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Oncology Times:
doi: 10.1097/01.COT.0000441839.09010.37
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Myeloma: Should Alkylators Be Used Upfront in Transplant-Ineligible Patients?

Carlson, Robert H.

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NEW YORK—The aim of a debate is not just to argue for agreement or disagreement with a premise, but also to explore and understand the granularity, the scale or level of detail, present in a set of data. A debate, therefore, can be fascinating to listen to even when two speakers basically agree.

Such was the situation here at the first of six debates at the Lymphoma & Myeloma International Conference: “Should alkylating agents be used upfront in patients with multiple myeloma who are transplant ineligible?”

Arguing the “pro” position was a difficult task because a key agent in standard regimens for many years has been melphalan, a drug with a reputation for toxicity, especially in the elderly, and an association with second primary malignancies.

Antonio Palumbo, MD, Chief of the Myeloma Unit of the University of Torino in Italy, spoke on that position and made points in favor of alkylator-containing regimens in the setting of transplant-ineligible patients. But he also agreed on several points with the “con” speaker, Joseph R. Mikhael, MD, Associate Professor in the Division of Hematology/Oncology at the Mayo Clinic in Scottsdale, Arizona, and Associate Dean of the Mayo School of Graduate Medical Education and Deputy Director for Education at Mayo Clinic Cancer Center, such as the value of cyclophosphamide in selected cases.

ANTONIO PALUMBO, MD
ANTONIO PALUMBO, MD
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JOSEPH R. MIKHAEL, MD
JOSEPH R. MIKHAEL, MD
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Palumbo: Use Alkylators Upfront for Transplant-Ineligible Myeloma

Palumbo admitted that he had a hard task justifying the use of melphalan in newly diagnosed multiple myeloma, even stating that in triplet combinations, which he said should be considered standard for fit patients, melphalan is too toxic and cyclophosphamide is better tolerated.

But alkylating agents are nonetheless effective in treating myeloma, he said, and in fact higher doses have been shown to be more effective. He cited a study in which patients with newly diagnosed myeloma received either low-dose melphalan-prednisone-lenalidomide (MPR) or high-dose melphalan alone (MEL200). The three-year progression-free survival rate was 60 percent for MEL200 vs. 36 percent for MPR (Cavallo F et al: EHA 2012;97:1142—abstract book accessed atbit.ly/1bfVMXB).

Palumbo also cited research comparing VMPT-VT (bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide) versus VMP (bortezomib-melphalan-prednisone) in newly diagnosed patients with a median age of 71 (Palumbo et al: ASH 2012, abstract 200).

With a follow-up of 54 months, progression-free survival was 35.3 months and time to next treatment was 46.6 months for VMPT-VT vs. 24.8 months and 27.8 months for VMP. And five-year overall survival rates were 61 vs. 51 percent, respectively. “I invite my opponent to show similar results in other studies,” he said.

Palumbo acknowledged melphalan's major disadvantages, and so discussed alternatives containing cyclophosphamide—i.e., VDCR (bortezomib-cyclophosphamide-lenalidomide-dexamethasone); VDR (bortezomib-lenalidomide-dexamethasone); VCD (bortezomib-cyclophosphamide-dexamethasone); and VCD-mod.

In the Phase II EVOLUTION trial those regimens were associated with very good partial responses of 58, 51, 41, and 53 percent for VDCR, VDR, VCD, and VCD-mod, respectively; complete response rates were 25, 24, 22, and 47 percent, respectively. The corresponding one-year progression-free survival rates were 86, 83, 93, and 100 percent, respectively (Kumar S et al: Blood 2012;119:4375-4382).

“We do not have randomized data on these [cyclophosphamide-containing regimens], but certainly 47 percent CR is a very nice rate,” he said.

Forty percent of myeloma patients are over age 71, and a geriatric assessment must be done in every elderly patient, Palumbo noted, adding that age under 75 vs. 75 and older does not by itself account for increasing separation of progression-free or overall survival curves, Palumbo said, but fit vs. frail does.

