full Efficacy Population (N = 45) Median duration of response 16.3 ( ) Median PFS 17.4 ( ) Median OS Not reached (18.8 to not reached) PFS significantly longer in low-risk vs high-risk subgroups (P = .0366) MM, multiple myeloma; R/R, relapsed/refractory. Sagar Lonial, MD: Even more so than the response rate, the PFS was striking: Median PFS was 17.4 months. By contrast, in previous phase III clinical trials, pomalidomide and dexamethasone alone had a median PFS of approximately 4 months.[23,24] Overall, the addition of pembrolizumab significantly improved median PFS and doubled the ORR compared with these historical controls. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

PD-L1 Marker Expression T-Cell Infiltrate Marker Expression
Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Biomarker Expression and Efficacy PD-L1 Marker Expression Response Negative (n = 10) Weakly Positive (n = 6) Positive (n = 27) ORR, % sCR CR VGPR PR MR + SD + PD 60 20 40 50 77 8 38 23 sCR + CR + VGPR, % 54* Median PFS, mos (95% CI) 17.4 ( ) 17.5 ( ) NR (3.7-NR)† T-Cell Infiltrate Marker Expression Response, % CD3+/ PD1+ (n = 6) PD1- (n = 10) CD3-/ (n = 22) Best response sCR CR VGPR PR MR + SD + PD 33 67 70 10 40 20 30 73 14 9 50 23 sCR + CR + VGPR, % 23%‡ Median PFS, mos (95% CI) 6.3 (2.6-NR) 16.5 ( ) 17.5¶ (11.7-NR) MM, multiple myeloma; MR, minimal response; NR, not reached; PD, progressive disease; R/R, relapsed/refractory; sCR, stringent CR; SD, stable disease; VGPR, very good PR. *P = .05 vs PD-L1 negative. †P = .5 vs PD-L1 negative. ‡P = .12 vs CD3+/PD-1+. ¶P = .05 vs CD3+/PD-1+. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Pembrolizumab/Pomalidomide/Dexamethasone for R/R MM: Investigator Conclusions
In this small study of pts with R/R MM, the combination of pembrolizumab/pomalidomide/dexamethasone appears active AEs occurred in ~ 50% of the study population Discontinuation in 10%; most AEs manageable These results suggest that future studies are warranted to further understand the role of PD-1/PD-L1 inhibitors in pts with MM AE, adverse events; MM, multiple myeloma; R/R, relapsed/refractory. Sagar Lonial, MD: This combination is really interesting, and one I look forward to seeing additional data on in the coming year. These phase I trials continue to progress and may also offer some insight on the potential for some biomarkers to predict for sensitivity to PD-1/PD-L1 agents,[25] and a randomized phase III study is also under way.[26] Shaji Kumar, MD: It is reassuring that the findings of extended PFS and improved ORR were seen across trials, and I look forward to seeing additional data from these trials as well. Slide credit: clinicaloptions.com Badros AZ, et al. ASH Abstract 490.

Venetoclax Monotherapy for Relapsed/Refractory MM: Phase I Results
MM, multiple myeloma.

Venetoclax Monotherapy for Relapsed/ Refractory MM: Background
Survival of MM cells promoted by proteins BCL-2 and MCL-1, which allow cells to evade apoptosis[1] In vitro studies: venetoclax induces MM cell death in cell lines and primary samples[1,2] Cells positive for t(11:14) particularly susceptible t(11;14) correlated with higher ratios of BCL2/MCL1 genes and BCL2/BCL2L1 (BCL-XL) mRNA Current phase I study seeks to evaluate safety and tolerability of venetoclax monotherapy in pts with previously treated MM and to determine feasibility and parameters for subsequent clinical studies[3] MM, multiple myeloma. 1. Touzeau C, et al. Leukemia. 2014;28: Punnouse EA, et al. Mol Cancer Ther. 2016;15: Kumar S, et al. ASH Abstract 488. Slide credit: clinicaloptions.com

