Fear, uncertainty, and pessimism accompany virtually every cancer diagnosis, especially if most patients, like those with myeloma, have never even heard the word before. Yet myeloma specialists are increasingly confident and optimistic that the vast majority of diagnosed patients have legitimate paths toward longevity, good quality of life, and will benefit from increasing treatment options and experience.
Drs. Leif Bergsagel, Matthew Fero, and Edward Libby explain why they are more optimistic about the prospects for newly diagnosed patients than they have ever been and why they are confident about the progress yet to be made. Dr. Sarah Lee will present them with two case studies that illustrate why they are hopeful about the future. All four answer questions submitted by viewers to conclude the first session of the Myeloma Crowd Round Table Interactive Webcast held on November 21, 2020:
Leif Bergsagel, MD, Mayo Clinic: The Ever-Changing Landscape of Treatment
- Seventy years of progress
- Dr. Bergsagel’s father, Daniel, was a member of the MD Anderson Cancer Center faculty
- In 1962, no regression of myeloma had ever been reported
- No treatment agent was effective in more than 20% of patients
- The expectation was that most treatment would be ineffective
- He proposed using a new agent, melphalan, in 11 patients and would move on to new drug if it did not have achieve a response rate of at least 90%
- A 1965 scientific paper showed that melphalan could drive down the M spike for prolonged periods of time, in half of IgG Kappa patients, but in none with IgG Lambda
- Additional uses of steroids and cyclophosphamide showed an increase of one-half of one percent improved in 5-year survival rates for the next 40 years
- The next major breakthrough was the development of thalidomide
- Dr. Bergsagel was contacted in November 1997 by the wife of a myeloma patient who was looking for treatment options for her husband
- He informed her about the research of Judah Folkman, who pioneered the idea of anti-angiogenesis in cancer, which did not treat cancer tumors, but blocked the ability of the tumor’s ability to nourish itself (called angiogenesis)
- The notorious drug thalidomide, which caused many birth defects, primarily in Germany, because of is anti-angiogenesis properties, was believed by Dr. Folkman to be effective in cancer
- Dr. Bart Barlogie, the patient’s physician, was first to use thalidomide, which eventually became the first drug to be effective in treating myeloma, an immunomodulatory drug (IMiD)
- It led to the development of lenalidomide (Revlimid ®), the most used drug in myeloma today, and pomalidomide (Pomalyst ®)
- Bortezomib (Velcade ®) was developed shortly after this
- It is a proteasome inhibitor (PI), the proteasome is a group of proteins that break down damaging proteins, such as cancer cells
- Dr. Marion Orlowski first identified the proteasome in 1960, and his son, Dr. Robert Orlowski of the MD Anderson cancer center, was the first physician who treated myeloma patients with bortezomib
- These two discoveries dramatically changed the 5-year survival rate to two percent per year, a rate which which should reach 100% by the year 2030
- If survival rate can be quadrupled with the new drugs and therapies that have been approved and are in development, 100% of patients diagnosed in the near future can expect at least a 5-year survival, 60% a 10-year survival
- Clonal tides or clonal heterogeneity
- Myeloma clones and sub-clones change the genetics of patients with each treatment cycle
- Combination therapies can respond to these changes by targeting differing sub-clones
- Combination and other novel therapies come at a high financial cost
- Drug effectiveness must be balanced with quality of life
- Transplant still has role to play in better progression-free survival (PFS) but maybe not in overall survival (OS) rates
- Complexity of using all the drug and treatment options available is becoming more understandable to physicians
Matthew Fero, MD, FACP, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM: An Increasing Arsenal of Therapeutic Options
- Overview of disease basics
- Goals of therapy
- Twelve new drug therapies have been approved in myeloma in the past 20 years
- Triple therapies are relatively standard in the U.S.
