Outlook for 2017: Myeloma, Lymphoma, and MPNs

Myeloma

New agents

Finding agents with novel mechanisms that can overcome resistance in the relapsed/refractory multiple myeloma population is of import. Selinexor, an inhibitor of XPO1, is an attractive new agent for high-risk disease and more advanced disease due in part to its induction of cell apoptosis independent of p53 signaling. The agent induces nuclear inhibition of tumor suppressor proteins, nuclear factor kappa B, and oncoprotein mRNA such as c-Myc and cyclin D. In phase II trials of so-called quad-refractory patients (those who had failed bortezomib, carfilzomib, lenalidomide, and pomalidomide) as well as penta-refractory patients (those also refractory to an anti-CD38 antibody), the overall response rate with selinexor was 21%. Even more surprising is that in such a refractory population, 5% achieved a very good partial response (VGPR). Nonetheless, certain toxicities were notable: 49% of patients had anorexia and 43% had vomiting. The next generation of this class of drugs are currently under development and could potentially cause fewer gastrointestinal side effects.[1]

Progress in myeloma can be achieved by using new agents, but also by repurposing already approved agents. Venetoclax, a small molecule inhibitor of BCL2 that has been approved for chronic lymphocytic leukemia by the US Food and Drug Administration (FDA), has shown great promise in myeloma. Interestingly, certain myeloma cell lines have shown high BCL2 expression.[2] Two phase I studies looked at the use of venetoclax either as a single agent or in combination with bortezomib. The first study, led by the Mayo Clinic, enrolled 66 patients and started with single-agent venetoclax, allowing dexamethasone at the time of disease progression.[3] The overall response rate was 21%. Of even greater interest was the response rate of 86% in a subgroup of patients with the cytogenetic translocation t(11;14). Further analysis showed that best responses occurred in a group of patients who expressed high BCL2 and low MCL1; this group largely comprised patients with the t(11;14) translocation. The second study enrolled 66 patients and investigated the combination of venetoclax and bortezomib, showing an overall response rate of 68%.[4] Twenty-one patients (32%) were bortezomib refractory. The response rate in the non–bortezomib-refractory group was 86%, which is higher than what would be seen with bortezomib and dexamethasone alone. This is supported by preclinical data that bortezomib upregulates NOXA, a pro-apoptotic factor that neutralizes MCL1, thereby further shifting the ratio of BCL2 to MCL1.

Preclinical science suggests that protease inhibitors may also be of benefit given the high protein turnover in multiple myeloma. Advanced patients are characterized by drug resistance, and in the case of proteasome inhibitor resistance, this may be due to downregulation of the unfolded protein response. Protease inhibitors used in the treatment of human immunodeficiency virus (HIV) can trigger unfolded protein activation and resensitize cells to proteasome inhibitors. Among the protease inhibitors, nelfinavir appeared to have the most potent activity in this regard. A phase I trial of bortezomib and nelfinavir showed unfolded protein response activation and signals of activity,[5] and a follow-up phase II trial of nelfinavir in combination with standard dose bortezomib in bortezomib-refractory patients confirmed the activity and tolerability of nelfinavir at a dose twice that used for HIV infection.[6]

Immune-based therapies

Much of the focus in myeloma has shifted to immunotherapy. This is in part due to the recognition that advanced myeloma is characterized by immune dysfunction, and that augmenting the innate immune response may ultimately lead to disease control. Monoclonal antibodies targeting either CD38 or SLAM-F7 have become an established part of the repertoire for relapsed disease. Recent data have explored the use of checkpoint inhibitors such as pembrolizumab; although single-agent activity is modest, its use in combination with immunomodulatory drugs has shown promise. However, a note of caution has been the side-effect profile. In a phase II trial of 48 patients treated with pomalidomide and pembrolizumab, 13% had pneumonitis.[7] The overall response rate in this pomalidomide-naive population was 56%, which is higher than what has been seen with pomalidomide and dexamethasone alone.

