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New Multiple Myeloma Treatments On The Horizon (ASCO 2012)

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Published: May 23, 2012 12:20 pm

During the upcoming annual meeting of the American Society of Clinical Oncology (ASCO), results will be presented from clinical trials involving potential new drugs under development for the treatment of multiple myeloma.

In particular, results for newer, lesser known agents that are in the early stages of clinical development will take center stage. These agents include obatoclax, siltuximab, daratumumab, and SNS01-T.

According to the recently released ASCO abstracts, the agents showed varying degrees of activity in relapsed and refractory myeloma patients. So it will be particularly interesting to see and hear how the myeloma experts react to the initial findings for these compounds.

The current article summarizes the preliminary results from these agents, based on the data available in the meeting abstracts.

Obatoclax

Obatoclax is being developed by the pharmaceutical company Cephalon, a subsidiary of Teva Pharmaceuticals (NASDAQ: TEVA). It is an inhibitor of the Bcl-2 family of proteins. This inhibition causes cell death in cancer cells, preventing tumor growth. Obatoclax is currently being investigated as a treatment for solid tumors as well as for a variety of blood cancers, including multiple myeloma, leukemia, and lymphoma.

MORE INFORMATION:

News articles about other potential myeloma treat­ments: BT-062, carfilz­omib, elotuzumab, marizo­mib, MLN9708, pano­bino­stat, peri­fo­sine, poma­lido­mide, Treanda, Zolinza.

At ASCO, Dr. A. K. Stewart from the Mayo Clinic in Arizona will discuss results of a Phase 1 study of obatoclax in combination with Velcade (bortezomib) for the treatment of relapsed multiple myeloma.

Since it is a Phase 1 trial, the study population is small. The abstract contains data from 11 patients. The median patient age was 62 years. The median time from diagnosis was 4.7 years.

Patients received a starting dose of 14 mg/m2 of obatoclax as a 24-hour continuous infusion on days 1, 8, and 15 of a 21-day treatment cycle, which was then amended to either 30 mg/m2 or 40 mg/m2 of obatoclax as a three-hour continuous infusion on days 1, 8, and 15. In addition, patients received 1.3 mg/m2 of Velcade on days 1, 4, 8, and 11.

Ten patients were evaluable for response; 40 percent of patients achieved a partial response and 10 percent achieved a minor response. None of the patients who received 40 mg/m2 of obatoclax as a three-hour continuous infusion responded.

The researchers did not observe any dose-limiting side effects at the 30 mg/m2 dose level, so it was determined to be the maximum tolerated dose.

The most commonly observed side effects were blood-related or neurologic in nature.

Siltuximab

Siltuximab is a compound that blocks the activity of IL-6, a protein that facilitates myeloma cell growth and resistance to dexamethasone (Decadron). It is being developed by Janssen Biotech, a Johnson & Johnson company (NYSE: JNJ), and has been investigated for the treatment of prostate cancer, ovarian cancer, metastatic renal cell cancer, and Castleman’s disease (excessive growth of lymphatic cells).

At ASCO, Dr. Robert Orlowski from the MD Anderson Cancer Center in Houston will present results from a Phase 2 study comparing siltuximab plus Velcade to Velcade alone in relapsed and refractory myeloma patients.

The study included 286 patients who received either 6 mg/kg of intravenous siltuximab twice weekly plus 1.3 mg/m2 of Velcade on days 1, 4, 8, 11, 22, 25, 29, and 32 in a 42-day treatment cycle or Velcade alone for a maximum of four treatment cycles. After that, Velcade was reduced to once weekly in 35-day treatment cycles.

Patients who progressed discontinued Velcade and could receive 40 mg of dexamethasone daily on days 1 through 4, 9 through 12, and 17 through 20 of a 28-day treatment cycle for a maximum of four cycles. In subsequent treatment cycles, dexamethasone was administered on days 1 through 4 until disease progression.

Patients who received siltuximab plus Velcade were slightly older (median age 64 years) than patients receiving Velcade alone (61 years).