- First consideration is determining whether one is transplant-eligible or ineligible
- Ineligible patients may actually have more therapy options because autologous stem cell transplant (ASCT) may preclude use of some therapies before transplant
- Fitness is a determining factor
- Depth of response to treatment predicts duration of response
- Combination therapy uses more therapies simultaneously
- Generally has higher response rates, longer response, but more side effects
- Sequential therapy uses one treatment after another
- Generally has lower response rates, fewer side effects, and less expensive
- ASCT is a way of giving more melphalan and more chemotherapy
- Mobilization is a procedure to harvest more stem cells to transplant
- Considerations to determine if ASCT is appropriate
- Age, fitness, is disease in remission, able to commit time needed, other health problems, are side effects manageable?
- Balancing risk and benefits is an individual decision
- Maintenance therapy keeps disease in remission longer, but not necessarily overall survival (OS) rates
- Timing and sequencing is may be more important
Edward Libby, MD, Seattle Cancer Care Alliance, Seattle, WA: Balancing Today with Tomorrow’s Opportunity
- IFM (Intergroupe Francophone du Myélome) Study comparing RVd (also known as VRd) induction vs. RVd plus ASCT, both with 1 year lenalidomide (Revlimid ®) maintenance is benchmark for how to treat newly diagnosed myeloma, in U.S. maintenance is often indefinite
- Progression-free survival (PFS) in transplanted patients was 14 months longer, but overall survival was similar, with 81% survival over 4 years
- Conclusion: standard therapy works well, tolerability of RVd is acceptable and allows normal quality of life and routine, maintenance is usually without dexamethasone
- Known as “backbone” therapy, with or without ASCT
- Next step is to add new therapies to backbone therapies
- Daratumumab (DARZALEX/DARZALEX Faspro ®), a monoclonal antibody (mAb) is promising, has minimal side effects [learn more about daratumumab here]
- Two new promising drugs are belantamab mafodotin (BLENREP ®) and selinexor (XPOVIO ®) [learn more about each here and here]
- A CAR T cell therapy will be approved soon, many in trials, used in isolation, may be candidate for combination therapy [to learn more, click here to the watch the Myeloma Crowd Round Table on CAR T therapy]
- Patients should be aware of side effects of various treatments [Myeloma Crowd Round Table on side effects will be published on this website in coming weeks]
- There is likely a day coming when ASCT will no longer be standard therapy, but that day is not here yet, it is still a part of standard, backbone therapy
- Still most used in myeloma [learn more about stem cell transplant here]
- Significant risks and side effects affect a very small population of patients
- Minimal residual disease (MRD) status might be a consideration of whether to transplant or not [to learn more, click here to the watch the Myeloma Crowd Round Table on MRD]
Sarah Lee, MD, Seattle Cancer Care Alliance, Seattle, WA, Leads a Discussion of Two Case Studies
Case study one
- 50 year-old diagnosed in 2014 with back pain and multiple compression fractures, continued with physical therapy as pain and nausea worsened
- Anemia, kidney injury and hypercalcemia evident
- Diagnosed with IgG Kappa and bone lesions with stage III myeloma using international staging system (ISS) criteria (which would be revised ISS stage II today
- Dr. Libby noted this was classic presentation of standard-risk disease and would use RVd for initial treatment
- Dr. Bergsagel noted normal FISH test was not typical, he would reorder a FISH test and to check genetics and if she were high-risk, consider using four drug combination of Dara-RVd, if standard-risk, RVd
- Because of renal problems, she had 7 cycles of cyclophosphamide, bortezomib and dexamethasone (CyBorD) and was moved to RVd as kidney function was restored
- She reached a very good partial response (VGPR) after a year of treatment
- Had to make a decision about whether to have transplant or stay on drug regimen
- Dr. Fero recommended collection of stem cells regardless of decision to bank them and not wait for disease to progress
- Patient did go on to ASCT with high dose melphalan, what would the doctors recommend for maintenance?
- Dr. Libby noted ASCT plus maintenance would create longer time for disease to return, lenalidomide (R) is the standard, perhaps with intermittent bortezomib (V)
- Dr. Fero would do same, but noted the decision has to be personalized, does patent want to keep disease in longer remission if OS is same?
