Multiple Myeloma Market Assessment

A Panel Discussion among Ten Hematologists/Oncologists

April 2007

study description and objectives

To understand multiple myeloma treatment practices and trends, including what determines therapy choice, importance and scale of free goods programs and trends in treatment.  Topics covered include:

• Use of specific agents – Revlimid® (lenalidomide), Velcade® (bortezomib),
• Thalomid® (thalidomide)
• Use of transplant versus medical management.
• In transplant patients:
• What induction, consolidation, maintenance therapies used for what patient segments
• What product is used in what patient segments
• What is the duration of therapy and duration of response; what would cause switch away from transplants toward chemo
• Has rate of transplanting changed in recent years
• For patients who do not get transplants:
• Primary chemotherapy and maintenance chemotherapy options
• Duration of therapy and response, rate of adverse events, frequency of dose reduction, drug discontinuation
• Treatment for relapsed patients: 1st line, 2nd line, 3rd line
• Rising and falling agents, duration of each agent, in practice rates of AE’s, frequency of dose reductions

companies and Products mentioned in this report

Key Findings

Current treatment overview:

• Most likely to receive transplant: <65 yrs, good performance status, progressive disease.  The majority of newly diagnosed (~50% nationally) receive transplants.  Less than 10% do NOT receive transplant OR chemotherapy
• Transplant patients
• Induction:  most common regimen – Thal/Dex for 3-4 cycles
• Less frequently: Velcade + Thal/Dex, vincristine/Doxil/dexamethasone, Velcade/Doxil or Adriamycin/dexamethasone
• Following induction: responders go straight to transplant; maintenance therapy or observation period follows
• Half of panel reports 50-60%, the others report 85%-95% of patients receive second line regimens, typically 18-36 months following the end of transplant consolidation
• Most common regimens, Rev/Dex, Vel/Dex for 6-12 months
• Non-stem cell transplant
• Front-line regimen: same as stem cell patient population – Thal/Dex
• Less frequently: Velcade + Thal/Dex, melphalan/prednisone/Velcade, Velcade/Doxil/dexamethasone, melphalan/prednisone +/- thalidomide
• Following first-line: for most, observation period; no data support other approaches
• 70% - 95% of patients treated with first-line chemo receive second line regimens, typically in 1-3 years following the end of their first-line regimen
• First-line treatment
• Factors influencing choice: efficacy, tolerance, QOL, out-of-pocket costs
• Typical duration:  4-6 months or 3-4 cycles
• 15%-30% of patients require (20%-50%) dose reduction due to adverse events
• Relapsed: previous treatment dictates choice – e.g., if Velcade initially, then Revlimid
• Third-line for relapsing patients: 50%-80% get third line, typically for 4-6 months, agents not already received:  Velcade, Revlimid, dexamethasone, Rev/Dex, Vel/Dex, MP
• Maintenance therapy: most do not use, lack of supportive data

Unmet needs in treating MM

• Curative therapy
• Less toxic treatment
• Risk stratification from onset, treatment for high risk (e.g., 13q del)
• Understanding of when to use maintenance therapy
• Non-clinical: financial assistance, cheaper long-term therapy, community-based trials

New therapies in development that will impact how MM is treated in next 2-4 years

• HSP-90 inhibitors (Kosan)
• Vaccines and cell therapy, e.g., anti-IL 6 antibody
• Proteasome inhibitors
• Defibrotide
• Immunomodulatory drugs (CC-4047)

Treatment trends

• No change in induction preferences for transplant/non-transplant patients in past 18 months
• Most expect no change in percent receiving transplants, awaiting data
• Landscape in three years, most common therapies:
• Transplant induction and first-line non-transplant:  Revlimid combo: Velcade and/or dexamethasone, melphalan
• Second-line for relapse: Vel/Rev or Doxil, CC4047, or Doxil-based therapy
• Third-line for relapse: Vel/Rev, Thal/dex, Cytoxan/Thal, or something new, e.g., novel proteasome inhibitors
• In next 5 years, expect median survival of MM patients to increase: 4-7 to 6-10 years

inclusion criteria

Hospitals Represented

• Dana Farber
• Columbia University/Bennett Cancer Center
• The Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins Oncology Center
• Arkansas Cancer Research Center
• Alvin & Lois Lapidus Cancer Institute
• Stanford Blood & Marrow Transplant Program
• Washington University School of Medicine
• New York University Department of Medicine
• Cedars Sinai Medical Center
• University of Michigan

