text:
The treatment armamentarium for MM has expanded significantly in recent years, with 4 new therapies approved by the FDA in 2015 alone. With so many agents and regimens to choose from, and more emerging therapies in clinical trials, it is crucial for oncology/hematology healthcare professionals to understand current treatment approaches for newly diagnosed and relapsed/refractory MM.
In this activity, a faculty panel will convene to discuss real-world patient cases, leveraging their expertise and perspectives in a tumor board style exercise. The faculty panel will address some of the most pressing questions facing clinicians today when formulating the most appropriate treatment plans for their patients with MM. Current and emerging evidence-based updates will be integrated to assist in translating this array of information into real-world treatment scenarios and shed light on the progress toward answering many of the clinical challenges faced in MM treatment.
Activity Information
Release date: May 13, 2016
Expiration date: May 12, 2017
Educational credits: 1.0 AMA PRA Category 1 Credit(s)TM
Estimated time to complete activity: 60 minutes
This activity is designed for hematologists, medical oncologists, and other healthcare professionals who treat or manage patients with multiple myeloma.
The goal of this activity is to identify and close knowledge, competence, and performance gaps by providing clinicians with appropriate context and practical application of the latest evidence-based data and guidelines on established and emerging agents and regimens for the treatment of patients with multiple myeloma to improve the quality of care delivery.
The treatment armamentarium for MM has expanded significantly in recent years, with 4 new therapies approved by the FDA in 2015 alone. With so many agents and regimens to choose from, and more emerging therapies in clinical trials, it is crucial for oncology/hematology healthcare professionals to understand current treatment approaches for newly diagnosed and relapsed/refractory MM.
In this activity, a faculty panel will come together to discuss real-world patient cases leveraging their expertise and perspectives in a tumor board style exercise. The faculty panel will address some of the most pressing questions facing clinicians today when formulating the most appropriate treatment plans for their patients with MM. Current and emerging evidence-based updates will be integrated to assist in translating this array of information into real-world treatment scenarios and shed light on the progress toward answering many of the clinical challenges faced in MM treatment.
At the conclusion of this activity, participants should better be able to:
- Identify the differential diagnosis, prognostic factors, and cytogenetics of multiple myeloma (MM)
- Evaluate current treatment modalities, in combination or alone, for newly diagnosed and relapsed/refractory MM to optimize patient outcomes
- Assess recent clinical trial data on novel and emerging therapies for the treatment of MM and the implications of these agents on clinical practice
- Explain appropriate strategies to manage adverse events and toxicities in patients with MM
Paul G. Richardson, MD
RJ Corman Professor of Medicine Harvard Medical School
Clinical Program Leader, Director of Clinical Research Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute Boston, Massachusetts
Sergio A. Giralt, MD, FACP
Chief, Adult Bone Marrow Transplant Service Melvin Berlin Family Chair in Myeloma Research Memorial Sloan Kettering Cancer Center Professor of Medicine
Weill Cornell Medical College New York, New York
Shaji Kumar, MD
Professor of Medicine
Mayo Clinic College of Medicine Consultant, Division of Hematology Mayo Clinic
Rochester, Minnesota
Accreditation Information
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Credit Designation
Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
For information about the accreditation of this program, please contact Global at 303-395-1782 or inquire@ globaleducationgroup.com
In order to receive credit for this activity, during the period, 05/13/2016, though 05/12/2017, participants must read the learning objectives and faculty disclosures, study the educational activity, and score a 75% or greater on the activity post-test. Your completed evaluation is requested.
Global Education Group (Global) requires instructors, planners, managers and other individuals and their spouse/ life partner who are in a position to control the content of this activity to disclose any real or apparent confl of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.
The faculty reported the following financual relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CME activity:
Paul G. Richardson, MD
Reported Financial Relationship
Member of advisory committee: Bristol-Myers Squibb Company; Celgene Corporation; Genmab; Johnson & Johnson; Millennium Takeda; Novartis Pharmaceuticals Corp.
Sergio A. Giralt, MD
Reported Financial Relationship
Grant/Research support: Celgene Corporation; Johnson & Johnson; Sanofi; Honoraria: Amgen, Inc.; Celgene Corp.; Johnson & Johnson; Sanofi
Shaji K. Kumar, MD
Reported Financial Relationship
Consultant/Independent contractor: Kesios Therapeutics; NOXXON Pharma; Skyline Therapeutics Limited; Consultant/Independent contractor (all to Mayo Clinic - Rochester): Amgen, Inc.; Bristol-Myers Squibb Co.; Celgene Corp.; Janssen Pharmaceuticals, Inc.; Takeda Pharmaceutical Co. Ltd; Grant/Research support (all to Mayo Clinic - Rochester): AbbVie; Celgene Corp.; Janssen Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corp.; Sanofi Takeda Pharmaceutical Co. Ltd.
The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Amanda Glazar, PhD, Andrea Funk, Laura Gilsdorf, Linda Gracie-King, MS, Ronald Viggiani, MD, Isabelle Vacher,
Deborah Middleton, MS and Jocelyn Timko, BS do not have any financial relationships or relationships to
products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and AXIS Medical Education do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the offi prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
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TumorBoard: Challenging Cases in Multiple Myeloma Patient Care
Paul G. Richardson, MD:
Welcome to this CME-certified activity. Dr. Giralt, Dr. Kumar, and I will be using a case-based approach to discuss multiple myeloma (MM) treatment. First, we will briefly discuss the pathophysiology, epidemiology, diagnosis, staging, and risk assessment for MM.
Sergio A. Giralt, MD, FACP:
One of the things that I'm getting more and more calls about is what's happening with the new diagnosis of MM and smoldering myeloma. With the new criteria—myeloma-defining events such as clonal bone marrow plasma cell percentage ³60%, more than 1 focal lesion on magnetic resonance imaging (MRI), and an involved versus uninvolved serum free light chain ratio of ³100—we know these people are at high risk of developing end-organ damage known as the CRAB criteria, which includes hypercalcemia, renal insufficiency, anemia, and bone lesions. The new definition of smoldering MM requires both criteria to be met: serum monoclonal protein (IgG or IgA) ³30 g/L or urinary monoclonal protein ³500 mg/24 hr and/or clonal bone marrow plasma cells 10% to 60%, and the absence of myeloma-defining events or amyloidosis (Rajkumar et al, 2014). According to the new guidelines, patients who meet these criteria actually require treatment now, and they require the same treatment as patients with stage I symptomatic myeloma. The International Myeloma Working Group (IMWG) revised diagnostic criteria for MM and smoldering MM no longer requires patients to exhibit end-organ damage before treatment is initiated (Rajkumar et al, 2014).
Dr. Kumar and I were speaking with community physicians at a large meeting recently and we realized that these new guidelines change their treatment paradigm a bit. In a sense, it does make things a little bit more straightforward. There are patients who they were very concerned about that may experience rapid disease progression, and now physicians have clear guidance that the patients should be treated. But the physicians were unclear about how the patients should be treated. We were making the case that these patients need to be treated as if they had symptomatic myeloma, with triple induction, consolidation, and maintenance therapy, if they were not going to participate in a clinical trial.
In the context of pathophysiology, although we're learning more and more about the biology of this disease, about the issue of clonal type and clonal waves, for all practical purposes we still are treating patients more or less all the same way.
Shaji Kumar, MD:
True. I think quite a bit has changed with respect to the diagnostic criteria. But again, taking a step back and just looking at the epidemiology of the disease, and the fact that we understand it's a spectrum of diseases, we are drawing the lines at a little different time point compared to what we were before. However, more than just the fact that the criteria changed, there is a consensus among every one of us in the field that we could actually start treating patients before something bad happens. I think that is really a paradigm shift for the disease overall. And that's not something we would have thought about 10 years ago when we did not have all the drugs that we have today.
I think a lot of it is driven by the ability for us to deliver effective regimens with less toxicity than we used to before. However, clearly, in terms of understanding the disease biology, I think we're certainly making great strides, especially understanding the genomic complexity and the understanding that we are not dealing with a single disease but rather a heterogeneous group of diseases probably driven by different underlying mechanisms but with a common phenotype.