Venetoclax Monotherapy for Relapsed/ Refractory MM: Phase I Study Design
Test dose cycle 1+ 21 days/cycle Accelerating lead-in Venetoclax 300 mg* Venetoclax 100 mg* (n = 6) Venetoclax 50 mg* Venetoclax 600 mg* Venetoclax 300 mg* Pts with previously treated MM with measurable disease; ECOG PS 0/1 and adequate organ function (N = 66) ≥ 70% refractory to bortezomib or lenalidomide; 61% refractory to both (n = 9) Venetoclax 100 mg* Venetoclax 900 mg* Venetoclax 600 mg* (n = 6) Venetoclax 300 mg* Venetoclax 1200 mg* Venetoclax 800 mg* (n = 9) Venetoclax 400 mg* DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; MM, multiple myeloma; MTD, maximum tolerated dose; PK, pharmacokinetics; PS, performance status; TTP, time to progression. Shaji Kumar, MD: Survival of MM cells, and tumor cells in general, depends on the BCL-2 family of proteins, especially BCL-2 and MCL-1.[27] Preclinical studies showed that a specific inhibitor of the BCL-2 protein, venetoclax, can induce MM cell death, particularly in tumor cells with the t(11;14) aberration, because they have very high levels of BCL-2 and relatively low levels of MCL-1.[28] These preclinical data led to the 2 initial phase I clinical trials of venetoclax in humans—one as a single agent[29] and one in combination with bortezomib/dexamethasone.[30] My colleagues and I[29] conducted the phase I study of venetoclax monotherapy, using escalating doses between 300 mg and 1200 mg daily, in 66 patients with relapsed/refractory MM. Of note, more than 70% were refractory either to bortezomib or lenalidomide, and 61% were refractory to both. Primary endpoints included safety and determination of the maximum tolerated dose, and secondary endpoints focused on efficacy. Venetoclax 1200 mg* Venetoclax 800 mg* (Safety cohort; n = 36) Venetoclax 400 mg* *Pts who progressed on venetoclax could add dexamethasone and continue on study. Primary objectives: safety, tolerability, MTD, recommended phase 2 dose, PK Secondary objectives: ORR, TTP, DoR, pharmacodynamics, predictive biomarker analysis Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488.

Venetoclax Monotherapy for Relapsed/ Refractory MM: Pt Disposition
Outcome Venetoclax Monotherapy (N = 66) Active at time of report, % 17 Median time on study, mos (range) 3.3 (0.2-27) Median time on venetoclax monotherapy, mos (range) 2.5 (0.2-25) Median time on venetoclax + dexamethasone,* mos (range) 1.4 (0.1-13) Reason for Discontinuation, % Venetoclax Monotherapy (N = 66) Disease progression 62 AEs† 8 Consent withdrawn 3 Lost to follow-up 2 Not specified 9 Death‡ 12 *Received dexamethasone after disease progression, n = 17. †Renal failure, n = 2; pulmonary disorder, n = 1; sciatica, n = 1; shortness of breath with pain, n = 1. ‡Disease progression, n = 6; lung disorder, n = 1; trauma with brain hemorrhage, n = 1. AE, adverse event; MM, multiple myeloma. Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488.

Venetoclax Monotherapy for Relapsed/ Refractory MM: AEs
Dose-limiting toxicity (600 mg): abdominal pain, nausea (n = 2) No tumor lysis syndrome documented Any Grade AE in ≥ 20% or Grade 3/4 AE in ≥ 10% of Pts, % Any Grade Grade 3/4 Total AEs 100 68 Thrombocytopenia 32 26 Neutropenia 27 21 Anemia 23 14 Leukopenia Lymphopenia 18 15 Nausea 47 3 Diarrhea 36 Fatigue 5 Back pain 8 Vomiting Heme Serious AE in ≥ 2% of Pts, % Venetoclax (N = 66) Pneumonia 8 Sepsis 5 Pain 3 Pyrexia Cough Hypotension AE, adverse event; MM, multiple myeloma. Shaji Kumar, MD: Single-agent venetoclax was a well-tolerated treatment regimen, with no tumor lysis syndrome documented with the stepwise dosing schema adopted in this trial. There were 2 instances of a dose-limiting toxicity at 600 mg: abdominal pain and nausea. Overall, few serious AEs were seen, but included pneumonia and sepsis in 8% and 5% of patients, respectively. Most grade 3/4 AEs were hematologic and could be managed easily with dose modifications. The most common grade 3/4 AEs were thrombocytopenia in 26% of patients and neutropenia in 21% of patients. Grade 3/4 gastrointestinal AEs, including diarrhea, nausea, and vomiting, occurred in 3% of patients and could be managed by dose modification or using any symptomatic therapy. Non- Heme Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488.

