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Module 2: First-Line Treatment of Multiple Myeloma

Section 2: Transplants

When are transplants indicated as the appropriate course of treatment?

Dr. William Bensinger: Although most physicians would agree that a transplant is indicated for patients who are responding to initial therapy, there is controversy regarding the role of transplants for patients with relapsed or refractory disease. Some studies indicate that delayed transplants, when compared with up-front transplants, are not associated with a significant degradation in survival, but conclusive evidence has yet to emerge. Clearly, more research needs to be done in this area. [View Reference]

Are there any research studies that could help answer these questions?

A large US study that has finished accrual and is undergoing analysis should help to answer the question of whether it is better to have a transplant as part of initial up-front therapy or whether to delay a transplant to the point of relapse or at the time of refractory disease. [View Reference]

Which patients are appropriate candidates for transplant procedures?

Patients who are suitable candidates for transplant generally have good performance status and are free of major organ dysfunctions such as kidney failure, heart failure, or lung difficulties. In general, they tend to be younger patients, although successful autologous transplants have been performed and reported for patients up to 80 years of age.[View Reference] Allogeneic transplants are generally performed in younger, healthier patients, although the newer allogeneic transplants, which are nonablative transplants, may be suitable for patients in their 70s. [View Reference]

Patients up to age 70 are generally considered for autologous stem cell transplant, although it is occasionally possible to perform an autologous transplant in patients up to 80 years of age. To be considered for a transplant, patients generally must have good organ function, which usually includes a pulmonary diffusion capacity for carbon monoxide (DLCO) of greater than 50% and a cardiac ejection fraction greater than 50%. Kidney function should be essentially normal with a creatinine less than 2 mg/dL, and patients should have no other serious medical problems.

Can patients on dialysis ever qualify to become transplant candidates?

Dr. David Roodman: There are data, at least from Arkansas, that show transplanted patients on dialysis have done well. [View Reference]

William Bensinger: That's true. That group is also the one that claims that transplants can be performed in patients older than age 70. I don't know how hard to push that.

Dr. Seema Singhal: Patients with renal failure and patients with dialysis-dependentrenal failure can be considered as transplant candidates, although they may havemore transplant-related morbidity. Some clinicians consider using lower dosesof melphalan for transplants under these circumstances.

Who are traditional candidates for allogeneic transplants?

Dr. William Bensinger: Allogeneic transplants can be considered if the patient has an HLA-matched sibling. To be a candidate for allogeneic transplant, patients generally have to be young (an age cutoff that is commonly used is 55), with good organ function with normal DLCO or DLCO above 50%, a cardiac ejection fraction greater than 50%, and normal kidney function.[View Reference]

Who can donate stem cells for an allogeneic transplant?

Dr. William Bensinger: Donors generally have to meet the normal blood bank eligibility requirements, which means they must be in good health, without any serious organ dysfunction, and would be considered suitable for donating blood or blood components for a normal blood bank. Donors generally undergo a routine physical examination and screening blood tests, chemistry tests, electrocardiogram, and, if suitable, then are considered either for marrow donation or donation of peripheral blood stem cells.

What are the HLA requirements for an allogeneic transplant?

Dr. William Bensinger: Most transplants are performed when the donor and recipient are HLA identical, which generally means matching for the A, B, C, and D major histocompatibility antigens. Mismatched transplants have been reported to be successfully performed but are much more difficult, and patients generally have considerably greater complications from these transplants. [View Reference]
Matched unrelated donor transplants can be considered when other options are unavailable, but the complication rates tend to increase dramatically, and, therefore, these transplants are used only later in the course of the disease.[View Reference]

Dr. David Roodman: I think it is important to discuss the costs associated with these procedures.

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Dr. William Bensinger: Autologous stem cell transplants can range in cost from approximately $50,000 to as high as $150,000, depending on the center. An important advance in lowering the cost of this treatment is the ability to perform most or all of the treatment procedures and follow-up on an outpatient basis. Allogeneic stem cell transplants are generally considerably higher in terms of cost, owing to the various complications and longer follow-up period that is necessary. The typical cost of an allogeneic transplant can range from $100,000 to as high as $250,000. Insurance companies generally have agreed to pay for autologous stem cell transplantation in recent years, and recently Health Care Financing Administration (HCFA) guidelines have been adopted to allow coverage for Medicare and Medicaid patients. Allogeneic stem cell transplants still require individual approval from each insurance company, and their decisions can be quite variable.