The median treatment duration was five months in both treatment groups, and the median follow-up time was 24.5 months.

More patients on siltuximab plus Velcade responded to treatment (55 percent) than patients on Velcade alone (47 percent). Complete response rates were 11 percent for patients receiving siltuximab plus Velcade and 7 percent for patients receiving Velcade alone.

The median progression-free survival time was longer for patients receiving siltuximab plus Velcade (8.1 months), compared to patients receiving Velcade alone (7.6 months).

However, the median overall survival was longer for patients receiving Velcade alone (36.9 months), compared to those receiving siltuximab plus Velcade (30.8 months).

More patients receiving siltuximab plus Velcade experienced severe or life-threatening side effects (91 percent) than patients receiving Velcade alone (74 percent).

Daratumumab

Daratumumab is being developed by the Danish pharmaceutical company Genmab.  It is a monoclonal antibody that binds to the CD38 molecule, which is found on the surface of multiple myeloma cells.  Daratumumab then signals for the immune system to kill the myeloma cells.

At ASCO, Dr Torben Plesner from Vejle Hospital in Vejle, Denmark, will present preliminary efficacy results from a Phase 1/2 study of daratumumab in relapsed and refractory myeloma patients.

Study participants received escalating doses of daratumumab ranging from 0.005 mg/kg to 24 mg/kg.

The data included in the abstract is based on data from 23 patients who received up to 4 mg/kg of daratumumab.

Daratumumab’s preliminary efficacy evaluation is based on the change in monoclonal (M) protein in the blood or urine.

Of the patients receiving up to 1 mg/kg of daratumumab, 18 percent of patients achieved a reduction in M-protein ranging from 12 percent to 19 percent. Of the patients receiving 2 mg/kg, a third achieved a reduction in M-protein of 55 percent. In the 4 mg/kg group, all patients achieved a reduction in the M-protein ranging from 49 percent to 64 percent.

In addition, all patients in the 4 mg/kg group showed a marked reduction in the percentage of plasma cells in the bone marrow ranging from 80 percent to 97 percent.

According to the researchers, the drug’s side effects at these doses are manageable.

SNS01-T

SNS01-T is being developed by the pharmaceutical company Senesco (NYSEAMEX: SNT). It selectively causes cells to die by targeting a protein called eIF5A, which is believed to be an important regulator of cell growth and cell death.  SNS01-T is a nanoparticle that has three components: the first part targets myeloma cells with the natural form of eIF5A; the second part causes the cells to create an ineffective version of eIF5A; and the third part is a polymer that is used to deliver the complex to the myeloma cells.

During a poster session on Monday, June 4, results will be presented from a Phase 1/2 trial investigating the safety and tolerability of SNS01-T in relapsed and refractory multiple myeloma patients.

The abstract currently does not include any study results. Dr. John Lust from the Mayo Clinic, the study’s lead investigator, stated to The Myeloma Beacon in request for further information that the study is a ‘trial in progress’ and that he cannot provide more information at this time than what is included in the abstract.

For more information, please see abstracts 8013 (obatoclax), 8018 (siltuximab), 8019 (daratumumab), and TPS8116 (SNS01-T) on the ASCO meeting website.

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20 Comments »

  • suzierose said:

    SNSO1-T, sounds extremely interesting.

    “preclinical studies have shown that modulation of unmodified eIF5A kills cancer cells through both the intrinsic (mitochondrial) and the extrinsic (cell death receptor) pathways via activation of MAPK/SAPK signaling pathways, up-regulation of p53, and activation of caspases. Our studies indicate that over-expression of unmodified eIF5A is non-toxic to normal cells….snip….
    Both hypusinated eIF5A and deoxyhypusine synthase, the enzyme that mediates eIF5A hypusination, have been identified as markers of neoplastic growth and metastasis. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells, while an accumulation of unhypusinated eIF5A is generally only observed during apoptosis.”
    http://www.senesco.com/eIF5A.htm

    eIF = eukaryotic Initiation Factor

  • Joanne Valdez said:

    i am sooo excited to hear about these treatments.