Dr. Richardson:
Next, please let's comment on what we're seeing in terms of myeloma epidemiology because we are seeing increases in incidence globally and particularly in certain countries.
Dr. Giralt:
I think environmental exposures definitely play a role. I also think, remember the population is definitely getting older, and to a certain degree—thanks to wonderful work that you and others, the Multiple Myeloma Research Foundation, and the IMWG in educating primary care providers—I definitely think there's much more awareness now about myeloma. So, when an older patient comes in with recurrent pneumonia, we are thinking that maybe this patient has underlying immune suppression, and we start thinking about myeloma.
Dr. Kumar:
I think overall we are seeing more patients with myeloma, but again when you look at age-adjusted population basis it may not be such a dramatic change over the years. But I think it's certainly understood more in terms of environmental exposures, in terms of ethnicity, how it's 2- to 3-fold higher in the black population compared to whites, less so in Hispanics or Asians (Greenberg et al, 2012). We also have, I think, a better understanding about the familial risk of it being 2- to 3-fold higher in first-degree relatives (Vachon et al, 2009). But again, we don't know how much of that is environmental exposures versus genetics in terms of familial risk.
Dr. Richardson:
I think in certain countries they're seeing certain changes. For example, in Taiwan, which has a relatively well-organized national system and in the Chinese population, myeloma is relatively uncommon. However, in the past 25 years, they've seen a 5-fold increase in the incidence of MM, particularly in certain populations, such as agricultural workers and, interestingly enough, healthcare workers (Huang et al, 2007). So, some interesting observational data are emerging.
As we know, there are other epidemiological factors that may be relevant. For example, we know that woodworkers are at risk for this disease, and that workers exposed to radiation and other particular organic chemicals may be at risk for MM (Jagannath et al, 2008). And finally, of course, we are aware now that professional firefighters have an increased risk for this disease, suggesting that chemical exposure associated with large factory- or warehouse-based fires may be more likely to cause the illness.
Dr. Kumar:
One other thing to highlight is risk assessment. We now have the revised International Staging System (R-ISS) from the IMWG that really incorporates a lot of what we have learned about the disease (Palumbo et al, 2015). The fact that genetic abnormality is clearly the major driver for prognosis, and combining that with lactate dehydrogenase (LDH) and the old ISS staging system really does make that staging system more current. The R-ISS combines the ISS with chromosomal abnormalities detected with interphase fluorescence in situ hybridization (FISH) to provide a simple and reliable prognostic staging system to stratify MM (Palumbo et al, 2015).
Dr. Richardson:
I agree, and the increasing use of additional imaging, with MRI and positron emission tomography/ computed tomography is helping to distinguish smoldering from active disease.
Dr. Giralt:
I think this is another area where we really do need to do much more work in divulgation, because we still have patients who are being treated outside of an academic center, and many of them don't have beta-2 microglobulins done at the time of diagnosis, or don't undergo a full FISH panel for myeloma performed. I think it's very important that community oncologists understand that this actually now will define what the best treatment is for many patients.
Dr. Richardson:
The treatment armamentarium for MM has expanded significantly in recent years, with 4 new therapies approved by the US Food and Drug Administration (FDA) in 2015 alone, and 1 additional approval for an existing drug as well as two others for expanded indications to a total of 7 in one year. New drugs include panobinostat, the first histone deacetylase inhibitor approved for MM (FDA News Release, 2015a); daratumumab, the first monoclonal antibody approved for MM (FDA News Release, 2015b); ixazomib, the first oral proteasome inhibitor approved for MM (FDA News Release, 2015c); and elotuzumab, a second monoclonal antibody targeting the SLAMF7 protein (FDA News Release, 2015d). Carfilzomib, which was initially approved in 2012, received an additional approval for relapsed MM in 2015 (FDA News Release, 2015e). This adds to the already approved immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), and proteasome inhibitors (bortezomib, carfilzomib). Table 1 provides a summary overview of currently available therapies for MM.
Dr. Richardson:
Please let's now turn our attention to the case studies in this activity.
Case Study #1
Dr. Richardson:
The first case is a 56-year-old man previously in good health. He presents with a 4-month history of lower back pain, classic left-sided chest discomfort, and progressive fatigue. His examination is noteworthy for some mild pallor and also some tenderness to palpation and muscle spasm in the lumbosacral region, as well as some tenderness to palpation in the chest wall. After an initial diagnostic workup (shown in Table 2 and Figure 1), MM was diagnosed.
Dr. Richardson:
So, let's discuss some management issues for this patient with newly diagnosed MM, including the choice of initial treatment, the utility of vertebroplasty/ kyphoplasty, and the role and timing of autologous transplantation.
Dr. Giralt:
We now have a lot of guidance about what the initial therapy should be with a patient like this who has normal renal function, stage II disease, and whose beta-2 microglobulin is still less than 5 mg/L, with a deletion 13 chromosome abnormality on metaphase cytogenetics.
Many of us think that patients who have abnormal cytogenetics by karyotype are probably a worse group of patients. Obviously this patient has symptomatic disease with bone involvement and other borderline metabolic abnormalities. So he needs treatment with an induction therapy that's effective and that will not affect stem cells to allow for stem cell collection. We now have 4 randomized trials conducted by European investigators comparing bortezomib- containing regimens to non-bortezomib containing regimens. These studies showed that in the context of symptomatic myeloma, the use of bortezomib as part of the induction regimen improved survival and progression-free survival (Kaufman et al, 2010; Rosinol et al, 2012; Reeder et al, 2009; Einsele et al, 2009). The question is, what should bortezomib be combined with—an immunomodulatory drug or the alkylator, cyclophosphamide?
The prospective IFM 2013-04 European trial that was presented at the American Society of Hematology (ASH) 2015 meeting that compared VTD to VCD showed improvement in overall response rates for VTD (92.3% vs 84%). Very good partial response and partial response rates were significantly higher in the VTD arm (P values = .04 and .02, respectively; Moreau et al, 2015).
I think many of us in the United States think that the combination that you developed, Paul, with lenalidomide, bortezomib, dexamethasone (RVD), is extremely well tolerated, extremely effective, and allows for the collection of stem cells (Richardson et al, 2010). So I think that would be the choice of initial therapy for this patient. Will the combination of carfilzomib, lenalidomide, dexamethasone (KRD) be better? It is too early to say. Published data on that combination showed very high response rates (Jakubowiak et al, 2012).
As for vertebroplasty and kyphoplasty, I would say that a patient who has a lytic lesion or a compression fracture that's symptomatic should be referred for interventional radiology. We have all been impressed by how these patients come in writhing in pain and suddenly after treatment by the interventional radiologist, their pain is gone; it's miraculous.
I think the role of autologous transplant based on the French IFM/DFCI 2009 trial presented at ASH 2015 should still be considered the standard of care for young patients (Attal et al, 2015). We are waiting to see what the American part of the trial will show, and I think at the end we will have enough data, particularly for patients to achieve minimal residual disease (MRD) negativity, to determine whether patients can opt to defer transplant.
I think patients need to be aware that if they do defer transplant, that there is no guarantee that they may actually get it later on, although two-thirds of the patients in Palumbo's study were able to get a second transplant when they were randomized to deferred transplantation. Transplant is a choice, but I think now we have much more information that patients can make an informed choice.
Dr. Richardson:
I agree and I think that the important message around the role of transplant is that it remains a standard of care in younger patients who are eligible. The issue of timing is very important however, because as patients live longer, and especially in the United States, where there are many salvage options can transplant be kept in reserve. Specifically, the question is, if you use a transplant early versus late, is there a survival benefit? That clearly is an open question and our data from our French colleagues did not give us guidance there yet as importantly there were competing causes of mortality in the French analysis (Attal et al, 2015). On one hand, although there were a higher number of myeloma-related deaths in the delayed transplant arm (83% vs 65%), there were a higher number of toxicity-related deaths, both acute and late, in the transplant arm (16% vs 8%). Hence the overall survival was similar for both arms, at 88% at a follow-up of 3 years (Attal et al, 2015) and 83% for the non-transplant versus 80% for the transplant arm respectively at a median follow up of 4 years. Although the updated analysis was not statistically significant, of course, it's an important observation that in the transplant arm 11% of the deaths were due to secondary acute myeloid leukemia, whereas only one death (2%) was seen in the non-transplant arm (Attal et al, 2015).
