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Practical Considerations in Managing Relapsed Multiple Myeloma
Accepted Manuscript Practical Considerations in Managing Relapsed Multiple Myeloma Amit Agarwal, Eric Chow, Manisha Bhutani, Peter M. Voorhees, Reed Friend, Saad. Z. Usmani PII:
S2152-2650(16)30873-4
DOI:
10.1016/j.clml.2016.11.010
Reference:
CLML 862
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 15 August 2016 Revised Date:
24 October 2016
Accepted Date: 8 November 2016
Please cite this article as: Agarwal A, Chow E, Bhutani M, Voorhees PM, Friend R, Usmani SZ, Practical Considerations in Managing Relapsed Multiple Myeloma, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.11.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Practical Considerations in Managing Relapsed Multiple Myeloma Amit Agarwal1, Eric Chow2, Manisha Bhutani2, Peter M. Voorhees2, Reed Friend2, Saad. Z. Usmani2. 1. Division of Hematology-Oncology, University of Arizona Cancer Center, Tucson, AZ. 2. Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC
Corresponding author: Saad Z. Usmani MD FACP Chief, Plasma Cell Disorders program Director of Clinical Research in Hematologic Malignancies Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC Clinical Professor of Medicine, UNC School of Medicine Email: [email protected]
Key words: multiple myeloma, relapsed, refractory, treatment, Daratumumab, Elotuzumab, Carfilzomib, Pomalidomide, transplant
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Word count: 4300 Abstract: Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma (RRMM), with numerous novel agents and combination strategies receiving regulatory approvals worldwide over the last several years. An increasing body of phase III data clearly demonstrates increased overall response rates, improved depths of response and more durable responses when a third novel agent is incorporated into Lenalidomide-Dexamethasone and BortezomibDexamethasone platforms, in most cases with acceptable toxicity. The CarfilzomibDexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. Herein we review the data supporting the use of these novel treatment paradigms in RRMM, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space and propose strategies to best utilize these regimens, taking into account disease, host and prior treatment factors.
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Introduction Multiple myeloma (MM) is a plasma cell malignancy that is characterized by the presence of a monoclonal plasma cell population in the bone marrow producing a monoclonal immunoglobulin, along with evidence of end organ damage that usually includes renal failure, anemia, bone lesions, hypercalcemia and immune dysfunction. The outcomes and management of MM in the US has changed dramatically over the last 15 years where the survival of an average MM patient has tripled 1. Even in the era of novel therapies, the natural history of multiple myeloma follows a relapsing-remitting course wherein with subsequent relapses, remissions tend to be shallower and the duration of response shorter. Thus, the majority of MM patients will relapse 2,3, requiring subsequent lines of therapy. We recognize that MM is not one disease, that the transition of monoclonal gammopathy of undetermined significance (MGUS) to MM may be more indolent for some patients and very rapid for others. Recognizing the heterogeneity in the biology and clinical presentation of newly diagnosed MM patients 4, current clinical investigations are now moving away from a “one-size fits all” treatment paradigm to both risk and response adaptive strategies. Management of relapsed/refractory MM (RRMM) can be highly challenging, and the clinician must account for disease biology (cytogenetics, FISH), prior therapy (depth & duration of response to previous therapy, treatment tolerability), disease burden (presence/absence of renal failure, symptomatic bone disease, plasma cell leukemia at relapse, presence of extra-medullary disease, etc.), host factors (age, co-morbidities, performance status, etc.), access to clinical trials and financial limitations (cost of therapy, insurance, etc.). As of now, there are ten drugs that have been FDA approved for use in MM (Thalidomide, Lenalidomide, Bortezomib, Doxil, Carfilzomib, Pomalidomide, Panobinostat, Daratumumab, Elotuzumab, Ixazomib), the last four approvals coming in 2015 alone. In addition, there are several new novel drug classes and immunotherapy approaches making their way through clinical development. The present review will highlight some of the novel agent combinations in clinical trials with recently approved anti-MM agents and how best to incorporate them in clinical practice. Specifically, data from the recent phase III trials in the relapsed and relapsed/refractory
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MM with 1-3 prior lines of therapy will be discussed in the context of practical management of RRMM patients.
Approach to relapsed multiple myeloma While ongoing studies are evaluating biomarker driven approaches to treatment, the selection of the appropriate drug combination currently hinges on clinical judgment and careful interpretation of results from clinical trials. When available, a clinical trial remains the most appropriate strategy as there remains a compelling need to develop safe, novel combination therapies that will extend survival. Factors that may be helpful in deciding choice of therapy include disease-, patient- and treatment-related factors.
Disease-related factors: An important question for patients that are relapsing is when to start new therapy. In recent years, the paradigm of upfront treatment of myeloma has shifted from fixed duration to continuous therapy 5,6. Thus, relapses often occur when the patient remains on treatment (e.g. Lenalidomide maintenance therapy). Regardless of whether the relapse occurs on or off therapy, the decision of when to start therapy can be challenging. It is important to determine if a relapse is associated with any clinical features (CRAB 7 features; expanding or new plasmacytomas; hyperviscosity) which would be an indication to start treatment immediately. For biochemical relapse, the pace of relapse is important and the IMWG has defined criteria indicating treatment initiation 8. These include doubling of monoclonal protein within 2 months, with an increase in the absolute levels of monoclonal protein of >1g/dL in serum or of >500 mg per 24 hours in urine, or involved free light chain level by more than or equal to 20 mg/dL (plus an abnormal FLC ratio) in 2 consecutive measurements separated by less than or equal to 2 months 9. A decision of whether to start a patient with a biochemical relapse on therapy should be made based on a risk-benefit analysis keeping in mind some of the other factors discussed below. On the other hand, if a patient has evidence of rapidly advancing disease, with rapid emergence of clinical features, therapy should
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match disease intensity and a three or four drug regimen would be most appropriate in that setting. The presence of high risk cytogenetics [ deletion17p, t(4;14), chromosome 1q gain]; extramedullary disease; circulating plasma cells or high ISS stage at relapse warrant the use of aggressive therapy. A symptomatic plasmacytoma may need attention with radiation therapy but it is important to remember that the goal of radiation in this setting is symptom management and this should not delay systemic treatment.
Patient-related factors: Patient-related factors are critical in deciding optimal therapy. In the early relapsed setting, and especially for those patients in first relapse, the goal should be to achieve as deep of a response as possible. Current data favor the use of triplets over doublets in terms of achieving a deeper response (VGPR or better) and appears to be associated with better progression free survival (PFS) (Tables 2-3). Nonetheless, performance status and patient comorbidities can play a critical role in determining optimal therapy. It is also important to assess transplant eligibility. While age is not a direct determinant of tolerance to therapy, frailty can be very important. Palumbo et al have shown that a frailty score based on age, comorbidities and cognitive and physical conditions can help predict survival for newly diagnosed myeloma patients 10
. In patients deemed to be frail, doublets may be most appropriate and dose
reductions should be implemented as appropriate. Table 1 provides some guidelines regarding choice of therapy for patients with select comorbidities. Patient preference must also be considered. For example, a patient who must travel far to receive therapy may elect to pursue an all oral treatment strategy. Similarly, cost and a patient’s socioeconomic situation may also impact treatment choice.
Treatment-related factors: A host of treatment-related factors can be used to guide future therapies. First, it is important to decide whether a patient’s MM is refractory to a certain therapy or can be retreated with that agent. Refractory disease is defined as disease that is nonresponsive while on therapy or progresses within 60 days of last
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therapy. However, it is important to note the dose and schedule of the agent at the time that refractoriness was determined. Disease progression in the face of Lenalidomide, Bortezomib and dexamethasone, utilizing a standard dose and schedule of Bortezomib, is very different than disease progression on Lenalidomide maintenance therapy or Bortezomib administered once every 2 weeks. In general, if the patient has previously responded well to an agent with minimal toxicity, they can be considered for retreatment. Nonetheless, response with re-treatment is not guaranteed and responses tend to be less durable. For example, in a study of Bortezomib (+/- Dexamethasone) retreatment for patients relapsing 6 months or longer after prior Bortezomib-based therapy, the overall response rate (ORR) was 40% and median time to progression (TTP) 8.4 months. As such, if re-treatment is entertained, use of the same agent should be done in the context of a novel combination strategy, particularly if relapse is rapid, associated with end organ manifestations or occurring in a patient with high risk disease biology. A lack of response or a short duration of response to a particular treatment would dictate use of non-cross resistant therapy. Secondly, toxicities to previous drug regimens should be considered when deciding future therapies. For example, a patient who previously has higher grade diarrhea on previous Bortezomib-based therapy may not be a good candidate for a Bortezomib-Panobinostat-Dexamethasone combination. In the case of overlapping toxicities, it may be helpful to ascertain if the toxicity was due to multiple agents or can be attributed to a particular agent that can be avoided in the future. The depth and duration of a previous transplant is an important consideration for salvage transplant as discussed below.
Lenalidomide-based combinations Lenalidomide (R) is an immunomodulatory drug (IMiD) that has been an important component of multiple myeloma therapy for the past decade. Within the past few years, it has been successfully combined with several other anti-myeloma agents for both upfront and relapsed disease. Lenalidomide based combinations may be considered for patients in their first relapse if they have: •
Lenalidomide naïve patients.
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•
Clinical or biochemical relapse: Received a Lenalidomide-based induction regimen (no maintenance) at the time of diagnosis with good tolerance and progression-free survival (PFS) of at least 12-18 months.
