Waldenstrom's macroglobulinemia: Drug options

By Steve Kirsch
Updated Sept 14, 2014

Newest drugs (just opening clinical trials right now):

Best new diagnostic

  • Use PCR on detecting the MYD88 L256P mutation in the peripheral blood (Xu at DFCI)

Newest drugs (from ASH 2013)

  • 5Z-7-oxozeaenol TAK1 inhibitor (Novak at Mayo)

  • CAL-101 (aka GS-1101) + Ibrutinib (Yang at DFCI)
  • Terameprocol (TMP) + Ibrutinib (Fulciniti, DFCI)
  • inhibit PD-1 signaling (Ansell)
  • b-AP15 (Mayo) for those who are resistant to Velcade
  • CaRD reduced bone marrow from 60% to 7.5%. No grade 2 or greater PN.
  • Oprozomib: 80% responded (Ghobrial, DFCI)
  • Idelalisib: 80% responded. Responses were durable beyond 1 year (Gopal, Univ of Washtington)
  • ABT-199 aka GDC-0199 (Davids, DFCI)

Top 5 drugs as of March 26, 2014

  • 1- Ibrutinib aka Imbruvica (this is the go to drug for most people due to efficacy and low side effects; 3 capsules/day; FDA approved)

  • 2- Oprozomib (although has side effects)

  • 3- Cytoxan/velcade/rituxan combination for more aggressive disease but velcade causes PN

  • 4- Carfilzomib/rituxan if we can get carfizlomib through insurance

  • 5- Bendamustine and/or rituxan

Here are the most important things you should know about drugs for WM (some of which apply to all diseases):

  • There are some drugs that can kill you if you over dose. So if you are going to deviate from what they told you, you should always deviate downwards unless you really know what you are doing and you've talked to your doctor about it.
  • The dosing regimens on virtually all WM drugs is not optimized for killing the disease and/or side effect on you. So for example, a lower Rituxan dose might work better and have fewer side effect. Similarly, we don't know if a spikey dosing regimen is better than a constant dosing regimen. Nor do we really know whether it is better to give Rituxan once a week for 4 weeks or for 8 weeks. Nobody has tried it longer than 8 weeks. It could work fantastically if they didn't stop early. But nobody knows. So it might be true that giving only 100 mg of Rituxan once a week for 52 consecutive weeks kills all your disease with minimal side effects. Or maybe it will backfire and kill your immune system. We just don't know. For many drugs, it is typically dosed by giving you less than the maximum tolerated dose with the thinking that more is better. That isn't always true. And it may be smarter to deliver the drug in spikes rather than continuously. And the dosing frequency can have a huge effect on side effects. For example, if you give Velcade once every 2 weeks instead of twice a week, the risk of PN is probably minimal. But nobody has tried this. So there is a lot that is unknown.
  • Listen to your body.... if you are taking a drug and it starts giving you PN or you start losing your short term memory, in my opinion you should forget the protocol and stop taking the drug. There are doctors who disagree and want you to take the drug no matter what (unless you are in danger). I know people who suffered permanent or long-lasting debilitating side effects because they kept to the protocol instead if listening to how their body reacts. These protocols never cover 100% of the patient reactions. They are geared to be safe for most people, not all people. My opinion is that it is better to be safe than sorry and pay attention to the signals your body is sending you. For example, I noticed a higher amount of blood in my nose while taking LBH-589. It turned out, my platelets dropped under 20 and I got an emergency transfusion that night. Had I just followed the protocol they gave me, I could have been dead.
  • Research the drug. A "good drug" is an oxymoron. For example, people have had excellent results on Bendamustine. But I also talked to a patient (a former nurse) who lost nearly all her short term memory after 4 cycles. Her IgM is 400, but she may never recover her short term memory. She started to lose it after taking the drug. Could the drug have caused it or was it just a delayed result from her other treatments? The moral is talk to as many people as you can who have taken the drug and ask about the side effects. In other cases, drugs like Fludarabine can dramatically increase the risk that your cancer mutates into a cancer that is much more deadly.
  • My philosophy has always been to triage the drugs by safety and side effects...try the safest drugs first, before you have to resort to the more dangerous ones. So I avoid drugs like Velcade and Fludarabine, for example, due to their potential side effects (PN and transformation, respectively). That's why I started with mono therapy Rituxan, then enzastaurin, then LBH-589, and if I fail that, I'll look at the RAD001 related drugs. No sense in using the heavy duty stuff now if the easy stuff works.
  • Subscribe to and read the WM talklist every day. The more you know as a patient, the better off you are. See http://www.iwmf.com/talklist.htm
  • If you ask 3 experts in WM what treatment they would recommend for you and your case, you'll often get 3 different answers. There is a lot of subjectivity in this disease with no "right" answer. You have only options. Carefully weigh the pros and cons of each option based on your own tolerance for risk. Your treatment should be your decision. Don't just pick a doctor and do what they say. Find a doctor who is willing to allow you to choose among acceptable alternatives.
  • Find a doctor who is flexible. There are lots of doctors who insist on treating you "by the book." But there are a lot of very smart doctors that will take your history into account and also how you react to the drug, e.g., give you less than the standard dose. My preference is to find those doctors that are willing to deviate from "the book."
  • If you are on a budget (e.g., Medicare, doughnut holes, etc.), then a clinical trial might be less expensive than a more proven solution since you get the drug for free. In general, other than a small handful of drugs (Rituxan, chlorambucil, RAD001, Velcade, Cytoxan, Fludarabine, etc), there aren't very many good FDA approved approved drugs for WM, so a clinical trial is often your best bet.
  • I tend to be of the school of get it under control now. I think waiting too long can be dangerous because it may take a while to find a drug that works for you. Most WM doctors however think you should only treat if there are symptoms that are causing problems. But if your IgM is going up, it is just a matter of time until you have problems.
  • There is now convincing evidence that Rituxan maintenance therapy leads to increase overall survival. Whether you do a maintenance regimen of once a week for 4 weeks every 6 months, or 1 infusion every 3 months seems to make no difference in outcome (they are pretty similar). Personally, I'd rather do the once every 3 months since that is a lot less drug.