Primary Question Index

TRANSCRIPTS

Multiple Myeloma Market Assessment

A Panel Discussion among Ten Hematologists/Oncologists

April 2007

Q1: Stem cell transplant decision

How do you decide what multiple myeloma patients receive stem cell transplants, and which patients do not?
What factors into this decision?
 

Panelist 4: age under 70 with progressive stage 2 or stage 3 myeloma without prohibitive comorbidity. all such patients are considered transplant candidates and initiate cytoreduction prior to high dose melp transplant. 

Panelist 2: I transplant them even (or rather especially) without progressive disease. I try to get

them into a nice remission and then proceed with the transplant. If they have progressive

disease, then I need to change my course of action and get them into remission with stronger

induction chemotherapy, perhaps DT-PACE. 

Panelist 10: The most important criteria is whether the patient is eligible for an open study, such as

the hi priority auto/mini-allo v tandem auto. If they are not, and under 60, most patients will undergo

induction followed by an auto transplant. If they are refractory to induction Rx and have an HLA-

matched sib, allo transplant will be considered. 

Panelist 2: I agree with this approach. allo transplant is more complicated than auto transplant

but offers a higher chance for cure. 

Panelist 9: age younger with 65 with good performance status 

Panelist 2: I agree, but if a patient is 70 or even more, and they have a good performance score I would still consider auto transplant. I believe we need to change our thoughts about age, and consider not only chronological age but also biological age, and that is very variable. 

Panelist 1: Patients under 65 with a HLA matched sibling are eligible for a mini allogeneic

transplant. Those without a sibling are eligible for an autologous stem cell transplant. Patients are

stage II or greater. Cytogenetics are checked but do not play a critical role in the decision.

Panelist 2: Mini allo transplants are sometimes difficult to get reimbursed because they are

considered experimental. The best is to register patients on open clinical trials so that we can

really learn whether mini allo transplant for those luckily few eligible patients with donors is

better than auto transplants in the long run. 

Panelist 5 : This decision is getting harder with the newer drugs available. In general, the younger

the patient with good PS...they are urged to consider a transplant option...under 40..allo BMT,

between 40-70..auto BMT off protocol or mini allo on protocol. Patients who have had short

remissions on therapy are also considered for mini allos or auto BMT

Follow-up ALL: Trends in transplants

Panelist 5 notes the decision to transplant is getting harder as newer drugs become available. Looking forward 2-3 years, what percentage of newly diagnosed multiple myeloma patients receiving stem cell transplants? More, less and why? 

Panelist 3: This is a good point. For the next several years, transplant will remain a major

therapy for these patients. 

Panelist 4: think new drugs will be used in conjunction with transplant until proven

otherwise. will need at least 5 years of follow up from randomized trial of new drugs +/-

transplant to know answer. until then, no change in %. 

Panelist 10: I agree it is getting harder, since the RCT do not involve the newer drugs in the non-txplt arm. We await new studies, but they will most likely not be available in 2-3 years (even though the Europeans are usually much faster in producing these data). Hard to predict the change in % txplted. 

Panelist 6: In the absence of randomized clinical trials showing a survival benefit for the

new drugs these drugs should be sequenced with transplant

Panelist 7: I don't think the numbers will change much without trials 

Panelist 9: Fewer transplantation in the future. don't know the number. But we still waiting

data from velcade based or rev/dex based induction tx follow with SCT. Survival data is

pending. 

Panelist 1: think that the number of standard auto stem cell transplants will decrease as use of chemo+newer agents increases. Will see increases in number of full allo BMT's as this platform improves in safety. 

