EHA 22nd Congress: Navigating the complex waters in RRMM

The MM Hub team were delighted to attend the 22^nd congress of the European Hematology Association held in Madrid from 22^nd-25^th of June. The first day began with an oral session entitled: Navigating the Complex Waters in Relapsed and Refractory Multiple Myeloma, and was chaired by Professor Meletios Dimopoulos, from the National and Kapodistrian University of Athens, Greece.

Looking back to shore: How did we get to relapsed and refractory (RR) multiple myeloma?

The opening talk was delivered by the co-chair of the MM Hub, Professor Philippe Moreau, from the University Hospital of Nantes, France. Professor Moreau began by highlighting the huge leaps that have been made in extending patient survival within the 20 years from 1982, with a progression from chemotherapy as the predominant drug regimen towards high-dose therapy. This then changed again in 2002, when we moved in to the ‘novel agent era’. Two cohorts of patients (n=1038) were followed between the years 2001-2005 and 2006-2010, with a median OS of 4.6 versus 6.1 years, respectively (P=0.002), and an estimated overall survival (OS) of 40% versus 51%, respectively, indicating a marked improvement in OS over time as a result of the emerging novel agents.

Following on from this, an overview of currently used regimens was given, starting with newly diagnosed (ND) elderly patients (≥65 years). Data from the GEM2010 study was presented, in which an alternating regimen of 9 cycles each of MPV (melphalan, prednisone and bortezomib) and Rd (lenalidomide and dexamethasone) was compared with a sequential scheme, starting with MPV followed by Rd. The alternating regimen resulted in high levels of efficacy, less probability of tumor escape and lower cumulative toxicity, as well as a higher overall 3-year survival rate: 74% (95% CI 66-75) versus 72% (95% CI 70-76). Next, the IFM/DFCI study was outlined in which NDMM patients were randomized to receive autologous stem cell transplant (ASCT) either before or after RVd (lenalidomide, bortezomib and dexamethasone) and lenalidomide maintenance.

It was proposed that the treatment sequence for patients eligible for ASCT should follow the ESMO Guidelines, with a choice based on either the IFM 2009 or EMN02 studies. The overarching goal of treatment must be to obtain the best response followed by a sustained response, and was illustrated with results of IFM2013-04 trial. Currently, VTD and VCD are used widely in Europe, but with the approval of lenalidomide, VRD (currently used routinely in the US) may be the future, as this appears to be equally effective but has lower levels of toxicity. The importance of maintenance therapy was also stressed, as sustained responses following ASCT are needed.

In transplant eligible patients with NDMM, there are several issues that need to be addressed, such as whether consolidation therapy should be routinely used, whether to use single versus tandem treatment regimens, as well as ways to improve current treatments, such as the addition of monoclonal antibodies, the use of KRd, and the use of conditioning regimens. With VMP there was a 31% of risk reduction in OS, although several studies have now built on this with suggested modifications in terms of how often to administer treatment and whether to include maintenance.

For elderly patients, data from the FIRST and SWOG S0777 trials was presented with a clear emphasis on continuous lenalidomide and low dose dexamethasone as the major regimen, with the S0777 trial highlighting a clear PFS benefit with the addition of bortezomib, along with an acceptable risk-benefit profile.

In the future, treatment will be based on MP therapies, such as VMP plus or minus daratumumab, (ALCYONE study), on RD based therapies: IRD versus RD (TORMALINE-1 study), elotuzumab-RD versus RD (ELOQUENT-2 study), or daratumumab-RD versus RD (MAIA study), or an alternating regimen of VMP/RD. The issue of frailty was touched upon, with the effect of frailty (now defined by the ‘frailty index’ outlined in the recent ESMO Guidelines - also described by the MM Hub here), having a greater effect on OS than a patient’s actual age. Patients of senior age (≥75 years) had a similar OS to those with high-risk disease, whereas patients separated via the frailty index had a worse OS in comparison; there was also a better prognosis for those who weren’t ‘frail’.

It was concluded that, in young patients, ASCT remains the standard of care. Consolidation, tandem ASCT, the impact of carfilzomib and the use of monoclonal antibodies, are all under evaluation. In elderly patients, RRMM is clearly a heterogeneous disease; VMP, Rd and VRd are the standard of care, although treatment until progression still remains a matter of debate.

Professor Moreau was asked how he would treat a 50-year old patient with RRMM and replied that he would choose VTD, ASCT and lenalidomide maintenance until progression, and a short regimen of induction.

Wind in our sails: Next generation therapeutic options in RRMM

The second talk was presented by Professor Dimopoulos. He began by outlining the two kinds of relapse: fast, symptomatic - which requires prompt treatment initiation and is characterized by symptoms, rapidly progressing disease, high tumor burden, organ involvement, high-risk cytogenetics and poor performance status, and slow, symptomatic - which has the opposite characteristics and for which observation is advised rather than immediate treatment. In reality, many patients lie somewhere ‘in-between’ these two scenarios, and therefore the challenge is to identify the appropriate time at which to initiate treatment.