Dr. Kumar:
After the SWOG study (Durie et al, 2015) results were presented, it's pretty clear between that data as well as the data from multiple European trials that a proteasome inhibitor plus immunomodulatory agent combination is the best initial therapy for these patients. Obviously some older patients may not be able to tolerate this combination and those patients can do well with lenalidomide/dexamethasone combination. I think for patients who can tolerate it, the proteasome inhibitor/immunomodulatory drug combination is the best choice. Whether it is VTD or whether it is RVD, obviously depends on the availability of the drugs and the cost involved. RVD is the only one that has shown an overall survival benefit compared with the VTD trials, where progression-free survival (PFS) is the only improvement that we have seen so far (Cavo et al, 2010). Having said that, I think VCD may still have some role in situations where cost may be a factor. If renal function is compromised, VCD could be a choice in those groups of patients as well.
Regarding the role of autologous stem cell transplant, I think what really needs to be highlighted is that despite all of these new drugs and combinations with really high efficacy, transplant still has a major role to play. I know we highlighted the increased treatment- related mortality in the transplant arm in the French IFM trial (Attal et al, 2015), but obviously there are variations in the expertise at individual centers, in terms of the total volume of patients with MM they see, and obviously that is one of the fallacies of studies that recruit patients from multiple centers. I know in most of the larger centers, the treatment-related mortality related to transplant in MM is very small. So I think that needs to be taken into consideration.
Nonetheless, I think between what the French trial showed, and what the 2 randomized trials that Dr. Palumbo conducted, it's pretty clear that stem cell transplant can still improve on that response, despite getting combinations of highly effective agents (Attal et al, 2015; Palumbo et al, 2014). Regarding the timing of transplant, I think the French trial still leaves the choice for patients to make if they are so inclined. However, as Dr. Giralt mentioned, we need to collect the stem cells ahead of time, and obviously these patients should try to get their transplant at the time of the first relapse rather than delaying it even further.
Dr. Richardson:
I do agree that the important message around timing is that patients have choices, particularly in the United States, and not least because of our highly effective salvage strategies that are available. I completely concur that early transplant versus late remains a critical question. Of course, in the US trial what remains a fundamental difference versus the French experience is the duration of maintenance therapy (Attal et al, 2015) and what we know from the MRD analyses is that maintenance really matters.
I do think that Dr. Giralt raised a very important point about new combinations building on the proteasome inhibitor, lenalidomide, dexamethasone backbone. In other words, we have shown that RVD obviously is better than lenalidomide and dexamethasone (RD) alone, with a survival benefi as well as PFS benefi (Durie et al, 2015). I am also impressed by the KRD data (Avet-Loiseau et al, 2015). I think that they are very provocative, particularly the quality of responses over time and the absence of significant neurotoxicity. Thus I do think KRD does offer a very attractive option to patients who are looking for a minimally neurotoxic approach, but also, of course, we do recognize there are some caveats to that with the emerging understanding of the vascular toxicity seen with carfi omib and its importance in terms of the thrombo-embolic hypertensive, pulmonary, cardiac, and renal side effects encountered. Fortunately, these are uncommon and, in the context of a serious form relatively rare.
Dr. Kumar:
I think the KRD data definitely look very promising. Unlike the transition from RD to RVD, where obviously there are preclinical data suggesting that there is synergy and it's actually a paradigm change; here we are looking at basically tweaking it further by using something that's potentially more efficacious. There are still obviously some concerns about toxicity and the impact on the quality of life; the patient has to come to the hospital twice a week to receive infusions. So I think this is the place where we really have to rely on head-to-head data from phase 3 clinical trials that are currently ongoing before we can say one versus another is definitely the way to go.
Dr. Richardson:
That's very fair, and I completely agree. In the same vein, this important question of the timing of transplant and who benefits from what, when, and the fact that clearly one size does not fit all, will also be answered by current ongoing randomized trials. So I think we've got some very exciting times ahead to further help us tailor treatment.
Dr. Giralt:
There's been dramatic progress in the treatment of patients who have myeloma. But we really think that, particularly for the transplant-eligible patients, it is essential to refer patients early on, to be able to collect enough stem cells, and whether patients opt for an early or late transplantation, a lot of it will depend on their personal factors. The preponderance of data does suggest that at least early transplant will be associated with a PFS benefit (Attal et al, 2015). The cost of treatment will also need to be incorporated into this because I think cost issues are starting to become part of the equation.
Dr. Richardson:
I think while our French colleagues have done a fabulous job of looking at MRD and assessments of MRD, another difference between the French and the US studies is that in the French study, there is no quality-of-life assessment, which we have in the US trial that is ongoing (Richardson et al, 2014). Moreover, we also have a cost analysis in the current study as well, which will hopefully be helpful (Richardson et al, 2014).
Case Study #2
Dr. Richardson:
The second case is a 68-year-old man with a history of hypertension and type 2 diabetes. He presented with progressive fatigue, night sweats, and dyspnea on exertion. This patient was evaluated by his local primary care physician and found to have a hemoglobin level of 8.3 g/dL, and a mean corpuscular volume of 101 fL.
With this symptomatic and profound anemia, and macrocytosis, he was referred to a hematology/ oncology specialist. Table 4 shows patient and disease characteristics, his initial treatment course, and his options for stem cell mobilization and harvest, which we will discuss next.
Dr. Giralt:
I think the data suggest that stem cells from this patient might be collected with filgrastim alone (Duhrsen et al, 1988; Weaver et al, 2000; Arora et al, 2004; Giralt et al, 2014; Duong et al, 2014). Most transplant programs are doing just-in-time plerixafor where CD34 level is monitored and if, on the fourth day of filgrastim, it is not over 5 or 10, they each have their algorithm and they'll give plerixafor that night (Smith et al, 2013; Li et al, 2011; Ferzoco et al, 2015). In places where CD34 selection or CD34 monitoring is not available, a lot of transplant programs have gone to upfront plerixafor and filgrastim (DiPersio et al, 2009).
Dr. Kumar:
My institution also has the same risk adapted approach, the just-in-time plerixafor strategy. With that approach, we use plerixafor only in approximately 50% of the patients, and the failure rate is practically 0, maybe 1% at the worst.
Dr. Giralt:
We are doing chemo-mobilization in patients who have more than 10% plasma cells. Data suggest that these are the people who have poor stem cell collections and that the chemo-mobilization actually helps them (Tuchman et al, 2015; Giralt et al, 2014; Duong et al, 2014).
Dr. Kumar:
We have been doing essentially the same thing, but not using bone marrow plasma cell percentage, but presence of circulating plasma cells. In people with significant residual disease and circulating plasma cells, we tend to use cyclophosphamide mobilization.
Dr. Richardson:
We've been more traditional and used cyclophosphamide and granulocyte colony- stimulating factor (G-CSF) because we like the additional cytoreduction that cyclophosphamide can offer. Preclinical data from a number of years ago showed that the viability of circulating tumor cells mobilized during stem cell mobilization was reduced when this was done in the context of cyclophosphamide use (Richardson et al, 2014).
Having said that, I do agree with you about plerixafor plus G-CSF, and G-CSF alone even, but we still do feel comfortable using cyclophosphamide simply because it's such a well-tolerated and potent chemotherapeutic. Generally speaking, we've seen great results when we've used it. To some extent, if there is a bit of a carryover also from the lenalidomide recommendations, which were to use cyclophosphamide to help get across any problems that one might run into with lenalidomide effects on mobilization.
Dr. Richardson:
Now, let's get back to the patient in our case. His mobilization and transplant approach and recovery are outlined in Table 5, along with maintenance therapy and consolidation considerations, which we will discuss next.
Dr. Richardson:
The question really is, in this man who's achieved a complete response, maintenance or no maintenance? If maintenance, what agent and what duration of maintenance therapy? Would we also consider consolidation and consolidation plus maintenance? Let's ask that first, consolidation or no consolidation?
Dr. Giralt:
I think the honest answer is that we don't know. The randomized trial from the Blood and Marrow Transplant Clinical Trial Networks (BMT CTN 0702) is asking the question in the context of lenalidomide maintenance, what is the role of consolidation with either a second high-dose melphalan or whether to use 4 more cycles of RVD (Blood and Marrow Transplant Clinical Trials Network, NCT01109004)? It is an important question.
