Wednesday, December 28, 2005

Tough News But We Continue Onward

We saw Dr. Rifkin today and went through the results from the bone marrow biopsy and the bone scan. The transplant is categorized as causing a minimal response. In fact, the degree of cancer/plasma cells in my bone marrow is around 30%, which is what it was in early October, in late August, and early August. We started in late March at 65% so there has been some progress, albeit all prior to August. In essence, the transplant didn't work. So, I will be starting with a new drug: velcade. This chemo regime is part of a clinical trial for which Dr. Rifkin is the principal investigator. I will start in mid January. I receive it through a shot given IV every 1st, 4th, 7th and 11th day--which consitutues one cycle. then a week off. I will go through 4 cycles, which will take about 3 months. The potential side effects include neuropathy (tingling and shooting pains in feet, hands, legs), nausea (which can be dealt with with medication) and low platelets and/or white cells, which they can also deal with. They will monitor my response every 2 weeks. I will also continue with the zometa, and received an IV of that today. As a result of going on the velcade, however, I will have to postpone the prostate surgery as the velcade would intefere with the healing from that surgery. So, I got another shot of the lupron today (hormone). So far, that has been effective in holding back the spread or growth of the prostate cancer.

Dr. Rifkin also said that if my response to velcade is good, then we are probably looking at another transplant in 6 months or so. This time he would like to use stem cells from one of my siblings. So, Mike, Tom and Kathy, you can expect to receive in the next month or so a testing kit or directions or something like that, to ask you to get your blood tested to see if any of you are a match for me. This is called a mini allogeneic transplant and although not as risky as a transplant from a stranger it is still much harder on me than the autologous. But, so be it, if that is what is necessary. I'll just have to work out a little more at the health club before the transplant to get in better shape.

There is a small bit of good news in all this. First, the skeletal survey (bone scan) does not show any further lesions or invasion of the bone by the myeloma as compared to the survey done in August. That survey showed two small lesions in each humerus, which were of no concern to Rifkin. I also learned today that, although I have a genetic abnormality that is at least partially the cause of this myeloma, it is not an abnormality of chromosome 13. An abnormality in that chromosome results in a very poor prognosis. I have known about this for some time, but quite frankly have not wanted to ask my doctor, for fear of the news. But today I asked and got the right answer.

So, I have some work left to do. Susan is quite understandably upset, but doing OK. The girls are also upset but their positivity will return shortly I am sure. (they are both curled up napping on the sofa next to me--wanting to stay close I suspect--this is so hard on them; they are quite understandbly scared, but want so desparately to be strong and supportive for me. As I have said before, this is one of the most painful parts of this--seeing their Dad struggle with this disease) We all know that this is a long road, and sometimes our hopes blur that fact. It has been difficult and I think we would all like a break from the underlying stress of it all, but that does not seem to be in the offing at this point. But, I am still feeling fairly well and hope that I can continue with my health club regime and just being able to go about my life as best I can. Stick with us and someday we will look back, shake our heads at the ordeal we've been through, and tip a glass of wine to our endurance, stamina, perseverance, friendship, love and support. I love you all, and I have confidence that this new year will bring unexpected blessings to us all. Dan

Tuesday, December 20, 2005

A Christmas Letter

We have traditionally (at least once every two years) sent a "Christmas Letter" to many of our friends and family at this time of year to bring them up to date on the happenings of our family during the past year. (We still will call this the Christmas letter, even though it may no longer be politically correct) We know that all bloggers have a sense of what this past year has been for us, so we will skip the details of my ordeal and provide the brief summary: 5 hospitalizations, 2 back surgeries, 4 rounds of chemo, 6 to 8 blood transfusions, and, oh yeh, a stem cell transplant. But I am doing better than I have in many many months. I am driving, going to the health club, going out to lunch, going to physical therapy and generally have more independence than I have enjoyed since June. I still struggle with lack of energy and returning to real work remains an insurmountable task. Most recently I just had a skeletal survey (xrays of every bone) and bone marrow biopsy to determine the stage of my disease. Results will be reported next week. That has been my world this year--my health. But as a part of this journey my heart has opened wide and I have received and learned love and compassion as never previously experienced. Read the previous blogs for details. I am very thankful for this holiday season, for feeling better, for my two daughters being home, and for the time our family will spend together.