He recommended dose adjustments in multiple myeloma according to patient age and vulnerability, citing a report of the European Myeloma Network for which he was first author (Blood 2011;118:4519-4529). And he said that while he thought a three-drug combination overall is better than a two-drug combination in myeloma, “when you are facing a frail person, you should go back to the two-drug combination, and at that time the combination should include dexamethasone.”

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Mikhael: No Melphalan

In his presentation, Mikhael argued that using a melphalan-based combination in upfront therapy of myeloma patients ineligible for transplant is no longer recommended: “The use of novel agents has proven to be as effective—if not more so—and considerably less toxic. The exception may be cyclophosphamide, which may be used, especially in combination with novel agents.”

Melphalan can be included in a patient's therapeutic options later in the disease course, he added, but “we now recommend lenalidomide-dexamethasone for standard-risk patients for initial therapy when not on a clinical trial.”

He said melphalan is no longer the standard of care for elderly patients because:

  • Novel agents are equivalent, if not superior, to melphalan plus a novel agent;
  • Melphalan-containing regimens result in greater short-term toxicity; and
  • As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity.

“This is a point we sometimes don't fully appreciate,” he said. “People are living longer with myeloma, the elderly as well, and we need to have a long-term approach to these patients.”

Mikhael showed data from a 2008 study in which median survival in patients diagnosed during or before 1996 was 29.9 months, versus 44.8 months afterward (Kumar et al: Blood 2008; 111:2516-2520).

It could be argued that the choice of using melphalan now or later is a matter of balance, Mikhael said: The clinician doesn't want to use everything possible for the patient first-line and not have options later, but at the same time does not want to undertreat the patient.

“Melphalan is known to cause both short-term and long-term marrow toxicity, and it is not one of the initial cards I want to play,” he said. “Even if I have a patient 75 years old, I'm not anticipating that they will live only two more years; in fact, I'm expecting them to live many more than that.”

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Second Primary Malignancies Are a Risk

The numbers have been quite convincing that melphalan can lead to increased second primary malignancies, particularly when combined with lenalidomide, Mikhael said. “There is an inherent risk in myeloma of a second primary malignancy regardless of the intervention, and also with almost every agent used in myeloma, so the baseline risk is not zero. But we don't want to enhance that risk in a strategy using melphalan up front.

“The older population is always going to be at greater risk of secondary malignancy, so we should be even more cautious in using melphalan.”

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CyBorD Replaces VMP

Mikhael said he might concede that cyclophosphamide is an alkylator for use in the upfront setting, but he does not consider it the same kind of alkylator as melphalan.

The “new” CyBorD regimen could be considered a mild alteration to VMP, replacing melphalan with cyclophosphamide. He said he prefers to use all three agents on a weekly basis, considering a cycle as four weeks without a “week off”:

  • Cyclophosphamide 300 mg/m2 orally;
  • Bortezomib 1.5 mg/m2 IV or SQ; and
  • Oral dexamethasone 40 mg orally.

The advantage is less neuropathy, more convenience, and equal efficacy—but always give viral prophylaxis, he cautioned, to prevent shingles.

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Pre/Post Debate Audience Survey

By means of technology that made it possible to register votes via the Internet from a tablet or phone in the meeting room, members of the audience were asked before and after the debate: “Should alkylators be used upfront in transplant-ineligible patients with multiple myeloma?” The responses showed that Mikhael's argument swayed many in the audience, with shifts in voting from “yes” and “not sure” to “no.”

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A poll of the audience showed that of the approximately 1,000 attendees, one-third were hospital based, one-third were from academic institutions, and 80 percent were hematologist/oncologists. About one-third of the audience said they see more than 30 patients per week.

Wolters Kluwer Health | Lippincott Williams & Wilkins

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