What are tandem transplants? Why are they done?

Dr. William Bensinger: To achieve a greater response rate and improved survival, several transplant groups have adopted so-called tandem transplants, using two cycles of very high-dose therapy with autologous stem cell transplantation. Although it clearly has been shown that these transplants are feasible, there is controversy about the benefit of one versus two transplants.[View Reference]

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Dr. William Bensinger: At present, there are four to five randomized trials under way (mainly in Europe) that may address some of these issues, but there are no hard data that tandem transplants improve survival compared with a single transplant.

What types of preparatory regimens are used for transplant candidates?

Dr. William Bensinger: Autologous stem cell transplants use very high-dose chemotherapy or chemoradiotherapy and autologous peripheral blood stem cells for reconstitution of the hematopoietic system. This treatment requires several steps including the collection of stem cells and the administration of high-dose therapy and reinfusion of stem cells.

The high-dose therapy preparative regimens can include chemotherapy only or chemotherapy combined with the use of total body irradiation (TBI). TBI has been used traditionally because it was historically one of the original modalities for transplant. [View Reference] In recent years, there are emerging data that TBI may not be necessary or even recommended for a transplant preparative regimen. At least one large randomized study comparing high-dose melphalan 200 mg/m2 with melphalan 140 mg/m2 plus 8 Gy of TBI showed no benefit in terms of response rates and actually improved survival for the group receiving high-dose melphalan. This improved survival was thought to be due to better salvage therapy administered to patients after relapse.[View Reference]

Dr. Brian Durie: TBI does not improve outcome but may increase toxicity.

Dr. William Bensinger: That study did show more toxicity with the TBI-based regimen.

Dr. Brian Durie: It did not improve outcome, is that correct?

Dr. William Bensinger: That's true, the response rates were the same, and they actually showed better survival for the melphalan group.

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Dr. William Bensinger: The study comparing high-dose melphalan alone with melphalan plus TBI was also remarkable because the group that received TBI had increased toxicities compared with the patients who received melphalan alone, and the survival rate was not improved with TBI.

What is the standard induction therapy for patients with multiple myeloma?

Dr. Robert Kyle: The standard induction therapy for multiple myeloma is VAD. If a patient has any evidence of peripheral neuropathy, vincristine should not be given. Other investigators have used dexamethasone alone. More recently, we have used dexamethasone plus thalidomide as the induction regimen. This has produced an objective response in about two thirds of patients. [View Reference]We have also had no difficulty in collecting an adequate number of stem cells following the three or four induction courses of thalidomide and dexamethasone.

Are there cases in which a typical treatment for multiple myeloma might interfere with the success of a transplant procedure?

Dr. Seema Singhal: It is well known that patients who have received long-term therapy with alkylating agents can have difficulty having their stem cells collected for autologous transplant. This is because of damage to their hematopoietic stem cells from the long-term exposure to alkylating agents. Ideally, patients who are candidates for high-dose therapy should not be exposed to alkylating agents before stem cell collection.[View Reference]

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Dr. Seema Singhal: However, we have shown that it is possible to collect stem cells in these patients, even in patients who have had one or even two previous transplants. Therefore, an attempt to harvest the cells must always be made, even with patients who have had extensive previous treatment.

Dr. Robert Kyle: Alkylating agents should not be given to patients with multiple myeloma if an autologous stem cell transplant is considered. The stem cells must be collected before the patient has been exposed to alkylating agent therapy. This is important to stress because many physicians do the opposite: They start patients on melphalan and prednisone to see how they do, and then if that does not work well, they send the patients to a center for collection of stem cells.

What are some of the complications associated with transplant procedures?

(Survival and Disease-Free Survival of Patients With Multiple Myeloma Who Undergo Allogeneic Transplant)

(Survival and Disease-Free Survival of Patients With Multiple Myeloma Who Undergo Allogeneic Transplant and Achieve a Complete Response)

(Stem Cell Tranplantation for Multiple Myeloma Nonrelapse Mortality)

(Stem Cell Transplantation for Multiple Myeloma Relapse or Progression)

Dr. William Bensinger: Complications from transplant procedures are generally due to toxicities associated with the high-dose chemoradiotherapy and complications from infections due to bacteria, viruses, or fungi during the period of neutropenia and the period of immune recovery following the autologous stem cell transplant.

