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Planning Treatment

Module 1: Screening, Diagnosis, and Staging of Multiple Myeloma

Section 4: Planning Treatment

What are the steps to be taken after a diagnosis of multiple myeloma has been confirmed?

Dr. Brian Durie: After confirming the diagnosis of multiple myeloma, assessing the stage of the disease and collating the prognostic factors are the critical elements in establishing a plan for ongoing therapy. For more than two decades, clinical staging has been used to assess the tumor burden and the clinical import of the disease for each individual patient.

Many new prognostic factors have been recognized over the last two decades. It is now possible to more precisely and systematically assess the prognostic implications in each patient. This knowledge is important both for individual patients as well as to assess the outcomes in larger clinical trials.

The basic parameters are obviously the age and the sex of the individual patient, the type of immunoglobulin, and any differences between IgG versus IgA and kappa versus lambda. Regarding the discrete prognostic factors, there is no doubt that serum beta2-microglobulin as a baseline is the single most predictive factor in terms of subsequent outcome: specifically, survival. In addition, the helpful factors include labeling index, if available; CRP; LDH level; and serum albumin. Other factors have been used by different groups around the world. However, with the available prognostic factors, it is now possible to characterize the type and aggressiveness of the disease and the likely outcome for the vast majority of patients with multiple myeloma.

What constitutes an emergency for a patient with multiple myeloma?

Dr. Robert Kyle: Patients with multiple myeloma who develop anorexia, nausea, vomiting, polyuria, weakness or fatigue, or a change in mentation should have a serum calcium level evaluation performed immediately. If hypercalcemia is detected, the patient needs immediate therapy. These patients need to be hydrated with intravenous saline and treated with oral prednisone, 25 mg, four times daily. Most patients with multiple myeloma will respond readily to this regimen. However, if patients do not respond, they should be treated with an intravenous bisphosphonate.

Another condition that must be kept in mind is spinal cord compression from an extramedullary plasmacytoma. This condition represents a true emergency. Patients who develop weakness of the lower extremities, paresthesis of the feet or legs, or difficulty in passing their urine or feces may have spinal cord compression. These patients must have MRI or CT scans for diagnosis and then receive treatment with corticosteroids and radiation to the lesion.

A third condition requiring emergency treatment is acute renal failure. These patients should be rehydrated and given appropriate electrolyte replacement. In addition there is some evidence that plasmapheresis will help reverse the acute renal failure. [View Reference] These patients should also be treated with chemotherapy consisting of vincristine, doxorubicin, and dexamethasone (VAD).

Severe bone pain is another indication for beginning therapy for multiple myeloma. These patients should be given adequate analgesia. There need be no concern about addiction to the opiates.

Hyperviscosity is rarely seen in multiple myeloma. When it does occur, it usually does so in patients with IgA monoclonal proteins or occasionally in patients who have IgG that aggregates. These patients can be treated very quickly and efficiently with plasmapheresis.

Which collection of symptoms or laboratory results, in the absence of overt symptoms, signals you to begin treatment of myeloma?

Dr. Robert Kyle: It is often difficult to decide when to treat a patient after the diagnosis of multiple myeloma. I do not think that the asymptomatic patient should be treated. In short, the patient with smoldering multiple myeloma or MGUS should be recognized as such and not treated. [View Reference]

If the physician has difficulty in deciding whether to treat a patient, he or she should hold back and reevaluate the patient in 2 months to see if there has been any change. In many instances the patient will remain asymptomatic, and the laboratory studies will remain stable.

This is a question that I would like to pose to my learned colleagues: When would you start therapy in patients with multiple myeloma?

Dr. Brian Durie: It is particularly difficult to reach a clear decision about starting therapy. Part of the problem is the definitions we currently use: monoclonal gammopathy of undetermined significance,  smoldering or  indolent myeloma, and then  myeloma, which is probably more accurately called  active myeloma. Because of the difficulties using these descriptions, the Prognostic Index Factor Group met during the recent workshop in Banff, chaired by Dr. Phil Griepp from the Mayo Clinic and Dr. Jesus San Miguel from Spain, with the express purpose of trying to clarify these terms. A preliminary draft of a document clarifying these terms has to be circulated to the working group.