I used get email all the time from people telling me to look at alternative therapies. None of these suggestions come with any studies showing consistent efficacy for WM. Nor have any of the more than 1,000 members of the IWMF talk list anecdotally confirmed efficacy of any alternative treatment. If there is an alternative treatment that produces a partial response (more than 50% drop in IgM) in at least 50% of patients, I'm interested. If there is no data, I'm not.

There are a small number of new drugs with relatively modest side effects that are being tested against WM with some success. My understanding is that the current thinking is to use a cocktail of these "low side effect" drugs in order to attack the disease simultaneously on multiple fronts. So it's basically the r-CHOP type of combination approach, but using drugs that individually have far less "collateral" damage than the normal chemo drugs. For instance, Perifosine alone has a very modest effect on your IgM (e.g., a 33% reduction). But when used in combination with other drugs, it's expected it will be surprisingly effective against WM. A major benefit of Perifosine is to chase the WM cells out from their hiding place in the bone marrow and bring them out into the open where they can be more easily killed. Perifosine on its own has some effect, but it may not be enough to be FDA approved on it's own. It's unfortunate that the FDA doesn't allow such two-drug combination clinical trials unless the other drug is already approved as the "standard of care" for that disease. So you cannot run a Velcade-Perifosine trial, but you can run a Rituxan-Perifosine trial. This is a chicken and egg problem resulting from old theories about cancer. The FDA has know about this problem for years, it was expressly pointed out again in Cliff Leaf's excellent Fortune cover story "The war on Cancer" (Fortune, March 22, 2004), but nothing has changed. It's also illegal for you to use a drug that is proven to be safe but that isn't yet proven effective unless you are in a clinical trial. So there are cancer drugs, such as Xcytrin that can extend your life for years, but since the FDA isn't satisfied on efficacy, your doctor has to leave you to die.

Old therapies can work well. One person went from 9240 to 251 in 6 months on Rituxan and CHP. Chlorambucil (in pill form) has worked well for many, for example, Jerry took 7mg/day (reduced from standard 8mg/day):

My Igm was over 6000 when I began chlorambucil treatment, in August 2005. When I completed treatment in January, 2007, my Igm was 2300. My last bloodtest in May 2008, showed an Igm of 1590. Since the termination of my treatment, my Igm has been consistantly been decreasing. During my previous remission, between 2003 to 2005, my Igm began to rise after 12 months, also following chlorambucil treatment.

My Igm did start dropping immediately, but slowly and in spurts. So I could lose several hundred points and then gain some back.Thus it took me about 12 weeks to drop my Igm from about 6350 to below 5000. Chlorabucil is continued.till the patient ceases to respond.

Thus when two to three consecutive bloodtests indicate no further progress, the treatment is discontinued. Based upon my readings of the talklist, It appears that many chlorambucil treatments are discontinued prematurly' due to the impatience, or lack of knowledge, of the doctor/ and or the patient., I'd like to add, that some patients respond to chlorambucil much faster than I did.

On the flip side, however, chlorambucil causes MDS and leukemia in the long run, so we avoid it in young people.. it is not that effective either.. Some studies show responses after a year of taking it.. Not he greatest drug to start with.

Solo Fludarabine works wonders for some people where Rituxan doesn't work and vice versa.

Daily cytoxan pills work, e.g.,

12/92 - dx: IgM a bit above 4700.
1/93 to 4/95 - tx #1: daily oral CYTOXAN, 150 mg; lowering IgM to 240.

Notes from Steve Treon talk (taken by Ron Draftz):

He didn't cover the gamut on treatments and that was both good and bad. Bad
only because there were a lot of members who are not familiar with the range
of treatments that are available. Good because he did spend a lot of time
talking Velcade which he clearly likes when given with Rituxan. He did
slightly promote a large trial (150 patients) of Velcade (B-Bortezomib),
Cytoxan, Dex and Rituxan (BCDR) that will be run against the same drugs
minus Velcade. It is his opinion that prolonged remissions come from
treatments that successively rid us of most of our tumor cells and he thinks
this BCDR is the better combo instead of CVP-R or CHOP-R which he states do
too much damage to our immune system and marrow. He also doesn't like
Fludara or Cladribine given with R because of the tendency for the
nucleosides to cause transformation to DLBCL in time. I had the impression
he was looking for some drug combo he could use over and over to produce
long intervals of remission until treatment again becomes necessary No
mention of Rituxan maintenance at all.

In spite of his desire to still hit the tumor cells hard he has continued
his willingness to use lower dose treatments for Thalidomide and Velcade to
overcome the PN problem. But he also said that WM patients don't really
need the aggressive treatments that are used for myeloma or other lymphomas.
He would hate my comparing his having finally using the approach that Mayo
has quietly pursued for a long time when it comes to moderate treatment
protocols. It will be quite interesting to see what happens in Stockholm
and whether the consensus panels finally begin to align when it comes to
using less aggressive treatments for first timers.

He made a very brief statement that RADOO1 looks like a drug that is producing extremely good results for WM. Perhaps we will see RAD001 (which I like to call RAD-ONE) used in combination once they better understand the outcomes of this drug. Those yet to be developed combo's may be what keeps all us going for a long, long time. Dr. Treon has only included WM patients in his RAD001 trial and accounts for 13 of the total of 19 WM patients at all trial sites. BTW, he is touting an unofficial disease-specific median survival of 16 to 19 years based on some recent, though yet unpublished, studies.

It's too bad he only could stay for 40 minutes of questions. We would have
enjoyed twice that. This was Steve at his best, almost as though all 56 of
us were seated and sipping coffee around a table as we discussed the outlook
for WM.