- Dr. Bergsagel agreed, noted he preferred up front transplant because first remission tends to be the longest remission, important to keep in mind possible future therapies
- Dr. Fero encouraged exploring entering clinical trial, he also noted cost, consider cheaper treatments first
- Patient went on lenalidomide maintenance, symptoms were alleviated
Case study two
- 42 year-old with back pain in 2010, pain worsened leading to imaging that showed bone metastases, ribs fractures
- Diagnosed with Kappa light chain myeloma
- Patient enrolled in induction clinical trial using Doxil + CyBorD, consolidated with high-dose melphalan and ASCT, R maintenance
- By December 2011, progressive disease returned
- Dr. Libby noted that initial tests indicating standard-risk so situation was worrying
- Dr. Bergsagel would consider patient to be high-risk and encouraged clinical trial, perhaps one that explored earlier use of CAR T therapy
- Dr. Fero said this was not a patient for whom 2nd transplant would be recommended
- Dr. Libby compared this to patient of his like this who responded to elotuzomab, a mAb
- Patient had allogeneic transplant in October 2012 with good response for four years
- Relapsed with plasmacytoma on chest, was found to have del17p high-risk marker and began treatment with radiation and Dara-Pd (pomalidomide, dexamethasone)
- Dr. Bergsagel noted with every relapse, the myeloma clones change
- Patient did not respond to treatment, was switched to carfilzomib (Kyprolis ®) with Rd (KRd) in June 2016 and was found to have new lytic lesions in August 2017, meaning he was penta-refractory (did not respond to five lines of treatment)
- Dr. Bergsagel noted that patient had t(11;14), a particular marker that can be treated with venetoclax and would try it either on or off a clinical trial
- Dr. Libby noted venetoclax may be the first truly targeted therapy in myeloma, only for t(11;14) patients, who compose 30-40 percent of myeloma patients
- Patient went on to more chemotherapy, a clinical trial, and then a CAR T clinical trial, then venetoclax plus bortezomib, his eighth line of treatment
- What drugs is faculty most excited about for patients like this should they need more therapy?
- Dr. Libby was interested in BiTE (bispecific T cell engager or bispecifics) therapy, at least a dozen being studied now
- Dr. Fero explained how BiTEs work, by connecting T cells to myeloma cells to engage immune effect
- Dr. Bergsagel said the BiTEs offer a number of new possible targets for myeloma treatment
Audience Questions & Answers
- 0:45 - What should a patient who has been diagnosed with plasmacytomas do?
- 2:30 - How does one reverse a Revlimid rash?
- 4:15 - What are your thoughts about using daratumumab as a monotherapy in post-ASCT maintenance?
- 6:28 - Cyclophosphomide is given in Europe as a part of apheresis, but not in the U.S. Are there studies that show the risks and benefits of this?
- 8:30 - Does myeloma detected by a kidney issue requiring dialysis, with no bone involvement detected by PET/CT, and t(4;14), does it indicate anything significant?
- 10:22 - Would it be possible to do a stem cell transplant from one’s own child’s umbilical cord?
- 13:15 - Is the benefit of progression-free survival (PFS) overrated in the face of no difference in overall survival (OS)?
- 15:50 - How can one tell if they have a good local transplant center if they are not close to a major transplant institution, especially in the COVID era when traveling long distances is more difficult and risky?
- 18:50 - When they become available, with COVID vaccines be same for myeloma patients in remission?
- 19:55 - What is the percentage of patients who might be cured and how might this be determined?
- 23:50 - If a patient is having a very good response to combination therapy during induction, has been in a deep remission for 2-3 years, and is of low risk for a genetic mutation, should that patient consider an ASCT?
- 25:04 - For a patient diagnosed with no symptoms other than protein in the urine, bone marrow and blood tests whose symptoms are more from the treatment than myeloma, what should the patient do?
- 27:57 - When should patients consider going from a three drug combination to a four drug combination? What are the indicators to do so?
- 30:47 - Program Director Rozalynn Hite describes the Myeloma Coach program.
Questions Answered in Chat Forum
- I was diagnosed this past July. My oncologist/hematologist told me that my survival rate was 8-10 years. Is that changing?
Dr. Bergsagel answered: Yes. It is improving over time.
- Are survival estimates from the time of diagnosis or when active cancer is present?
Dr. Bergsagel answered: Active cancer.