Venetoclax Monotherapy for Relapsed/ Refractory MM: ORR
Outcome, % Overall Population (N = 66) Pts With t(11;14) (n = 30) Pts Without t(11;14) (n = 36) Pts With High BCL2/BCL2L1 (n = 9) Pts With Low (n = 15) ORR 21 40 6 88 20 sCR 3 4 11 CR 10 33 VGPR 8 13 PR 7 MM, multiple myeloma; sCR, stringent CR; VGPR, very good PR. Shaji Kumar, MD: More than 20% of the 66 patients receiving venetoclax achieved a PR or better. Of interest, among the 30 patients with t(11;14), the ORR was 40%, validating suggestions of efficacy for this patient population in the preclinical data. Furthermore, in patients with t(11;14) who had high BCL2/BCL2L1 gene expression ratio (n = 9), the ORR was 88%, which is very impressive. In subset analysis of pts with t(11;14), similar ORR seen across subgroups with MM refractory to various single agents or multiple agents Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488.

Venetoclax Monotherapy for Relapsed/ Refractory MM: TTP and DoR
Not Progressed (%) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 22 24 Mos Since First Dose All pts t(11;14) Non-t(11;14) Not Progressed (%) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 22 24 Mos Since First Dose High BCL2:BCL2L1 Low BCL2:BCL2L1 Gene expression ratio among t(11;14) pts DoR, duration of response; MM, multiple myeloma; TTP, time to progression. Shaji Kumar, MD: Responses were reasonably durable: Although the median PFS in this study was just longer than 2 months in the overall population, the time to progression in patients with t(11;14) was more than 6 months. In patients with t(11;14) cytogenetics and a high BCL2/BCL2L1 gene expression ratio, the time to progression was more than 10 months. Pts at Risk, n Pts at Risk, n All pts t(11;14) Non-t(11;14) 66 30 36 33 20 13 27 19 8 17 3 16 9 7 2 1 High BCL2:BCL2L1 Low BCL2:BCL2L1 9 15 11 8 5 6 2 3 1 Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488. Reproduced with permission.

Venetoclax Monotherapy for Relapsed/ Refractory MM: Conclusions
In pts with previously treated MM, venetoclax monotherapy was safe and tolerable ORR: 21% for total population Higher ORR, deeper responses, and greater time to progression in pts with vs without t(11;14) Venetoclax activity independent of previous treatment history in pts with t(11;14) Higher ORR also seen in pts with high vs low BCL2/BCL2L1 ratio These phase I results support further studies of venetoclax in combination with other therapies in this setting MM, multiple myeloma. Shaji Kumar, MD: These data suggest the possibility of biomarker-driven therapy in MM. Clearly, t(11;14) does not define a major subgroup of patients, but the findings in this study attests to the fact that better understanding of biology, even in MM, can help direct therapy for specific patients. In addition, the combination of venetoclax with bortezomib and dexamethasone, as mentioned earlier, also demonstrated a high rate of efficacy—nearly 70% of patients responded to treatment.[30] In this study, venetoclax, bortezomib, and dexamethasone was particularly effective in patients who were not refractory to bortezomib, with an ORR of 97%, but even 31% of patients who were refractory to previous bortezomib-based therapy responded. Based on these data, venetoclax could be used as a single agent based on a particular biomarker profile or combined with other MM regimens to potentially enhance its efficacy. Obviously, all these hypotheses need to be proven with larger phase III trials, but this is certainly a very interesting early start for this agent. Sagar Lonial, MD: To me, the data with venetoclax were one of the most exiting data sets presented at ASH It really does highlight the idea of a true precision medicine approach for patients with MM, and the data are quite striking for these patients with t(11;14) cytogenetics. Slide credit: clinicaloptions.com Kumar S, et al. ASH Abstract 488.