The tandem question has never been answered in the context of modern treatments with a proteasome inhibitor and an immunomodulatory drug. That actually when we look at some randomized trials that were done in Europe, patients who were in countries where they received 2 transplants did better than those who received only 1, and this actually holds for people with high-risk disease (Sonneveld et al, 2012).
I think it is fair to say that in the context of lenalidomide maintenance, we are uncertain what the role of consolidation is. We all know that depth of response is important. This patient has achieved a complete remission. He actually had a complete remission prior to going to transplant. So he may be a patient for whom no maintenance would be appropriate; the group of patients before we had late maintenance lenalidomide were the ones who did the best. This is the hardest conversation I have in clinic today.
Dr. Kumar:
I completely agree. I think the role of consolidation is really hard to determine, but there's enough tangential evidence to suggest that there's a role for additional therapy, whether we use it in a short duration, more intense consolidation versus a more longer duration, less intense maintenance (McCarthy et al, 2012; Attal et al, 2012; Palumbo et al, 2014).
At the end of the day, I think it's probably the additive effect of both of these approaches.
Dr. Richardson:
I agree. We're fairly convinced by the consolidation data, by first of all Michele Cavo's study of VTD versus TD, showing that improvement in response also translated in PFS benefit comparing VTD to TD post SCT (Cavo et al, 2010). A Nordic study group showed that bortezomib consolidation resulted in an improvement in PFS (Mellqvist et al, 2013). Michel Attal and colleagues have become strong advocates of consolidation (Roussel et al, 2014). In that regard, in our prospective trial, the DETERMINATION study, we're looking at RVD for a total of 2 cycles of consolidation post-transplant followed by our maintenance (Dana-Farber Cancer Institute and Richardson, NCT01208662).
In my experience, consolidation is generally very well tolerated after transplant. The one thing to be careful about is the neurotoxicity of bortezomib in this context. Alkylating therapy can increase neurotoxicity across the whole procedure, be it cyclophosphamide or melphalan, and I would argue perhaps that they're going to be some very interesting data about consolidation with carfilzomib in the future.
Dr. Kumar:
I think we know that carfilzomib is an effective proteasome inhibitor. I think all the new drugs probably should be considered for consolidation, especially the monoclonal antibodies. One could argue monoclonal antibodies should have a role in consolidation because that is an agent that patients would not have been exposed to up until that time. Perhaps a totally different class of drug has much more efficacy as a consolidating agent.
Dr. Richardson:
We've had experience with carfilzomib consolidation. It's been generally very well tolerated from a stand- point certainly of neurotoxicity. I have to say, though, it's not been without issues in terms of fatigue. There also have been some instances of pulmonary hypertension being seen as well as other vascular phenomena (Jakubowiak et al, 2015), but these are limited data so one has to be careful about overinterpreting the results from them.
Dr. Giralt:
We have experience with carfilzomib consolidation, particularly in patients who have suboptimal responses to induction to RVD. These are people who we then put on carfilzomib as consolidation and maintenance. As you say, for the most part it's very well tolerated. However, there is a cardiopulmonary signal that cannot be ignored there.
Dr. Kumar:
We are not using carfilzomib in the setting of consolidation, at least that's not a common practice at my institution. There may be some selected patients in whom we might end up using this approach, especially the younger ones with residual disease, but in general it's not a routine practice for us.
Dr. Richardson:
I would stress that we're only doing this in the context of clinical trials. Specifically, we've done it as part of Andre's study post-transplant with KRD (Jakubowiak et al, 2015). But, again, I've been impressed by the absence of neurotoxicity, but, just as you pointed out earlier, there are other side effect profiles that are important to bear in mind, including this vascular signal which we need to better understand.
Dr. Giralt:
I think the immunomodulatory alone, lenalidomide, has been established as the standard of care based on the CALGB/ECOG/BMT CTN 100104 trial, which showed a PFS difference and a survival difference in the United States (Holstein et al, 2015; NCT00114101). There are other 2 trials where lenalidomide maintenance has been used, showing a PFS difference. We do recognize that in people with high-risk disease based on cytogenetics, lenalidomide alone may not be enough, or is probably not enough. I've been very intrigued from the data that come from Emory with a double maintenance therapy with the immunomodulatory agent and the proteasome inhibitor. Likewise the data coming from the Nordic trial in which prolonged treatment with a proteasome inhibitor, bortezomib, actually reduced, abrogated the bad risk of deletion 17 (Mellqvist et al, 2013).
So I think, although we don't have data from randomized trials to help inform practice, I am routinely using a combination maintenance with bortezomib and lenalidomide for patients with high- risk disease. I'm doing it until progression, until we get a better idea of what MRD negativity means.
Dr. Kumar:
For patients with high-risk disease, our approach has been to give them bortezomib maintenance to progression. Patients with standard-risk disease, with residual disease, we always give lenalidomide-based maintenance and the ones who are in complete response or even MRD negative post-transplant, we have a discussion about the pros and cons of maintenance, and that may be one group that we may not lean as strongly toward maintenance as with other patients.
Dr. Richardson:
Our practice very much refl Dr. Giralt's in this regard. We use lenalidomide maintenance, typically 3 weeks on, 1 week off, because the continuous dosing we sometimes fi more challenging outside of a protocol, and we like to use bortezomib every 2 weeks in high- risk patients (defi by either cytogenetics and/or ISS stage or an inadequate response to initial treatment followed by residual disease post-transplantation). The tolerability profi we found with that is generally fairly good, especially with the every-2-week bortezomib and the use of subcutaneous administration.
Dr. Giralt:
Good point. There is a signal, heard anecdotally, that the syncopated lenalidomide 3 weeks on, 1 week off, not only is better tolerated, but actually may be associated with a lower risk for second primary malignancies.
What's your take on that? Because it's not the way the trials were done (McCarthy et al, 2012; Attal et al, 2012).
Dr. Richardson:
I personally think it is a very interesting point because I think that the continuous dosing does generate the real challenge of tolerance. I can tell you from the French American studies, we are seeing some important differences post-transplant. In other words, the ability to tolerate continuous dosing of lenalidomide on the non-transplant arm does appear to be easier than it is on the transplant arm in our preliminary results from the IFM DFCI 2009 study.
This is fascinating because it does suggest that post- high dose alkylation in autologous transplant, perhaps a better approach would be 3 weeks on, 1 week off. Indeed, a number of studies are now starting to look at that and I think it's a great observation, which requires further evaluation.
Dr. Kumar:
What I found is that patients tend to tolerate it better when you give it 3 weeks on, 1 week off. I agree that's increasingly using that approach in the maintenance setting.
Dr. Richardson:
There are data to support this from the original O14 study in relapsed refractory MM with lenalidomide monotherapy, where we did use a 3-week-on, 1-week- off regimen as part of the continuum of treatment, and tolerability was remarkably good (Richardson et al, 2009). So it's not as if this is a "data-free zone," but I agree, the post-transplant studies have not validated this regimen per se, other than in the context of dose reduction and schedule change for toxicity.
Sergio, where do you think people are going with this syncopated schedule?
Dr. Giralt:
I think the whole issue of maintenance, particularly the duration of maintenance, is going to become the next important question that we have to address. The determination trial with both the French arm compared to the American strategy will help a lot for both our patients and our colleagues to decide whether it should be until progression or not. It will be interesting; we are preparing proposals that we now have a large subset of patients out there who are on lenalidomide maintenance. We now have 2 MRD assessment strategies: one with one next-generation sequencing and the other with multiparameter fl w cytometry. We think we need to develop clinical trials looking at what the role of these MRD assessments are.
Dr. Richardson:
Table 6 describes the patient's post-transplant course.
Relapsed/Refractory Treatments
Dr. Richardson:
Table 7 describes the patient's salvage therapy options, which we will discuss next. Remember, this patient was treated with RVD followed by transplantation followed by R maintenance thus far. Table 8 specifically reviews new agents for relapsed/refractory MM that were approved by the FDA in 2015.