Panelist 8: The newer agents are potent with significantly higher response rates or more in-depth response rates. However, there is essentially no large trials of EFS in these patients. The MM003 trial had a median EFS of 22.4 months reported by Rajkumar with thal/dex. Upfront velcade +/- dex had a median EFS 15 mo reported by Jagannath. Upfront revlimid + dex had 66% remission at 2 years (only 21 patients) reported by Lacy. None of these reach the durability, at this time, of a single or tandem transplant. Therefore, transplant is still one of the standards of care. In the future, it may be relegated to later in the disease. For the present, it is still the standard approach to transplant as part of initial therapy. 

Panelist 5 : same for next few years. then it may change if randomized trials are completed 

Panelist 2: as new treatments are introduced, we need to consider whether they will induce

as good remissions as transplants. this will take time to get used to these drugs, try them,

and learn from their responses. if the responses are as good as transplants, then they will

automatically be preferred since it would be a simpler, safer treatment (probably). 

Panelist 2: If the patient is in good general condition and is under 65 years of age, I usually will

prepare to send the patient for stem cell transplantation. 

Panelist 7: All patients with good performance status up to age 75 are eligible for auto or auto/allo

protocols

Panelist 6: I offer autologous stem cell transplant to all patients below age 70 as part of initial

therapy as long as they are in good health I am a more selective in patients above 70 years of age. 

Follow-up ALL: Percentage receiving transplants

What percentage of newly diagnosed multiple myeloma patients receive stem cell transplants in your center? In your overall area? Nationally? What percentage of myeloma patients with progressive disease do not receive either chemotherapy or stem cell transplant? (i.e., too old, complicated medically or decline treatment)?

Panelist 3: 70% proceed to transplant, 30% unable to proceed 

Panelist 4: 70/70/70 10

Panelist 10: I must admit, I do not know the answer to any of these questions. I have not looked at a database at our institution to answer this question and I have no idea about the local or national #'s. Nor do I know the answer to the answer to the progressive disease pts. 

Panelist 6: q1:70%/30%/30% q2:10% 

Panelist 7: 75% in my center. Not sure about national numbers. 5% don't get therapy

Panelist 9: 10% receive SCT overall. 2% in on observation only due to overwhelming

comorbidity and residual side effect. 

Panelist 1: 10/60/50 5%

Panelist 8: Approximately 75% of our newly diagnosed patients referred to us receive

transplants as initial therapy. In our area, probably 50%, nationally 35%. Rare patients receive

no chemotherapy < 10% since there are so many treatment options. 

Panelist 5 : since it is rare for me to see a patient under 65 in the community setting. about 10% go to Tx, where I am on service at the academic center. about 60%, nationally about 50%. I think less than 5% receive no therapy these days 

Panelist 3: Patients under the age of 70. Those less than 65 with hla identical siblings can be

considered for allogeneic. 

Panelist 8: Adequate physiologic organ status. Patient consent. Age usually less than 70 but select patients into the mid 70s. Adequate stem cells. Patients do NOT have to demonstrate remission status to be considered candidates for transplant (i.e. primary refractory patients are candidates). 

Panelist 8: Adequate physiologic organ status, stem cell collection, patient willingness, age usually

less than 70 but select patients into their mid 70s. 

Panelist 2: If they are in good general condition, with performance score of 0 to 1, and if they are

under 65 years of age, and if they agree, then I consider them for stem cell transplantation. Of

course their pulmonary and cardiac function must be good, and they must not be smokers. 

Q2: Induction treatment for stem cell transplant patients

What is your preferred induction regimen for myeloma patients and duration of treatment? What percentage of your myeloma stem cell transplants patients get this regimen? What is your second preference for induction in stem cell transplants? What percentage get this regimen? Have you changed your preferred induction regimen in the past 18 months? If so, why?

Panelist 4: preferred is velcade/doxil/dex for 4-6 months. second choice is currently thal/dex, but

will become rev/dex or rev/velcade once mobilization data with rev becomes available and

demonstrates can be done. yes. changed from dvd to velade/doxil/dex because of higher response

rates.

Panelist 10: This is also protocol driven. If eligible for a study, induction will follow that study. If no

study, or no preference in study, currently thal/dex. Probably 80% of pts get this regimen. 2nd is

rev/dex (~10% get this). No change in last 18 mo, await more data. 

Panelist 3: thal/dex for 4-6 months prior to tx. Velcade/Dex second line. 