Comments from Irene Ghobrial:

by next year we should have the following oral drugs tested and some possibly very active in WM:
LBH589 (oral drug)
BEZ235 (oral drug)
Amd3100 and RItuxan

We will also have the following combination trials:
RAD001 and rituxan
Rad001, velcade and rituxan

WM patients normally have:

  • monoclonal IgM spike
  • low Hct
  • low PLT
  • low WBC

Criteria for treatment is typically:

  • Hgb<10
  • PLT<100,000
  • >4 viscosity
  • any amount of PN
  • misc other serious symptoms (such as cryoglobulinemia, etc.)

Older drugs:

  • Fludaribine and cladribine: Can cause your WM to transform to a more deadly lymphoma. Seldom used today, and if used, seldom more than for 4 cycles. There are both short and long term risks to consider. Shingles is one of them, which is why we strongly recommend prophylaxis with acyclovir or valtrex. Depression of the neutrophil count for short as well as long periods of time is another important toxicity. The long
    > term side effects are also important to consider as well.
  • Cytoxan: One person wrote: Cytoxan caused my bladder to bleed after 5.5 years (with prednisone). I'd been warned. It was effective, but not benign.
  • Rituxan: Maintenance strategies that work are 4 doses every 6 months. Another is 1 dose every 3 months. One person wrote: "Rituxan is my treatment of choice. I have had nothing else for 8 years  and having been doing just fine. I get four standard 375mg/ M^2 every 6 months and have now completed 64 treatments.my HGB is 13.9 which is below the normal mean but still in the normal range."


  • green tea extract: reduced lymph nodes 50% in 11 out of 12 patients. See WM Torch Oct 2009 issue, page 14

Will drugs that target overexpression of MyD88 be the silver bullet that cures WM?

Perhaps. Perhaps not. The problem is if you knock it out, there may be too much collateral damage. Colin Perrott writes:

Although aberrant hyperactivity of the IRAK-4 / MyD88 pathway has been observed in several malignancies (now including WM), deficiency of IRAK-4 / MyD88 presents several problems through diminished protection at the central and peripheral checkpoints for self-reactive B-cells as well as skewing of the antibody repertoire as a whole. So it seems to me that Maxwells' Silver Hammer is still somewhat beyond reach, that therapeutic methods developed from these observations will need refinement according to the circumstances to achieve levels of control more subtle and durable than following a simple knock-out philosophy... Hence we should not yet divert our interest from established techniques.

There is a general review of the immune role of IRAK-4 / MyD88 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807984/  .

Newer WM drugs include:

G'day Steve. I have posted a few reports to the IWMF but folks over there haven't seemed too interested at the moment. Imbruvica seems to be the go in the US.

I started on the trial in July of last year. Absolutely no side effects, although I know others have reported some diarrhea, low Hgb and low platelets.

My initial response to the drug was quite rapid and my Igm feel from 5300 to around 1900. It hasn't changed much in the past three months but I have a review and tests at the end of September which will confirm, or otherwise, my status. Hgb was initially 98 and climbed to 125, but has fallen back to 113 at last blood tests. What I can say is that 15 months ago I was struggling in many respects: stamina, tiredness, etc. At this port of call I'm out cutting my lawn and chopping wood, as well as getting out and about as any normal person would.

I should point out that I've had WM for around 20 years now and I suspect that the illness is developing quite a bit of resistance to treatment options. How long before that happens with ABT 199 remains to be seen

  • Oprozomib, which is oral velcade like proteasome inhibitor. It has an amazing response in WM and no neuropathy. There is one complete remission and others having amazing lymph nodes and bone marrow response. 

  • A CXCR4 antibody that we are presenting in ASH and it works in the patients who have the CXCR4 mutation in WM. I will send you the paper but we showed that CXCR4 mutation causes more aggressive disease in WM and we can target this in WM with a new antibody.

  • 12/4/13: IMO-8400. Now opening trials for WM. Targets MYD88 pathways.

  • 10/24/13: Sandoz and Novartis (yes, drug makers), published in the Journal BioDrugs, showing that they found GP2013 to be similar to Rituximab. GP2013 has been used in several phase III clinical trials

  • 10/23/13: Interesting study results pointing to the possibility of using lenalidomide, dex, and rituxan together, whereby the lenalidomide makes it possible for rituximab to work in patients who previously were resistant to it...  The study, however, didn't include WM or LPL patients...still, something to consider...Combined Lenalidomide, Low-Dose Dexamethasone, and Rituximab Achieves Durable Responses in Rituximab-Resistant Indolent and Mantle Cell Lymphomas

  • ublituximab (TGTX-1101): Ublituximab, a novel, third generation chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen, has been bioengineered for enhanced biological activity with an increased ability to trigger an immune response, delivering superior ADCC effects to aid in B-cell depletion. Created by TG Therapeutics, Inc. (OTCBB:TGTX). "Anti-CD20 monoclonal antibody therapy is a critical treatment component in WM; however patients continue to relapse. This data highlights the excitement for ublituximab, a new optimized anti-CD20 monoclonal antibody in the treatment of WM," stated Professor Veronique Leblond, MD, PhD, Head of Hematology, Hospital Pitié-Salpêtrière, Paris, France.

  • CX-5461: Cylene Pharmaceuticals today announced that research collaborators at the Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia have established, for the first time, that RNA Polymerase I (Pol I) activity is essential for cancer cell survival and that its inhibition selectively activates p53 to kill tumors. Published today in Cancer Cell, the findings show that Cylene's Pol I inhibitor, CX-5461, selectively destroys cancer by activating p53 in malignant but not in normal cells.
    PR Newswire (http://s.tt/1hpwd). clinical trials to be done later this year (2012) with lymphoma & leukaemia patients

  • The studies being performed with a HuCAL antibody (fully human antibody - see: http://tinyurl.com/hucalMOR103 amd http://www.morphosys.com/technologies/morphosys-technologies/hucal) that targets GM-CSF (granulocyte macrophage-colony stimulating factor).  THis could be of benefit to WM patients, as it could block the proliferation of WBC if the GM-CSF was modulated successfully.  Particularly what will bear watching is a sister product produced by this company called MOR108, which targets CD19 (and is an Fc-enhanced human antibody)...