In general, these complication rates are lower compared with allogeneic stem cell transplants.

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Dr. Bensinger: The overall mortality with an autologous transplant is approximately 5%; the complete response rates range from a low of 20% to as high as 40%; and, in general, the survival improvement when compared with conventional-dose chemotherapy is 1 to 2 years as a median. [View Reference] Allogeneic stem cell transplants generally have higher complication rates, owing to slower immune reconstitution and the complications of GVHD.[View Reference]

When undergoing an allogeneic stem cell transplant, the patient requires a considerable period of time for the immune system to recover, and during this time, the patient is being treated with immunosuppressive drugs that can further increase the risk of infectious complications. GVHD is a unique disorder that occurs primarily due to the reaction of the incoming donor graft against the patient's tissues. GVHD can cause severe skin rashes. It can lead to severe liver dysfunction, liver failure, or gastrointestinal complications causing nausea, vomiting, diarrhea, or hemorrhage. [View Reference]

GVHD has also been reported to result in pulmonary dysfunction with a peculiar syndrome known as BOOP or bronchiolitis obliterans. [View Reference] GVHD may require prolonged treatment with immunosuppressive drugs, especially if chronic GVHD develops, in which case patients often are treated for several years.[View Reference]

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Dr. Bensinger: Standard allogeneic transplants have considerably higher mortality rates, ranging from a low of 20% to as high as 50%, depending on the patient's age, disease status, and organ function. [View Reference] It should be noted, however, that allografts are perhaps the only modality with the potential for long-term disease-free survival and possible cure.

Would you recommend a transplant? Is it currently the only pathway to a cure?

Dr. William Bensinger: Well, it is very controversial. Some clinicians do not believe any patient is cured, even with allografts. Approximately 15% of our patients have survived 10 years or more without evidence of disease.

Dr. David Roodman: That means 85% of patients do not appear to be cured by the procedure.

Dr. William Bensinger: One of my patients has had no evidence of disease for approximately 17 years.

Dr. Brian Durie: The relapse rate is 13% per year, no matter how you look at it. [View Reference]

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Dr. William Bensinger: The issue of cure in multiple myeloma is controversial. Some patients at our center are surviving beyond 10 years and up to 17 years with no evidence of disease. [View Reference] In addition, we have a smaller group of patients who are surviving 5 to 10 years after autologous transplant, who also show no evidence of disease. Whether they are cured or not I think is an open question, but the fact that these patients can survive long term without any clinical evidence of multiple myeloma or without any laboratory evidence of multiple myeloma is in itself remarkable.

Dr. Brian Durie: I think there are several aspects related to whether ornot cure occurs with treatment in myeloma. The first point is that with all kindsof treatments that are being used from melphalan and prednisone to stem celltransplants long-term survivors have been reported without evidence of disease.And in some cases, autopsies have been performed that have shown no evidence ofdisease in patients who may have died of other causes such as heart attack. Andso we do know that some patients can have dramatic benefit, regardless of whichtreatment they have received.

Even if we're not talking about a "cure," do transplants improve survival?

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Dr. Brian Durie: One critical question is whether or not allogeneic transplant is more likely to be associated with this type of long-term disease-free survival versus other types of therapy. This is the controversial point: For allogeneic transplant, the possibility of long-term disease-free survival must be balanced against the up-front morbidity and mortality related to the transplant procedures. [View Reference] Is it worth accepting the up-front risks of morbidity and potential mortality that can range from 20% to as high as 50%? Is it worth accepting that up-front risk for a small chance of long-term benefit? I believe that it is not worth it because the chance of long-term disease-free survival is more patient related than treatment related. There are some patients who do well long term. To what extent their success is related to treatment is not clear.

Dr. William Bensinger: I think this underscores the importance of continuing to study patients who receive allogeneic transplants and the importance of clinical trials. I believe that no patient should receive an allogeneic transplant of any kind outside the context of a clinical trial and that this should be performed at major transplant centers that have the ability to monitor these patients and treat them accordingly.