  • Gary said:

    Thank you for providing this summary. It is great. I was pretty disappointed in the results but I am a negative type of guy. Joanne perhaps you could share why you are so excited about the treatments? I want to be be excited too.

  • Kevin said:

    Look into the animal studies SNS01-T has gone thru…amazing results, and very high incidences of complete tumor eradication when used in combination with lenalidomide

  • TerryH said:

    Hmmm … I hate to say it, but it doesn’t look like siltuximab is going to go too far as a myeloma treatment. When you look at these results, and combine them with the results reported here,

    http://www.myelomabeacon.com/news/2012/02/03/siltuximab-may-be-effective-in-certain-patients-with-advanced-multiple-myeloma-ash-2011/

    you have to wonder if J&J is going to go forward with additional trials of the drug in myeloma patients. The drug doesn’t give much a kick in terms of response rates, yet it’s also quite toxic. Not a good combination.

    It’s unfortunate that the daratumumab results are not presented in the typical way. Can anyone translate the results as they’re presented here into the usual response rates that are seen in other study results?

    I would suggest being very cautious about SNS01-T until there is some hard data for us to look at. Pre-clinical results are always interesting, but I don’t think you really can tell much about a drug until it’s tested in patients.

    Plus, the stock of the company that is developing SNS-01T is essentially a penny stock, so there are all sorts of people pumping SNS01T as “the next best thing” just so they can make a buck or two on swings in the stock’s price.

  • suzierose said:

    Hey TerryH,

    I think the results for daratumumab are presented that way as it was a dose-ranging study, which means they are looking to see which dose is giving the largest percent drop in B2 microglobulin vs. looking for a clinical response of PR, VGPR etc. As the dose escalates there was a greater percent drop in the B2 microglobulin and that was verified with Bone Marrow correlating to significant decline parallel with dosing increase.

    Based on the results presented the optimum dose appears to be 4mg/kg vs. 2mg/kg. The paper Plesner presented at ASH 2011 gave a 2mg/kg cut off.
    https://ash.confex.com/ash/2011/webprogram/Paper36726.html

    I am cautiously optimistic about SNSO1-T.

    I find the MOA fascinating more than anything particular the degree of specificity as that is the only protein in the body that undergoes hypusination. Also, they are finding eIF to be effective in diabetes….very intriguing protein. It is also notable that eIF is part of the ubiquitin protesome pathway….time will tell if this is a significant leap given that it upregulates TP53 which, as you know, is dysfunctional/mutated in 50% of all cancers.

    Fascinating indeed…I also like that it is a nanoparticle

  • suzierose said:

    Hi Kevin,
    Do you have a link for those studies?

  • Dan D said:

    On the general subject of new therapies, the following study describes yet another CURATIVE approach. Yes, I like the word cure; in fact, it is the ONLY word that excites me about this F$%K&^*G disease.

    It describes studies in cell culture as well as in animal models and it also provides an explanation for the failure of current therapies to completely eradicate the disease — a failure that is overcome by the drug combination of TRAIL (a cell-death inducing ligand) and doxorubicin (a drug that is already used to treat some myeloma patients I believe).

    PLoS One. 2012;7(5):e35830. Epub 2012 May 16.
    Targeting Tumour-Initiating Cells with TRAIL Based Combination Therapy Ensures Complete and Lasting Eradication of Multiple Myeloma Tumours In Vivo.
    Vitovski S, Chantry AD, Lawson MA, Croucher PI.
    Source: The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.

    Abstract: Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138(+) and CD138(-) cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138(-) MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138(-) cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138(+) cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138(+) cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138(-) cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138(-) cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.