Targeted therapy with monoclonal antibodies is now a mainstay of treatment for relapsed disease (eg, the anti-CD38 antibody daratumumab). The POLLUX trial compared daratumumab, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone[8]; the daratumumab arm demonstrated a markedly superior depth of response and progression-free survival. The CASTOR trial, which combined daratumumab with bortezomib and dexamethasone also showed superiority compared with bortezomib and dexamethasone alone.[9]

A still-nascent immune therapy in myeloma involves the use of modified chimeric antigen receptor (CAR) T cells. This approach has utilized various targets. The initial results were with a T-cell construct against CD19, which showed responses in a group of patients with highly advanced myeloma.[10] The authors hypothesized that while CD19 is not expressed on plasma cells, the observed therapeutic activity was due to CD19 targeting of myeloma precursors. Alternate approaches currently under investigation use CAR T cells to target BCMA, which is expressed on myeloma cells. A study from the University of Pennsylvania screened 11 patients and six were treated; five of these patients had cytokine release and one had severe posterior reversible encephalopathy syndrome.[10] One patient did achieve a stringent complete remission, which has been maintained for 7 months. Another trial using a different T-cell construct to target BCMA has also shown promise, and with fewer side effects.[11]

Stem cell transplantation

Autologous stem cell transplantation remains a mainstay of therapy in myeloma. A large randomized trial by the European Myeloma Network, EMN02/HO95, has shown superior progression-free survival for patients treated with high-dose therapy followed by transplant compared with those treated with conventional therapy (median not reached vs 44 months).[12] Also of interest was the role of post-transplant therapies such as consolidation, tandem autologous transplant, and maintenance therapy. The BMT CTN 0702 trial showed no benefit to either tandem transplant and maintenance, or consolidation for 4 cycles of lenalidomide, bortezomib, and dexamethasone followed by maintenance compared with single autologous transplant and maintenance therapy.[13]

The treatment of myeloma continues to evolve. High-dose therapy and autologous stem cell transplantation remains a backbone of upfront treatment. Relapsed disease now can be treated with a variety of approaches including new drugs, old drugs that have been repurposed, and immunotherapy. One can expect continued improvement in survival for patients with myeloma.

Lymphoma

Hodgkin lymphoma

This past year has been very exciting for the treatment of Hodgkin lymphoma, particularly with the approval of nivolumab, a PD-1 inhibitor. This drug showed an excellent overall response rate (87%) and safety profile in a phase I setting.[14] A phase II trial focusing on the population of patients who relapsed after both autologous stem cell transplantation and brentuximab vedotin confirmed the phase I efficacy data with an overall response rate of 63%.[15] Nivolumab received accelerated FDA approval for patients with Hodgkin lymphoma in this setting.

Another PD-1 inhibitor, pembrolizumab, also demonstrated an excellent overall response rate (65%) and safety profile in a phase I setting.[16] The results of a large phase II trial were presented at the 2016 European Hematology Association, American Society of Clinical Oncology, and American Society of Hematology (ASH) annual meetings, demonstrating a response rate of 73%.[17] Pembrolizumab should also receive FDA approval soon, and its indication may be broader than that of nivolumab. Another trial for which results are highly anticipated in 2017 is the ECHELON-1 trial, which is comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with doxorubicin, vinblastine, and dacarbazine (AVD) plus brentuximab vedotin for the frontline treatment of advanced Hodgkin lymphoma. If the results are positive, this trial would change the standard of care for these patients.

Non-Hodgkin lymphoma

Unfortunately, in diffuse large B-cell lymphoma, the long-awaited results of a large randomized phase III study comparing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) were negative. The results were reported at ASH this year and showed no difference in event-free survival or overall survival between the two regimens. Biologic correlatives and subset analyses are still pending and could reveal a difference between the two treatment groups.[18]

In follicular lymphoma, the results of the large randomized phase III GALLIUM trial were reported this year at ASH. The trial compared the efficacy of chemotherapy (bendamustine; CHOP; or cyclophosphamide, vincristine, and prednisolone [CVP]) plus either obinutuzumab or rituximab, followed by maintenance with obinutuzumab or rituximab. The experimental arm using obinutuzumab showed an improved 3-year progression-free survival compared with the control arm (80% vs 73%).[19] Obinutuzumab will likely receive FDA approval in this setting in 2017.

Waldenström macroglobulinemia. In January 2015 ibrutinib was the first agent to be FDA-approved specifically for Waldenström macroglobulinemia based on a phase II trial of 63 relapsed/refractory patients[20] that demonstrated a response rate of 90.5% (73% major responses; VGPR < 15%), an estimated 2-year progression-free survival of 69.1%, and an estimated 2-year overall survival of 95.2%.

Genomic subclassification of Waldenström macroglobulinemia by the presence or absence of the MYD88^L265P mutation and/or CXCR4^WHIM-like mutation showed three possible genotypes: MYD88^WT (10%), MYD88^L265PCXCR4^WT (60%), and MYD88^L265PCXCR4^WHIM (30%).[21] Clinically, patients with MYD88^WT have a poor response to ibrutinib and a poorer overall outcome than patients with MYD88^L265P disease. In the latter subset, patients with MYD88^L265PCXCR4^WT have very good responses to ibrutinib and good outcome compared with MYD88^L265PCXCR4^WHIM patients.