Dr. Brian Durie: I would absolutely accept that.

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Dr. Robert Kyle: I'm reluctant to recommend an allogeneic transplant, even for young patients. The mortality is in the range of 25%; GVHD is a problem; and furthermore, there is no evidence that these patients are cured. [View Reference] It is advisable to look at modifications of a standard allogeneic transplant, such as nonmyeloablative transplantation [View Reference], or perhaps depletion of T cells. Until we achieve better outcomes or find definitive evidence of cure associated with allogeneic transplant, we face the challenge of finding ways to obtain the benefit of this treatment with lower morbidity and mortality.

More About Single Versus Double (Tandem) Transplants

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Dr. Seema Singhal: The big question we all face today in the treatment of myeloma is the issue of single versus double autologous transplantation. Although many centers are performing tandem transplants, the question really has not been addressed in a systematic, prospective, randomized trial. In Europe, there are multiple ongoing trials, but the issue still is unresolved.

[View Reference]

One of the points in favor of tandem transplants is that a greater number of patients undergoing this type of procedure achieve complete remission. However, the overall survival is not improved. The results of single versus double transplants are being studied with longer follow-up on patients. [View Reference]

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Dr. Brian Durie: It is disappointing that so many double or tandem transplants have been done without our being able to determine which patients are benefitting. To me, it is quite possible that some patients can benefit from double or tandem transplant; the question is, which ones? One practical way to approach this would be to look at patients who do not achieve complete remission with a first transplant and address the question of whether patients who have partial remission with a first transplant benefit from a second transplant. But this question can only be answered in a randomized, prospective fashion. At present, that question is not being addressed.

The randomized French studies have helped us to understand that there is not a major overall survival benefit with double transplant, but we still don't know if a subset of patients may benefit in either the short term or possibly in the long term. [View Reference]

Dr. William Bensinger: I think that may always be problematic because there is always attrition between the first and second transplant in these studies. Patients who are not in good condition after the first transplant never proceed to the second transplant. Frequently, patients who progress in-between never proceed to the second transplant; consequently, selection bias occurs. Although these randomized studies will help us define the benefit, these selection biases result in some patients never having the opportunity to have a second transplant, and, therefore, the potential effect on that population remains unknown.

Dr. Brian Durie: We must approach this issue in the context of the practicalities of treatment. If a significant subset of patients is not able to proceed with a second transplant, are we looking at this issue in the most useful way? Ultimately, we want to have treatment that can be administered reliably.

Dr. David Roodman: You could address that by just taking patients who are eligible for a second transplant who are only in partial response and randomize that group.

Dr. William Bensinger: That would be one way to address the issue, and that might help answer some of the critical questions that you've posed.

I'm all in favor of randomized studies, but I think that their value can be overinterpreted. For example, an ECOG study in leukemia that looked at autologous transplants was reported in the New England Journal of Medicine. In that trial, only 50% of patients actually received a transplant. Patients who were randomized to transplant and then relapsed in the interval before the transplant were counted as if they were transplanted, although they had not received transplants. The net effect was that there was no benefit of transplant. [View Reference] In fact, only approximately half the patients were actually transplanted. I have difficulty comprehending that transplant is not beneficial, but it certainly is not beneficial if the patient does not receive one.

Dr. Brian Durie: Right.

Dr. Seema Singhal: Brian, you made a point about the second transplant perhaps being useful in patients who achieve only partial remission after their first transplant. However, in most instances, the second transplant is done about 3 months after the first. We have noted that patients can achieve their best response after a single transplant 3 to 6 months after the first transplant. Therefore, it is not known whether the ultimate response that the patient achieves should be attributed to the second transplant or not. So it is difficult to determine, even in that particular subset of patients, if the second transplant is really indicated.

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Dr. Brian Durie: That is an important point. I think we need to ask to what extent is complete remission in itself necessarily correlated with longer remission or longer survival.

Survival does not necessarily correlate with the magnitude of initial reduction in myeloma tumor burden. With some patients, achieving stability of disease is the most important goal. In those cases, the presence of residual disease is acceptable, provided it does not progress, create symptoms, or cause organ damage.