  • suzierose said:

    “In the present study, we demonstrate that bone marrow stromal cells and osteoblastic cells can protect myeloma cells from apoptosis induced by TRAIL…snip..TRAIL has been proposed as a potential anti-tumour therapy, but within the bone marrow microenvironment OPG produced by osteoblastic cells may interfere with its action and thus limit its effectiveness in multiple myeloma”

    http://www.nature.com/leu/journal/v21/n4/full/2404518a.html

  • TerryH said:

    Thanks, Dan D, for pointing out that new study. It certainly looks quite interesting and quite promising, and I plan to keep tabs on it.

    That said, I’ll repeat what I said earlier … As promising as a drug may seem in the laboratory, I really think caution is in order until clinical trial results are available.

    Let me give a simple example (and, based on what I’ve heard from various myeloma specialists, there are plenty more). Here is a summary of the preclinical and early clinical trial work that was done related to panobinostat.

    http://www.pagepress.org/journals/index.php/hmr/article/download/526/606

    As you’ll see, panobinostat “was able to arrest growth in [myeloma] tumor cells” in pre-clinical studies and showed “potent anti-tumor activity” across a broad range of blood cancer and solid turmors. In fact, for a form of lymphoma known as CTCL, panobinostat was able to bring about “complete tumor regression” in mouse models implanted with human CTCL cells.

    So how did panobinostat do in clinical trials? Well, we all know that there is now no hope of panobinostat being a standalone therapy for myeloma. It’s not even clear it will ever get approved for use in combination with other anti-myeloma drugs.

    More importantly, despite the fact that panobinostat brought about “complete tumor regression” in the laboratory CTCL mice studies, at best 6 of 95 patients in a phase 2 trial of the drug in CTCL patients achieved a complete response (see page 3 [35] of the document I linked to above for the study results).

    As I said, lab results certainly can be interesting. But clinical trials with humans are the real test.

  • Dan D said:

    Thanks SR. The paper you cite does not include drug combinations with DOX — which was required for efficacy in the Vitovski article above. So I wonder how DOX addition would impact the results in the study you cite.

    Regardless, the authors in the paper you cite state that non-native agonists of TRAIL receptors, such as antibodies, may overcome the OPG interference seen with the native TRAIL ligand. Indeed that is a central point of their paper: “Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment.”

    So I am keeping my fingers crossed that there may be a possible path forward; let’s keep hope alive!

    P.S. Here is the link to the TRAIL-DOX study:

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035830

  • Dan D said:

    TerryH

    I actually work for a drug company and could not agree more that human studies are the only real deal. But animal studies are important and useful as well — just less predictive.

    That said, my feeling is that most traditional therapeutic strategies seem to rest on a foundation of velcade/carfilzomib and revlimid/pomalidomide (along with DEX and the frequent addition of another ingredient to the mix). This may buy time — and this is good — but I don’t think it will ever buy a cure.

    It seems to me that if we are to find a cure, we may have to think about a new drug foundation (be it a TRAIL receptor antibody + DOX, or something else)……and then consider the currently used drugs as optional add-ons.

    As for stem cell transplants…..well I think that it is a hot button issue that I will avoid for the moment.

  • TerryH said:

    @Dan D – I think we are in agreement on a lot of key points. I agree, for example, that it will take something innovative — like the TRIAL approach you’ve described — to bring about a true cure.

    There are, however, some innovative approaches already being tested. For example, the gene therapy technique mentioned in this article,

    http://www.myelomabeacon.com/news/2011/08/12/gene-therapy-advance-in-leukemia-suggests-new-treatment-options-for-multiple-myeloma/

    There are also the vaccine-based approaches that have been discussed in different articles here at the Beacon.

    There is another possibility that we also shouldn’t ignore. As one or two people here often point out, there are real advances being made toward making allo transplants a more effective, and less risky, option. If you combine those advances with more standard upfront therapies that bring about deeper and deeper responses in more and more patients, you are likely to get allo transplants effectively curing a greater percentage of patients.

    (I didn’t mention allo transplants to bait you, by the way. If we’re going to talk about potentially curative approaches, I don’t think you can avoid discussing allo transplants.)

  • Dan D said:

    TerryH

    Thanks for expanding on this theme….and I do hope we can improve upon allo approaches.