Panelist 9: preferred induction is thal/dex (70%) duration is about 3-4 cycle prior to SCT second preference is high dose dex I have not change my preference in past 18 mo, b/c the oral Thal/dex is effective and convenient to my pts 

Panelist 1: Either thal/dex or dex alone for 3-4 cycles. About 3/4 of patients get this regimen. If

there is a trial open we will try this regimen, such as revlimid/dex (the rest of the patients). There

has been no change in the recent past. 

Panelist 5 : I standardly use vincristine, doxil decadron. I am changing over to velcade, doxil

decadron because of more rapid responses. In a small percentage of patients who are diabetics,

with baseline neuropathies and hard to control glucose. I have used melphalan 50 mg/m2 prior to

stem cell mobilization and transplant 

Follow-up Panelists 4 and 5

Panelist 4, you indicate your first preference is Velcade/Doxil/Dex. Please indicate what percentage of your patients get your first preference. Approximately what percentage get the full course and dose? Panelist 5, you indicate you routinely use Vincristine/Doxil/Dex and are switching over the Velcade/Doxil/Dex. Please indicate currently what percentage of your patients get Vincristine//Doxil/Dex and what percent get Velcade/Doxil/Dex. 

Panelist 4: 80% get regimen of which 80% get full course/dose. 

Panelist 9: 80% receive first preference majority receive full dose in first cycle\ I do not use Dveld as frontline tx 

Panelist 7: NA

Panelist 5 : 80% get V(incristine)DD at this moment, 20% Velcade doxil dex...only reason there are not more is because I am trying to finish up on a clinical trial for this

Panelist 2: I start with thal/dex in all patients. If they don't respond quickly, I add velcade. I do this for about 4-6 cycles and then send them for transplant if they achieve complete remission. Otherwise, I sometimes add DT-PACE chemotherapy before sending them. this is different from the regimen I used to use, VAD. 

Panelist 6: Most patients are started on therapy by their referring physicians before I am consulted. Thalidomide and dex has accounted for 70% of treatments. Velcade and VAD/DVD account for approx 10% each. There is a trend to increasing use of revilimd and velcade before transplant over the last 18 month and if consulted prior to transplant I am tending now recommend revilimid or velcade in these patients as well as they produce better ORR/CR rates which MAY in future prolong survival.

Panelist 7: Thalidomide/Dex X 4 About 75% get this regimen The rest get Velcade/Thal/Dex No

change in past 18 months 

Follow-up ALL: Duration

Several panelists did not include the duration of treatment. Panelists who did include that information

noted Thal/Dex is typically given for 3-4 cycles, and Velcade/Doxil/Dex is given for 4-6 months, and

Thal/Dex/Velcade for 4-6 cycles. Please indicate if you administer these regimens for a duration of

treatment DIFFERENT from that listed above.

Panelist 4: give all 4-6 months

Panelist 10: I agree with the 3-4 cycles for thal/dex

Panelist 6: I use it for 4-6m

Panelist 2: I also use 4 to 6 months. 

Panelist 7: I agree

Panelist 9: agree 

Panelist 8: No, this is the usual duration of therapy. 

Panelist 5 : agree with this

Panelist 8: We prefer to enroll patients on clinical trials. Outside of clinical trial, my preferred regimen is lenalidomide plus low dose dexamethasone as induction therapy for 4 months. Approximately 75% of my patients receive this regimen. Since our practice is referral base, the most common regimen for referred patients is thalidomide plus dex for 4 cycles. My second choice for my own patients is thal/dex. Yes, with the approval of lenalidomide, the preferred regimen has changed.

Q3: First Line treatment for non-stem cell myeloma patients

What is your preferred front-line regimen for non-stem cell myeloma patients and duration of treatment? What percentage of your myeloma non-stem cell transplants patients get this regimen? What is your second preference for front line therapy of non-stem cell myeloma patients? What percentage get this regimen? Have you changed your preferred front line regimen in the past 18 months? If so, why? What is most important in determining what first-line treatment to use for multiple myeloma patients who have do not receive a stem cell transplant? 