At the International Workshop on Waldenström’s Macroglobulinemia meeting in Amsterdam this year, there were several presentations on novel agents in clinical or preclinical trials, including BGB-3111 (a new Bruton tyrosine kinase inhibitor), a CXCR4 antibody, a IRAK1/4 inhibitor, and the BCL2 inhibitor venetoclax.

The 2016 ASH meeting showcased BGB-3111, an oral agent with much fewer off-target effects than ibrutinib. A phase I study with the agent is still ongoing but 31 patients have already been treated; after a median follow-up of 7.6 months (2–21 months), the overall response rate was 92% (22 of 24 evaluable patients). The major response rate was 83%, with VGPR (defined as > 90% reduction in immunoglobulin M [IgM] and a reduction in extramedullary disease) in 33% and partial response (defined as a 50% to 90% reduction in IgM and a reduction in extramedullary disease) in 50%. This treatment was well-tolerated with two cases of atrial fibrillation (one grade 1, the other grade 2) and one severe infection with grade 3 cryptococcal meningitis. Only one patient discontinued BGB-3111 due to exacerbation of pre-existing bronchiectasis while in VGPR. There have been no cases of disease progression.

A retrospective look at bendamustine plus rituximab vs dexamethasone, rituximab, and cyclophosphamide in Waldenström macroglobulinemia was reviewed this year at ASH as well.[22] Although both regimens show activity and comparable toxicities, the bendamustine/rituximab regimen showed a trend for superior progression-free survival in patients with Waldenström macroglobulinemia, both in the treatment-naive and relapsed/refractory setting. No difference was seen in time-to-next therapy. MYD88^L265P mutation status does not appear to impact activity of either regimen. Randomized controlled trials are needed to confirm these findings.

Ongoing trials of interest in Waldenström macroglobulinemia include:

• Dana-Farber Cancer Institute phase II venetoclax trial;

• BeiGene phase III BGB-3111 vs ibrutinib trial; and

• Dana-Farber Cancer Institute phase II ixazomib, dexamethasone, and rituximab trial.

Preliminary data from the latter trial was presented at ASH: 26 previously untreated patients had a response rate of 88% (VGPR, 6%; partial response, 44%; minor response, 38%) with a major response rate of 50%.[23]

Myeloproliferative Neoplasms

Over the last few years, significant progress has been made in defining the molecular pathogenesis of myeloproliferative neoplasms (MPNs), which include essential thrombocythemia, polycythemia vera, and myelofibrosis. Since 2005, when the JAK2 V617F mutation was first discovered, two additional driver mutations have been described-MPL and CALR. In addition, there are a number of secondary molecular mutations such as ASXL1, TET2, and DNMT3A that contribute to the pathogenesis and prognosis of these diseases.[24] The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-plus are the preferred clinically based prognostic scoring systems in use, but new scoring systems that incorporate molecular profiles have been developed, and will likely be utilized to improve prognostication and treatment decision-making for patients with MPNs.[25-27]

The identification of the JAK2/STAT pathway as a key step in the pathogenesis of MPNs led to the development and FDA approval of ruxolitinib, a JAK1/2 tyrosine kinase inhibitor, for treatment of myelofibrosis in 2011 and as second-line therapy for polycythemia vera in late 2014. Multiple other candidate drugs have been or are being tested to treat these diseases. Several of these agents target the JAK2 pathway, such as momelotinib and pacritinib[28]; others focus on alternative pathways, such as telomerase inhibition with imetelstat,[29] fibrogenesis with PRM-101, and hedgehog inhibition with glasdegib or vismodegib. The road to FDA approval has been a rocky one for several of the JAK inhibitors such as fedratinib and pacritinib due to unexpected toxicities. Combinations of agents are being evaluated in which a second drug-a hypomethylating agent, a histone deacetylase inhibitor, a hedgehog inhibitor, or interferon-is added to ruxolitinib. These trials are based on preclinical data suggesting that these agents may synergize with a JAK2 inhibitor in targeting the neoplastic stem cells.