•
Clinical or biochemical relapse: Received a Bortezomib (V)-based induction regimen at the time of diagnosis with poor tolerance and/or PFS of less than 12 months.
•
Biochemical relapse: Received (R)-based induction regimen at the time of diagnosis followed by low-dose Len maintenance with good tolerance and PFS of at least 24 months.
The results of 4 randomized trials have been recently reported (Table 2) 11-14. The ASPIRE 11 study randomized patients to receive either Carfilzomib with Lenalidomide and dexamethasone (KRd) or Rd alone. The data showed better overall response rates (ORR) and median PFS in favor of KRd compared with Rd (Table 2). The 2-year survival rates were 73.3% and 65% respectively, p=0.04. However, the KRd group had higher rates of grade 3/4 fatigue (7.7 vs 6.4%), dyspnea (2.8 vs 1.8%), hypokalemia (9.4 vs 4.9%), hypertension (4.3 vs 1.8%), cardiac failure (3.8 vs 1.8%) and ischemic heart disease (3.3 vs 2.1%). The incidence of peripheral neuropathy was similar in the two arms (17.1 vs 17.0%, all grades), demonstrating that the risk of neuropathy with Carfilzomib is low. As discussed below, Carfilzomib and Dexamethasone combination (Kd) is also approved for patients with 1-3 prior lines of therapy based on the ENDEAVOR study. It is important to remember that the dose of Carfilzomib used in the ASPIRE study was 20 mg/m2 followed by 27 mg/m2 starting day 8 while in the ENDEAVOR study it was 20 mg/m2 followed by 56 mg/m2 starting day 8.
The ELOQUENT-2 12 trial compared Rd with Rd plus Elotuzumab (ERd), a monoclonal antibody targeting SLAMF7, a surface antigen expressed on plasma cells (normal and malignant), natural killer cells and a subgroup of other immune cells. The study showed statistically significant ORR and median PFS benefit for the ERd arm
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(Table 2). Elotuzumab was associated with infusion reactions in 10% of patients, with most reactions being grade 1 or 2 and occurring with the initial dose. No grade 4 or 5 infusion reactions were seen. Overall, ERd showed a favorable safety profile and was well tolerated with similar rate of discontinuation due to study drug toxicity. Of note, 20% patients in this study were 75 years or older making it a good choice for elderly patients.
Ixazomib (Ixa) is an orally bioavailable, reversible inhibitor of the 20S proteasome with a low rate of peripheral neuropathy. A recommended phase II dose of 2.23 mg/m2 per week was converted into a fixed dose of 4.0 mg based on population pharmacokinetic analyses 15. TOURMALINE-MM113 compared Ixazomib-Lenalidomidedexamethasone (IRd) to Rd in a double-blind, placebo-controlled, randomized phase III study. The data validated the superiority of the PI/IMiD combination with regards to PFS (20.6 months vs. 14.7 months) and ORR (78 vs 72%). The median time to response was 1.1 months in the Ixazomib group and 1.9 months in the placebo group. The rates of serious adverse events were similar in the two groups (47 vs 49%). Grade 3/4 adverse events that were more common in the Ixazomib arm included rash (5 vs 2%), diarrhea (6 vs 2%) and thrombocytopenia (19 vs 9%). Thus, the IRd regimen represents an effective and well tolerated all oral regimen.
Lastly, the most recent data come from the POLLUX 14 trial presented at the European Hematology Association 2016 annual meeting where Daratumumab-Rd (DRd) was compared with Rd. Daratumumab is a human monoclonal antibody that targets CD38, a transmembrane glycoprotein that is highly expressed on myeloma cells and also on normal lymphoid and myeloid cells. It functions as an ectoenzyme involved in regulating intracytoplasmic signaling 16. The DRd arm showed significantly delayed TTP vs Rd (not reached [NR] vs estimated median of 18.4 mths; hazard ratio 0.34; p<0.0001). The ORR also improved (93 vs 76%) as did rates of VGPR or better (76 vs 44%) and CR or better (43 vs 19%). The most common adverse events were neutropenia (59 vs 43%), diarrhea (43 vs 25%), fatigue (35 vs 28%) upper respiratory tract infection (32 vs 21%). Infusion reactions were see in 48% of patients receiving D
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but of these only 5% were grade 3 and no grade 4 toxicity was seen. Most reactions occurred during the first infusion (92% of all reactions). Treatment discontinuation rates were similar between the two arms (7 vs 8%). Thus, the DRd combination may represent a new standard for Lenalidomide based therapy in relapsed multiple myeloma. It is important to appreciate that the patient populations in the four studies were different (prior therapies received, cytogenetics/risk categories). The ELOQUENT-2, ASPIRE and POLLUX trials primarily had patients with Bortezomib exposed/refractory patients, Lenalidomide refractory patients were excluded from all studies. The ELOQUENT-2 trial appeared to have a higher proportion of high risk cytogenetics compared with the other two trials, although this may have occurred due to the centralized evaluation of cytogenetics/FISH. The first three studies (ELOQUENT-2, ASPIRE, TOURNMALINEMM1) led to drug approvals for their respective drug combinations, whereas POLLUX may lead to a label change for Daratumumab later this year. Table 2 summarizes some practical considerations on how best of use these four regimens.
Bortezomib-based combinations Bortezomib (V) was the first proteasome inhibitor to be approved for multiple myeloma and has been commonly used in upfront and relapsed myeloma treatment. V-based combination may be considered for patients in their first relapse if they have: •
Bortezomib naïve patients.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with good tolerance and PFS of at least 12-18 months. Especially for translocation (4;14) patients.
•
Clinical or biochemical relapse: Received R-based induction regimen at the time of diagnosis with poor tolerance and/or PFS of less than 12 months.
•
Biochemical relapse: Received V-based induction regimen at the time of diagnosis followed by low-dose V maintenance with good tolerance and PFS of at least 24 months. Especially for translocation (4;14) patients.
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For patients who are eligible for Bortezomib-based regimens, there are two relevant Phase III studies (Table 3) – PANORAMA-117 and the CASTOR 18. PANORAMA-1 was a phase III, randomized, double-blind, placebo controlled trial which enrolled relapsed myeloma patients to receive either Panobinostat-Bortezomib-Dexamethasone (FVd) or placebo-Bortezomib-Dexamethasone (Vd). Panobinostat is an oral pan-deacetylase inhibitor that had been shown to have synergy with Bortezomib in preclinical studies. The study met its primary end point of improvement in PFS for the panobinostat group (11.99 vs 8.08 mths) and also reported higher CR rates (27.6 vs 15.7%) in the panobinostat group. The PVd regimen was associated with adverse events including grade 3 or 4 thrombocytopenia in 67%, diarrhea in 26% and asthenia or fatigue in 24% of patients. More patients discontinued treatment due to adverse events in the panobinostat group (24%) compared to the placebo group (12%). Perhaps the use of intravenous Bortezomib and a more intensive Panobinostat schedule were reasons for the higher rate of adverse events, and other combinations and dosing strategies are under investigation. The PVd benefit, however, was even observed in patients with prior PI and IMiD exposure (median PFS: PVd 12.7 months vs. Vd 4.7 months) and the FDA has granted approval for this subgroup of patients. The CASTOR study compared Daratumumab and Bortezomib-dexamethasone (DVd) with Vd (V 1.3 mg/m2 subcutaneously on days 1, 4, 8 and 11 of a 21-day schedule). The study demonstrated that DVd resulted in better PFS (NE vs 7.16 mths; HR-0.39, p<0.0001) compared to Vd alone. The ORR also improved from 63% for the Vd group to 83% for the DVd group with 59% patients achieving a VGPR or better in the DVd arm. Most common grade 3/4 adverse events were thrombocytopenia (59 vs 44%), anemia (14 vs 16%) and neutropenia (13 vs 4%). 45% of patients developed D-associated infusion reactions with the majority being grade 1 or 2 (grade 3/4, 9%/0%). One drawback of this study was that patients received Vd for 8 cycles, whereas the DVd arm received D till progression. Table 3 summarizes some practical considerations on how to best use these two regimens.
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Carfilzomib-based combinations Carfilzomib (K) is a tetrapeptide epokyketone proteasome inhibitor that binds irreversibly to the constitutive 20S proteasome and immunoproteasome. K-based combinations may be considered for patients in their first relapse if they have: •
Clinical relapse: Received combined V/R-based induction regimen at the time of diagnosis and PFS of <12 months.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with poor tolerance and PFS of <12 months.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with poor tolerance (significant peripheral neuropathy or GI toxicity).