Panelist 4: first line also velcade/doxil/dex - 60% second line is mpt -30% have switched to velcade/doxil/dex because of excellent tolerance, no issues with compliance with iv regimens, less out-of pocket expenses for patient, coverage of the del 13 population, and high response rates. the above rationale is why I chose. 

Panelist 10: Preferred front line thal/dex and probably 80% get this. 2nd choice involves more elderly patients: melphalan and prednisone. No real change, although thoughts to rev/dex. Most important 1st line treatment is efficacy. 

Panelist 9: my preferred front line regimen is MPT for non SCT pts. duration of tx is about 4-6 month, until max response is achieve. about 30% of pts is on the regimen. I recently changed to MPT base on French and Italian data of MPT vs MP and SCT which show MPT has survival advantage over conventional treatment. 

Panelist 1: We use thal/dex until best response in most patients (about 75%). MP is used in most of the other patients or high dose steroids. Have used revlimid/dex as an induction regimen in patients with prior peripheral neuropathy, but have not switched to using this as the front line. Performance status and the need for a rapid response are usually the criteria that determines the regimen chosen. 

Panelist 5 : I have been using melphalan prednisone and velcade..since I have seen how well it works on the international study. I may be adding thal or rev to this in the future. I have also used velcade/doxil =/- decadron in about 20% of patients Compliance and Medicare part D are large factors in choosing a regimen. Since all our chemotherapy is hospital infusion center delivered. it makes sense to use injectables. Many patients will not. and can not handle the "donut" for the oral drugs

Panelist 2: For non stem cell transplant patients, I also use thal-dex, and add velcade if there is an inadequate response, and add in dt-pace if there is resistance. For patients who do not respond well, I use melphalan with prednisone an d consider adding in thalidomide or velcade. I use revlimid if patient does not tolerate thalidomide or does not have good enough response to thalidomide. 

Panelist 6: 80% of the patients I see are transplant eligible. For the non transplant eligible patients I am now favoring mel/pred/thal since the European data is showing a survival advantage. About 50% get this regimen. Second preference has been MP (in 30%)but is now starting to change to rev/dex due to better efficacy and good tolerability of revilimid. Overall survival is the major determinant of therapy though quality of life is a major factor that is considered as well. 

Panelist 7: These patients typically get the same regimen as the stem cell candidates. No change in the past 18 months. Some will get a melphalan-based regimen 

Follow-up ALL: Most important

Panelists mention the following as being important in determining first-line treatment: a) Tolerability b) Compliance c) Out-of-pocket expense to patient d) Response Rate e) Overall Survival f) Performance status and need for quick response g) Quality of Life What two factors, from this list or otherwise, are most important in determining first-line therapy for this patient segment and why?

Panelist 4: e,c

Panelist 10: Response rate is the easiest to measure (compared to OS) and would be the most important and when this is satisfied, tolerability would be 2nd.  Panelist 6: e&c Panelist 7: e & g Panelist 9: a and f Panelist 1: a and f Panelist 8: Quality of life and response.  Panelist 5 : B&D Panelist 2: survival benefit and need for quick response to control acute situation are my

primary considerations on starting therapy. 

Follow-up ALL: Duration

a) What is the usual duration of first line treatment with the regimen you identified? b) What percentage of your patients require dose reduction due to adverse events? c) How much is the usual dose reduction and for what drugs? 

Panelist 4: 4-6 months 20% 20% for velcade
Panelist 10: Duration 8 cycles Dose reduction about 30% Thal reduced to 200 
Panelist 6: 4-6m 20% require dose reduction with thal from 200 to 100mg
Panelist 7: 4 months 25% usually decrease dose of thalidomide by 25-50% 
Panelist 9: 3-4 cycles. dose reduction occur about 20% 
Panelist 1: a 3-4 cycles b 25 c thal 25-50%
Panelist 8: 6 months or until a plateau. Dose reductions with MPT less than 25%. Dose
 

reduction is for thalidomide-neuropathy or other toxicities. 
 