Dr. Robert Kyle: I think it is important to define complete response, and which can be done in a variety of ways. If there is no evidence of a monoclonal protein in the serum or in the urine with immunofixation, many clinicians believe that this constitutes a complete response. However, we have found that the bone marrow in a number of these patients contains a monoclonal population of plasma cells. If a monoclonal population of plasma cells in these patients is not present, we next look for tumor DNA using PCR. We almost always find tumor DNA using that analysis, which indicates that the patients do not really have a complete remission.

Dr. Brian Durie: You highlight an important point: What we are addressing is a therapeutic question, when actually what we have are the biologic questions: Why do these patients relapse, and what can be done to prevent it? If we could understand the biology of residual disease better, we would know whether it is more appropriate to attempt further cytoreduction or perhaps work more to improve immune responsiveness or some other aspect. I would highly recommend more detailed biologic studies of patients who achieve remission to study minimal residual disease and assess which options to explore next.

Dr. Robert Kyle: What you're really saying is that we would like to convert the symptomatic patient with multiple myeloma to a patient with smoldering myeloma or monoclonal gammopathy of undetermined significance.

Dr. Brian Durie: Right, absolutely.

Are there chromosomal abnormalities that suggest a poor prognosis for transplantation?

View Topic Summary by Seema Singhal, MD

Dr. Seema Singhal: One of the questions that I have often been asked is about whether patients who have chromosome 13 deletions should be considered good transplant candidates, given the poor results seen with single and double transplants in these patients. My response is that these patients are going to have poor outcomes, irrespective of the type of treatment that they are given. In that context, the best outcome, although not good enough, is with high-dose therapy. Therefore, even patients who have deletion 13 should be considered for a transplant, although they must be warned that the outcome is not going to be as good as the outcome for patients who do not have the same poor prognostic features. [View Reference]

Dr. David Roodman: Those are all retrospective data. No patients who have deletion 13 have been randomized to chemotherapy versus autologous transplant to see if they actually do better prospectively.

Dr. Seema Singhal: I agree, although when you look at chromosome 13 deletion as an adverse prognostic feature, it turns out to have significance regardless of the type of treatment given to the patient.

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Dr. David Roodman: With the cost of the transplant at up to $150,000, and with an unknown benefit in that group of patients, it is important that there be a study that randomizes those patients to standard treatment versus autologous transplant, if nothing else than for economic considerations.

Dr. Brian Durie: I would support that point. I think that it highlights the question of what we are trying to accomplish with high-dose therapy and stem cell rescue for a patient who has a chromosome 13 abnormality, or for any patient, for that matter. The first goal is certainly to achieve a good-quality remission. The second goal is to have as long a remission as possible, and the third goal is to have as long survival as possible. And so the question is, for example, if you have chromosome 13 abnormality, what is the impact on those three goals?

I think one thing that Dr. Singhal was saying is that high-dose therapy is probably a good way to achieve the best response that you can get. If a patient has aggressive disease, high-dose therapy with stem cell rescue may be the best way to get that good first remission, although it may not contribute to a better or longer remission or survival. Nonetheless, it may be worth it for that first remission. We need to address the question of what a transplant can contribute beyond achieving good-quality remission. To what extent does it have impact on duration of remission and survival? My interpretation of the data is that the extension of remission and survival is much more questionable; it is not so clearcut. I would be interested in other thoughts.

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Dr. William Bensinger: I would argue that patients with chromosome 13 deletion would be considered more readily for allografts because these patients do poorly with chemotherapy and autologous stem cell transplant. Although I agree with you that we do not have data from randomized studies, I also think conducting those studies would be difficult, as patients with chromosome 13 deletions represent a relatively small minority of the overall population. The logistics of that kind of study would require recruiting hundreds of patients with myeloma to obtain a small number of patients with chromosome 13 deletions who could then be randomized prospectively. Therefore, I think that allografts may be the best modality for these patients, certainly in the context of clinical trials.

Dr. Brian Durie: I think that is a good idea, and one strategy that we are using for this subset of patients is to proceed with the up-front autotransplant and then use a mini-allotransplant at the point of first relapse as the next step, so that these patients would get a combination of auto plus mini-allo in that setting.