The ENDEAVOR trial compared Carfilzomib-Dexamethasone (Kd) with Vd and was the first study to compare two different proteasome inhibitors. Patients received K (56 mg/m2, 30 min IV infusion on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle – 20 mg/m2 on days 1 and 2 of cycle 1) or V (1.3 mg/m2 IV or SC; on days 1, 4, 8 and 11 of a 21day cycle). The study reported an improvement in PFS (18.7 mths vs 9.4 mths; HR= 0.53, p<0.0001) as well as superior ORR (76.9% vs 62.6%; p< 0.0001). Specific grade 3 or 4 adverse events of interest included acute renal failure (3 vs 2%), cardiac failure (4 vs 1%), pneumonia (6 vs 7%) and peripheral neuropathy (2 v 8%). The trial had patients who were previously exposed to Bortezomib, but the benefit in the Carfilzomib arm was seen in patients irrespective of Bortezomib exposure prior to study enrollment. Despite the fact that 79% of the patient on the Bortezomib arm received subcutaneous injection, 48% required dose reductions due to adverse events compared to 23% in the Carfilzomib arm. Cardiotoxicity is a class effect of proteasome inhibitors but is seen more often with Carfilzomib. The exact mechanism is yet to be completely understood but baseline ejection fractions may not be a good marker for patients that will develop cardiac toxicity19. Table 3 summarizes practical considerations on how best of use K-
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based regimens compared to V-based regimens. Carfilzomib has been combined with several other agents including Cyclophosphamide 20, Panobinostat 21 and Pomalidomide 22. The combination of Carfilzomib with Pomalidomide and dexamethasone has shown good clinical activity in heavily pretreated patients. In a phase 1 study with mainly double refractory patients (R and V refractory), an overall response rate of 50% was observed with a PFS of 7.2 months. While small, this study shows that this combination may be effectively used for this otherwise difficult to treat population.
Pomalidomide-based combinations Pomalidomide (P) and dexamethasone is currently approved for the treatment of patients with multiple myeloma who have received at least two prior lines of therapies, including Lenalidomide and Bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. The study that led to this approval was a randomized open label phase II study of Pomalidomide alone or Pomalidomide plus low dose dexamethasone. In patients that were treated with pomalidomide and low dose dexamethasone an overall response rate of 29% was observed with a median response duration of 7.4 months 23,24. In this study, refractoriness to Lenalidomide or resistance to both Lenalidomide and Bortezomib did not affect the outcomes with Pomalidomide and low dose dexamethasone. Pomalidomide has also been combined with Bortezomib 25,Cyclophosphamide 26,27, Carfilzomib 22, Ixazomib 28, Daratumumab 29
, Pembrolizumab 30 and Clarithromycin 31 in various other studies (Table 4). For
patients who are relapsing on a R-based combination, replacement of R with P to recapture response may be an emerging strategy in these different combinations.
Daratumumab based combinations Daratumumab (Dara) is currently approved for use in multiple myeloma patients who have received at least three prior lines of therapy including a PI and IMiD or who are double-refractory to a PI and IMiD agent. A phase I/II study established the dose of
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Dara in 104 patients with RRMM 32. Patients were administered Dara at doses of 0.05 mg/kg to 24 mg/kg. A maximum tolerated dose was not established and 16 mg/kg dosing was selected based overall responses (36% in the 16 mg/kg cohort and 10% in the 8 mg/kg cohort). In the registration Phase II study, patients who had received at least three lines of treatment or were double refractory to a PI and IMiD were treated with Dara 33, showing an ORR of 29%. Daratumumab was well tolerated with infusion reactions occurring in 50% patients (Gr 3- 5%, Gr 4-0%), and fatigue and anemia in 40% and33% of patients, respectively. The overall response rate was 29% with 12% having a VGPR or better. The median time to response was 1 month and in this heavily pretreated population the PFS was 3.7 months with a median overall survival of 17.5 months. More recently, a combined analysis of the two studies demonstrated an ORR of 31% and OS benefit for patients achieving stable disease or better 34. These studies have led to the approval of Dara as a single agent but as the results of the POLLUX and CASTOR trials discussed above show, the real advantage of this agent may be in combination with other anti-myeloma agents.
Role of Salvage Autologous Transplant The role of high dose melphalan followed by autologous stem cell transplantation (ASCT) for patients in first remission is well established, but the role of salvage transplant has been less clear. While prospective data are needed in this setting, the American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation and the International Myeloma Working Group have recently issued a consensus statement to summarize best evidence regarding use of salvage ASCT in relapsed MM 35. These guidelines recommend that a salvage transplant be considered in patients who are transplant eligible but did not get a transplant after primary therapy and in patients who relapsed after primary therapy that included a transplant but achieved at least 18 months of remission with their first ASCT. In one phase III study performed in the UK, patients who had relapsed myeloma after at least 18 months after a previous transplant were randomized to induction therapy with
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Bortezomib, Doxorubicin and dexamethasone followed by either high dose melphalan (200 mg/m2) plus ASCT or oral cyclophosphamide (400 mg/m2 per week for 12 weeks) 36
. The study showed an improved PFS for the ASCT group (19 months vs 11 months).
However, oral cyclophosphamide is not widely used as a single agent in this setting and hence the comparator arm of this study may not have been optimal. Several other retrospective analyses have shown that the remission duration after the first transplant is most predictive of outcomes after the second transplant 37-39. The consensus statement stressed the need to explore appropriate post-transplant maintenance in this setting to include monoclonal antibodies, IMiDs and PIs. The statement also highlights the need for prospective studies to address the role of salvage transplant compared to some of the currently available ‘best non-transplant therapy’ options.
Role of Salvage Allogeneic Transplant The role of allogenic transplant is an open question that needs further answers with very few prospective studies. In a small study, 49 patients received a conditioning regimen consisting of melphalan (140mg/m2), fludarabine (90mg/m2) and antithymocyte globulin (60mg/kg body weight) 40. The overall response rate was 95% including 46% CRs but the 1-year treatment related mortality rate was 25%. After 43 months follow up, the 5 year PFS and OS were 20% and 26% respectively. Several studies are also looking at incorporating novel agents into various stages of allogeneic transplant. Further studies will be needed to assess the role of allogeneic transplant, balancing the potential for long term remission with the higher treatment-related mortality especially in the era of growing alternative therapies. Currently, this option should be considered for young, fit relapsed MM patients with higher risk disease, ideally in the context of a clinical trial.
Future Directions
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Management of RRMM is becoming increasingly complex with the arrival of new drug classes and combinations. Our understanding of the mechanisms of resistance to different drugs and drug classes is improving and a biomarker driven approach would be ideal. But it may not be feasible (time, resources, etc.) to do the necessary clinical trials to tease out which regimens are most suitable for particular subgroups of RRMM patients but gaining cautious insights from subgroup analyses may help guide the clinicians, as outlined in this review of data. Some of these regimens may move to the front-line setting and we may need phase III studies to examine the best combination strategies along with sequencing. These issues make biomarker and response (MRD) driven treatment studies more important.
Conflict of Interest: SZU reports consulting for Celgene, Millennium Takeda, Onyx, and Sanofi; speaker’s fees for Celgene, Millennium Takeda, and Onyx; and research funding from Array Biopharma, Celgene, Janssen Oncology, Onyx, Pharmacyclics, and Sanofi. PMV reports consulting for Celgene, Millennium Takeda, BMS, Novartis, Array Biopharma, Janssen; research funding from GSK, Janssen, Merck, Amgen, Oncopeptides and Acetylon. AA reports speaker’s fees from Novartis, Amgen, Janssen and Millennium.
REFERENCES 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111(5): 2516-20. 2. Usmani S, Ahmadi T, Ng YJ, Lam A, Potluri R, Mehra M. Analyses of Real World Data on Overall Survival in Multiple Myeloma Patients with at least 3 prior lines of therapy including a PI and IMiD, or double refractory to a PI and IMiD. The Oncologist 2016. 3. Kumar SK, 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(1): 149-57. 4. Chng WJ, Dispenzieri A, Chim CS, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia 2014; 28(2): 269-77. 5. Palumbo A, Gay F, Cavallo F, et al. Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol 2015; 33(30): 3459-66. 6. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014; 371(10): 906-17.
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7. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15(12): e538-48. 8. Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 2014; 32(6): 587-600. 9. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117(18): 4691-5. 10. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 2015; 125(13): 206874. 11. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372(2): 142-52. 12. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015; 373(7): 621-31. 13. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016; 374(17): 1621-34. 14. Dimopoulos AM, A. O, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomie, and dexamethasone (DRD) versus lenalidomide and dexamethasone (RD) in relapsed or refractory multiple myeloma (RRMM): POLLUX. European Hematology Association 2016; Copenhagen; 2016. 15. Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 2014; 124(7): 1047-55. 16. Malavasi F, Deaglio S, Funaro A, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 2008; 88(3): 841-86. 17. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; 15(11): 1195-206. 18. Palumbo A, Chanan-Khan A, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. American Society of Clinical Oncology. Chicago, Illinois: J. Clin. Oncol.; 2016. 19. Rosenthal A, Luthi J, Belohlavek M, et al. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J 2016; 6: e384. 20. Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 2014; 124(1): 639. 21. Berdeja JG, Hart LL, Mace JR, et al. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Haematologica 2015; 100(5): 670-6. 22. Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood 2015; 126(20): 2284-90. 23. Vij R, Richardson PGG, Jagannath S, et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). ASCO Annual Meeting Proceedings; 2012; 2012. p. 8016.