The main randomized trials for treatment of RRMM before 2015 compared doublet versus singlet regimens. However, with the development of so many new agents, doublet and even triplet combinations are the mainstay, with daratumumab-based regimens also a therapy of choice for those who have access. He went on to describe the complex environment for treatment decisions, with multiple factors affecting the choice of agents, such as both patient-related factors - age, comorbidities, renal impairment, VTE risk, performance status, drug availability, lifestyle/quality of life and prior history of malignancy, as well as disease/treatment factors - prior treatment received, refractory status, toxicity from prior regimens, cytogenetic risk status, pre-existing neuropathy and tumor burden. The benefit of a transplant at first relapse was discussed, with data from the UKMF Myeloma X study presented to illustrate a median PFS benefit of 19 months for transplant, versus 11 months for oral cyclophosphamide therapy.

The consensus guidelines for salvage ASCT in RRMM were also revised and the different options for therapy at first relapse were outlined. In particular, decisions based on the duration of the previous response post-ASCT were covered. For early relapse (< 1-year post ASCT) the main goal is to overcome drug resistance, and therefore a combination of non-cross-resistant agents, such as VTD (KRD)-PACE plus daratumumab and RIC-allo (reduced intensity conditioning allogenic transplant) is suggested. If the relapse is intermediate (1-3 years post-ASCT), then the major aim is to prolong survival until curative treatments are developed, with the use of sequential novel agent combinations, such as daratumumab plus pomalidomide/dexamethasone or KRd. If patients are younger than 55 years then RIC-allo is a possibility. Late relapse is defined by >3 years post ASCT and an aggressive relapse at this stage is treated by re-induction (KRd plus daratumumab) and a second ASCT, with the same for biochemical relapse.

Professor Dimopoulos commented on the different options for therapy at first relapse, for which, if ASCT is not possible, there is a choice between either IMiD-based or PI-based combinations. Data from ENDEAVOR, ASPIRE and TOURMALINE studies were all presented as valid options. The mechanism of action of monoclonal antibodies was presented, with promising results obtained when used as single agents - 26% SD for elotuzumab and 30-35% ORR for daratumumab and isatuximab.

Updated studies of several clinical trials were mentioned: ELOQUENT-2, CASTOR, POLLUX, PANORAMA-1, because subgroup analyses of these trials indicate that multiple factors should be considered when determining the next therapy at relapse. For example, the number of previous lines of therapy, whether patients are refractory to PIs or IMIDs, as well as cytogenetic risk status, and age, should all be taken into account.

It was concluded that treatment at relapse after 1-3 lines of therapy would include novel combinations using Rd or Vd as backbones (KRD, DaraRD, DaraVD, IRD, EloRD and PanVd). KRd and DaraRd are recommended for aggressive relapses when rapid control is required. KRd and IRd Iixazomib are currently the best options for patients with high-risk cytogenetics, whereas suitable new standards of care for elderly patients are DaraRd, EloRd, Kd and DaraVd.

In terms of the number and type of prior lines of therapy, patients that are PI-refractory or PI-sensitive the option would be KRd after 1 and ≥2 lines, and IRd after 2-3 prior lines for primary refractory patients. After PIs, regardless of PI sensitivity, DaraRd and EloRd would be the major options, Kd and DaraVd after PIs/IMIDs, and REP in lenalidomide-refractory patients. Regarding comorbidities and cumulative toxicity, caution should be taken with carfilzomib in moderate/severe cardiac comorbidities, with bortezomib/ixazomib in case of peripheral neuropathy, daratumumab in severe CPOD/asthma, and with IMIDs in cases of severe thrombotic events.

What’s on the near horizon? New targets in R/R MM

The next talk was delivered by the second co-chair of the MM Hub Professor Lonial, from the Emory University School of Medicine. He began by describing the wave of new agents that have become available since 2012, in chronological order: carfilzomib, pomalidomide, ixazomib, daratumumab, panobinostat, elotuzumab plus len/dex platforms, and daratumumab/IMiD and PI platforms. New therapies being investigated include the following agents or targets: XPO1 (Selinexor), BCL-2 (ABT-199), BCMA, PD-1, CART and eEF1 (plitidepsin).

The mechanism of action of Selinexor was described. Exportin (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR) and the elf4E-bound oncoprotein mRNAs. Selinexor is the first in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids to suppress oncoprotein expression. The first phase I trial of selinexor in combination with dexamethasone showed a 27% ORR in heavily pre-treated MM patients. This has been followed by a phase II trial – the STORM study, in which relapsed MM patients (who relapsed at a median of 4-years post-diagnosis) and heavily pre-treated (median of 7 prior regimens received) were treated and gave ORR results of over 20%. Treatment was effective even in patients with high-risk cytogenetics. Selinexor was then tested in phase I combination trials with PIs, in which rapid and durable responses were able to overcome carfizomib resistance. The BOSTON study is a phase 3 trial of selinexor plus bortezomib and low-dose dexamethasone currently underway, and has recruited 364 patients with RRMM who have received 1-2 prior therapies.