Dr. Robert Kyle: Dr. Bensinger, are you recommending standard allogeneic transplantation or nonmyeloablative?

Dr. William Bensinger: I think it is very hard to recommend standard allografts for any patients because of the relatively high morbidity and mortality. [View Reference] Therefore, the nonmyeloablative, or mini-allogeneic, transplants are probably preferable. At our center, the results with mini-allografts are less than favorable if the patient does not have a significant degree of cytoreduction to either initial or salvage therapy. And to that end, we have adopted a tandem transplant strategy as initial therapy, using an autologous transplant with high-dose melphalan followed 40 to 120 days later by a mini-allograft. [View Reference]

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Dr. William Bensinger: When we perform nonablative or mini-allograft as the only therapy in a salvage situation (and granted these are often patients who have either failed an autologous transplant or cannot get an autologous transplant because they never responded at all and are refractory), the only patients who tend to do well in terms of getting either a very good partial or complete response are the patients who can achieve some degree of cytoreduction before undergoing the mini-allograft.

What are the relative merits of early versus late transplant?

(Scenarios for late transplant, including harvesting and cautions against use of
alkylating agents before harvesting)

Dr. Brian Durie: As part of the evaluation of the role of transplant, it is important to consider early transplant versus using transplant at the time of first relapse. There are some published data on this point to help guide us. [View Reference]

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Dr. Brian Durie: This is helpful because the randomized French study, for example, does show that the overall outcome is similar in patients who receive the transplant at that second timepoint at which relapse has occurred. [View Reference] What is the overall quality of life during this whole period of time? The initial analysis shows that with the early transplant, overall quality of life during that first remission may be better, and most certainly so in terms of the need for ongoing therapy, maintenance therapy, and so forth.

However, these considerations are rather personal, and I think that we need to look at them on a patient-by-patient basis. We do need to research the usefulness of harvesting stem cells and having them available for future use, as opposed to automatically going ahead with that early transplant as an initial therapy.

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Dr. Robert Kyle: One of the important points is that the mortality of autologous stem cell transplant today is only 1% to 2%. When we proposed and encouraged a delayed transplant, the mortality was approximately 10%. If one proceeds with the autologous transplant up front, the patient is not exposed to alkylating agents over this period of time, and, consequently, the risk of myelodysplasia and acute leukemia is lower. Therefore, it is reasonable to proceed with an autologous stem cell transplant up front and then to reserve alkylating agent therapy for the patient who subsequently relapses.

Dr. Brian Durie: The landscape and the options in therapy have changed since we started to use transplant as a first treatment option. Initially, we were concerned about the possibility of major medical complications. [View Reference] Now, that is not such a concern; rather, the concern now is whether we have the possibility of avoiding transplant completely by shifting to some of the newer biologic approaches. We now have an opportunity to study this in a randomized fashion; to examine the role of thalidomide and some other biologic agents versus high-dose therapy; and to evaluate the quality of the remission, the length of remission, and survival.

Dr. Robert Kyle: I agree.

Dr. David Roodman: Wouldn't you argue that, at present, the only modality that has shown a true prolongation of survival is autologous transplant?

Dr. Brian Durie: No, I don't agree with that at all.

Dr. William Bensinger: Why is that?

Dr. Brian Durie: I think that thalidomide could be in that category. [View Reference]

Dr. Seema Singhal: We only have long-term experience with this drug in patients with relapsed disease, which is quite a different setting, but in that population, patients who do have an excellent response to the drug thalidomide tend to relapse once again about 8 to 9 months later. So when you use this drug up front, it is likely that there will not be a survival of 5 years duration.

Dr. Brian Durie: If we compare the remission duration and survival with nontransplant versus transplant therapy, there is a prolongation of benefit by approximately a year. [View Reference] If thalidomide is administered to a patient who is relapsing, survival may be extended by a year or two (which we can do right now). That is equivalent to what we achieved with up-front transplant. [View Reference] We might be taking a major step forward with the introduction of new agents, such as immunomodulatory drugs (IMiDs) (also called thalidomide analogs), or some other biologic approach. With high-dose therapy, we may have maxed out; we may have seen all that is possible with high-dose therapy.