There is one thing I would like to highlight in this particular patient scenario: a patient who is on lenalidomide maintenance and who experiences disease relapse 30 months after transplant—I would consider them to be relatively high risk considering the median—the clinical trials were showing 44 months with maintenance (McCarthy et al, 2012; Attal et al, 2012). Otherwise, in terms of the particular regimens for these patients, I always like to use something, some class of drugs that they are not receiving. So in my practice, the patients who are experiencing disease relapse on lenalidomide maintenance, I tend to use the VCD combination, if there is no contraindication to using bortezomib in the form of neuropathy and so forth.
The data that we have from phase 3 trials—the ASPIRE trial of KRD, and the ELOQUENT-2 trial of elotuzumab/ lenalidomide/dexamethasone (Stewart et al, 2015; Lonial et al, 2015; Dimopoulos et al, 2015)—both of these trials are really not in the group of patients who are experiencing active disease relapse while on maintenance therapy. Extrapolating the data becomes a little bit more difficult. However, my second choice in this particular patient certainly would be a lenalidomide/ dexamethasone-based combination, if you just go by what is available from these phase 3 trials.
Dr. Giralt:
This is an interesting population because we really don't have data from phase 3 trials to inform us. I think we would go with the basic principle that you would like to use drugs that the patient has not been exposed to already. I think a carfilzomib-based salvage with a triplet would be appropriate, for example, KRD (Stewart et al, 2015) or carfilzomib/ pomalidomide/dexamethasone (Shah et al, 2015). Another option is actually the bortezomib/ dexamethasone/panobinostat triplet. The randomized phase 3 PANORAMA-1 trial of patients who had 1 or 2 prior therapies showed that the combination of bortezomib/dexamethasone/panobinostat did better than bortezomib/dexamethasone in terms of median PFS (San-Miguel et al, 2014). The patient in this case has not received a proteasome inhibitor in a long time.
Obviously, the best thing is to offer these patients is clinical trials (Anderson et al, 2016), the results of which can inform not only the treatment of today, but also the treatment of tomorrow. The patient in our case scenario did have a long remission, more than 12 months from his first transplant. And many of us, based on Gordon Cook's data, would suggest that he may benefit from a second transplant (Cook et al, 2014). One of the things we're learning in every situation is that depth of response is important.
Dr. Richardson:
I agree entirely that pomalidomide and dexametha- sone would be a very good treatment option for this man based upon his lenalidomide resistance and having not had an exposure to a second-generation proteasome inhibitor. In that same vein, we have very nice data from the 2015 ASH meeting on the combination of ixazomib and pomalidomide and dexamethasone in the phase 1 Alliance A061202 study, which was well tolerated and very active (Voorhees et al, 2015).
I think the other combination worth mentioning is po- malidomide, bortezomib and dexamethasone— that's the current combination under evaluation in the OPTIMISMM trial (Celgene Corporation, NCT01734928). Then finally, elotuzumab plus bortezo- mib and dexamethasone is not an unreasonable option based upon Dr. Palumbo's promising randomized phase 2 data presented at ASH 2015 (Palumbo et al, 2015).
Finally, I would like to point out that daratumumab may well be an antibody of choice in combination in this setting in the future (Lokhorst et al, 2015). We really don't have current data to use in the early relapse setting at this point, although intuitively we would expect it to be very effective.
Dr. Giralt:
We get a lot of calls now for people with disease that is failing on lenalidomide maintenance asking about the role of adding elotuzumab.
Dr. Kumar:
There aren't really any data backing that approach. One could argue that all the synergy that we see with elotuzumab is not really the impact of lenalidomide on the tumor cell, but actually on the immune cells. If that is the case, then that should be fine, but unfortunately it has not been tested in that population. I prefer to go with something that we know for sure has activity in that setting for somebody who is experiencing active disease relapse on lenalidomide.
Dr. Giralt:
I think in the case we're talking about, an active treatment is essential because this patient has a symptomatic relapse.
Dr. Richardson:
I would agree. And to Shaji's point, this gentleman's progressive disease should be considered a relatively higher-risk relapse because it is within 30 months, while on maintenance, and after having achieved complete remission. The other point to make is that obviously cytogenetic information on this patient's bone marrow would be helpful.
Case Study #3
Dr. Richardson:
Our final case is an 81-year-old woman who presents with bilateral hip pain and anemia and was hospitalized for pain management. Her diagnostic workup and options for therapy are described in Table 10 and Figure 3.
Dr. Richardson:
There are a number of things to think about here, on protocol and off protocol.
Dr. Kumar:
We talk about the combination of proteasome inhibitor and an immunomodulatory agent as being the optimal therapy, but this is a patient who is obviously older, likely to be more frail. This is the group of patients where the data from the FIRST trial really are applicable, and I think a lenalidomide/ dexamethasone combination would be a very appropriate choice (Facon et al, 2013). At the same time, I consider whether to give older classes of drugs, at reduced doses for both. So, for example, the RVD-lite approach is something that certainly should be considered, and the data from the clinical trials are certainly intriguing (O'Donnell et al, 2014).
Dr. Giralt:
This is a situation where I think if you go with the data from the FIRST trial, lenalidomide/dexamethasone plus prolonged lenalidomide would be the standard (Facon et al, 2013). But I think we're all very intrigued with the RVD-lite (O'Donnell et al, 2014). Here is where comorbidity assessment and frailty assessment are essential because you want to make sure that you can control the disease without making things worse for this older woman.
Dr. Richardson:
I agree and I think the thing that we were struck by in her case is the extent of bone disease. In this context, the RVD-lite data (led by my colleagues Jacob Laubach and Elizabeth O'Donnell) have been really very provocative with high rates of response and excellent tolerability seen (O'Donnell et al, 2014). I also wonder about the role of a drug such as ixazomib emerging in that group of patients.
Dr. Kumar:
The data with ixazomib/lenalidomide/dexamethasone is restricted to the phase 2 study at this point, but I think what was quite striking from the phase 2 trial was the tolerability of the drug (Kumar et al, 2014). Now you think, especially somebody at this age with significant back pain issues, having to come into the clinic once a week, versus being able to come back once a month, can make quite a bit of difference. I think the oral proteasome inhibitors clearly would have some advantage in this particular patient and the ixazomib/lenalidomide/dexamethasone data is certainly interesting.
Dr. Richardson:
I would agree with this as a great option for this patient, particularly if she had a cardiac and/or thrombotic history. In the absence of these worries, I wouldn't rule out carfilzomib, would you?
Dr. Giralt:
No, I would not. This is where each of these patients needs to be evaluated individually. If she has good cardiopulmonary function, carfilzomib is definitely a possibility in the event of failing primary therapy.
Dr. Richardson:
Right. Currently we would have to say that, but in the future with randomized data the highest level of evidences could guide the choices. For example, the CHAMPION study, comparing carfilzomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone, hopefully will give us insights into this. Results from the phase 1/2 CHAMPION-1 trial presented at the 2015 ASH annual meeting showed an overall response rate of 77% with once-weekly carfilzomib at a dose of 70 mg/m2 with dexamethasone in these patients, and a generally manageable safety profile although there were at least 2 toxic deaths reported, which is a concern (Berenson et al, 2015).
Dr. Richardson:
So, to review, we hope we've been able to summarize the importance of stem cell transplantation in younger eligible patients. There is excitement around stem cell mobilization and the feasibility of doing this particularly with the advent of newer drugs, such as plerixafor. But critically to talk about the timing and place of transplant and the critical nature of clinical trials in assessing who benefits best from what, when.
In the immunomodulatory drug field, we've talked about lenalidomide and pomalidomide primarily, so please, let's comment briefly also on thalidomide.
Dr. Giralt:
Thalidomide is very nonmyelosuppressive, so people with very poor marrow function. Jatin Shah had a study looking at alternating thalidomide and lenalidomide and there were responses. Thalidomide can be given orally at very low doses, which is an advantage. For people who cannot tolerate lenalidomide because of myelosuppression, I use every-other-day thalidomide maintenance. However, you cannot give it for a long time.