  • Ublituximab (3/2012) has reportedly been bioengineered for enhanced biological activity with an increased ability to trigger an immune response, delivering superior antibody-dependent cell-mediated cytotoxicity (ADCC) effects to aid in B-cell depletion. Ublituximab has displayed high single agent activity in a Phase I/II trial in patients with relapsed chronic lymphocytic leukemia (CLL). It is being developed in multiple oncology and autoimmune indications and was granted orphan status in Europe and in the U.S. for B-cell CLL.

  • 27 Oct 2011: Biovest ... today announced that the FDA has granted Orphan Drug Designation to BiovaxID® for the treatment of WM. This milestone advances Biovest's plans to develop and commercialize BiovaxID as an autologous active immunotherapy (personalized cancer vaccine) for the treatment of multiple subtypes of B-cell non-Hodgkin's lymphomas. We believe WM is an ideal indication for BiovaxID to potentially provide significant clinical benefit for patients by extending remissions and potentially delaying and/or avoiding alternative treatment options such as stem cell transplant or removing the patient's spleen. Our study data to date suggests that BiovaxID-treated patients who express a certain type of protein isotype called IgM on their lymphoma cells are much more likely to remain cancer-free longer after achieving a remission following induction therapy. Since most WM patients express this IgM isotype, we look forward to conducting future clinical trials to evaluate our vaccine's utility in treating this rare B-cell blood cancer."
  • Azacitidine: see http://jco.ascopubs.org/content/early/2011/06/29/JCO.2011.35.8283 which describes using this drug with Rituxan and getting a complete remission of WM. This is quite amazing. 60% infiltration and now the bone marrow is free of lymphoma.
  • AVL-292: (from Avila Therapeutics) A Btk inhibitor, co-funded by LLS, should be in trials in late 2010. WM Patients have had good results on this drug (holds IgM steady after several weeks of treatment).

After being put in the ineligible category for the PCI trial due to more than 4 previous treatments, I am now on the waiting list for the newer Btk inhibitor, AVL 292, at the Cleveland Clinic under Dr. Hill. AVL is in phase 1b with a fixed dose. The trial is available at many sites for B cell NHL, CLL and Waldenstrom's - can be found at www.clinicaltrials.gov. There is no limit on the number of previous treatments for this trial. It's too soon to know if AVL will work as well as PCI. My wait for the trial is probably about 2 months. I've heard that PCI will probably be approved for CLL within 2 years. Dr. Treon makes it clear that you need to have MYD88 in order for Ibrutinib to work

  • PCI- 32765 aka Ibrutinib: David Sellers (who is in the trial in NY and started with Hgb of 10.5...which had been as low as 9 posted on the IWMF talklist on 4/27/10: I am starting tomorrow on a trial of a new Btk inhibitor drug named PCI- 32765. It is hoped that the drug will inhibit the growth of B-cell malignancies. The drug is administered in the form of a daily pill. I will take the pill daily four four weeks, have one week off and then take it again for another four weeks. My doctor has several CLL patients on the trial who are having positive responses. I will be his first (THE first??) Waldenstrom's patient in the study.

    I mentioned a few weeks ago that I was participating in a phase 1 trial of the btk inhibitor drug PCI-32765. It is taken in pill form. After 3 weeks on the drug, my hemoglobin has risen from 11.2 to 12.7, and my IgM has dropped from 4820 to 2880. I feel better than I have in years. The only downside so far is that my platelets have taken a hit (down to 64), but not so low that I need to be infused with any. I have had no other side effects so far. I'll keep the list informed as the trial continues. I should also mention, that my lymphadenopathy and splenomegaly are both responding as well. My spleen is greatly reduced in size, and my swollen nodes are shrinking. I am fully aware that this is only a phase 1 trial, but I am hopeful.

    I had a two week break while I was out of the country. Normally, this would be a one week break according to the trial protocol, but I had a previously planned vacation. Anyway, my hemoglobin fell back to 10.1 while I was away, and my IgM went back up to 3910.  Platelet count went back up to 198.  I started another 4 week cycle last Thursday. I will have my blood tested tomorrow.  Anecdotally, I can see that my nodes are shrinking again, and I already feel more energetic.

    Date: Sat, 25 Sep 2010 07:41:26 -0400
    From: David Sellers
    Subject: My Progress on PCI-32765 Trial

    I have been on the trial drug PCI-32765 now for 5 months. Here are my current numbers compared to those on the day I started the trial:

    4/27/2010 4820
    9/23/2010 2010

    4/27/2010 11.2
    9/23/2010 14.2

    4/27/2010 123
    9/23/2010 86

    04/27/2010 IgA <6.67 09/
    23/2010 IgA 7.0

    04/27/2010 IgG 212
    09/23/2010 IgG 306

    As you can see, there has been marked improvement in my IgM and hemoglobin levels. The only negative side effect has been a reduction in my platelet level, but not so low that I have ever needed a transfusion. I have not had a BMB since the one I had at the start of the trial, but I recently had a CT which showed reduction in the size of my lymph nodes and spleen.

    Bottom line for me is that I feel better than I have in years. My hgb is in the normal range for the first time since I was diagnosed in 2001. The drug is easy--it's in pill form which I take at home once daily. No reactions, no chills, no hives, no pre-meds, no sitting in the hospital for hours.

    I am very happy, and I think that since I am the first WM patient in the world to receive this drug, it should be named after me.

    Joyfully yours, David Sellers 55 yo dx 10/2001

    Mitch Orfuss wrote: Since starting Ibrutinib, my IgM decreased in steps from 1800 (baseline prior to starting), to 770, and to 574 -- then to 420 yesterday. So it's flattening toward normal range in a series of smaller and smaller improvements. My IgG has stayed fairly steady, within 20 points of 174. IgA has gone from 11 to "<26" -- maybe the lab now lumps everything below 26 that way now.