    As one more addition to curative paradigms, a while back I posted on a curative one-shot approach with an engineered virus being developed at the Mayo Clinc. This particular report was based on studies in mice — I know — but clinical translation is underway, including with a different virus: the measles virus.

    I like this shock and awe approach, as it precludes the development of resistance and quickly harnesses the power of our immune systems to mop up any residual myeloma cells.

    Leukemia. 2012 Mar 19. doi: 10.1038/leu.2012.70. [Epub ahead of print]
    Curative one-shot systemic virotherapy in murine myeloma.
    Naik S, Nace R, Federspiel MJ, Barber GN, Peng KW, Russell SJ.
    Source: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.

    Abstract: Current therapy for multiple myeloma is complex and prolonged. Antimyeloma drugs are combined in induction, consolidation and/or maintenance protocols to destroy bulky disease, then suppress or eradicate residual disease. Oncolytic viruses have the potential to mediate both tumor debulking and residual disease elimination, but this curative paradigm remains unproven. Here, we engineered an oncolytic vesicular stomatitis virus to minimize its neurotoxicity, enhance induction of antimyeloma immunity and facilitate noninvasive monitoring of its intratumoral spread. Using high-resolution imaging, autoradiography and immunohistochemistry, we demonstrate that the intravenously administered virus extravasates from tumor blood vessels in immunocompetent myeloma-bearing mice, nucleating multiple intratumoral infectious centers that expand rapidly and necrose at their centers, ultimately coalescing to cause extensive tumor destruction. This oncolytic tumor debulking phase lasts only for 72 h after virus administration, and is completed before antiviral antibodies become detectable in the bloodstream. Antimyeloma T cells, cross-primed as the virus-infected cells provoke an antiviral immune response, then eliminate residual uninfected myeloma cells. The study establishes a curative oncolytic paradigm for multiple myeloma where direct tumor debulking and immune eradication of minimal disease are mediated by a single intravenous dose of a single therapeutic agent. Clinical translation is underway. (Leukemia advance online publication, 20 April 2012; doi:10.1038/leu.2012.70.)

  • Pat said:

    I am very familiar with Senesco’s SNS01-T. It has shown to be unbelievably potent when combined with Revlimid in treating mice with both MM and Mantle cell lymphoma.

    They just released results that you can read about here.

    http://www.businesswire.com/news/home/20120501005698/en/Combination-Lenalidomide-SNS01-T-Effective-Cancer-Model

    In sum, 5 of 6 mice treated with both drugs on the high dose were tumor free after 6 weeks. While these are just mice, these are highly unusual results with MM. I’m told they are much better than the currently approved drugs.

    Their current phase 1/2a trial, among refractory patients is currently ongoing at the Mayo clinic, Arkansas medical center and at West Virginia University. The company feels they may have a potential breakthrough treatment that acts on cell biology further upstream than current treatments.

  • Mark said:

    TerryH,

    I have mentioned in the Forums that I do not think the vaccine approach developed at UPENN that was used on the CLL patients could ever gain widespread use due to practical reasons. The vaccine was not only killing the cancer cells but also the patients B Cells. They had no ability to fight infection at the time the story was written. They were all getting monthly IVIG infusions. This what IVIG is:
    “Intravenous immunoglobulin (IVIG) is a blood product prepared from the serum of between 1000 and 15 000 donors per batch. It is the treatment of choice for patients with antibody deficiencies.”
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809480/

    Unfortunately there would not be enough to go around if thousands of patients suddently needed monthly IVIG. While it helps to fight off infection, patients taking it need to be extremely careful to avoid crowds, etc. In Myeloma patients the vaccine would likely be killing off plasma cells. This is what plasma cells do:
    “The new study focuses on plasma cells, which are a component of the immune system known for producing large quantities of antibodies – targeted disease-fighting proteins. The new study, however, shows plasma cells also act in a negative feedback loop, the end result of which affects the function of other higher-ranking immune cells called follicular helper T cells (TFH).