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Dr. Brian Durie: I think the focal point as far as the decision to treat is to identify in a positive fashion those patients who have active myeloma. The major criterion agreed upon, at least tentatively, by the group was organ dysfunction. Using this criterion, patients who have bone problems that are progressing would be defined as having active myeloma. Patients who have abnormal renal function that is progressing also would be considered to have active myeloma. Patients who have anemia or marrow dysfunction reflected by thrombocytopenia or neutropenia would meet this criterion. There also could be another category to include patients exhibiting miscellaneous neurologic problems, perhaps severe infections or other features of the disease that are clearly progressive manifestations of active myeloma. Having these criteria should allow us to precisely categorize patients for appropriate treatment. It also will enable us to make more legitimate comparisons between the outcomes of different studies and clinical trials.

Dr. Seema Singhal: I basically agree with what Dr. Kyle said about not treating patients who are asymptomatic.

Dr. Seema Singhal: However, there are some situations in which one might consider treating such patients. For instance, if a patient is not symptomatic, but serial monitoring of the numbers shows that over a period of 6 to 8 months his or her disease is clearly progressing, then we might consider starting therapy for that patient. Another case for intervention might be a patient who does not have symptomatic disease but has renal dysfunction that one can attribute to the myeloma. A physician would not want to chance putting the patient at risk for developing more severe renal dysfunction and becoming dialysis dependent. What do you think?

Dr. Robert Kyle: I think that is a reasonable assessment, and I would agree with that 100%. I would also add that occasionally one will find a patient who has multiple lytic lesions that are rather modest in size but with one large asymptomatic lesion. I think in patients like that, one must proceed with systemic therapy and, perhaps, orthopedic intervention as well.

Dr. Seema Singhal: I get many calls from physicians saying,  It s stage 2, or  It s stage 3, and they want to know if there is some  across the board rule when one should definitely treat. The rest of you on the panel probably also receive these inquiries.

Dr. William Bensinger: I think questions like those underscore a point on which I may disagree with you. I think that there are scenarios in which patients are overtreated. For example, let us consider a patient who starts out with smoldering myeloma. Their immunoglobulin level is rising from 3 to 3 1/2 grams and then to 4 and 4 1/2 grams. But there is no anemia; they do not have bone disease; they are totally asymptomatic in every other respect. All they have is an IgG level that is slowly, but steadily, creeping up. I do not treat those patients. I believe that you can hold off treatment for those patients. There does not seem to be anything gained by jumping in with early treatment, and I am not aware of any data that suggest that you do these patients a favor by aggressively treating them earlier in the course of their disease.

Dr. Robert Kyle: You would wait until they develop anemia or bone lesions or renal insufficiency?

Dr. William Bensinger: I would wait for some evidence of organ dysfunction, as Dr. Durie suggests. I would not treat a rising IgG level.

Dr. Seema Singhal: But sometimes you can have anemia that is so insidious the patient is not really symptomatic. Hemoglobin levels can drop from 14 to 11 without the patient really having any symptoms.

Dr. William Bensinger: Well, that is part of the monitoring process. You follow those things.

Dr. Brian Durie: I think that the criteria for disease progression or organ dysfunction include or maybe do not include symptoms. Some of these patients for example, patients with rising creatinine levels that could be threatening may still be asymptomatic.

Dr. David Roodman: This points out the importance of follow-up. There are some physicians who have patients with IgG levels of 4 and who are otherwise asymptomatic. Then, the levels rise to 7, and although the patients are still asymptomatic, the physician will consider starting treatment to prevent the complications of the disease. This is already at a level of monoclonal protein that physicians begin to get very nervous about because, as the patient s tumor burden increases, physicians are starting to worry about organ dysfunction. Deciding when to intervene is very difficult for any physician caring for the asymptomatic patient, but in the patient with symptomatology or obvious organ dysfunction, those decisions become much easier. As for prophylactic chemotherapy, I see no role for that with these patients, unless we can develop curative therapy.

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Dr. Robert Kyle: I think it is important to look at the whole patient; that is, listen to the history of the patient, the physical examination, and all the laboratory data that are available. One should not make a decision to treat simply because there is a large serum M-spike or if the hematopathologist states that the diagnosis is multiple myeloma. One must look at the total picture, and only then make a decision to treat if the patient is symptomatic or has impending complications.

Dr. Brian Durie: I completely agree with that. These decisions need to be made on an individual basis. Some patients can develop symptomatic disease when the M-spike is low. They may become anemic. These anomalies require you to assess the whole picture for each individual patient.

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