Julia, our 18 year old, started at Colorado College in Colorado Springs this fall. It is a small liberal arts school nestled in a very conservative community. Classes are on the block system, i.e., taking only one class for 3 1/2 weeks, a 4 day break and then start the next class. She is made for college (and getting away from her parents). In addition to doing well academically, she also is participating in 6 intramural sports, as well as skiing on weekends. She is a quick witted, no nonsense, straight shooting young lady. Look out world!

Catherine, our 22 year old, is in her last year at the University of Colorado at Boulder. She is majoring in Finance and International Business and will graduate in May. She already has a job as a research analyist with a pension consulting firm in Denver, which she will start part time in January and full time in June. She is attending college on a full scholarship and has achieved much success in the past 4 years, not the least of which included working as a research analyst for the famed business author, Jim Collins, ("Built to Last" and "Good to Great".) This work has opened many doors for her. As a result she was being courted by firms in Charlotte, NC, Atlanta, GA, and Los Angeles, but she decided to stay in Denver, primarily because of my health issues. This is one of the most difficult parts of this illness--seeing how it affects my girls. I wish they could go about their lives without having to worry about their Dad. Catherine is also learning how to cook under her mother's tutelage. She has spent the last 3 days making Christmas cookies. Julia and I are encouraging her in this pursuit! Catherine has her mother's heart and brings light to our home every time she visits.

Susan is quite simply an angel and the nicest person I have ever met. Why she married me remains a mystery, but I will gladly be the beneficiary of her lack of judgment. I could not have gotten through these past 7 months without her. She helped me out of bed, washed me, drove me to the doctors, and maintained vigil over me during the many months when I was either too sick to care for myself or too disabled from back problems to walk or even get out of bed. She has been a source of strength and support like no other. Her many friends (she makes friends just walking down the street) have also been tremendous support for her and me. She still has her outrageous laugh and is in good spirits these days. She has had to take on the responsiblity of bill paying, supervising workmen, and many other matters that I used to attend to. Now that I am "coming to" after these long months, she finds my involvement to be "meddling" and sometimes, jokingly says, she preferred me when I was sedated. Not really.

So having to face one of life's most difficult challenges this year, we remain strong. We have become a closer and more loving family. We are so deeply appreciative for all we have received from all of you. My health issues have forced us to confront what our lives are about and how we should be living them. It is no longer an academic pursuit. We have learned that a life lived with love and compassion is our most important purpose. You, our friends and family have taught us this. I wish I had the vocabulary, as well as the time and space, to adequately express how deeply I feel about the important role all of you have played in my recovery this year. We give thanks for you, and all you have done for us, and wish you the very best this holiday season.

Love, Dan, Susan, Catherine & Julia

Wednesday, December 14, 2005

Laughter Continues to Be the Best Medicine

Last night I couldn't sleep, so I toss and turn and toss and turn. Susan does the old Jackie Gleason attack on Norton (me), "will you knock it off". Soon, we are chatting,laughing, giggling and wondering how we can laugh so hard in the midst of such chaos. No answer to that question, but our spirits have definitely picked up since a few months ago. Our friend, Gail, had lunch with us the other day and called me soon after to say it is obvious Susan and I are more in love now than we ever were. As Susan says, all my hard edges are gone and I'm back to being the nice guy she married (I want to know who she thinks I was all those years in between, as I am sure I was not as bad as she is trying to create). Our spirits are good as we go into the holiday season.