MGUS/Smoldering Myeloma (SMM)
[Find more information in the Myeloma Crowd Round Table on MGUS/SMM here.]
- Wouldn’t treatment be more effective if was applied during MGUS or SMM stages when a person is in a healthier state than after they have progressed further with the disease?
Dr. Fero answered: Good question. The issue is that some patients with MGUS can go their whole life without the disease progressing the point to cause symptoms.
- Can you comment on vaccines for high-risk smoldering (SMM) or myeloma? Can mRNA technology help?
Dr. Bergsagel answered: Patients with high-risk SMM should consider participation in ongoing clinical trials. SMM is probably too advanced for vaccines to be effective. Vaccines may be better for standard-risk SMM.
- Do you recommend Velcade for low to intermediate risk SMM?
Dr. Fero answered: I would only a recommend it as part of a clinical trial.
- If someone is older and more at risk of advancing to active myeloma, would that make it more of a reason to treat an older person SMM who is still healthy?
Dr. Lee answered: Not necessarily. In general, the treatments are well tolerated and more importantly can be modified based on patient’s age and risk factors. One might consider a single agent, two drugs vs. three drugs, reduced doses, etc. We have patients in their 80s and 90s who are being treated and maintain a good quality of life.
- I was diagnosed with SMM earlier this year. Should I consider asking for treatment?
Dr. Lee answered: If you have high-risk SMM, then it might be reasonable to consider. I think more importantly, having more information over time will inform how rapidly the protein will evolve. If the M-protein remains stable, then observation may be best, even with high-risk SMM.
- Do you recommend 21 days cycle or 28 days cycle of RVd for induction?
Dr. Fero answered: I prefer 28 days, but only because I like to check on a patient (and get labs) every 4 weeks vs. every 3 weeks.
- I understand that daratumamab is not FDA approved for first line of treatment. What evidence exists about safety and effectiveness?
Dr. Fero answered: Daratumumab generally is well tolerated. The National Comprehensive Cancer Network (NCCN) guidelines list it as an option for upfront therapy in patients not fit for transplant.
- Does data exist on the use of Dara-Rd without a proteasome inhibitor?
Dr. Bergsagel answered: Yes, Dara-Rd is approved for use in the frontline setting. Works great.
- If one gets neuropathy with Velcade can one take another similar medication and possibly not have neuropathy?
Dr. Bergsagel answered: Yes, carfilzomib (Kyprolis).
- If neuropathy occurs with one protease inhibitor does it mean one should not use another protease inhibitor?
Dr. Lee answered: No. Carfilzomib has less neuropathy than bortezomib. But it does have a higher risk for cardiac toxicity. Ixazomib (oral PI) also has less neuropathy, but more GI side effects.
- If neuropathy occurs with one protease inhibitor, is it a problem for medications in this class?
Dr. Fero answered: Not necessarily.
- I was diagnosed three months ago with SMM and I am a professional musician, so my oncologist at UCSF suggests no Velcade because of neuropathy issues and I need my hands. What would he substitiute with again?
Dr. Bergsagel answered: Carfilzomib (Kyprolis).
- I'm just starting treatment. My oncologist is suggesting an antiviral in addition to RVD to control possibility of shingles. Is this a standard approach?
Dr. Bergsagel answered: Yes, acyclovir.
- Does daratumamab take a transplant completely off the table?
Dr. Lee answered: No. There is no contraindication to transplant with prior exposure to daratumumab. There are clinical trials that now incorporate daratumumab to VRD backbone as induction, prior to transplant.
- I am on Dara-Vd. Should I be concerned that I am not on Revlimid?
Dr. Fero answered: That is a great 3 drug regimen.
- What is the estimate of out of pocket costs under Medicare for Dara-VRd? I’m 74, recently diagnosed, and had my first treatment yesterday. The $500K per year cost mentioned by Dr. Bergsagel was pretty scary.
Dr. Fero answered: Medicare part D covers outpatient oral therapies, but different plans have different copays. Ask if the drug company has a copay assistance program.
Transplantation [Find more information about this treatment in the Myeloma Crowd Round Table on Stem Cell Transplantation here.]
- What is the age factor with whether to do transplants. Would it not depend more on the person’s individual health independently of age?