    More info: http://clinicaltrials.gov/ct2/show/NCT01109069
  • CAL-101: a P13K delta inhibitor Study to Investigate CAL-101 in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia. Paul Listen wrote: Aug 3 I begin a phase 2 clinical trial for CAL-101. http://www.seattlecca.org/clinical-trials/lymphoma-NCT01282424.cfm It is an phosphatidylinositol 3 kinase (PI3K) delta inhibitor. As I understand it, PI3K-delta is especially important in the proliferation of B cells. While this drug affects all B cells, theoretically it affects malignant B cells moreso because they rely on PI3K-delta much more than normal B cells.

    The one thing in particular they watch carefully on folks taking this drug is liver function. In phase 1 studies, a good number of folks had their liver enzymes go up, but most of them came back to baseline after stopping the drug and most resumed the drug at a lower dosage.

    Dr. Maloney in Seattle is who I'll be seeing once a month during the trial.

    He said there have been few WM/LPL patients take it thus far, but quite a few CLL folks. With CLL they've been amazed at how readily CAL-101 pushes the bad B-cells out of lymph nodes and into circulation. For folks like me with bulky disease, that would be a useful thing.

    They have just opened this trial in Seattle, and I am one of the first to enroll. Paul reports lot of side effects: anemia, low platelets, low white counts, low liver enzymes. Hgb low (two transfusions in a month!).


    CAL-101 Summary: For eight weeks, August and September, we saw phenomenal
    improvements: I went from being transfusion dependent to hemoglobin level of
    14.2 g/dL and lymphadenopathy reduced 50% in only 8 weeks. But then it stopped.

    My main observation: compared to other treatments, the CAL-101 was remarkable in how quickly benefit was seen, especially with regard to lymphadenopathy. For me personally, neither R-CHOP nor Fludarabine was as effective as CAL-101 in reducing lymph nodes.

    Although, paul had fanatstic results after 8 weeks, after 16 weeks was back to needing transfusions and BMB was worse than before he started. the swollen lymph nodes remained shrunken

  • BEZ235 should be better than CAL-101. CAL101 is a PI3K delta inhibitor- BEZ235 is a pan-PI3K and mTOR inhibitor- so it will be even more phenomenal- clinical trial to open soon.

  • LBH-589 (aka Panobinostat) is a HDAC inhibitor. Fairly low side effects and can drop your IgM by 50% in a month. This drug is hard to beat. I'm on it. the 30mg dose is too much for most people; it will drop your platelets dangerously low (so low for me that I needed a transfusion). The 20mg dose is a nice level: minimal side effects for me while still being effective (although not as effective as 30mg). If you feel too nauseated or have a terrible headache, I suggest you skip a dose. I've been using this drug for almost 2 years and my numbers are stable.
  • R7159/GA101 is a third generation "humanized " anti-CD20 monoclonal antibody in phase I/II clinical trials made by Roche. In the lab, this drug is way more effective (in terms of overall killing power) than Rituxan and it should work even on people who are refractory to Rituxan. I'm very excited about this drug.
  • Blinatumomab: BiTE antibody causes T-cells to attack CD19+ cells. Has been used in WM successfully. This is interesting because the side effects are minimal and reversible, the treatment is for 2 months, and because it attacks the cells at an earlier stage of development, it has the potential to permanently cure WM. There is a clinical trial in Germany now and they are looking for WM patients. See http://www.micromet.de/index.php?id=64 and Clinical Data Published in 'Science' Show Tumor Regressions in Relapsed Lymphoma Patients Treated with T Cell Engaging BiTE Antibody Blinatumomab First T cell engaging antibody (BiTE) showing clinical benefit in cancer patients; Blinatumomab enables patients own T cells to recognize and attack cancer cells

BETHESDA, Md. , June 14 /PRNewswire-FirstCall/ -- Micromet, Inc. (Nasdaq: M=

ITI) today announced the presentation of updated results from a Phase 1 trial of the Company's lead product candidate blinatumomab (MT103) in patients  with relapsed non-Hodgkin's lymphoma (NHL). A high objective response rate was maintained among patients treated with blinatumomab using an adapted schedule, comparable to that previously reported in patients receiving  constant dosing. Blinatumomab is the first in a new class of agents  called BiTE antibodies, designed to harness the body's T cells to kill cancer cells.

Amgen is to acquire Micromet Inc., producers of blinatumomab, a Bispecific T cell Engager (BiTE) antibody, with proposed uses in ALL and non-Hodgkins lymphoma. I believe that Amgen will accelerate the development of this promising Mab - they have much deeper pockets than Micromet. The drug mobilizes T-cells to attack B-cells which express CD19, and has shown good results so far. (Reported at the December 11 2011 ASH conference.) Another 'bullet' in the pipeline! See the link: http://tinyurl.com/88tujug