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24. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014; 123(12): 1826-32. 25. Lacy MQ, LaPlant BR, Laumann KM, et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM). Blood 2014; 124(21): 304-. 26. Baz RC, Martin TG, 3rd, Lin HY, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood 2016; 127(21): 2561-8. 27. Larocca A, Montefusco V, Bringhen S, et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood 2013; 122(16): 2799-806. 28. Krishnan A, Kapoor P, Palmer J, et al. A phase I/II study of ixazomib (Ix) pomalidomide (POM) dexamethasone (DEX) in relapsed refractory (R/R) multiple myeloma: Initial results. ASCO Annual Meeting. Chicago, Il; 2016. 29. Chari A, Lonial S, Suvannasankha A, et al. Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma ASH Annual Meeting. Orlando, Fl; 2015. 30. Badros A, Kocoglu M, Ma N, et al. A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) ASH Annual Meeting. Orlando, Fl; 2015. 31. Mark T, Boyer A, Yadlapati S, et al. Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Overcomes Negative Prognostic Impact of Adverse Cytogenetics and Prior Resistance to Lenalidomide and Bortezomib ASH Annual Meeting. Orlando, Fl; 2015. 32. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015; 373(13): 1207-19. 33. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatmentrefractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016; 387(10027): 1551-60. 34. 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(1): 37-44. 35. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant 2015; 21(12): 2039-51. 36. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, openlabel, phase 3 trial. Lancet Oncol 2014; 15(8): 874-85. 37. Sellner L, Heiss C, Benner A, et al. Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients. Cancer 2013; 119(13): 2438-46. 38. Michaelis LC, Saad A, Zhong X, et al. Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant 2013; 19(5): 760-6. 39. Gonsalves WI, Gertz MA, Lacy MQ, et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant 2013; 48(4): 568-73.
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40. Kroger N, Shimoni A, Schilling G, et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br J Haematol 2010; 148(2): 323-31.
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TABLE 1: Comorbidities to consider in selecting therapies for relapsed MM patients
Comorbidity
Comments
Neuropathy
Velcade (16% Gr 3/4 with IV and 6% with SQ) 1 Thalidomide (15% need treatment interruption) 2 Ixazomib (1% Gr 3/4) 3
Heart disease
Carfilzomib- 4% (Gr 3/4 cardiac failure), 9% (Gr 3/4 hypertension) 4 Panobinostat- 12%- Arrhythmia, 4%Cardiac ischemia 5,6
Acute renal failure
Lenalidomide- Dose adjustment is necessary.
Diabetes mellitus
Steroids- Need careful management of blood sugars.
1. 2. 3. 4. 5. 6.
Moreau P. et al. Lancet Oncol May 2011;12: 431-40 Mileshkin L. et al. J Clin Oncol. Sep 2006; 24(27): 4507-14 Kumar S. et al. Blood Aug 2014; 124(7): 1047-55 Dimopoulos M. et al. Lancet Oncol Jan 2016; 17: 27-38 Panobinostat package insert San-Miguel J.F. et al. Lancet Oncol, Oct 2014; 15: 1195-206
Prior Therapies Median no (range)
HR (95% CI)
Median OS m HR (95% CI)
2 (1-3)
2 (1-3)
87
67
79
26.3
17.6
19.4
* Dose 27 mg/m2
Rd (n=362)
2 (1-3)
DRd (n=286)
Rd (n=283)
1(1-3)
1(1-3)
66
78
72
93
76
14.9
20.6
14.7
NE
18.4
0.7 (0.57-0.85)
0.742 (0.587-0.939)
0.37 (0.27-0.52)
p=0.0001
p=0.0014
p=0.012
P <0.0001
NE
NE
43.7
0.79 (0.63-0.99)
39.6
NE
NE
NE
NE
0.77 (0.61-0.97) p=0.257
Well tolerated, PI refractory not excluded, benefit in high risk patients
All oral, benefit was noted in high risk patients
Best depth of response (93%), perhaps longest PFS, but requires long infusions
Slow Biochemical Relapse OR Elderly Patients with High Risk Features
Rapid Clinical Relapse for Elderly Where Oral Regimen is Preferred
Rapid Clinical Relapse in both Young and Elderly – especially where proteasome inhibitor may be contra-indicated (neuropathy, cardiac issues, etc.)
EP
Long PFS
AC C
Where to Practically Use the Regimen?
IxaRd (n=360)
Pollux
0.69 (0.57-0.83)
p=0.04 Notes
Rd (n=325)
D
Median PFS in months
EloRd (n=321)
TE
ORR (%)
Rd (n=396)
Tourmaline-MM13
M AN U
KRd* (n=396)
Eloquent-22
SC
APSIRE1
RI PT
Table 2: Options for Lenalidomide-based Combinations
Rapid Clinical Relapse in Younger/Fit Patients
1Stewart
AK et al. N Engl J Med. 2015;372:142; 2Lonial S et al. N Engl J Med. 2015;373:621; P et al. N Engl J Med. 2016;374:1621; 4 Dimopolous M et al, EHA 2016
3Moreau
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Table 3: Options for Proteasome Inhibitor-based Combinations Panorama11 PanoVd (n=387 Prior Therapies Median no (range)
Endeavor2 Vd (n=381)
Kd* (n=465)
2 (1-3)
ORR (%) Median PFS in months
2 (1-3)
DVd (n=251)
Vd (n=247)
2 (1-3)
2 (1-3)
55
77
63
83
63
11.99
8.08
18.7
9.4
NE
7.4
0.63 (0.52-0.76)
0.53 (0.44-0.65)
HR: 0.39 (0.28-0.53)
p=0.0001
p=0.0001
p <0.0001
33.64
HR (95% CI)
Vd (n=464)
61
HR (95% CI) Median OS in months
Castor3
30.39
NE
NE
NE
NE
0.87 (0.69-1.10)
0.79 (0.58-1.08)
p=0.026
p=0.13
Notes
Marked increase in thrombocytopenia, diarrhea, asthenia/fatigue, nausea/vomiting; Benefit in LEN and BTZ exposed
Slight increase in cardiac toxicity (5% vs 1%) and hypertension, reduced neuropathy
Benefit seen across all subgroups. Vd given for only 8 cycles in each arm with high PN rates.
Where to Practically Use the Regimen?
Double Refractory, Young Patients
PI Sensitive, Young Patients
PI sensitive/Len refractory, all ae groups
* Dose 56mg/m2 1San-Miguel
JF et al. Lancet Oncol. 2014;15:1195; 2Dimopoulos MA et al. Lancet Oncol. 2016;17:27; 3Dimopoulos MA et al. EHA 2016
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Table 4. RRMM: Studies of Pom-based Combinations
San 1 Miguel
Baz
Larocca3
Mark
Shah
Treatment
Pd
+cyclo
PCP
+clarithromycin
Phase
III
I/II
I/II
302
70
Median No. prior lines
5
ORR (%)
2
4
5
Badros6
Chari7
Krishnan8
+CFZ
+Pembro
+ dara
+Ixa
II
I
II
II
I/II
69
114
32
33
75
25
4
3
5
6
6
4
2 (1-5)
31
65
51
56
50
59
71
44
PFS (mos)
4.0
9.2
10.4
7.7
7.2
NR
NR
NR
Prior Len (%) Prior BTZ (%)
100 100
100 71 Bor refractory
100 78
100 78 Bor refractory
100 97
97 82 PI refractory
100 76 PI refractory
100 68 Bor refractory
Study
N
Data from separate clinical trials, comparative clinical significance has not been proven. 1) San Miguel et al. Lancet Oncol. 2013;14:1055-66; 2)Baz et al. Annual ASH Meeting; 2014 [Abstract 303]; 3) Larocca et al. Blood. 2013;122:2799. 4) Mark et al. Annual ASH Meeting; 2013 [Abstract 1955]; 5) Shah et al. Blood 2015:126:2284; 6) Badros et al, Annual ASH Meeting; 2015;10 [Abstract 506 ) 7) Chari et al. Annual ASH Meeting; 2015;10 [Abstract 508] 8) Krishanna et al; ASCO 2016 [Abstract 509 ]
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Figure 1. Treatment Approaches in Early RRMM Early relapse (1-3 prior lines) Participate in clinical trials with novel agents IMiD-based regimen • No Prior IMiD exposure • Prior IMiD use with good tolerance, durable response and PFS • Prior PI exposure
PI-based regimen • No Prior PI exposure • Prior PI use with good tolerance, durable response and PFS • Prior IMiD exposure • Especially for t(4;14) patients
Len-naïve/sensitive
BTZ-naïve/sensitive
KRd, EloRd, IxaRd, DRd
Kd, KRd, IxaRd, DVd
BTZ-refractory
Len-refractory
EloRd, DaraRd
Kd, PanoVD, KPd, DVd
Autologous transplant • Long remission post 1st transplant (>24 months without maintenance, >36 months with maintenance) • Transplant not part of primary therapy
Adapted from Usmani SZ, Lonial S. Clin Lymphoma Myeloma Leuk. 2014;14 Suppl:S71.
Table 5: Dosing regimens for common combinations Proteasome inhibitor
IMiD
KRd (28 day cycle)
Car- 27mg/2 IV D1,2,8,9,15,16. (C1D1,2-
Rev- 25 mg PO D1-21
20 mg/m2) Infusion time- 10 minutes
M AN U
IRd (28 day cycle)
Rev- 25 mg PO D1-21
SC
ERd (28 day cycle)
Ixa- 4 mg PO D1,8,15
DRd (28 day cycle)
Car- 27mg/2 IV D1,2,8,9,15,16. (C1D1,2-
D
KPd (28 day cycle)
Elo- 10 mg IV Once a week for C-1 and 2. Then once every 2 weeks
Rev- 25 mg PO D1-21 Rev- 25 mg PO D1-21
Other Dex- 40 mg weekly
Dex- 36 mg on days of E. 40 mg if not receiving E.