Saw Dr. Rifkin today and all the blood counts are good: white cells, neutrophils, red cells and platelets are all strong. Bone marrow biopsy is scheduled for 12/20--this will be my 4th. I think I also will have a full body bone scan. We asked that the appointment to review all the "numbers" be delayed until after Susan's birthday (12/23) and Christmas--so we will see Dr. Rifkin on December 28 to see where we are after the transplant. Until then, and even after then, regardless of the news, we will be in good cheer and we wish same for you. Happy Holidays, Dan

Friday, December 09, 2005

The Next Surgery

Well, we now have a date scheduled for my radical prostatectomy--February 7th. My urologist will be doing the surgery laproscopically so that he expects I will only be in the hospital over night. Recovery is anticipated to be 4 to 5 weeks. I won't go into the details here for those of you who are less curious, but there are, of course, potential complications. But my prostate cancer was diagnosed relatively early --it is Stage II B and is located on only one side of the gland and is not in the margins--all good signs. In addition, while my multiple myeloma was being treated I received 2 hormone shots to contain and prevent any spread of the prostate cancer. In fact, the hormone shots shrunk the tumor, which is also a good result. In light of all that I have gone through over the last 9 months, this next procedure feels manageable. I am glad the surgery won't occur until February as that will allow us to enjoy the holidays.

No further news on the myeloma front; next appointment is 12/14 and I'm not sure whether I will get any new info at that time. We'll probably schedule the bone marrow biopsy for later in the year or first part of next year. I continue to gain strength and am trying not to push myself too hard in the recovery effort. I do try to get the health club daily to walk, ride the bike and occasionally lift weights. I am dragging Susan with me--I think she wants me to go back to work! It feels so slow and some days I get slammed with a lack of energy, which always surprises me. I've also started physical therapy and am getting some help in relieving the soreness and stiffness in the back.

We are so looking forward to having the 2 girls (young ladies) home for the holidays. Susan already has the Christmas tree up and her brother, "Uncle Gary," has sent more boxes of presents than we have room for. His generosity always overwhelms us and this year he appears to have outdone himself.

I'll let you know what happens at next week's visit with Dr. Rifkin. In the meantime, enjoy the holiday spirit. Love, Dan

Thursday, December 01, 2005

Zometa, IGG's, and Physical Therapy, but Feeling Well

Ah, the long awaited doctor's visit. The white cells, although down a bit, are fine, red cells are up and platelets are way up. I received an IV of zometa today, which is a bone strengthening drug. Much more info on zometa is set forth below. The infamous IGG's are unfortunately trending UP, not Down. Went from 2440 to 3200. But my doctor was adamant that I should not concern myself with this, as there are way too many factors that could account for this...including the fact that my body is producing good immunoglobulins which could be counted in this number. He plans to do a much more definite and comprehensive blood test next visit (but not a bone marrow biopsy). Notwithstanding his dismissal of these numbers, I was disappointed as I know he would liked to have seen a downward, not upward trend. I did pull one of the nurses aside after I received the IV of zometa and grilled her a bit more on the numbers. She, who is a straight shooter, also told me they have many patients whose numbers don't move downward after transplant but they are able to control their myeloma with maintenance drugs. It would not surprise me to be put back on the steroid, dexamethasone, which was very effective in my early treatment in bringing the IGG's way down. I don't particularly like my body's response to the dex (shakes, and irritability), but it was quite effective. There is apparently a study by the French that shows this to be an effective measure following transplant. Ah, it is the acceptance of the fact that this is a long voyage that is so difficult at times. I am also going to start physical therapy for my back to relieve some of the stiffness and can return to the health club to try to get back into shape (staying out of the hot tub and pool). I also am likely to have my prostate surgery within the next month or so. Dr. Rifkin asked that I get back in touch with my urologist and get that going. He suggested we might try to do that around the same time as the restaging (bone marrow biopsy, etc.) So, it looks like the holidays may be busy. But I feel better every day and now that I can start working out and going to physical therapy I will probably start feeling even better. Today feels like one of those difficult days. But Susan refuses to be lead down the negative path--"I know you'll be fine and you can't pay attention to those numbers", she tells me. So, I will accept that approach--after a good night's sleep. Next visit is December 14th.

Zometa (zoledronic acid)
What It Is
Zometa® (zoledronic acid) is an intravenous, nitrogen-containing bisphosphonate marketed by Novartis Pharmaceuticals. It was initially approved in the US in 2001 for the treatment of hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH). It was approved in 2002 for the treatment of bone lesions in myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard cancer therapy.