Go Online for More CCO Coverage of ASH 2016!
Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms References Jackson GH, Davies FE, Pawlyn C, et al. Response adapted induction treatment improves outcomes for myeloma patients; results of the phase III Myeloma XI study. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 244. Roussel M, Lauwers-Cances V, Robillard N, et al. Frontline therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) induction followed by autologous stem cell transplantation, Krd consolidation and lenalidomide maintenance in newly diagnosed multiple myeloma (NDMM) patients: primary results of the Intergroupe Francophone du MyéLome (IFM) Krd phase II study. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 1142. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120: Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015;1: McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366: Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). Program and abstracts of the 2016 American Society of Clinical Oncology Annual Meeting; June 3-6, 2016; Chicago, Illinois. Abstract 8001. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with len maintenance (ACM), tandem autoHCT with Len maintenance (TAM) and autoHCT with len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract LBA-1 Sonneveld P, Beksac M, van der holt B, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (mm): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM trial). Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 242. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375: Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375: Avet-Loiseau H, Casneuf T, Chiu C, et al. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 246. Nooka AK, Joseph N, Boise LH, et al. Clinical efficacy of daratumumab, pomalidomide and dexamethasone in relapsed, refractory myeloma patients: utility of retreatment with daratumumab among refractory patients. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 492. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128:37-44. Usmani SZ, Nahi H, Mateos MV, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 1149. Kumar S, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26: Bringhen S, Magarotto V, Liberati AM, et al. A multicenter, open label phase I/II study of carfilzomib, pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma (MM) patients. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 1145. Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015;126: Turner JG, Dawson JL, Grant S, et al. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors. J Hematol Oncol. 2016;9:73. Vogl DT, Dingli D, Cornell RF, et al. Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory Multiple Myeloma (MM): STORM Study. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 491. Bahlis NJ, Korb R, Sebag M, et al. Selinexor in combination with bortezomib and dexamethasone (SdB) demonstrates significant activity in patients with refractory multiple myeloma (MM) including proteasome-inhibitor refractory patients: results of the Phase I Stomp trial. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 977. Jakubowiak A, Jasielec J, Rosenbaum CA, et al. Final results of phase 1 MMRC trial of selinexor, carfilzomib, and dexamethasone in relapsed/refractory multiple myeloma (RRMM). Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 973. Badros AZ, Hyjek E, Ma N, et al. Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM). Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 490. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14: Dimopoulos MA, Palumbo A, Corradini P, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128: ClinicalTrials.gov. 1454GCC: phase I/II anti-PD-1 (MK-3475) and IMiD (pomalidomide) combination immunotherapy in relapsed/refractory multiple myeloma. Available at: Accessed February 16, 2017. ClinicalTrials.gov. A phase III study of pomalidomide and low dose dexamethasone with or without pembrolizumab (MK3475) in refractory or relapsed and refractory multiple myeloma (rrMM) (KEYNOTE 183). Available at: Accessed February 16, 2017. Touzeau C, Dousset C, Le Gouill S, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28: Punnouse EA, Leverson JD, Peale F, et al. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15: Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 488. Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Program and abstracts of the 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, California. Abstract 975. clinicaloptions.com/oncology

December 3-6, 2016; San Diego, California

Similar presentations

Presentation on theme: "December 3-6, 2016; San Diego, California"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

December 3-6, 2016; San Diego, California

Similar presentations

Presentation on theme: "December 3-6, 2016; San Diego, California"— Presentation transcript:

Similar presentations

About project

Feedback