Recent studies have shown that magnetic resonance imaging can be utilized to detect prefibrotic stages of myelofibrosis and possibly to predict disease progression and response to therapy.[30]

The National Comprehensive Cancer Network (NCCN) has convened a MPN panel this past year for the first time, and new guidelines to diagnose and treat myelofibrosis have been published. Additional guidelines for essential thrombocythemia and polycythemia vera are forthcoming from the NCCN in 2017

Ruxolitinib and other JAK inhibitors are known to mediate anti-inflammatory effects in addition to the inhibition of the growth and activity of neoplastic stem cells. These properties have been exploited to treat a variety of chronic inflammatory and immune-mediated conditions including acute graft-vs-host disease (GVHD). Based on encouraging preliminary reports describing the efficacy of ruxolitinib in treating refractory GVHD,[31] the FDA has awarded Breakthrough Therapy Designation to this drug to encourage the rapid conduct of prospective trials to evaluate its efficacy and safety in this setting. Several trials have been initiated that explore the optimal strategy for using ruxolitinib as treatment of refractory acute and chronic GVHD, as prophylaxis against the development of GVHD, and as a peritransplant adjunct to optimize the clinical status of patients about to undergo allogeneic stem cell transplantation for treatment of myelofibrosis and perhaps to prevent relapse post-transplant.

Systemic mastocytosis with an associated hematologic non–mast cell lineage disorder is a rare, difficult to treat subtype of MPNs that is usually associated with a KIT mutation. A major study was published this past year demonstrating that midostaurin, a multi-kinase inhibitor, has significant activity in treating systemic mastocytosis, including patients with aggressive systemic mastocytosis with an associated hematologic non–mast cell lineage disorder, with an overall response rate of 60%. It is anticipated that this drug will obtain FDA approval for this indication, as well as for treatment of FLT3-positive acute myelogenous leukemia in the near future.[32]

References:

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2. Punnoose EA, Leverson JD, Peale F, et al. Expression profile of BCL2 BCLX and MCL1 predicts pharmacological response to the BCL2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1-13.

3. Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Blood. 2016;128:abstr 488.

4. Moreau P, Chanan-Khan AA, Roberts AW, et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Blood. 2016;128:abstr 975.

5. Driessen C , Kraus M, Joerger M, et al. Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08). Haematologica. 2016;101:346-55.

6. Driessen C, Müller R, Novak U, et al. The HIV protease inhibitor nelfinavir in combination with bortezomib and dexamethasone (NVd) has excellent activity in patients with advanced, proteasome inhibitor-refractory multiple myeloma: a multicenter phase II trial (SAKK 39/13). Blood. 2016;128:abstr 487.

7. Badros AZ, Hyjek E, Ma N, et al. Pembrolizumab in combination with pomalidomide and dexamethasone for relapsed/refractory multiple myeloma (RRMM). Blood. 2016;128:abstr 490.

8. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-31.

9. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib and dexamethasone for multiple myeloma. New Engl J Med. 2016;375:754-66.

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15. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17:1283-9.

16. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016; Jun 27. [Epub ahead of print]

17. Moskowitz CH, Zinzani PL, Fanale MA, et al. Pembrolizumab in relapsed/refractory classical Hodgkin lymphoma: primary end point analysis of the phase 2 Keynote-087 Study. Blood. 2016;128:abstr 1107.

18. Wilson WH, sin-Ho J, Pitcher BN, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-Cell lymphoma: CALGB/Alliance 50303. Blood. 2016;128:abstr 469.

19. Marcus RE, Davies AJ, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study. Blood. 2016;128:abstr 6. 

20. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372:1430-40.

21. Hunter ZR, Xu L, Yang G, et al. Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. Blood. 2016;128:827-38.

22. Paludo J, Abeykoon JP, Hesse AB, et al. Bendamustine and rituximab versus dexamethasone, rituximab and cyclophosphamide in patients with Waldenstrom macroglobulinemia (WM). Blood. 2016;128:abstr 2968.

23. Castillo JJ, Gustine J, Meid K, et al. Ixazomib, dexamethasone and rituximab in previously untreated patients with Waldenström macroglobulinemia. Blood. 2016;128:abstr 2956.

24. Langabeer SE, Andrikovics H, Asp J, et al. Molecular diagnostics of myeloproliferative neoplasms. Eur J Haematol. 2015;95:270-9.

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29. Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908-19.

30. Matsuura S, Patterson S, Lucero H, et al. In vivo magnetic resonance imaging of a mouse model of myelofibrosis. Blood Cancer J. 2016;6:e497.

31. Mori Y, Ikeda K, Inomata T, et al. Ruxolitinib treatment for GvHD in patients with myelofibrosis. Bone Marrow Transplant. 2016;51:1584-7.

32. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530-41.