Dex- 40 mg weekly Dara- 16 mg IV Once a week for C1 and 2, once every 2 weeks for C3-6 and once every 4 weeks thereafter
Pom- 4 mg PO D1-21
Dex 40 mg weekly. Split 20 mg on day of and 20 mg day after Daratumumab infusion. Dex- 40 mg weekly
Car-56 mg/m2 IV D1,2,8,9,15,16. (C1D1,2-
Dex- 40 mg weekly
EP
Kd (28 day cycle)
TE
20 mg/m2) Infusion time- 10 minutes
20 mg/m2) Infusion time- 30 minutes.
FVd (21 day cycle)
Vel- 1.3 mg/m2 IV/SQ; D1,4,8,11
AC C
PI based combinations
Monoclonal antibody
RI PT
Len based combinations
Regimens
DVd (28 day cycle)
Vel- 1.3 mg/m2 SQ D1,4,8,11
Pano 20 mg PO (D 1,3,5,8,10/12) Dex 20 mg on day of and 20 mg day after Vel. Dara- 16 mg IV Once a week for C1 and 2, once every 2 weeks for C3-6 and once every 4
Dex 20 mg on day of and 20 mg day after Vel.
S2152-2650(16)30873-4
DOI:
10.1016/j.clml.2016.11.010
Reference:
CLML 862
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 15 August 2016 Revised Date:
24 October 2016
Accepted Date: 8 November 2016
Please cite this article as: Agarwal A, Chow E, Bhutani M, Voorhees PM, Friend R, Usmani SZ, Practical Considerations in Managing Relapsed Multiple Myeloma, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.11.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Practical Considerations in Managing Relapsed Multiple Myeloma Amit Agarwal1, Eric Chow2, Manisha Bhutani2, Peter M. Voorhees2, Reed Friend2, Saad. Z. Usmani2. 1. Division of Hematology-Oncology, University of Arizona Cancer Center, Tucson, AZ. 2. Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC
Corresponding author: Saad Z. Usmani MD FACP Chief, Plasma Cell Disorders program Director of Clinical Research in Hematologic Malignancies Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC Clinical Professor of Medicine, UNC School of Medicine Email: [email protected]
Key words: multiple myeloma, relapsed, refractory, treatment, Daratumumab, Elotuzumab, Carfilzomib, Pomalidomide, transplant
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Word count: 4300 Abstract: Considerable advances have been made in the treatment of relapsed and relapsed/refractory multiple myeloma (RRMM), with numerous novel agents and combination strategies receiving regulatory approvals worldwide over the last several years. An increasing body of phase III data clearly demonstrates increased overall response rates, improved depths of response and more durable responses when a third novel agent is incorporated into Lenalidomide-Dexamethasone and BortezomibDexamethasone platforms, in most cases with acceptable toxicity. The CarfilzomibDexamethasone doublet has also demonstrated promising activity. With this rapid progress has come many new questions. Herein we review the data supporting the use of these novel treatment paradigms in RRMM, discuss the place of autologous and allogeneic hematopoietic stem cell transplantation in this rapidly evolving treatment space and propose strategies to best utilize these regimens, taking into account disease, host and prior treatment factors.
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Introduction Multiple myeloma (MM) is a plasma cell malignancy that is characterized by the presence of a monoclonal plasma cell population in the bone marrow producing a monoclonal immunoglobulin, along with evidence of end organ damage that usually includes renal failure, anemia, bone lesions, hypercalcemia and immune dysfunction. The outcomes and management of MM in the US has changed dramatically over the last 15 years where the survival of an average MM patient has tripled 1. Even in the era of novel therapies, the natural history of multiple myeloma follows a relapsing-remitting course wherein with subsequent relapses, remissions tend to be shallower and the duration of response shorter. Thus, the majority of MM patients will relapse 2,3, requiring subsequent lines of therapy. We recognize that MM is not one disease, that the transition of monoclonal gammopathy of undetermined significance (MGUS) to MM may be more indolent for some patients and very rapid for others. Recognizing the heterogeneity in the biology and clinical presentation of newly diagnosed MM patients 4, current clinical investigations are now moving away from a “one-size fits all” treatment paradigm to both risk and response adaptive strategies. Management of relapsed/refractory MM (RRMM) can be highly challenging, and the clinician must account for disease biology (cytogenetics, FISH), prior therapy (depth & duration of response to previous therapy, treatment tolerability), disease burden (presence/absence of renal failure, symptomatic bone disease, plasma cell leukemia at relapse, presence of extra-medullary disease, etc.), host factors (age, co-morbidities, performance status, etc.), access to clinical trials and financial limitations (cost of therapy, insurance, etc.). As of now, there are ten drugs that have been FDA approved for use in MM (Thalidomide, Lenalidomide, Bortezomib, Doxil, Carfilzomib, Pomalidomide, Panobinostat, Daratumumab, Elotuzumab, Ixazomib), the last four approvals coming in 2015 alone. In addition, there are several new novel drug classes and immunotherapy approaches making their way through clinical development. The present review will highlight some of the novel agent combinations in clinical trials with recently approved anti-MM agents and how best to incorporate them in clinical practice. Specifically, data from the recent phase III trials in the relapsed and relapsed/refractory
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MM with 1-3 prior lines of therapy will be discussed in the context of practical management of RRMM patients.
Approach to relapsed multiple myeloma While ongoing studies are evaluating biomarker driven approaches to treatment, the selection of the appropriate drug combination currently hinges on clinical judgment and careful interpretation of results from clinical trials. When available, a clinical trial remains the most appropriate strategy as there remains a compelling need to develop safe, novel combination therapies that will extend survival. Factors that may be helpful in deciding choice of therapy include disease-, patient- and treatment-related factors.
Disease-related factors: An important question for patients that are relapsing is when to start new therapy. In recent years, the paradigm of upfront treatment of myeloma has shifted from fixed duration to continuous therapy 5,6. Thus, relapses often occur when the patient remains on treatment (e.g. Lenalidomide maintenance therapy). Regardless of whether the relapse occurs on or off therapy, the decision of when to start therapy can be challenging. It is important to determine if a relapse is associated with any clinical features (CRAB 7 features; expanding or new plasmacytomas; hyperviscosity) which would be an indication to start treatment immediately. For biochemical relapse, the pace of relapse is important and the IMWG has defined criteria indicating treatment initiation 8. These include doubling of monoclonal protein within 2 months, with an increase in the absolute levels of monoclonal protein of >1g/dL in serum or of >500 mg per 24 hours in urine, or involved free light chain level by more than or equal to 20 mg/dL (plus an abnormal FLC ratio) in 2 consecutive measurements separated by less than or equal to 2 months 9. A decision of whether to start a patient with a biochemical relapse on therapy should be made based on a risk-benefit analysis keeping in mind some of the other factors discussed below. On the other hand, if a patient has evidence of rapidly advancing disease, with rapid emergence of clinical features, therapy should
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match disease intensity and a three or four drug regimen would be most appropriate in that setting. The presence of high risk cytogenetics [ deletion17p, t(4;14), chromosome 1q gain]; extramedullary disease; circulating plasma cells or high ISS stage at relapse warrant the use of aggressive therapy. A symptomatic plasmacytoma may need attention with radiation therapy but it is important to remember that the goal of radiation in this setting is symptom management and this should not delay systemic treatment.
Patient-related factors: Patient-related factors are critical in deciding optimal therapy. In the early relapsed setting, and especially for those patients in first relapse, the goal should be to achieve as deep of a response as possible. Current data favor the use of triplets over doublets in terms of achieving a deeper response (VGPR or better) and appears to be associated with better progression free survival (PFS) (Tables 2-3). Nonetheless, performance status and patient comorbidities can play a critical role in determining optimal therapy. It is also important to assess transplant eligibility. While age is not a direct determinant of tolerance to therapy, frailty can be very important. Palumbo et al have shown that a frailty score based on age, comorbidities and cognitive and physical conditions can help predict survival for newly diagnosed myeloma patients 10
. In patients deemed to be frail, doublets may be most appropriate and dose
reductions should be implemented as appropriate. Table 1 provides some guidelines regarding choice of therapy for patients with select comorbidities. Patient preference must also be considered. For example, a patient who must travel far to receive therapy may elect to pursue an all oral treatment strategy. Similarly, cost and a patient’s socioeconomic situation may also impact treatment choice.
Treatment-related factors: A host of treatment-related factors can be used to guide future therapies. First, it is important to decide whether a patient’s MM is refractory to a certain therapy or can be retreated with that agent. Refractory disease is defined as disease that is nonresponsive while on therapy or progresses within 60 days of last
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therapy. However, it is important to note the dose and schedule of the agent at the time that refractoriness was determined. Disease progression in the face of Lenalidomide, Bortezomib and dexamethasone, utilizing a standard dose and schedule of Bortezomib, is very different than disease progression on Lenalidomide maintenance therapy or Bortezomib administered once every 2 weeks. In general, if the patient has previously responded well to an agent with minimal toxicity, they can be considered for retreatment. Nonetheless, response with re-treatment is not guaranteed and responses tend to be less durable. For example, in a study of Bortezomib (+/- Dexamethasone) retreatment for patients relapsing 6 months or longer after prior Bortezomib-based therapy, the overall response rate (ORR) was 40% and median time to progression (TTP) 8.4 months. As such, if re-treatment is entertained, use of the same agent should be done in the context of a novel combination strategy, particularly if relapse is rapid, associated with end organ manifestations or occurring in a patient with high risk disease biology. A lack of response or a short duration of response to a particular treatment would dictate use of non-cross resistant therapy. Secondly, toxicities to previous drug regimens should be considered when deciding future therapies. For example, a patient who previously has higher grade diarrhea on previous Bortezomib-based therapy may not be a good candidate for a Bortezomib-Panobinostat-Dexamethasone combination. In the case of overlapping toxicities, it may be helpful to ascertain if the toxicity was due to multiple agents or can be attributed to a particular agent that can be avoided in the future. The depth and duration of a previous transplant is an important consideration for salvage transplant as discussed below.