Zoledronic acid is 100-fold more potent than pamidronate. Because of this fact, the dose of zoledronic acid required is substantially lower and can be administered in a shorter period of time than pamidronate (15 minutes versus 2-4 hours).
What It Does
Zoledronic acid inhibits bone resorption, which is the breakdown of bone by osteoclasts. Although the exact mechanism of action is not completely understood, several things are thought to occur. In the laboratory, zoledronic acid inhibits osteoclast activity and induces apoptosis (programmed cell death) of osteoclasts. It also binds to bone and may block resorption. In addition, zoledronic acid inhibits the increased osteoclast activity and skeletal calcium release induced by various stimulatory factors released by tumors.
How It Is Administered
Zoledronic acid is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 4 mg administered as a 15-minute infusion, given every 3 to 4 weeks. The optimal duration of therapy is not yet known. However, in clinical studies in myeloma, patients were treated for up to 12 months, and patients have received the drug for longer periods of time. Data from long-term administration (24 months of therapy) have been submitted to the regulatory authorities.

Patients receiving zoledronic acid should also take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

Benefits in Myeloma
Zoledronic acid has been shown to be more effective than pamidronate in normalizing serum calcium levels in patients with hypercalcemia of malignancy. In 2 studies that were analyzed together, zoledronic acid (4 mg) normalized calcium by day 10 in 88% of patients compared to 70% with pamidronate. In addition, the median duration of response was significantly longer with zoledronic acid (32 days compared to 18 days). (Major et al. J Clin Oncol. 2001;19:558-567.)

In patients with myeloma, various studies have shown that zoledronic acid is as effective as pamidronate in treating bone lesions. For example
Zoledronic acid and pamidronate each reduced the number of skeletal events and the need for radiation therapy to bone in a study of patients with myeloma. (Berenson et al. Cancer. 2001;91:1191-2000.)
Results of a Phase III trial comparing zoledronic acid and pamidronate showed equal efficacy and tolerability of the drugs in the treatment of bone lesions in myeloma and breast cancer over the period of 1 year. (Rosen et al. Cancer J. 2001;7(5):377-387). Long-term (25 month) data from the study showed that both agents reduced the overall proportion of patients with a skeletal event. However, compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications (including hypercalcemia) as determined by multiple event analysis by an additional 16%. In patients with breast cancer, zoledronic acid was significantly more effective than pamidronate, reducing the risk of skeletal events by an additional 20% compared with pamidronate and by an additional 30% in patients receiving hormonal therapy. (Rosen et al. Cancer. 2003;98(8):1735-1744.)
Results of a small Phase II study in elderly patients with symptomatic refractory myeloma showed that the combination of zoledronic acid and targeted radiotherapy (Quadramet® [Samarium Sm-153 lexidronam], Cytogen) was an effective palliative option. For the eight patients in the study, one to three courses of therapy with these two agents was sufficient to produce long-term improvement in symptoms, particularly bone pain. (Iuliano et al. J Clin Oncol. 2004;22(14S). Abstract 6737.) Patients received a standard dose of 4 mg of zoledronic acid every 4 weeks and slightly more than half of the standard dose of Quadramet. No severe adverse effects were noted; two patients experienced transient grade 2 hematologic toxicity. Interestingly, M-protein levels decreased more than 25% in 4 out of the 8 patients and were still stable at 19 months follow up.
• Get more information on bone disease in myeloma
Guidelines for Use of Zometa in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease.