    “These plasma cells are not only capable of secreting highly specialized antibodies, but they are also involved in the regulation of the process that generates the mature immune response,” said Nadège Pelletier, a research associate in the McHeyzer-Williams lab and first author of the new paper.

    Previous to this work, scientists thought of plasma cells as simple soldiers in the fight against the body’s foreign invaders and lacking in the ability to direct the course of future battles.”
    http://www.dddmag.com/news/2010/11/role-plasma-cells-immune-system-redefined

    A therapy that is actively killing plasma cells is a terrible side effect that would significantly lower a patients quality of life. Of course never ending cycles of Revlimid, Dex and Velcade/carfilzomib are not that great for QOL either. While this gene therapy research is exciting and most importantly 3 people are alive and with their families, it is not something I could see becoming standard therapy any time soon as long as it is associated with such a severe side effect.

    Mark

  • TerryH said:

    Hi everyone … Sorry I’ve been away a while. It looks like there’s been a lot of interesting discussions going on in this comment thread and over in the forum. Anyway …

    @DanD: I missed your earlier posting about this engineered virus. It certainly looks interesting. Thanks for sharing the abstract with everyone again.

    @Mark: I also missed your postings in the forum about the UPenn vaccine trial and the drawbacks of that approach. I just checked the forum, and it turns out that it’s in the same thread as where DanD originally posted the abstract about the engineered virus. Here’s the link to the part of the thread where that discussion started:

    http://www.myelomabeacon.com/forum/advances-in-cancer-drugs-t958.html#p4585

    I agree, Mark. There do seem to be some significant drawbacks to the UPenn vaccine approach. Thanks for the additional information.

  • suzierose said:

    Hi Dan,

    TRAIL has lots of possibilities, and has moved beyond mice.

    I understand there was a Phase I clinical trials at NIH utilizing TRAIL with bortezemib. http://bit.ly/KjbqcV

    ” Immuno-therapy has taken a lead among the new cancer therapeutic approaches. It is one of the most promising new therapeutic approaches that exploit the innate immune mechanism of an individual to fight against a certain disease.

    Natural killer (NK) cells are a form of cytotoxic lymphocytes which constitute a major portion of the innate immune system. NK cells have tumor cytotoxic properties independent of tumor specific antigens and have been shown in murine models to control and prevent tumor growth and dissemination. Inactivation of NK cells potentially allows cancer cells to evade host NK-cell-mediated immunity. Ligation of killer immunoglobulin like receptors (KIRs) by MHC class I on both normal and malignant tissues suppresses the function of NK cells.

    The present invention relates to treating cancer and other hyperproliferative disorders by administering an enriched composition of allogeneic or autologous (KIR/KIR ligand incompatible) NK cell population. This enriched composition can potentially override the inactivation of NK cells by self HLA molecules or MHC class I expressing tumors. Claims cover compositions of enriched NK cell populations and method of treating malignancies or prevent recurrence of malignancies and treating any hyperproliferative disorders with these enriched compositions. Claims also cover a method to sensitize malignancies to NK cell TRAIL-mediated killing by pretreatment with bortezomib.

    http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=1492

    Phase I dose escalating clinical trial with bortezemib and TRAIL
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133963/

    This innovation may offer realistic possibilities to those who have dismal outcomes with high dose chemotherapy.

  • suzierose said:

    Ahhhhh, finally…the acronym is

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)

  • jim byrd said:

    this is wonderful, four new possible treatments that could bring valuable benefit but nary a mention of side effects except that they are manageable. i am all for the development of new drugs that can effectively treat or possibly cure but this all comes at a cost to our bodies that seems to be forgotten. i am reminded of a story about a truck driver who successfully finished treatment and was deemed in remission but due to the maintenance chemo and fatigue he is unable to continue his job driving trucks. the doctors are thrilled that he has successfully recovered but he feels far from recovered since he can’t earn the living that he once enjoyed. he now sees himself as a failure and sits around the house all day. don’t forget the patient. the article is not valid for it is missing the other part of the equation, QUALITY OF LIFE.