  • Bortezomib (Velcade PS-341): a Proteasome inhibitor that causes WM cells to die because nobody comes to pick up the waste products from the cell. In high dosages, causes neuropathy, mostly reversible. If you get it once a week, a lot of people go 6 months without problems. 72 hour efficacy time. Combining with Rituxan, you get practically no flare. The problem is that the PN (which has a much higher incidence for WM patients than other diseases) is not always reversible!
  • Perifosine: an oral bioactive novel AKT inhibitor which prevents homing of the WM cells back into the bone marrow. It also has some killing effect on its own. It does not affect the white cell count, does not cause anemia, or neuropathy. The possible side effect is some nausea, vomiting. It does not suppress the immune system. It works slowly so it takes about 3 months to start seeing a response, although one patient had a 78% decrease in IgM the first month. Another had a 50% decrease, and two have 20% and 22% decreases and this is just in the early months. Early findings indicate the drug is safe and well-tolerated, with many having decreases in tumor burden of 50% or greater, but it varies by patient of course. The reason this drug is getting very interesting is because: 1) it attacks the signaling pathway in the development of most cancers; 2) it is often effective in cancers that are resistant to other forms of cancer therapy; and 3) it doesn't cause a toxicity response and is, in fact, well-tolerated. Not since Rituxan have we seen a drug that is this well-tolerated, and seemingly effective.  We do not have a single "approved" drug for Waldenstroms yet, so this trial is very important to us all. Trial started in March 2007 in WM patients. Seems to reduce Hgb in several people and when you stop it, the anemia gets better. It causes bone or joint pain in some. One person reported thinning hair. One person's numbers get worse, but most are stable or get better. One patient wrote: "I tried the perifosine due to falling counts, but found the side effects to be unmanageable and the benefits to be little. Daily vomiting and diarrhea with weight loss and fatigue continued through my use of it. The psychological impact and the 50 lb. weight loss left me flat on my back! I did have a slight reduction in igm, but had to pull out of the trial as my total other blood counts pushed me into a critical state."
  • AMD-3100 (aka plerixafor): is a failed anti-HIV treatment. It is a stem cell mobilizer and CXCR4 inhibitor. It produces mobilization effects of WM cells out of the bone marrow and prevents homing. So like Perifosine, but the effect is more pronounced. 2 hours after injection, the cells are out of the bone marrow. Within 24 hours, they are all back in hiding. This looks very powerful in combination with Rituxan. Irene Ghobrial is doing experiments in mice with this combination.AMD3100 released white blood cell progenitors from the bone marrow into the bloodstream. Because of this activity, last December the U.S. Food and Drug Administration approved AMD3100 for stem cell mobilization prior to autologous stem cell transplant in multiple myeloma and non-Hodgkin lymphoma. The drug enables more efficient capture of stem cells from the blood.
  • G-CSF and Plerixafor: These cause stem cells and presumably WM cells to leave the bone marrow where they can be killed by Rituxan if you combine the drugs. Guy Sherwood and Hank Stupi have done G-CSF and it seemed to work well, but G-CSF isn't that good a mobilizer; AMD3100 is much better, but it is pricey.
  • MDX-1338: a human anti-CXCR4 antibody proposed for therapeutic application in AML and ALL. Possibly better than AMD3100. Unlike AMD3100, it's an antibody and stays around longer.
  • Lenalidomide (Revlimid): A nicer version of thalidomide. This is a pill that you take and people with WM have had great results with it. This looked very promising. Unfortunately, Lenalidamide (Revlimid) not recommended for WM because of its role in precipitating acute anemia in WM patients (just ask Dr. Treon about his "nightmare" phase II trial with Revlimid in WM). Out of 12 patients evaluated, 4 had to quit to be hospitalized for anemia. 10/12 experienced unexpected acute drops in hematocrit within 2 weeks and 6/8 dropped out before 28 days. Also 4 cases of grade 3/4 neutropenia (which is as bad as it gets). Thalidomide/Rituxan is probably a better choice. However, instead of giving out 25mg/day, it would be far smarter to start at a lower dose and ramp up. If you do that, you can get excellent response without ongoing side effects.
  • Belimumab (Lymphostat B): prevents the creation of all B-cells. There is a trial of Belimumab just beginning for Waldenstrom's patients at two hospital in Melbourne, Australia
  • Thalidomide: Use with Rituxan to enhance response. Unfortunately, it causes PN.
  • Afinitor aka RAD001 (Everolimus): This is what I'll try if solo Rituxan stops working for me. Great response rate (about 70% of the patients respond), low side effects. It's a pill you take once a day. At 2 5mg pills per day, it can cause myelosuppression, e.g., red cell production, platelet counts and WBC can plummet and people have had to be hospitalized so watch out for this. Reducing dose to 5mg/day results in higher IgM levels, but more normal blood counts (except maybe Hgb). David wrote on iwmf talklist on 5/18/10:
    • I was on the RAD001 study at Rochester.  The initial dose was too high and though it did bring my igm down significantly, it also led to shingles and pneumonia.  When the dosage was reduced, the igm did not go down but my hemoglobin did.  In the end my igm jumped from 5000 to 10,000 in one month (it eventually climbed to 13,000).  I am not sure that was a result of the RAD, but I suspect so.
    • In the first 28 days RAD001 cut the IgM from 6000 to 3000. In the second 28 days it cut it to1000. The drug has worked fantastically well for me. To this day I remain in the RAD001 study and my IgM remains around 1000. I have been on the RAD001 study at Mayo, MN for about 15 months now.

      If you have had the opportunity to read the "Consent Form", I experienced about one fourth of the side effects listed. The most severe were; the mouth sores in the beginning, the fatigue (all the time), PN somewhat controlled by medication and anemia (requires a blood transfusion every 4 weeks or so). My last BMB showed about a 25% involvement. it was my dentist dr. connie winters who applied debacterol to some  initial mouth sores that cure them instantly