Lenalidomide-based combinations Lenalidomide (R) is an immunomodulatory drug (IMiD) that has been an important component of multiple myeloma therapy for the past decade. Within the past few years, it has been successfully combined with several other anti-myeloma agents for both upfront and relapsed disease. Lenalidomide based combinations may be considered for patients in their first relapse if they have: •
Lenalidomide naïve patients.
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•
Clinical or biochemical relapse: Received a Lenalidomide-based induction regimen (no maintenance) at the time of diagnosis with good tolerance and progression-free survival (PFS) of at least 12-18 months.
•
Clinical or biochemical relapse: Received a Bortezomib (V)-based induction regimen at the time of diagnosis with poor tolerance and/or PFS of less than 12 months.
•
Biochemical relapse: Received (R)-based induction regimen at the time of diagnosis followed by low-dose Len maintenance with good tolerance and PFS of at least 24 months.
The results of 4 randomized trials have been recently reported (Table 2) 11-14. The ASPIRE 11 study randomized patients to receive either Carfilzomib with Lenalidomide and dexamethasone (KRd) or Rd alone. The data showed better overall response rates (ORR) and median PFS in favor of KRd compared with Rd (Table 2). The 2-year survival rates were 73.3% and 65% respectively, p=0.04. However, the KRd group had higher rates of grade 3/4 fatigue (7.7 vs 6.4%), dyspnea (2.8 vs 1.8%), hypokalemia (9.4 vs 4.9%), hypertension (4.3 vs 1.8%), cardiac failure (3.8 vs 1.8%) and ischemic heart disease (3.3 vs 2.1%). The incidence of peripheral neuropathy was similar in the two arms (17.1 vs 17.0%, all grades), demonstrating that the risk of neuropathy with Carfilzomib is low. As discussed below, Carfilzomib and Dexamethasone combination (Kd) is also approved for patients with 1-3 prior lines of therapy based on the ENDEAVOR study. It is important to remember that the dose of Carfilzomib used in the ASPIRE study was 20 mg/m2 followed by 27 mg/m2 starting day 8 while in the ENDEAVOR study it was 20 mg/m2 followed by 56 mg/m2 starting day 8.
The ELOQUENT-2 12 trial compared Rd with Rd plus Elotuzumab (ERd), a monoclonal antibody targeting SLAMF7, a surface antigen expressed on plasma cells (normal and malignant), natural killer cells and a subgroup of other immune cells. The study showed statistically significant ORR and median PFS benefit for the ERd arm
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(Table 2). Elotuzumab was associated with infusion reactions in 10% of patients, with most reactions being grade 1 or 2 and occurring with the initial dose. No grade 4 or 5 infusion reactions were seen. Overall, ERd showed a favorable safety profile and was well tolerated with similar rate of discontinuation due to study drug toxicity. Of note, 20% patients in this study were 75 years or older making it a good choice for elderly patients.
Ixazomib (Ixa) is an orally bioavailable, reversible inhibitor of the 20S proteasome with a low rate of peripheral neuropathy. A recommended phase II dose of 2.23 mg/m2 per week was converted into a fixed dose of 4.0 mg based on population pharmacokinetic analyses 15. TOURMALINE-MM113 compared Ixazomib-Lenalidomidedexamethasone (IRd) to Rd in a double-blind, placebo-controlled, randomized phase III study. The data validated the superiority of the PI/IMiD combination with regards to PFS (20.6 months vs. 14.7 months) and ORR (78 vs 72%). The median time to response was 1.1 months in the Ixazomib group and 1.9 months in the placebo group. The rates of serious adverse events were similar in the two groups (47 vs 49%). Grade 3/4 adverse events that were more common in the Ixazomib arm included rash (5 vs 2%), diarrhea (6 vs 2%) and thrombocytopenia (19 vs 9%). Thus, the IRd regimen represents an effective and well tolerated all oral regimen.
Lastly, the most recent data come from the POLLUX 14 trial presented at the European Hematology Association 2016 annual meeting where Daratumumab-Rd (DRd) was compared with Rd. Daratumumab is a human monoclonal antibody that targets CD38, a transmembrane glycoprotein that is highly expressed on myeloma cells and also on normal lymphoid and myeloid cells. It functions as an ectoenzyme involved in regulating intracytoplasmic signaling 16. The DRd arm showed significantly delayed TTP vs Rd (not reached [NR] vs estimated median of 18.4 mths; hazard ratio 0.34; p<0.0001). The ORR also improved (93 vs 76%) as did rates of VGPR or better (76 vs 44%) and CR or better (43 vs 19%). The most common adverse events were neutropenia (59 vs 43%), diarrhea (43 vs 25%), fatigue (35 vs 28%) upper respiratory tract infection (32 vs 21%). Infusion reactions were see in 48% of patients receiving D
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but of these only 5% were grade 3 and no grade 4 toxicity was seen. Most reactions occurred during the first infusion (92% of all reactions). Treatment discontinuation rates were similar between the two arms (7 vs 8%). Thus, the DRd combination may represent a new standard for Lenalidomide based therapy in relapsed multiple myeloma. It is important to appreciate that the patient populations in the four studies were different (prior therapies received, cytogenetics/risk categories). The ELOQUENT-2, ASPIRE and POLLUX trials primarily had patients with Bortezomib exposed/refractory patients, Lenalidomide refractory patients were excluded from all studies. The ELOQUENT-2 trial appeared to have a higher proportion of high risk cytogenetics compared with the other two trials, although this may have occurred due to the centralized evaluation of cytogenetics/FISH. The first three studies (ELOQUENT-2, ASPIRE, TOURNMALINEMM1) led to drug approvals for their respective drug combinations, whereas POLLUX may lead to a label change for Daratumumab later this year. Table 2 summarizes some practical considerations on how best of use these four regimens.
Bortezomib-based combinations Bortezomib (V) was the first proteasome inhibitor to be approved for multiple myeloma and has been commonly used in upfront and relapsed myeloma treatment. V-based combination may be considered for patients in their first relapse if they have: •
Bortezomib naïve patients.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with good tolerance and PFS of at least 12-18 months. Especially for translocation (4;14) patients.
•
Clinical or biochemical relapse: Received R-based induction regimen at the time of diagnosis with poor tolerance and/or PFS of less than 12 months.
•
Biochemical relapse: Received V-based induction regimen at the time of diagnosis followed by low-dose V maintenance with good tolerance and PFS of at least 24 months. Especially for translocation (4;14) patients.
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For patients who are eligible for Bortezomib-based regimens, there are two relevant Phase III studies (Table 3) – PANORAMA-117 and the CASTOR 18. PANORAMA-1 was a phase III, randomized, double-blind, placebo controlled trial which enrolled relapsed myeloma patients to receive either Panobinostat-Bortezomib-Dexamethasone (FVd) or placebo-Bortezomib-Dexamethasone (Vd). Panobinostat is an oral pan-deacetylase inhibitor that had been shown to have synergy with Bortezomib in preclinical studies. The study met its primary end point of improvement in PFS for the panobinostat group (11.99 vs 8.08 mths) and also reported higher CR rates (27.6 vs 15.7%) in the panobinostat group. The PVd regimen was associated with adverse events including grade 3 or 4 thrombocytopenia in 67%, diarrhea in 26% and asthenia or fatigue in 24% of patients. More patients discontinued treatment due to adverse events in the panobinostat group (24%) compared to the placebo group (12%). Perhaps the use of intravenous Bortezomib and a more intensive Panobinostat schedule were reasons for the higher rate of adverse events, and other combinations and dosing strategies are under investigation. The PVd benefit, however, was even observed in patients with prior PI and IMiD exposure (median PFS: PVd 12.7 months vs. Vd 4.7 months) and the FDA has granted approval for this subgroup of patients. The CASTOR study compared Daratumumab and Bortezomib-dexamethasone (DVd) with Vd (V 1.3 mg/m2 subcutaneously on days 1, 4, 8 and 11 of a 21-day schedule). The study demonstrated that DVd resulted in better PFS (NE vs 7.16 mths; HR-0.39, p<0.0001) compared to Vd alone. The ORR also improved from 63% for the Vd group to 83% for the DVd group with 59% patients achieving a VGPR or better in the DVd arm. Most common grade 3/4 adverse events were thrombocytopenia (59 vs 44%), anemia (14 vs 16%) and neutropenia (13 vs 4%). 45% of patients developed D-associated infusion reactions with the majority being grade 1 or 2 (grade 3/4, 9%/0%). One drawback of this study was that patients received Vd for 8 cycles, whereas the DVd arm received D till progression. Table 3 summarizes some practical considerations on how to best use these two regimens.
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Carfilzomib-based combinations Carfilzomib (K) is a tetrapeptide epokyketone proteasome inhibitor that binds irreversibly to the constitutive 20S proteasome and immunoproteasome. K-based combinations may be considered for patients in their first relapse if they have: •
Clinical relapse: Received combined V/R-based induction regimen at the time of diagnosis and PFS of <12 months.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with poor tolerance and PFS of <12 months.