Panelist 5 : 4-6 months, 15%, 25%  Panelist 3: Thal dex in the majority, MP for others.  Panelist 8: First choice would be melphalan plus prednisone for 2 cycles. If no response, add

thalidomide. Treat for 6 cycles or until plateau. Probably 40% of our non-transplant patients receive this regimen. Other regimens include thal/dex, lenalidomide/dex, occasional velcade/dex. Yes, this has changed over the past 18 months with the data from the Phase III trials from Italy and France. Quality of life and responses. 

Q4: Strategy following induction for stem cell transplants

Following induction treatment for stem cell treatment patients, do you most commonly recommend: a) consolidation chemotherapy immediately b) a no treatment observation period c) maintenance chemotherapy (systemic treatment for responders who have not yet progressed in an effort to delay potential relapse) d) another strategy? What affects your decision to choose a particular strategy? 

Panelist 4: move right on to either a single or double high dose mel pbsct as I think the data is strongest that this approach improves progression free survival. 

Panelist 10: Major issue is what study protocol determines, so this applies for 80% of transplanted patients. If not on protocol, will use thal maintenance. 

Panelist 9: currently, there is no recommendation tx for post-SCT. I typically observe my pts only after SCT

Panelist 1: just observation

Panelist 7: If patients respond to induction, they typically go straight to stem cell transplant. 

Panelist 5 : either c or a..I go with a for protocol patients especially if this is tandem transplant.. bad chromosomes. other such risk factors..move me to transplant faster 

Panelist 2: After induction I send them right away for stem cell transplantation considering that as consolidation therapy. If they have not yet achieved remission, I may add velcade or DT-PACE to help them achieve remission before sending them for SCT.

Follow-up Panelists 4, 2, 7

What is your strategy after stem cell transplant for this patient population?

Panelist 4: observation without maintenance. 

Panelist 7: observation following transplant if not on a clinical trial 

Panelist 9: observation only

Panelist 5 : NA

Panelist 6: We do not give consolidation chemotherapy. We have had trials with novel agents for maintenance. If not on trial have till recently kept patients on observation alone. Now have started to recommend thal as maintenance off study for patients with less than a vgpr after singe/tandem transplant since randomized French study recently published shows a survival advantage. 

Panelist 7: If patients respond to induction, they typically go straight to stem cell transplant. 

Panelist 3: proceed to transplantation. After transplant no therapy unless guided by protocol. 

Panelist 4: follow up without maintenance except in nonsecretory disease or patients with significant and irreversible end organ damage (nondialysis renal failure) who receive either velcade maintenance (del 13 [+] or can't handle out of pocket expenses - weekly schedule 4 of every 6 weeks) or rev or thal (without del 13 and can handle out of pocket expenses - low dose tahl 50 qd or rev 10 qd x 21 days/28 days) 

Panelist 8: Most patients are recommended to receive maintenance post transplant. This, preferably on a clinical trial. Outside of clinical trial, we are using lenalidomide 10 mg 21 of 28 days starting at 3 months for standard risk and two months for high risk patients.

Q5: Strategy following first-line for non-stem cell transplants

Following first-line treatment for non-stem cell patients, what is most influential in your decision to prescribe either: a) second-line therapy immediately following first-line b) a no treatment observation period c) maintenance therapy (systemic treatment for responders who have not yet progressed in an effort to delay potential relapse) d) another strategy? Which strategy do you most commonly employ for non-stem cell transplant patients, and why?

Panelist 4: no treatment observation. no convincing data yet that maintenance improves overall survival. so, prefer treatment holiday with reinitiation of therapy at disease progression. 

Panelist 10: If patient reaches excellent response, will consider either maintenance thal of maint. pulse decadron. If elderly may just watch and wait. Systemic therapy only for poor responders or those who relapse. 

Panelist 9: b. no treatment observation period. b/c there is no data in showing the benefit of maintenance tx 

Panelist 1: observation only

Panelist 5 : b..no data supporting any other approach  Panelist 2: Following first line treatment for non stem cell transplant patients, I maintain patients with dex-thal for as long as they tolerate it. 

Panelist 6: I generally treat for two cycles beyond best response (for minimum 6 months) and then resume same drugs a progression 

Panelist 7: If patients have a good response and tolerate the induction therapy (Thal/Dex), they typically remain on the drugs until plateau, then generally will go on less dexamethasone.