The Bcl-2 inhibitor ABT-199 (venetoclax) and its use in MM for Bcl-2-dependent tumors, was described. Studies have shown a clear benefit from using venetoclax either alone, or in combination with bortezomib, reaching an ORR of 94% in bortezomib non-refractory patients who had received 1-3 prior therapies. The ability to predict sensitivity to venetoclax can now be obtained using a single sample, within 48 hours.

Monoclonal antibodies, as well as conjugated antibodies and bi-specific T-cell engagers (BiTEs) are at the forefront of future perspectives. To this end, BCMA is a prime target for MM, as it is almost exclusively restricted to plasma cells and many of these agents have shown huge success in early trials. See previous MM Hub article.

The talk then focused on the strategy of PD-1 targeting using a combination of pembrolizumab plus pomalidomide and dexamethasone administered in 28-day cycles. The initial analysis measured an overall OR of 65%, with 68% in double refractory patients and 56% in patients with high risk cytogenetics; a median PFS of 17.4 months was also reported – see previous MM Hub article for more details of this study. CAR-T data in MM was also touched upon, with a comparison of the various trials using different modalities, all targeting BCMA. One of the major differences is the requirement for pre-testing to establish BCMA expression, which was required by all except the fully humanized BCMA-targeted BCMA CAR-T CD3zeta/41BB modality - for more detailed information of this trial see previous MM Hub article.

A novel compound - plitidepsin, is a cyclic depsipeptide, derived from the marine tunicate Aplidium albicans, which is an FDA-approved starting material. Plitidepsin targets the eEF1A2 protein, which is a proto-oncogene overexpressed in MM and is involved in cytoskeletal rearrangement favoring cell migration and invasion, regulation of oxidative stress and inhibition of apoptosis. Blocking eEF1A2 protein by plitidepsin results in induction of oxidative stress and activation of the Rac1/JNK pathway, which induces ER stress and ultimately drives apoptosis. The APL-A-012-13 phase I trial of plitidepsin plus bortezomib and dexamethasone was reported, with trial patients averaging 3 or more prior regimens, and achieving an ORR of 55%. A phase III trial (ADMYRE study) to compare the efficacy of plitidepsin plus dexamethasone to dexamethasone alone, is currently underway with patients who have had 3-6 prior lines of therapy.

In conclusion, new targets and mechanisms are currently in early development to help treat refractory MM. Identifying biomarkers to predict sensitivity is a key goal, and next steps will include finding out which therapies are best suited to be combined with these novel targets.

Avoiding treacherous waters: Balancing efficacy and adversity

The final talk in this session was given by Dr. Enrique Ocio from The University of Salamanca, Spain and focused on treatment-related adverse effects (AEs) and how to manage them. The main treatment-associated adverse effects (TEAEs) associated with novel agents were listed, and included: peripheral neuropathy, DVT, infusion-related reactions, CV toxicity, GI symptoms, infections, cytopenias, skin rash, asthenia and renal toxicity. The AEs observed in studies and potential physiopathologic mechanisms to explain these toxicities were described.

The incidence of TEAEs has in some cases decreased dramatically due to dose reductions and active management, such as asking patients regularly about symptoms and taking prompt action – dose reduction, schedule changes, symptom relief etc. Such is the case with peripheral neuropathy (PN), particularly associated with bortezomib, for which pharmacologic interventions were listed, as well as other supplements and treatments that can help. In other instances, toxicity is potentially reversible, allowing patients to be treated repeatedly with a given agent once the effect has been dealt with, which is the case with the cardiovascular (CV) toxicity associated to carfilzomib. A lower dose of carfilzomib markedly reduced the CV effects - 27 mg/m² in ASPIRE study gave lower toxicity compared with the higher dose of 56 mg/m² used in the ENDEAVOR study. Hydration was of particular importance in administering carfilzomib and decreased CV toxicity dramatically, although this was recommended for only one cycle in order to limit fluid overload.

Finally, infusion related reaction (IRR) associated with daratumumab in 43% of treated patients, was described. More than 90% of these reactions reportedly occur with the first infusion, so prevention and effective management is critical.  Administering a pre-infusion cocktail of acetaminophen, an antihistamine, methylprednisone and leukotriene inhibitor, and methylprednisolone post-infusion, was recommended. 

Dr. Ocio concluded that, although novel agent combinations have substantially improved the outcome of RRMM, AEs might impact overall quality of life, survival, and efficacy. In fact, 10-15% RRMM patients discontinue treatment due to AEs. Management of AEs must be early and active, and follow guidelines and recommended dose reductions. The main AEs associated with each drug/combination must be taken into account: PN with bortezomib, CV with carfilzomib, IRR with MoAbs, GI with Ixazomib, Bts, Panob and IMIDs, rash with IMIDs and Ixz, DVT with IMIDs, HZV with PI and MoAbs, and renal dysfunction with Cfz and lenalidomide. For more details on this topic you can listen to Dr. Ocio talking to the MM Hub in both Spanish and English.

In conclusion, the era of novel agents has hugely improved the prognosis for RRMM patients, which is now better than ever before. Long-term treatments are now balanced with management of AEs to improve quality of life, and many of the newest therapies will likely be combined with standard of care regimens to provide yet more options, that can potentially be tailored to each patient based on individual relapse criteria.