•
Clinical or biochemical relapse: Received V-based induction regimen at the time of diagnosis with poor tolerance (significant peripheral neuropathy or GI toxicity).
The ENDEAVOR trial compared Carfilzomib-Dexamethasone (Kd) with Vd and was the first study to compare two different proteasome inhibitors. Patients received K (56 mg/m2, 30 min IV infusion on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle – 20 mg/m2 on days 1 and 2 of cycle 1) or V (1.3 mg/m2 IV or SC; on days 1, 4, 8 and 11 of a 21day cycle). The study reported an improvement in PFS (18.7 mths vs 9.4 mths; HR= 0.53, p<0.0001) as well as superior ORR (76.9% vs 62.6%; p< 0.0001). Specific grade 3 or 4 adverse events of interest included acute renal failure (3 vs 2%), cardiac failure (4 vs 1%), pneumonia (6 vs 7%) and peripheral neuropathy (2 v 8%). The trial had patients who were previously exposed to Bortezomib, but the benefit in the Carfilzomib arm was seen in patients irrespective of Bortezomib exposure prior to study enrollment. Despite the fact that 79% of the patient on the Bortezomib arm received subcutaneous injection, 48% required dose reductions due to adverse events compared to 23% in the Carfilzomib arm. Cardiotoxicity is a class effect of proteasome inhibitors but is seen more often with Carfilzomib. The exact mechanism is yet to be completely understood but baseline ejection fractions may not be a good marker for patients that will develop cardiac toxicity19. Table 3 summarizes practical considerations on how best of use K-
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based regimens compared to V-based regimens. Carfilzomib has been combined with several other agents including Cyclophosphamide 20, Panobinostat 21 and Pomalidomide 22. The combination of Carfilzomib with Pomalidomide and dexamethasone has shown good clinical activity in heavily pretreated patients. In a phase 1 study with mainly double refractory patients (R and V refractory), an overall response rate of 50% was observed with a PFS of 7.2 months. While small, this study shows that this combination may be effectively used for this otherwise difficult to treat population.
Pomalidomide-based combinations Pomalidomide (P) and dexamethasone is currently approved for the treatment of patients with multiple myeloma who have received at least two prior lines of therapies, including Lenalidomide and Bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. The study that led to this approval was a randomized open label phase II study of Pomalidomide alone or Pomalidomide plus low dose dexamethasone. In patients that were treated with pomalidomide and low dose dexamethasone an overall response rate of 29% was observed with a median response duration of 7.4 months 23,24. In this study, refractoriness to Lenalidomide or resistance to both Lenalidomide and Bortezomib did not affect the outcomes with Pomalidomide and low dose dexamethasone. Pomalidomide has also been combined with Bortezomib 25,Cyclophosphamide 26,27, Carfilzomib 22, Ixazomib 28, Daratumumab 29
, Pembrolizumab 30 and Clarithromycin 31 in various other studies (Table 4). For
patients who are relapsing on a R-based combination, replacement of R with P to recapture response may be an emerging strategy in these different combinations.
Daratumumab based combinations Daratumumab (Dara) is currently approved for use in multiple myeloma patients who have received at least three prior lines of therapy including a PI and IMiD or who are double-refractory to a PI and IMiD agent. A phase I/II study established the dose of
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Dara in 104 patients with RRMM 32. Patients were administered Dara at doses of 0.05 mg/kg to 24 mg/kg. A maximum tolerated dose was not established and 16 mg/kg dosing was selected based overall responses (36% in the 16 mg/kg cohort and 10% in the 8 mg/kg cohort). In the registration Phase II study, patients who had received at least three lines of treatment or were double refractory to a PI and IMiD were treated with Dara 33, showing an ORR of 29%. Daratumumab was well tolerated with infusion reactions occurring in 50% patients (Gr 3- 5%, Gr 4-0%), and fatigue and anemia in 40% and33% of patients, respectively. The overall response rate was 29% with 12% having a VGPR or better. The median time to response was 1 month and in this heavily pretreated population the PFS was 3.7 months with a median overall survival of 17.5 months. More recently, a combined analysis of the two studies demonstrated an ORR of 31% and OS benefit for patients achieving stable disease or better 34. These studies have led to the approval of Dara as a single agent but as the results of the POLLUX and CASTOR trials discussed above show, the real advantage of this agent may be in combination with other anti-myeloma agents.
Role of Salvage Autologous Transplant The role of high dose melphalan followed by autologous stem cell transplantation (ASCT) for patients in first remission is well established, but the role of salvage transplant has been less clear. While prospective data are needed in this setting, the American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation and the International Myeloma Working Group have recently issued a consensus statement to summarize best evidence regarding use of salvage ASCT in relapsed MM 35. These guidelines recommend that a salvage transplant be considered in patients who are transplant eligible but did not get a transplant after primary therapy and in patients who relapsed after primary therapy that included a transplant but achieved at least 18 months of remission with their first ASCT. In one phase III study performed in the UK, patients who had relapsed myeloma after at least 18 months after a previous transplant were randomized to induction therapy with
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Bortezomib, Doxorubicin and dexamethasone followed by either high dose melphalan (200 mg/m2) plus ASCT or oral cyclophosphamide (400 mg/m2 per week for 12 weeks) 36
. The study showed an improved PFS for the ASCT group (19 months vs 11 months).
However, oral cyclophosphamide is not widely used as a single agent in this setting and hence the comparator arm of this study may not have been optimal. Several other retrospective analyses have shown that the remission duration after the first transplant is most predictive of outcomes after the second transplant 37-39. The consensus statement stressed the need to explore appropriate post-transplant maintenance in this setting to include monoclonal antibodies, IMiDs and PIs. The statement also highlights the need for prospective studies to address the role of salvage transplant compared to some of the currently available ‘best non-transplant therapy’ options.
Role of Salvage Allogeneic Transplant The role of allogenic transplant is an open question that needs further answers with very few prospective studies. In a small study, 49 patients received a conditioning regimen consisting of melphalan (140mg/m2), fludarabine (90mg/m2) and antithymocyte globulin (60mg/kg body weight) 40. The overall response rate was 95% including 46% CRs but the 1-year treatment related mortality rate was 25%. After 43 months follow up, the 5 year PFS and OS were 20% and 26% respectively. Several studies are also looking at incorporating novel agents into various stages of allogeneic transplant. Further studies will be needed to assess the role of allogeneic transplant, balancing the potential for long term remission with the higher treatment-related mortality especially in the era of growing alternative therapies. Currently, this option should be considered for young, fit relapsed MM patients with higher risk disease, ideally in the context of a clinical trial.
Future Directions
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Management of RRMM is becoming increasingly complex with the arrival of new drug classes and combinations. Our understanding of the mechanisms of resistance to different drugs and drug classes is improving and a biomarker driven approach would be ideal. But it may not be feasible (time, resources, etc.) to do the necessary clinical trials to tease out which regimens are most suitable for particular subgroups of RRMM patients but gaining cautious insights from subgroup analyses may help guide the clinicians, as outlined in this review of data. Some of these regimens may move to the front-line setting and we may need phase III studies to examine the best combination strategies along with sequencing. These issues make biomarker and response (MRD) driven treatment studies more important.
Conflict of Interest: SZU reports consulting for Celgene, Millennium Takeda, Onyx, and Sanofi; speaker’s fees for Celgene, Millennium Takeda, and Onyx; and research funding from Array Biopharma, Celgene, Janssen Oncology, Onyx, Pharmacyclics, and Sanofi. PMV reports consulting for Celgene, Millennium Takeda, BMS, Novartis, Array Biopharma, Janssen; research funding from GSK, Janssen, Merck, Amgen, Oncopeptides and Acetylon. AA reports speaker’s fees from Novartis, Amgen, Janssen and Millennium.
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24. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014; 123(12): 1826-32. 25. Lacy MQ, LaPlant BR, Laumann KM, et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM). Blood 2014; 124(21): 304-. 26. Baz RC, Martin TG, 3rd, Lin HY, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood 2016; 127(21): 2561-8. 27. Larocca A, Montefusco V, Bringhen S, et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood 2013; 122(16): 2799-806. 28. Krishnan A, Kapoor P, Palmer J, et al. A phase I/II study of ixazomib (Ix) pomalidomide (POM) dexamethasone (DEX) in relapsed refractory (R/R) multiple myeloma: Initial results. ASCO Annual Meeting. Chicago, Il; 2016. 29. Chari A, Lonial S, Suvannasankha A, et al. Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma ASH Annual Meeting. Orlando, Fl; 2015. 30. Badros A, Kocoglu M, Ma N, et al. A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) ASH Annual Meeting. Orlando, Fl; 2015. 31. Mark T, Boyer A, Yadlapati S, et al. Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Overcomes Negative Prognostic Impact of Adverse Cytogenetics and Prior Resistance to Lenalidomide and Bortezomib ASH Annual Meeting. Orlando, Fl; 2015. 32. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015; 373(13): 1207-19. 33. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatmentrefractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016; 387(10027): 1551-60. 34. 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(1): 37-44. 35. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant 2015; 21(12): 2039-51. 36. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, openlabel, phase 3 trial. Lancet Oncol 2014; 15(8): 874-85. 37. Sellner L, Heiss C, Benner A, et al. Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients. Cancer 2013; 119(13): 2438-46. 38. Michaelis LC, Saad A, Zhong X, et al. Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow Transplant 2013; 19(5): 760-6. 39. Gonsalves WI, Gertz MA, Lacy MQ, et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant 2013; 48(4): 568-73.