Dr. Richardson:
I agree. I reach for thalidomide more often than I would have thought I would, after pomalidomide and lenalidomideintoleranceand/orfailure, simplybecause I find it so helpful in the context of myelosuppression. In fact I am struck that it, in combination with other platform drugs such as carfilzomib and bortezomib, can be very useful in selected patients. I am also struck by some of the data around its partnering with even some of the newer monoclonal antibodies; for example, the French data would suggest it is very active when given with bortezomib, dexamethasone, and daratumumab (Moreau et al, 2015).
Dr. Kumar:
I think it is mainly the same setting, patients who have signifi bone marrow suppression from all of the prior therapies. It is acomponent of the VTDPACE regimen that we sometimes use in patients with aggressive disease, as a bridge to something else more defi e. I think, though, the combination with monoclonal antibodies may have a uniqueness, especially in the patients with limited marrow reserve, allowing you to deliver 2 or 3 effective agents without causing myelosuppression.
Dr. Richardson:
In the proteasome inhibitor space, we spoke comprehensively about bortezomib. We also touched on the combinations of proteasome inhibitors with immunomodulatory agents, and the excitement around elotuzumab, daratumumab, and ixazomib.
In addition there are some very important new agents in the pipeline. Some of the most exciting are the next-generation histone deacetylase inhibitors, which appear to be better tolerated and very active, particularly ACY-1215 (Raje et al, 2015), and more recently its counterpart which is in oral tablet form, ACY-241—particularly in combination with pomalidomide where early data are very promising for both activity and tolerability (Niesvizky et al, 2015). There is also a new CD38-targeting antibody, isatuximab, which is a promising combination partner with pomalidomide and appears to be very active in a current ongoing phase 1/2 trial (Sanofi, NCT02283775).
Dr. Giralt:
I think another investigational therapy of importance is immunotherapy. I think we were all very impressed with the use of pembrolizumab with lenalidomide that was presented by Jesus San Miguel at the 2015 ASH conference (San Miguel et al, 2015). It brings a whole new and different therapeutic strategy to the treatment of MM, where we know that the immune system is so powerful.
Also, although there have only been case reports, the use of chimeric antigen receptor–modified T cells has been reported: a personalized therapy against a specific target in the malignant plasma cell. I think that is the one that's most exciting; it is actually the one being done by the US National Institutes of Health targeting B-cell maturation antigen.
I'm still skeptical about CD19 as a target for myeloma, although that data need to be seen with a larger number of patients. Now, stellar therapies have been associated with toxicities. I was impressed by how well pembrolizumab was tolerated in the context of lenalidomide/dexamethasone. I think this is where a whole new era is going to open up.
Dr. Richardson:
Checkpoint inhibition in combination with IMiDs as immunotherapy has been stunning. Interestingly, whilst we didn't see much as monotherapy, clearly in combination things are different. Specifically, when you combine with other drugs and immunomodulatory drugs in particular, the results are remarkable.
Dr. Kumar:
I think immunotherapy is definitely the biggest focus, but other small molecules, the BCL2 inhibitor, venetoclax, is pretty exciting, especially for patients with the 11-14 translocation (Kumar et al, 2015; Moreau et al, 2015). The AKT inhibitor (afuresertib) data look pretty interesting in combination with proteasome inhibitors (Spencer et al, 2014). Obviously, that is something that should be going ahead. The selinexor data so far look interesting and that's also in clinical trials (Chen et al, 2014). Then there are data with fi , which is a kinesin spindle protein inhibitor (Shah et al, 2015; Lonial et al, 2013). That data look pretty interesting in combination with dexamethasone.
Dr. Richardson:
I do agree and I do think the AC241 platform in combination with pomalidomide is also impressive and well tolerated with the specifi targeting of HDAC6, an area of promise. I also concur that the other small molecules are opportunities that are well worth exploring and in aggregate provide our patients and us as their caregivers with exciting and increasingly hopeful treatment options for the future. •
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Palumbo A, Cavallo F, Gay F, et al. Autologous Transplantation and Maintenance Therapy in Multiple Myeloma. N Engl J Med. 2014;371(10):895-905.
Raje NS, Bensinger W, Cole CE, et al. Ricolinostat (ACY-1215), the First Selective HDAC6 Inhibitor, Combines Safely with Pomalidomide and Dexamethasone and Shows Promising Early Results in Relapsed-and-Refractory Myeloma (ACE- MM-102 Study). Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper84847.html. Accessed May 5, 2016.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. LancetOncol.2014;15:e538-e548.
Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114(4):772-778.
Richardson P, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679-686.
Richardson PG, Laubach JP, Munshi NC, et al. Early or delayed transplantation for multiple myeloma in the era of novel therapy: does one size fit all? ASH Education Book December 5, 2014 vol. 2014 no. 1; 255-261.
Richardson PG. ASH/FDA Joint Symposium on Late-Breaking Drug Approvals. Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida.
Richardson PG, NCT01208662. Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). https://clinicaltrials.gov/ct2/show/NCT01208662. Accessed April 15, 2016.
Roussel M, Lauwers-Cances V, Robillard N, et al. Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014;32(25):2712-2717.
San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, 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. LancetOncol.2014;15:1195-1206.
San-Miguel J, Mateos MV, Shah JJ, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Keynote-023. Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper85801.html. Accessed April 19, 2016.
Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood 2015;126:2284-2290.
Shah J, Feng L, Thomas SK, et al. Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM). Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper82345.html. Accessed May 5, 2016.
Shah JJ, Feng L, Manasanch EE, et al. Phase I/II Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma. Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper85061.html. Accessed May 5, 2016.
Smith VR, Popat U, Ciurea S, et al. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization. Am J Hematol. 2013;88:754-757.
Spencer A, Yoon SS, Harrison SJ, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014;124(14):2190- 2195.
Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27):5436-5443.
Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.
Tuchman SA, Bacon WA, Huang W, et al. Cyclophosphamide- based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma. J Clin Apher 2015;30:176-182.
Usmani S, Weiss B, Bahlis N, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper79029.html. Accessed April 19, 2016.
Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009;114(4):785-790.
Vij R, Kumar S, Zhang MJ, et al. Impact of Pretransplant Therapy and Depth of Disease Response before Autologous Transplantation for Multiple Myeloma. Biol Blood Marrow Transplant 2015;21(2):335-341.
Vishnu P, Roy V, Paulsen A, Zubair AC. Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization. Transfusion2012;52:55-62.
Voorhees PM, Mulkey F, Hassoun H, et al: Alliance A061202, a phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: phase I results. Presented at the ASH 57th Annual Meeting & Exposition; December 5-8, 2015; Orlando, Florida. https://ash.confex.com/ash/2015/webprogram/Paper82846.html. Accessed April 19, 2016.
Weaver CH, Schulman KA, Wilson-Relyea B, et al. Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells. J Clin Oncol. 2000;18(1):43-53.


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Start Your Path Toward a High Demand Medical Career
With Baby Boomers aging and Millennials having children, the demand for skilled healthcare workers is on the rise. Pair this with the passing of the Affordable Care Act, and the need for more medical professionals will continue on through the decade. According to the United States Bureau of Labor Statistics (BLS), the healthcare industry is
Earning an Applied Associate Degree – A Ticket to a Greater Future
In recent years there has been increased focus on encouraging Americans to get a college degree…and for good reason. A postsecondary degree can mean the difference between poverty and a living wage. It can mean the difference between sustainable employment and unemployment. In a speech earlier this year, President Obama stated that a college degree is
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An education at a quality career college can improve your life in many ways. But, quality career training comes at a cost. Here's how you can pay for your education: Through your Future Earnings When you put money toward your education, you set yourself up for a bright future. An associate's degree can offer a
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Wednesday, 19 April 2017
The resignation of the Chief Executive of the Central Adelaide Local Health Network (CALHN) Len Richards leaves Health Minister Jack Snelling with no option but to return from leave and take control of the move to the new Royal Adelaide Hospital.
"The State Government is in the middle of the technical assessment period of the most expensive hospital in the world, the executive responsible for leading the transition to the nRAH has resigned yet the Health Minister intends to continue his leave," said Shadow Treasurer Rob Lucas.
"The nRAH is already $640 million over budget and more than a year overdue yet the Weatherill Government is happy for the project to drift along leaderless at this critical juncture.
"The fact Len Richards has resigned less than three months after being appointed to take charge of the transition to the new Royal Adelaide Hospital highlights the level of dysfunction in SA Health.