Dr. Fero answered: There is not a hard cutoff. Over the age 70 it is more toxic and often the drug dose needs to be reduced, so it is also less beneficial.
- Does the three year PFS for ASCT include ongoing lenalidomide maintenance? If not, what should maintenance be?
Dr. Fero answered: The average PFS after ASCT is around three years if the disease was in first remission and longer if maintenance is used. PFS is shorter if the myeloma is not in remission at the time of transplant or if the patient has had many lines of prior therapy.
- What, if any, is the benefit of a second stem cell transplant after a successful first transplant.
Dr. Fero answered: A patient who has a long response after the first transplant can have a long duration of response after a second.
- Why six weeks at a transplant center? I was in hospital for 14 days, and then had to stay two weeks in 'isolation' outside of the hospital.
Dr. Bergsagel answered: It is six weeks for patients that fly in to the Mayo Clinic for transplant as well. Two weeks before the transplant in order to perform tests, collect the stem cells, and then the patients need to stay within 30 miles for the next month. They do not need to be admitted to hospital unless they suffer a complication.
- Do you think the only chance for a “cure” or a functional cure is an allo transplant or an auto-allo combination?
Dr. Fero answered: Auto/allo “tandem” transplants were a cause of much interest and study around ten years ago. Relapses still happened so it did not seem to be curative. It might be different if it was done earlier in the course of the disease, but has so many side effects, no one really wants to try it.
- What is the effect of ASCT on a myeloma patient who also has multiple sclerosis (MS)?
Dr. Fero answered: That is very tricky and will depend on the severity of each. ASCT can help both conditions, but only a few specialized centers do ASCT for MS.
- I am 47 and was diagnosed with myeloma about 2 years ago. I have been treated with Revlimid combinations, ASCT was discussed, and remains on the chart. What I heard today is that staying on Revlimid may make stem collection impossible. Are there any triggers or indicators I need to be monitoring when my blood work is done.
Dr. Fero answered: I would ask for a consultation with a bone marrow transplant (BMT) specialist.
- Can we stay on maintenance therapy for 5-10 years?
Dr. Fero answered: We need more studies to learn how much maintenance therapy is best!
- I am two years post-ASCT, have a stringent complete remission (sCR), and have been on Revlimid maintenance. What are the pros and cons of going off maintenance?
Dr. Fero answered: Revlimid cons: cost, side effects. Revlimid pros: longer duration of remission. Unknown: if longer vs. shorter maintenance matters.
- I recently had a transplant and plan to be on Darzalex faspro as a maintenance therapy. I have not heard anyone talking about this as maintenance therapy.
Dr. Fero answered: It is not FDA approved for this purpose. The Southwest Oncology Group (SWOG) is conducint a study of Revlimid with and without Darzalex faspro. [Find more information about this treatment in the Myeloma Crowd Round Table on Novel Therapies here.]
- What is the recommended maintenance treatment with Revlimid for younger patients given long-term side effects?
Dr. Fero answered: One standard approach for younger MM patients is: 1. induction with RVd, 2. ASCT, 3. Revlimid maintenance. The same benefit can come from other approaches however.
- My maintenance therapy is Vd twice a month and medrol every other day. If I interrupt my therapy for a reason unrelated to my disease or treatment, would this be detrimental to my treatment?
Dr. Fero answered: There is no known long term impact on overall survival of maintenance unless it is after ASCT. I do not recommend medrol and other steroids as maintenance because of the long term side effects.
- What is the role of dexamethasone in maintenance?
Dr. Lee answered: We usually try to omit dex for long-term maintenance. It can have many bad side-effects with prolonged use. Save it for when you need active treatment.
- After transplant, my family member started Revlimid maintenance. One of the studies Dr. Libby cited had patients receive an additional two cycles of RVd post-ASCT in July 2020 before going on Revlimid maintenance. Is my family member at a disadvantage because they didn't receive additional cycles of RVd before going on maintenance? Should I inquire about my family member receiving the additional cycles of RVD now?