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40. Kroger N, Shimoni A, Schilling G, et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br J Haematol 2010; 148(2): 323-31.
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TABLE 1: Comorbidities to consider in selecting therapies for relapsed MM patients
Comorbidity
Comments
Neuropathy
Velcade (16% Gr 3/4 with IV and 6% with SQ) 1 Thalidomide (15% need treatment interruption) 2 Ixazomib (1% Gr 3/4) 3
Heart disease
Carfilzomib- 4% (Gr 3/4 cardiac failure), 9% (Gr 3/4 hypertension) 4 Panobinostat- 12%- Arrhythmia, 4%Cardiac ischemia 5,6
Acute renal failure
Lenalidomide- Dose adjustment is necessary.
Diabetes mellitus
Steroids- Need careful management of blood sugars.
1. 2. 3. 4. 5. 6.
Moreau P. et al. Lancet Oncol May 2011;12: 431-40 Mileshkin L. et al. J Clin Oncol. Sep 2006; 24(27): 4507-14 Kumar S. et al. Blood Aug 2014; 124(7): 1047-55 Dimopoulos M. et al. Lancet Oncol Jan 2016; 17: 27-38 Panobinostat package insert San-Miguel J.F. et al. Lancet Oncol, Oct 2014; 15: 1195-206
Prior Therapies Median no (range)
HR (95% CI)
Median OS m HR (95% CI)
2 (1-3)
2 (1-3)
87
67
79
26.3
17.6
19.4
* Dose 27 mg/m2
Rd (n=362)
2 (1-3)
DRd (n=286)
Rd (n=283)
1(1-3)
1(1-3)
66
78
72
93
76
14.9
20.6
14.7
NE
18.4
0.7 (0.57-0.85)
0.742 (0.587-0.939)
0.37 (0.27-0.52)
p=0.0001
p=0.0014
p=0.012
P <0.0001
NE
NE
43.7
0.79 (0.63-0.99)
39.6
NE
NE
NE
NE
0.77 (0.61-0.97) p=0.257
Well tolerated, PI refractory not excluded, benefit in high risk patients
All oral, benefit was noted in high risk patients
Best depth of response (93%), perhaps longest PFS, but requires long infusions
Slow Biochemical Relapse OR Elderly Patients with High Risk Features
Rapid Clinical Relapse for Elderly Where Oral Regimen is Preferred
Rapid Clinical Relapse in both Young and Elderly – especially where proteasome inhibitor may be contra-indicated (neuropathy, cardiac issues, etc.)
EP
Long PFS
AC C
Where to Practically Use the Regimen?
IxaRd (n=360)
Pollux
0.69 (0.57-0.83)
p=0.04 Notes
Rd (n=325)
D
Median PFS in months
EloRd (n=321)
TE
ORR (%)
Rd (n=396)
Tourmaline-MM13
M AN U
KRd* (n=396)
Eloquent-22
SC
APSIRE1
RI PT
Table 2: Options for Lenalidomide-based Combinations
Rapid Clinical Relapse in Younger/Fit Patients
1Stewart
AK et al. N Engl J Med. 2015;372:142; 2Lonial S et al. N Engl J Med. 2015;373:621; P et al. N Engl J Med. 2016;374:1621; 4 Dimopolous M et al, EHA 2016
3Moreau
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Table 3: Options for Proteasome Inhibitor-based Combinations Panorama11 PanoVd (n=387 Prior Therapies Median no (range)
Endeavor2 Vd (n=381)
Kd* (n=465)
2 (1-3)
ORR (%) Median PFS in months
2 (1-3)
DVd (n=251)
Vd (n=247)
2 (1-3)
2 (1-3)
55
77
63
83
63
11.99
8.08
18.7
9.4
NE
7.4
0.63 (0.52-0.76)
0.53 (0.44-0.65)
HR: 0.39 (0.28-0.53)
p=0.0001
p=0.0001
p <0.0001
33.64
HR (95% CI)
Vd (n=464)
61
HR (95% CI) Median OS in months
Castor3
30.39
NE
NE
NE
NE
0.87 (0.69-1.10)
0.79 (0.58-1.08)
p=0.026
p=0.13
Notes
Marked increase in thrombocytopenia, diarrhea, asthenia/fatigue, nausea/vomiting; Benefit in LEN and BTZ exposed
Slight increase in cardiac toxicity (5% vs 1%) and hypertension, reduced neuropathy
Benefit seen across all subgroups. Vd given for only 8 cycles in each arm with high PN rates.
Where to Practically Use the Regimen?
Double Refractory, Young Patients
PI Sensitive, Young Patients
PI sensitive/Len refractory, all ae groups
* Dose 56mg/m2 1San-Miguel
JF et al. Lancet Oncol. 2014;15:1195; 2Dimopoulos MA et al. Lancet Oncol. 2016;17:27; 3Dimopoulos MA et al. EHA 2016
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Table 4. RRMM: Studies of Pom-based Combinations
San 1 Miguel
Baz
Larocca3
Mark
Shah
Treatment
Pd
+cyclo
PCP
+clarithromycin
Phase
III
I/II
I/II
302
70
Median No. prior lines
5
ORR (%)
2
4
5
Badros6
Chari7
Krishnan8
+CFZ
+Pembro
+ dara
+Ixa
II
I
II
II
I/II
69
114
32
33
75
25
4
3
5
6
6
4
2 (1-5)
31
65
51
56
50
59
71
44
PFS (mos)
4.0
9.2
10.4
7.7
7.2
NR
NR
NR
Prior Len (%) Prior BTZ (%)
100 100
100 71 Bor refractory
100 78
100 78 Bor refractory
100 97
97 82 PI refractory
100 76 PI refractory
100 68 Bor refractory
Study
N
Data from separate clinical trials, comparative clinical significance has not been proven. 1) San Miguel et al. Lancet Oncol. 2013;14:1055-66; 2)Baz et al. Annual ASH Meeting; 2014 [Abstract 303]; 3) Larocca et al. Blood. 2013;122:2799. 4) Mark et al. Annual ASH Meeting; 2013 [Abstract 1955]; 5) Shah et al. Blood 2015:126:2284; 6) Badros et al, Annual ASH Meeting; 2015;10 [Abstract 506 ) 7) Chari et al. Annual ASH Meeting; 2015;10 [Abstract 508] 8) Krishanna et al; ASCO 2016 [Abstract 509 ]
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Figure 1. Treatment Approaches in Early RRMM Early relapse (1-3 prior lines) Participate in clinical trials with novel agents IMiD-based regimen • No Prior IMiD exposure • Prior IMiD use with good tolerance, durable response and PFS • Prior PI exposure
PI-based regimen • No Prior PI exposure • Prior PI use with good tolerance, durable response and PFS • Prior IMiD exposure • Especially for t(4;14) patients
Len-naïve/sensitive
BTZ-naïve/sensitive
KRd, EloRd, IxaRd, DRd
Kd, KRd, IxaRd, DVd
BTZ-refractory
Len-refractory
EloRd, DaraRd
Kd, PanoVD, KPd, DVd
Autologous transplant • Long remission post 1st transplant (>24 months without maintenance, >36 months with maintenance) • Transplant not part of primary therapy
Adapted from Usmani SZ, Lonial S. Clin Lymphoma Myeloma Leuk. 2014;14 Suppl:S71.
Table 5: Dosing regimens for common combinations Proteasome inhibitor
IMiD
KRd (28 day cycle)
Car- 27mg/2 IV D1,2,8,9,15,16. (C1D1,2-
Rev- 25 mg PO D1-21
20 mg/m2) Infusion time- 10 minutes
M AN U
IRd (28 day cycle)
Rev- 25 mg PO D1-21
SC
ERd (28 day cycle)
Ixa- 4 mg PO D1,8,15
DRd (28 day cycle)
Car- 27mg/2 IV D1,2,8,9,15,16. (C1D1,2-
D
KPd (28 day cycle)
Elo- 10 mg IV Once a week for C-1 and 2. Then once every 2 weeks
Rev- 25 mg PO D1-21 Rev- 25 mg PO D1-21
Other Dex- 40 mg weekly
Dex- 36 mg on days of E. 40 mg if not receiving E.
Dex- 40 mg weekly Dara- 16 mg IV Once a week for C1 and 2, once every 2 weeks for C3-6 and once every 4 weeks thereafter
Pom- 4 mg PO D1-21
Dex 40 mg weekly. Split 20 mg on day of and 20 mg day after Daratumumab infusion. Dex- 40 mg weekly
Car-56 mg/m2 IV D1,2,8,9,15,16. (C1D1,2-
Dex- 40 mg weekly
EP
Kd (28 day cycle)
TE
20 mg/m2) Infusion time- 10 minutes
20 mg/m2) Infusion time- 30 minutes.
FVd (21 day cycle)
Vel- 1.3 mg/m2 IV/SQ; D1,4,8,11
AC C
PI based combinations
Monoclonal antibody
RI PT
Len based combinations
Regimens
DVd (28 day cycle)
Vel- 1.3 mg/m2 SQ D1,4,8,11
Pano 20 mg PO (D 1,3,5,8,10/12) Dex 20 mg on day of and 20 mg day after Vel. Dara- 16 mg IV Once a week for C1 and 2, once every 2 weeks for C3-6 and once every 4
Dex 20 mg on day of and 20 mg day after Vel.