Dr. William Bensinger: I agree with you in part, Brian. I think that these new agents are very exciting and may be shifting the paradigm about whether we want to use transplant, but I do not think we are going to know that until the appropriate prospective studies are done. Thalidomide is a promising agent, but it has not been studied up front. Those trials are under way, and until we have those kinds of data, autologous stem cell transplant should remain one of the early up-front options available to patients.

Dr. Brian Durie: I agree. It absolutely needs to be part of the armamentarium, but I think we have reached the point at which we can study and compare with the realistic possibility that equivalent or better outcomes could come from a different new strategy.

Could each of the faculty members now summarize their views on transplants?

Dr. David Roodman: With the current data, I think that autologous transplant should be used as an early option because of the probability of having longer survival.[View Reference] Biologic agents and newer agents, such as thalidomide, have tremendous promise to change that therapeutic paradigm, but until that data are available, early transplant is an important therapeutic approach to patients with myeloma.

Dr. William Bensinger: I think the available data suggest that an early transplant is the best therapeutic option compared with a delayed transplant. Although survival may be equivalent, the quality of the remission appears to be better with an early transplant, and there may be ways to avoid some of the later complications, such as myelodysplasia, by avoiding exposure to alkylating agents. [View Reference]

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Dr. Seema Singhal: I believe that the current evidence indicates that transplants should have a role early in the course of treatment of myeloma. It is certainly worth considering a trial comparing these new agents. Now that the scenario of treatment has changed with the advent of thalidomide, proteasome inhibitors, and other agents, perhaps another trial should be conducted in which we give induction treatment with these new agents and then compare the results of early versus delayed transplants. Until we have a little more experience with these agents, however, we should continue using the transplant early on.

Dr. Brian Durie: The availability of high-dose chemotherapy with stem cell rescue as treatment for multiple myeloma is very important. It is a decisive way to achieve the best remission possible, and with the development of better technologies, this therapy can be administered safely. The overall role of high-dose therapy in the future remains to be established, particularly with the advent of new biologic approaches.

Dr. Robert Kyle: Today, I believe that all patients younger than 70 years of age who have symptomatic multiple myeloma should be offered the opportunity of an autologous peripheral blood stem cell transplant, provided that they have adequate pulmonary, renal, and cardiac function. An autologous stem cell transplant also may be done for patients older than 70 years of age, provided that they are physiologically younger than their chronologic age. The stem cell transplant should be done after recovery from the peripheral blood stem cell collection.

Dr. William Bensinger: Tandem autologous transplants can be considered a potentially innovative strategy to apply for patients with poor prognostic factors, such as chromosome 13 deletions or high beta2-microglobulin, who might be expected to do poorly with only a single transplant.

Dr. Seema Singhal: True. The survival curve in these cases has not been good.

Dr. William Bensinger: It is also possible to assess patients with bad prognostic factors to offer them allografts or tandem transplants in certain situations. It is a fairly complex schema, but it may address, in part, some of these issues.

Dr. Brian Durie: The other possible interpretation is that some patients with good prognostic factors will benefit more from these procedures.

Dr. Seema Singhal: They could be the patients who will have the greatest benefit.

Dr. Brian Durie: Right.

Dr. William Bensinger: I'm worried about that because I think those are precisely the patients who were going to do well anyway. The patients who have low beta2-microglobulin and indolent disease may come out on top, whether you give them one transplant or two, or perhaps no transplant at all.

What options are there for patients not eligible for transplants?

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Dr. Robert Kyle: Many patients with multiple myeloma who require therapy are not candidates for autologous stem cell transplantation. For these patients, melphalan and prednisone given orally is a reasonable combination. The melphalan is given by mouth in a dosage of 8 to 10 mg daily for 7 days or for a period of 4 days and then repeated at 4- to 6-week intervals. It is very important to measure the leukocyte and platelet counts 3 weeks after beginning the melphalan and prednisone because the melphalan may be absorbed poorly, and the physician may need to increase the dosage of melphalan to obtain a pharmacologic effect. [View Reference]