  • Enzastaurin: An oral protein kinase inhibitor from Eli Lilly. Irene Ghobrial is running a clinical trial in WM with this now. It seems to be working very well. The first 2 pts, one had a drop of 1000 points within one month and the other already has a 50% reduction ( from 4000 to 2000) in 2 months. About half the patients respond to this drug. Side effects are milder than RAD001 (which also has low side effects). I've been using Enzastaurin for almost a year now (since 1/28/09). I had no side effects whatsoever and it has kept my WM which had been growing aggressively from getting any worse. A great drug. I highly recommend it.
  • NPI-52: 72 hour efficacy time
  • AZD0350
  • Arzerra aka HuMax-CD20 (Ofatumumab):  from Danish drug company Genmab which reportedly works better than Rituxan and less allergic effects since it is a fully human antibody (instead of an antibody from a mouse like Rituxan). This article, Monoclonal Antibodies, explains why Rituxan is from a mouse instead of a human, and the problem with HAMA. HuMax might be a lot better than Rituxan or could be about the same effect as Rituxan. It was approved Oct 26, 2009 by the FDA for use in CLL, so it can be used off-label for treating WM. WM patients who are allergic to Rituxan have been able to use Arzerra (with the proper pre-meds) and it has been amazingly effective for some, more than Rituxan. Mitch wrote:
    • It was way more effective--for me. I did not respond to Rituxan when I tried it a year earlier, though my doc would not come out and say that it didn't work--maybe it kept me flat when my numbers may have otherwise skyrocketed, but that's of course idle speculation. Rick Furman, who practices across the hall from my doctor (John Leonard, Cornell-Weill), said that Ofa invades CD-20 in a different way from Rituxan and was designed (?) in part to work for patients for whom Rituxan failed. I had pretty severe allergic reactions to the Ofa during the first infusion (as I did to Rituxan, by the way) but I wasn't concerned or unnerved aside from discomfort. (No pain, just amazingly hellish itching, I wanted to tear my scalp off with a dull knife!, but how bad is that? These pass quickly when the nurses are on the case, as they were.
    • For anyone interested: I've been on Dr. Richard Furman's single-agent Ofatumumab trial at Cornell-Weill. 18 months after the only 4 infusions I had, my CBC continues to be pretty strong--all but a couple of measures in the normal range. WBC is a fraction low, and Platelets are 139. HgB is 14.6, and I'd thought this might be slowly declining so was happy to see it this high. Before the trial, my HgB was 6.7 and I needed a transfusion. The Proteins report will deliver in a couple of days; three months ago IgM was 800. I feel fine. Best wishes to all.
  • Epratuzumab
  • SGN-70 (an antibody that interferes with mast cell signaling): Looks very promising): the problem is that the company that makes this is not good at getting drugs to market.
  • Campath (alemtuzumab): a mAb that targets CD52 found on WM and mast cells. Notorious for T-cell depletion. But it is effective in WM.
  • Gleevec (Imatinib): targets CD117 which is expressed in WM cells. This can work for some people.
  • HB22.7: kills cancerous B-cells while leaving healthy cells untouched.
  • KX2-391 (KX01): now in phase I trial at MD Anderson, is an Src kinase inhibitor. Said to be effective against all cancer types.
  • Zevalin or Bexxar: one shot of zevalin brings complete remission in 76% of NHL cases (36 month effectiveness). Can't use it if you have high bone marrow involvement (>25%) since it will kill too many good cells.
  • PS-341: a reversible proteasome inhibitor that has shown remarkable efficacy in myeloma and appears to have activity in other hematological malignancies including lymphoma and WM. PS-341 is administered i.v. twice weekly for a varying number of weeks followed by 1 week of rest. With this scheduling, it is generally well tolerated and appears to have minimal myelosuppression. A Canadian NCIC study using this agent in a phase II study for symptomatic WM is in progress.
  • UCN-01 (a protein kinase C inhibitor)
  • Treanda (bendamustine): Bendamustine hydrochloride is an alkylating agent recently approved by the FDA for treatment of Chronic Lymphocytic Leukemia (CLL). ORR 75%, MRD: >9.2 months, with 20% CR. This trial for indolent NHL was in people refractory to Rituxan. Side effects are was low white blood cell count with fever and pneumonia. This medication differs from many other chemotherapy agents in that it can be given infrequently. Indeed, a recent study suggested that once-every-three weeks administration of bendamustine can be effective. One WM doctor said "it is like fludarabine- effective, but most likely has long term side effects that we don't know yet." Dr. Treon doesn't think it will be nearly as bad a fludarabine. I've heard of several cases where this drug has been miraculous for people. One person went into complete remission after 3 treatments of Bendamustine + Rituxan (given once a month) . However, beware that one patient after 4 treatments, got a great IgM result, but now has almost completely lost her short term memory. But that is very rare. So there are significant risks. Hardening of veins is common after just two treatments.

    For those of you that plan to be treated with Bendamustine, I would suggest that you speak to your doctor or nurse about infusing it concurrently with a saline drip at least for the first infusion to avoid possible vein irritation.  I am told that the irritation of my vein may take as much as six months to heal itself.  Also, keep an eye on the vein area just above the needle puncture to see if any progressive redness develops during the infusion. 

    One person wrote: "All in all, with possible vein damage, collapsing immune system, need for a port etc.  bendimustine sounds less and less like a desirable treatment.  Chemo is scary enough with plenty of unexpected consequences, now I don't know what to do. "

    One person wrote me:

    My experiences are not typical but they do represent the concept that all patients are unique and that a drug that works for 78% of the subjects or 95% or even just a mere 20% may not work for ME or YOU... or it may, and that a drug that is not recommended may be an absolute miracle drug for someone.

    I was diagnosed in Jan 2009 and began treatment with Rituxan and Thalidomide in March.  I already had PN in my rt foot and it did not exacerbate it.  The real problem came when we increased to the recommended dosage.  I went into hypercalcemia within 3 days and nearly died from it.  My calcium levels were over 16.  Dr River (my onc) then proceeded to use Treanda with the Rituxan (which was his preference in the first place).  In just two doses spaced 3 weeks apart my IgM went from over 6500 to 1250 in 3 weeks and to <400 after 6 weeks.  My IgM is now in the normal range at 267.  Side effects were minimal with nausea and fatigue being the sum total of them.  I never had a fever nor pneumonia or anything else for that matter.
    Your articles are excellent.  I am just very glad I had not read them before I went for treatment because I probably would not have agreed to the use of the drug that saved my life.  Your work in this area is fantastic and appreciated.  It is very much aimed at the masses.  I am just the oddball in that crowd.
  • SNS-032: A Phase I clinical trial of SNS-032, one of the first in a new class of drugs that inhibit cyclin-dependent kinases, demonstrated the drug's safety and potential clinical action against advanced chronic lymphocytic leukemia (CLL). Cyclin-dependent kinases are enzymatic proteins that are integrally involved in cellular metabolism, renewal and signaling, and are thought to play key roles in the growth of cancers. The drug did not demonstrate any clinical effect against advanced multiple myeloma, although researchers hope it might still prove to have some benefit against this blood cancer as part of combination therapy. The paper is published online in the Journal of Clinical Oncology.

    "No drugs that target this cancer mechanism are on the market today," says study author David S. Siegel, M.D., Ph.D., Co-Chief, Multiple Myeloma, John Theurer Cancer Center at Hackensack University Medical Center. "I am hopeful that larger studies will show that this targeted therapy is useful against a number of advanced B cell malignancies."