For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous zoledronic acid (Zometa) 4 mg infused over 15 minutes or pamidronate (Aredia®) 90 mg infused over 2 hours every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
• Get the complete summary of the guidelines for bisphosphonates
Potential Antitumor Effects
Zoledronic acid also appears to have several potential antitumor effects. For example,
It reduces the secretion of the growth factor interleukin 6 (IL-6) by myeloma cells grown in the laboratory. IL-6 is known to play an important role in the growth and survival of myeloma cells
In laboratory studies, zoledronic acid inhibited growth and induced apoptosis (programmed cell death) in human myeloma cell lines
Zoledronic acid exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)
When combined with dexamethasone in the laboratory, the effect of zoledronic acid on inhibiting growth and inducing apoptosis of myeloma cells was enhanced. (Tassone et al. Leukemia. 2000;14:841-844.)
The drug inhibited angiogenesis (the growth of new blood vessels) in an animal model. (Wood et al. Proc 36th ASCO Annual Meeting, New Orleans. 2000;19:664a.)
It is able to prevent the development of bone disease in a mouse model of myeloma. In this model, treatment with zoledronic acid was associated with a decrease in tumor burden and a significant increase in disease-free survival. (Croucher et al. J Bone Miner Res. 2003;18(3):482-492.)
Zoledronic acid appears to affect bone marrow stromal cells taken from patients with active myeloma, which could contribute to its antitumor effects. In the lab, the agent reduced bone marrow stromal cell proliferation, increased apoptosis, and modified the expression of adhesion molecules on their surface. (Corso et al. Blood. 2003;102(11). Abstract 1619.)
In blood cells taken from patients with myeloma, zoledronic acid induced anti-myeloma activity by activating a particular type of T cell. Zoledronic acid also enhanced the sensitivity of myeloma cells to killing by these T cells. (Mariani S et al. Leukemia. 2005 Mar 3. [Epub ahead of print])
However, it is not known whether zoledronic acid has the same effects in patients with myeloma.
Potential Side Effects
Zoledronic acid is generally well tolerated and the side effects are similar to those seen with pamidronate. Some patients may experience mild and transient side effects, such as fever, flu-like symptoms, fatigue, gastrointestinal effects, or anemia, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or zoledronic acid infused in less than
15 minutes can affect the kidneys. For this reason, patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. In addition, serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly.

Upon treatment initiation, dosage adjustments are recommended in myeloma patients with mild or moderate kidney impairment. (See How It Is Administered.) Treatment with zoledronic acid is not recommended in patients with severe kidney impairment because studies in this patient population have not been conducted. In myeloma, the risk of kidney dysfunction may be increased when it is used in combination with thalidomide or drugs known to affect kidney function (ie, nonsteroidal antiinflammatory drugs). There are animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, zoledronic acid should not be used during pregnancy unless a physician feels the benefits outweigh the risks.

Long-term therapy with zoledronic acid appears to be safe. Results of a recent study of 22 patients who received intravenous zoledronic acid or pamidronate for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)

A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Ongoing Clinical Trials
Trials are evaluating the use of zoledronic acid as an integral part of a treatment regimen for patients with early-stage or newly diagnosed myeloma to see if it can help prevent or delay the development of bone lesions. An additional trial is being conducted to determine the effect of zoledronic acid on the bone density of patients with bone loss with monoclonal gammopathy of undetermined significance (MGUS).

A study is also being conducted to investigate if lengthening the duration of infusion, in conjunction with increased volume of liquid the zoledronic acid is administered in, will provide renal protective effects.

The combination of zoledronic acid and the targeted radiotherapeutic Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is being evaluated for the treatment of pain associated with metastatic bone disease in patients with recurrent or refractory myeloma.

Ongoing zoledronic acid clinical trials in myeloma are listed in the table below.

Ongoing Zometa Clinical Trials in Myeloma as of May 2005
Phase IV
A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa (zoledronic acid) 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information
UARK 2004-43, A Multicenter, Open-Label, Randomized trial evaluating the duration of infusion of Zometa 4 mg IV in Multiple Myeloma Patients with Bone Metastases
• View trial information

Phase III
A Phase III Randomized Trial of Thalidomide plus Zoledronic Acid versus Zoledronic Acid Alone in Patients with Early Stage Multiple Myeloma
• View trial information

Phase II
First-line Treatment of Newly Diagnosed Multiple Myeloma with Combination of Low Dose Thalidomide, Zometa, and Dexamethasone
• View trial information

Phase I/II
A Phase I/II Trial of Zometa in Patients with Monoclonal Gammopathy of Undetermined Significance (ZOMGUS-001)
• View trial information