Dr. Cowan answered: The RVd after transplant is referred to as “consolidation.” Although studies commonly use this, it is not usually given in most oncology practices. Depending on the respone to the transplant, and having already had eight cycles of RVd, I suspect further consolidation is not necessary, and staying on maintenance with Revlimid is probably fine.
Minimal Residual Disease (MRD) [Find more information in the Myeloma Crowd Round Table on MRD here.]
- Can MRD negativity guide treatment given existing sample bias?
Dr. Fero answered: Sample variation occurs since myeloma levels may vary from one spot to another on a biopsy. We have not good way to account for this. It may help to know if your disease is “patchy” or whether it is evenly spread out on imaging. Or you can biopsy both sides!
- What is the most accurate test for MRD?
Dr. Bergsagel answered: ClonoSEQ, a next generation sequencing test performed on the bone marrow biopsy.
- Could CAR T therapy potentially cure the disease?
Dr. Bergsagel answered: Yes. [Find more information in the Myeloma Crowd Round Table on CAR T here.]
- What is your view on maintenance post CAR T? Clinical trials do not contain maintenance, but would maintenance prolong response to CAR T?
Dr. Fero answered: We don’t know yet!
Bone Disease [Find more information in the Myeloma Crowd Round Table on Bone Issues here.]
- If myeloma-related bone fractures occur, do they heal? Is this similar to "normal" bone-breaks?
Dr. Fero answered: If you get the myeloma under control, then the fractures can heal normally. A compression fracture in the spine will remain compressed, however, so a patient may have chronic pain and loss of height.
- My mom, 71 was diagnosed with myeloma this part summer. She is in RVd and here doctor wants to do a bone biopsy to see how the treatment is working. She is experiencing lumbar pain. Should this be done?
Dr. Fero answered: If a patient can lie down comfortably on his/her side or stomach then a biopsy is usually is fine and is a good way to monitor progress.
Genetics and Risk [Find more information about this treatment in the Myeloma Crowd Round Table on Myeloma Genetics here.]
- Is "loss of RB1 (13q14) locus (153/200)" in a FISH report considered high-risk?
Dr. Bergsagel answered: No.
- If each clone reproduces a single abnormal antibody and there are several clones by the time of a new diagnosis, why is there only one M spike on SPEP?
Dr. Bergsagel answered: There is only one clone, making one monoclonal antibody. There are multiple subclones with different genetic mutations, but all making the same monoclonal antibody.
- The graphs shown do not distinguish between standard- and high-risk. I assume if they were stratified between standard- and high-risk graphs, they would look strikingly different. To what extent? For one who is diagnosed with t(4;14), would the graphs look the same?
Dr. Bergsagel answered: Modern therapy overcomes most of the high-risk that was previously associated with t(4;14), which is still high risk if one is ISS stage III.
- Is gain of 1q chromosome still associated with poorer outcomes?
Dr. Bergsagel answered: Yes.
- Do the PFS and OS graphs shown reflect high-risk or standard-risk myeloma?
Dr. Fero answered: The graphs I showed did not separate patients this way, it was everyone lumped together. Importantly, how the disease responds to treatment is also a strong predictor, regardless of what the genetic/mutation analysis shows.
- Is the risk of new mutations higher with transplant due to the toxicity of melphalan?
Dr. Fero answered: Dr. Libby mentioned a small risk of leukemia or other cancers from melphalan. The risk of second cancer has been reported as 10% for patients who live 25 years. That is not much higher than the rate in non-myeloma patients.
Plasma Cell Leukemia
- I am 54 and have plasma cell leukemia with 13del genetics. I had a tandem transplant in 2015, and have been MRD negative and in remission since August 2015. I have not had any treatment for three years. A constant question is: should I be on a low dose of treatment? I was MRD negative on my last biopsy in September 2020 and have had no treatment since November 2017.
Dr. Fero answered: I know of no data to answer that question directly. You would need to extrapolate from other situations (after auto alone, or after induction alone) but that may not be correct.
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about the author
Greg Brozeit has been with the HealthTree Foundation since 2015 when he began volunteering for the Myeloma Crowd. Prior to that he worked with Dr. Bart Barlogie and the International Myeloma Foundation, inaugurating many myeloma patient advocacy and education programs.