  • AVN-944: IMPDH inhibitor. They would love WM patients for a phase I clinical trial they are doing. Contact J. Michael Hamilton, M.D.,
    Avalon Pharmaceuticals, 301-556-9894
  • Veltuzumab: humanised anti-CD20 antibody now in phase I/II trials
  • ONXO912 (a chymotrypsin-like (CT-L) actrivity inhibitor): Found two articles today in a recent issue of the journal Blood about a relatively new type of orally available drug that may be a better approach to treating WM....it's a special class of oral proteosome inhibitor, that inhibits chymotrypsin-like activity (CT-L). Paper from Kirsch Lab at DFCI on this. This is a velcade-like drug, but it doesn't cause PN. There is an IV version (carfilzomib) and this one is the pill form (PR047). The IV is not easy since it is 4 days a week, but the oral is not available until next year.
  • PR-171 (Carfilzomib)- a proteasome inhibitor made by Proteolix has had good results in WM patients. It's like Velcade, but without the PN. DFCI did pre-clinical work. It was in clinical trials for WM in two places but the study was closed due to slow accrual of patients. DFCI is looking at opening up a trial there using the next generation of this drug. See Proteolix clinical trials for more info. David Sellers wrote:
    • I'm on a trial for a targeted drug called carfilzomib. Works like velcade but without the danger of neuropathy as a side effect. In six weeks of treatment, my IgM has declined by about one third with no significant side effects. Still, it's not perfect, I guess...my hemoglobin remains in the 8's, and I therefore feel pretty crappy. I'm going to do at least one more round of treatments over the next 3 weeks, and then will evaluate whether to continue.
  • CNTO-328: Monoclonal antibody to IL-6 made by Centocor. 4 WM patients were in a trial at NY Hospital and did well. Side effects are supposed to be quite minimal. Robin was the first patient in the trial and wrote:
    • I have had great success! I had tried Rituxin and 2Cda (with no success) and finally was getting plasmapherised twice a week or as needed just to keep my IgM down and to feel okay. When the CNTO Trial opened up I was in the right place at the right time. I was on it for almost two years and have been stable for almost a year in Sept!
  • BDR: this is velcade, Dexamethasone, rituxan: Very fast response and 22% get complete remission. But a lot get PN and it wasn't all reversible. Also, they should give you Valtrex during treatment because the Velcade puts you at risk for shingles
  • Note: one of these treatments puts you at risk for shingles and taking valtrex during treatment can prevent that
  • Rituxan maintenance: doing 1 full dose once every 3 months can keep things in check. The 2 years was an arbitrary cutoff. People have been using this for longer and it seems to work well.
  • tunicamycin: pre-clinical studies against WM look good (done at DFCI). But it is not a drug, just a lab compound to test if ER stress is important.

I am currently enrolled in clinical trial for statin treatment of WM. It's essentially Zocor; a pill you swallow once a day. The hope is that this might completely stop the disease from progressing. But I had to drop out since my IgM had started to affect my vision.

Unlike most cancers which you want to treat early and aggressively, for WM the recommended procedure is to only treat if there are symptoms. That makes sense since the treatment can kill you (or cause serious or permanent side effects) and has not been shown to substantially increase survival time. So treatment is normally started only when it is absolutely necessary to address the symptoms due to quality of life issues, i.e., when the disease clearly becomes worse than the treatment. Unfortunately, for some people, when the symptoms start to appear, the effects are permanent.

So I think that it's wrong. I think it is much smarter to treat the disease before it takes root. Once you allow it to grow, it is much harder to kill. And so what happens, you'll develop some serious symptom requiring you to treat the disease. Then you'll find you have no time. So you end up using really harsh treatments like chemo. That further weakens you and if it doesn't work, they use either stronger stuff. It is way smarter to do all of this while the disease is young. You can then find out what works, starting with the mildest treatments first. You have time.

In general, the treatments are also a huge guessing game, even among the top experts. Nobody knows which therapy is best for you or how you will respond because the response is quite variable from patient to patient, even if you have exactly the same numbers as another patient. It is "try this... ok, that didn't work...let's try this..." One top expert told a patient who wasn't getting any better with aggressive treatment "let's watch and wait" while another doctor told him to go on maintenance Rituxan. He did the latter and his health and his numbers both improved. Unfortunately, the cancer adapts to avoid being killed by the treatments so treatments that worked before can't be relied on to work later. Since there are only a handful of drugs that are effective, the number of times you get to experiment are limited.

Combinations that are lower dose than recommended can have low side effects but still be effective.

From: Ken Warner
Subject: Re: Drug Quantities Used for Treon's BDR Trial

I would never submit myself to enduring that particular protocol.

It's another scorched earth attack.

I get 1.6mg V; 10mg Dex; 750mg R every two weeks. It's working SLOWLY and I have none of the side effects listed in Treon's paper.

Shock and awe looks good only on TV -- don't devastate the body to cure it.

From International Workshop on Waldenstrom's Macroglobulinemia (Venice, Italy)
Good news - The new Mab GA101 is very good - better than Rituxan. RAD001 doing good things - new trial soon with Rituxan (what about GA101???). Combos still the best. Very early work started on identifying the "target" of WM IgM - surprisingly, different WM patients have quite similar IgMs (fluke finding?). Rituxan + Bendamustine the new holy grail. T-cells becoming more and more important. Lots of new young researchers from all over the planet.

Bad news - WM seems to "march" on, even if your counts "stable" or in "remission" - indolent doesn't mean arrested. Watch and Wait may not as wise as folks might think. If you get treated, go for the kill, don't be happy with a "25-50% reduction" in IgM many now think. Harvest your stem cells. Newer targeted therapies mean that bone marrow biopsies are more important than ever - not doing a BMD when appropriate is dumb. $$ for research tight.

Steve Kirsch's Waldenstrom Macroglobulinemia links