"...Click here for full story
Treasurer Rob Lucas said today another leak of a confidential Weatherill
Government Cabinet document was a major embarrassment for Mr Weatherill.
latest leak relates to a decision taken by Cabinet on 31 October 2016 to
transfer the management of all new workers compensation claims from 1 July 2017
to ReturnToWorkSA.
controversial decision is being strongly opposed by many stakeholders including
the Public Service Association (PSA) and Self Insurers of SA (SISA) and affects
the jobs of up to 200 people (139 FTE).
copy of the confidential report presented to Cabinet entitled 'Review of the
Management of Work Injuries within the SA Government' (Phillip Bentley and
Chris Latham, 21 June 2016) has been leaked to the State Liberals.
report raises very serious questions about the reasons for the Weatherill
Government decisions and casts doubt over some of the supposed benefits.
...Click here for full story
Welcome to the website of the Hon Rob Lucas MLC. Rob is a member of the Liberal Party and an Opposition Member of the Legislative Council in the South Australian Parliament. He is also the Shadow Treasurer and Shadow Minister for Finance, Industrial Relations, Public Sector, Business Services and Consumers and Gambling in Steven Marshall's State Liberal Team.
This website is to provide you with information on what Rob has been doing in his capacity as a Legislative Councillor. If you have any issues you would like to raise, or information you think he may find useful, please feel free to contact him.
Alternatively, you can follow Rob's movements on social networking sites Facebook and Twitter.
The Hon. Rob Lucas MLC
You can write to Rob at his
Parliament House office:
North Terrace, Parliament House
His parliamentary office contact
numbers are:
Telephone: +61 8 8237 9313
Fax: +61 8 8237 9562
Alternatively, you can email Rob with any issues or feedback.


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Excellent service, friendly atmosphere. The food is awesome, love the prime rib. I highly recommend The Golden Valley.
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Thanks for helping!Share another experience before you go.
Excellent service, friendly atmosphere. The food is awesome, love the prime rib. I highly recommend The Golden Valley.
Service and food were terrific, a little noisy. Hard to find a "quiet" table for romantic dinner, but if you dont care, go for it!! the menu offered a lot of delicious choices and we were very satisfied with the plates we ordered.
The food was awesome, even if a little pricey. Service was excellent. Only complaint would be that they really need to update the look of the interior.
To begin with a regular customer saw me looking to hang up my coat, so he did it for me. Service was friendly and timely. Our meal was excellent and the quiet atmosphere, in this crowded restaurant, made conversation enjoyable and easy to hear one another.
went there before my nephew's son's hockey final. Ordered a club sandwich not toasted no mayo. Server was too busy to upsell sides at extra coat to pay attention to my order. Sandwich came out toasted which I hate. Server never once came back and asked how everything was. good food, lousy server.
Food and service are great. You definitely get what you pay for. Never had a bad meal. Great options for the kids aswell. Definitely recommend.
Been here before always good food and efficient service. Nice and clean. 2 sets of washrooms. There is even an upstairs dining Love the bar it's fully stocked too.
The food is OK. I don't think they've changed their decor or their menu in 25 years. It is pretty standard fare, nothing spectacular. However, it tastes fine, and the servers are all very nice. Not fine dining but Ok if you are a family.
I personally always get it to go, the inside is usually busy and I'm honestly not pleased with the decor. The last time I dined in the server was rude. But never had any problems with the gentlemen at takeout. Very friendly there. But I'm very fond of the food!
We will be going there for our anniversary this February. Perhaps with some friends or on our own, not quite sure as yet. But I know it will be most enjoyable.
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.Claim Your Listing
It states you serve pizza and yet I don't see it on your menu and also I have adobe reader but I'm having issues trying to upload your website menu.. All I get is a bunch of letters all across my screen. I'm wondering if there's an issue with your website?
The menu form the Golden Valley Restaurant website is not visible to me. I had to view it using the Trip Adviser website.
This should be corrected ASAP.


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(Click Image To Enlarge)
Title: Die Statt Lubeck . . .
Map Maker:
Sebastian Münster
Place / Date: Basle / 1570 ca
Coloring: Uncolored
Size: 15 x 4 inches
Condition: VG
Price: $145.00
Inventory ID: 26167
Early double page birdseye view of the city of Lubeck, with Heraldic images in the sky.
Munster's Cosmography was one of the most influential georgraphical works of the 16th Century. It was published in a number of editions over a half century and was continuously revised and updated to include new illustrations and updated information.
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City Plans & Views of European Cities
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text:
Entertainment News
Posted on 31 January, 2017 7:07
Pharrell is now a father of four! The singer and his wife Helen Lasichanh welcomed triplets last month. "The family is happy and healthy!" Pharrell's rep says in a statement. The babies join older brother Rocket, 8. No other details were released.
Pharrell Williams and wife Helen Lasichanh welcomed three new additions to the family in January


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"The existing arrangements on television have, on balance, served clubs and fans well. The biggest problem is the financial disparity between the top league and the rest." So spoke representatives of a delegation of the all-party football committee of MPs earlier this year on the eve of a meeting with European Commissioners in Brussels.
"The existing arrangements on television have, on balance, served clubs and fans well. The biggest problem is the financial disparity between the top league and the rest." So spoke representatives of a delegation of the all-party football committee of MPs earlier this year on the eve of a meeting with European Commissioners in Brussels.
Since then the Commission has ruled against the Premier League's new three-year contract with Sky, insisting that up to eight live matches per season be made available to other broadcasters as from next season and determining that from 2007 there must be no exclusive broadcaster. No details are yet available of the terms on which Sky will release the matches next season under the deal, which is currently worth £1.02bn to the Premier League.
So does the action of the Commission indicate that the Sky steamroller is finally being halted, that all the lobbying was to no avail? One Premiership chairman said of the Brussels intervention: "They're no more than a bunch of raving lunatics, a cancer growing at the heart of Europe which will destroy us unless it's stopped. They're not accountable to anybody, they're just unelected bureaucrats fuelled by rampant socialism. They're doing their best to be bloody-minded, undemocratic and have two objectives: to damage Sky and promote a European league. They don't understand a thing about football."
What that chairman might consider is whether the end result of the anti-competition thrusts, both here and in Uefa, might turn out eventually to benefit a global operator such as Rupert Murdoch far more than a cursory examination of domestic media markets might reveal. After all, Sky already covers the Champions' League and Murdoch operates in the Far East and the United States.
Anyone seeking an eye-opening read to come out of the holiday torpor should get hold of The Murdoch Archipelago by Bruce Page, which recounts Murdoch's garnering of influence over three continents in fascinating detail. In the United Kingdom, difficult though it may be to believe, he influenced Margaret Thatcher via the columnist Lord Wyatt, and later I believe no one was surprised when Tony Blair's government overruled the firmly argued recommendations of Gavyn Davies's committee on the development of digital television because they would have disadvantaged Murdoch. (But Mr Page does overlook Stephen Byers' rejection of the Manchester United takeover by Sky).
The European Commission wants more matches available for live coverage when the next negotiations take place in 2006 for 2007-08. Sky will have to give up their exclusivity. When Football Association contracts were shared it was the BBC who took turns with Sky usually. ITV and Sky were uncomfortable bedfellows.
The availability of more matches should be good news for fans, as Mario Monti of Brussels desires, but the attraction of Sky to the Premier League has always been flexibility of scheduling. Presumably new ITV and BBC channels would come into play if they were bidders next time? Would Sky reduce subscription charges after losing exclusivity, given that the sports channels were originally a free service? Would they also cut down on the proprietorial smugness that afflicts many of their presenters and commentators and instruct them to ask questions that don't insult the viewers' intelligence?
Having demonstrated they were unable to handle the previous windfalls that the satellite revolution brought, the clubs have now been given two years to make some sense of their sorry finances before the exclusivity premium is phased out. Those MPs who travelled largely in vain to Brussels have to produce a report - expected in February - on the state of football's finances.
The Chancellor, Gordon Brown, has already announced tax relief for supporters' trusts in his pre-Budget statement and is reported in certain political circles to be keenly awaiting the latest report with a view to initiating further reform in the game, re-opening the "fit and proper persons" test for club directors which the FA has been working on for what seems like an age now. In their impressive testimony to the parliamentary inquiry earlier in the year, both Supporters' Direct and the Football Supporters' Federation despaired at the lack of transparency in the game.