Unfortunately, even if melphalan and prednisone are used in the ideal fashion, the objective response is only 50% to 60%. To improve upon this, many investigators over the past 30 years have developed a variety of combinations of alkylating agents. In general, these combinations produce an objective response in 60% to 70%. [View Reference] In a meta-analysis published almost a decade ago, the investigators concluded that patients who received a combination of alkylating agents had a higher percentage of response. They also thought that those patients who had favorable prognostic factors did better with melphalan and prednisone, whereas those patients with unfavorable prognostic factors appeared to do better with a combination of alkylating agents.[View Reference]

In a more recent meta-analysis of almost 5000 patients, the Oxford Myeloma Trialists Group found that the combination of alkylating agents did produce a higher response rate than did melphalan and prednisone. However, there was no difference in survival of the two groups of patients. They also did not find evidence that patients with unfavorable prognostic factors did better with a combination of alkylating agents.[View Reference] Consequently, most physicians today use melphalan and prednisone as the initial therapy for these patients.

Dr. Seema Singhal: Today, steroids as well as thalidomide and various combinations of these drugs, can be used as an alternative to initial therapy or in patients who cannot have immediate transplant. There are advantages and disadvantages to each of these options. Our lengthy experience with steroids assures us that these drugs do not bring about irreversible damage to the stem cells or to other organs. As a result, steroids do not seem to jeopardize future treatments, such as transplant.

In fact, steroids can be problematic as long-term therapy. They have well-known side effects that can complicate chronic diseases such as diabetes or hypertension. Furthermore, long-term use of steroids can result in bone loss as well as cataracts. And, finally, because steroids can induce psychosis, they are not practical for long-term use in patients who experience steroid-induced psychosis. Under the best of circumstances, even when they are a good option for patients who can tolerate the drugs, steroids have the potential to induce immunosuppression. This potential outcome raises significant concerns about patients on long-term therapy becoming susceptible to infections. Such a potential makes steroids drugs with side effects that clinicians must consider carefully not only before prescribing but particularly so when considering them for long-term therapy.

There are various types of steroids used for the therapy of myeloma. Prednisolone is the best tolerated. Dexamethasone is used most often, is given in very high doses orally, and is most likely to cause steroid-induced psychosis because of the manner in which it is given. Prednisone is given in lower doses, is a more gentle form of treatment, and is tolerated better, especially by older patients. Methylprednisolone sodium succinate has been used for the treatment of myeloma, especially in the UK. It is really not known if one particular steroid is more efficacious than the other. Different centers choose particular steroids based on their experience.

Standard administration of dexamethasone is a 40-mg single dose, given orally on days 1 to 4, 9 to 12, and 17 to 20 of a 35-day cycle. However, this may be difficult for patients to tolerate, and there are many variations currently being used. I have used half the dose in patients who are older and patients who do not tolerate the abrupt stopping of the drug on the fourth day. In some cases, I have tapered down in 20-mg or 10-mg increments, continuing administration beyond day 4 to days 5 or 6. There are anecdotal reports of clinicians administering steroids on a weekly basis, giving it only for the first 4 days of the week, so that patients can more easily follow the dosing regimen. It is not known if one type of administration is superior to the other in terms of efficacy, so the regimen commonly is adjusted based on the patient's tolerance and ability to comply.

Prednisone is used in various doses. On average, patients are given 1 mg/kg/day for a total of 50 mg to 60 mg daily. However, prednisone is given in various frequencies, sometimes once a week and sometimes three times a week. When used in combination with an alkylating agent, such as melphalan, it is given every 4 to 6 weeks. There is no standard way of giving prednisone for treatment of myeloma.

The side effects of steroids can be managed with the help of supportive drugs. Hyperglycemia and hypertension should be treated. Steroids can predispose a person to develop ulcers and, therefore, should always be used along with gastric-protecting agents such as H2 receptor antagonists. Steroids induce immunosuppression; therefore, I always place my patients on protective antimicrobials and prophylactic acyclovir or fluconazole as well as prophylaxis for Pneumocystis carinii pneumonia (PCP). Patients on steroids can be very agitated and find it difficult to sleep. Sometimes mild sedatives given at night can help them withstand the side effects.

Other panelists: That sounds reasonable.

Dr. Seema Singhal: I prescribe acyclovir prophylactically as opposed to waiting for an outbreak.

Overview of Treatment Options | Transplants | Thalidomide | Radiotherapy, Bisphosphonates, and Other Supportive Therapies for Multiple Myeloma

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