Maybe, just maybe, the days of excess are behind us, if it is only exclusivity that Europe was attacking and the Premier League is allowed to continue negotiating future deals collectively. Free-for-alls would lead to lunacy and in that respect at least our reactionary Premier League chairman was right. He and his colleagues might just as well have posted their chequebooks off to Old Trafford if it had become all for one and one for all.
As things stand, there is a chance of sanity returning.Reuse content


text: Seller: danmurphys_au (5,020) 98.7%, Location: Sydney, Ships to: AU, Item: 302127382870 VISIT OUR STORE El Dorado 3 Year Old White Rum 750mL bottle Varietal: RumLiquor Style: White Rum* $59.99per bottle Description: This multi Award-winning Rum - named outstanding at the 2014 International Wine and Spirit Awards - is aged in oak casks and filtered under pressure to maintain the flavours its acquired from its maturation barrels. It is balanced with a smooth citrus and vanilla nose enhanced by notes of chocolate and raisins. It has a smooth and rounded palate evoking coconut and other tropical fruits and a dry balanced finish. --> Product Detail VarietalRumLiquor StyleWhite RumAge3+ Years OldBottled InGuyanaStandard Drinks23.7DistilleryDiamond DistilleryWebsitewww.quittintime.com.au Brand NameEl DoradoSize750mLAlcohol Volume40CountryGuyanaClosureScrew CapDistillerDemerara Distillers Categories Red Wine White Wine Champagne Dark Spirits Light Spirits Beer Help FAQs Delivery Returns & Refunds We accepts Dan Murphy's supports the Responsible Service of Alcohol. New South Wales: Liquor Act 2007. It is against the law to sell or supply alcohol to, or to obtain alcohol on behalf of, a person under the age of 18 years.Victoria: WARNING: Victoria Liquor Control Reform Act 1998: It is an offence to supply alcohol to a person under the age of 18 years (Penalty exceeds $17,000), for a person under the age of 18 years to purchase or receive liquor (Penalty exceeds $700). Western Australia: WARNING. Under the Liquor Control Act 1988, it is an offence: to sell or supply liquor to a person under the age of 18 years on licensed or regulated premises; or for a person under the age of 18 years to purchase, or attempt to purchase, liquor on licensed or regulated premises. South Australia: Liquor Licensing Act 1997, Section 113. Liquor must NOT be supplied to persons under 18. Queensland: Under the Liquor Act 1992, it is an offence to supply liquor to a person under the age of 18 years. For more specific legislation in your state or territory visit our Liquor Licensing Acts page. ABN 88 000 014 675. © 2016 Dan Murphy's. All rights reserved Varietal: Rum, Brand Name: El Dorado, Liquor Style: White Rum, Size: 750mL, Age: 3+ Years Old, Alcohol Volume: 40, Bottled In: Guyana, Country: Guyana, Standard Drinks: 23.7, Closure: Screw Cap, Distillery: Diamond Distillery, Distiller: Demerara Distillers, Website: www.quittintime.com.au, Brand: El Dorado


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Skyscrapers blog by tag: jobs
Passionate Cloud Engineer(s)Published on February 20, 2017 by Frederik Denkens
You are passionate about open source technology, public cloud, devops and modern application architectures and workflows? Then you might be the person we're looking for! We are searching for a cloud engineer to join our distributed team. You will be building reliable cloud platforms, supportand advise our customers developers on the best way forward. You'll […]
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With Brian Cashman scheduled to rappel off a 22-story building dressed as an elf, we have put together our top five items the Yankees GM needs to consider:
1. Make sure Derek Jeter is tucked away in Tampa and nowhere near Cashman's rappelling in Stamford, Conn.
Cashman is rehearsing on Friday, but he'll don his elf costume on Sunday. If he sees any No. 2 jerseys, Cashman may want to watch his back.
2. Cashman volunteered to leap from a 350-foot building, but when he did so he didn't know he would be in a heated negotiation with The Captain and that the rehearsal would be televised on "Fox & Friends."
Get this: Jeter's agent is Casey Close. Close is married to Gretchen Carlson. Carlson is one of the hosts on "Fox & Friends." Will Carlson be "baffled" by Cashman's repelling?
3. Avoid the "reality potion."
Even though it takes guts to volunteer to jump off a building -- harness or no harness -- without a net, it would be a little embarrassing to back out at the last minute. So Cashman would be ill-advised to have any "reality potion" with his bacon and eggs Friday morning.
4. Bring Mo Rivera along.
We all know that nobody closes better than Rivera. Plus, Rivera's agent, Fern Cuza, and Cashman have been on the same page throughout their negotiations. A Rivera pep talk about how to handle pressure couldn't hurt. Maybe Rivera could even let Cashman borrow his song.
5. Make sure the Texas Rangers don't sneak in and sign Cliff Lee.
Even though in reality, Cashman's jumping off a building will have no impact on the offseason and is kind of cool, if not weird, he will hear about it forever if the offseason doesn't go right.


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Tiny Cottons: Warm Ears Chapka Knit Hat - Blue
Tiny Cottons: Warm Ears Chapka Knit Hat - Blue
14.00 32.00
Tiny Cottons
We are our emotions! Good feelings are to share, be generous: spread them, live them! Take the bad moments as lessons. Be your own hero, be yourself. This winter Tiny Cottons collection is all about emotions and their faces, discover them piece by piece and explore the graphic world of feelings! We are our emotions. Face them. Face your faces!
One size. Age 2 - 6
- 70% cotton, 30% extrafine merino wool
- light blue base, navy hands pattern
- chapka model with side cords
Add To Cart


text:
Yes California: #Brexit vote historic and inspiring
The Yes California Independence Campaign announced this evening that while it does not take a position on whether the United Kingdom should or should not have voted to exit the European Union, it applauded the process as a shining example of the right of peoples to self-determination.
"It was exciting to watch self-determination in action, and in the end the majority of the British people determined for themselves in a historic and inspiring election that their future would be better off independent of the European Union. Today's results provide us with a modern-day, western-world example of peaceful and legal secession from a political union and we intend to mimic that process here in California by putting an independence referendum on the ballot so we can exercise our right to self-determination and vote to leave or remain part of the American Union," Louis J. Marinelli, the president of the organization said.
The organization argues that now as the sixth largest economy in the world, California is more economically powerful than France and has a population larger than Poland.
"California is the 7th largest economic power in the world. We're competing with nations like Brazil and France, not states like Florida," Governor Brown wrote in a letter to the Florida governor earlier this year before new economic data moved California into sixth place.
Yes California sees parallels between the #Brexit vote to exit the European Union and its planned referendum on California leaving the American Union and cites (1) how power has shifted from the state to the federal level for decades, (2) that the federal government is a broken, corrupted, and bureaucratic mess, (3) that lobbyists, special interests, corporations, and wealthy campaign contributors control the country due to the Supreme Court's ruling in Citizens United, (4) that the country's flawed immigration system forces millions of Californians to live without documents and makes it illegal for them to work, and (5) that California is forced to subsidize the other states with its taxes all as reasons justifying independence.
"Our continued membership in the American Union means California will continue subsidizing the other member states to our own detriment and to the detriment of our children," Marinelli said. "Whether we discuss issues of peace and security, government and elections, trade and regulation, health, education, and infrastructure, or natural resources and the environment, California is better off independent of the American Union and the District of Columbia just as the British people have now determined their future will be better off independent of the European Union and Brussels."
June 23rd's #Brexit vote resulted in 52% of the United Kingdom voting to leave the European Union. An informal poll of 9,000 Californians conducted by the organization this past February resulted in 41% in favor of California leaving the American Union.


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Bibliographic Details
Title: The Normal Course In Reading: Second Reader,...
Publisher: Kessinger Publishing, LLC
Publication Date: 1896
Binding: Hardcover
Book Condition: Fair
1164976222 Worn from age and use, but has held up remarkably well and can withstand normal handling., jacket: Shelf wear on cover. Bookseller Inventory # 150115033
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